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[ { "id": "passage-0", "type": "abstract", "text": [ " Serial measurements of antineutrophil cytoplasmic autoantibodies in patients with systemic vasculitis. PURPOSE: To assess the value of serial determinations of antineutrophil cytoplasmic autoantibodies (ANCA) for monitoring disease activity in patients with systemic vasculitis. PATIENTS AND METHODS: Forty-three patients with histologically proven vasculitis (21 with Wegener's granulomatosis, 17 with microscopic polyangiitis, and 5 with renal-limited vasculitis) were studied for a median follow-up of 22 months. Disease activity was prospectively assessed and quantified by the Birmingham Vasculitis Activity Score. A total of 347 sera were analyzed for ANCA determination. RESULTS: Relapses occurred in 23 (54%) of 43 patients. Diagnostic category (Wegener's granulomatosis vs micropolyangiitis and renal-limited vasculitis), severity of initial symptoms (mean vasculitis activity score, mean number of organs involved), and ANCA pattern [cytoplasmic-ANCA (c-ANCA) vs perinuclear-ANCA (p-ANCA)] did not significantly differ between relapsers and nonrelapsers. Lung involvement was more frequent at onset among relapsers [16 of 23 ( ) vs 6 of ( ); P = 0.02]. Relapses were slightly, but not significantly, more frequent in patients with Wegener's granulomatosis or a c-ANCA pattern. The percentage of relapsers was greater in patients with persistently positive ANCA than in patients with negative or decreasing ANCA titers (86% vs , P = 0.0001). However, the predictive value of an increase in ANCA titers for the occurrence of a subsequent relapse was only 28% (4 of 14) for c-ANCA, 12% (2 of 17) for anti-proteinase 3-ANCA, and 43% (6 of 14) for anti-myeloperoxidase-ANCA. An increase in ANCA occurred before or during relapse in 33% ( of ) of cases for c-ANCA/anti-proteinase 3 antibodies, and 73% (11 of 15) of cases for anti-myeloperoxidase antibodies. CONCLUSION: The persistence of ANCA positivity is strongly associated with relapses. However, an increase in ANCA titers has a poor value for the early prediction of a subsequent relapse and should not be used as a sole parameter for therapeutic intervention. In addition, our results suggest that serial anti-myeloperoxidase determination may be useful as a prognostic marker in patients who are p-ANCA positive." ], "offsets": [ [ 0, 2301 ] ] } ]

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[ { "id": "passage-1", "type": "abstract", "text": [ "The synthesis of a range of 3-hydroxy-4(1H)-pyridinones with potential for the chelation of iron(III) is described. The pKa values of respective ligands and the stability constants of their iron(III) complexes are presented. The distribution coefficient values of a range of 48hydroxypyridinones and their corresponding iron(III) complexes between 1-octanol and MOPS buffer (pH 7.4) are reported. The range of log Dcomplex values covers 7 orders of magnitude. The results suggest the existence of a biphasic relationship between the distribution coefficient values of the chelator and the correspondingiron (III) complexes. For ligands with a log Dligand = -1, a linear relationship exists with a value of the slope 2.53, whereas with ligands with a log Dligand < -1, a linear relationship exists with a slope of 0.49. The reduced slope for the more hydrophilic molecules of the series offers some advantage for this type of hydroxypyridinone as the distribution coefficients for such complexes do not change so rapidly with increasing ligand hydrophilicity. The ability of selected 3-hydroxypyridinones to facilitate the excretion of iron in bile was investigated in non-iron-overloaded, bile duct-cannulated rats and in a [59Fe]ferritin-loaded rat model. Both systems compare the ability of chelators to remove iron from the liver, the prime target organ in thalassemia. The N-(hydroxyalkyl)-3-hydroxypyridin-4-ones are demonstrated to be orally active under the in vivo conditions adopted. Thus both 1-(hydroxyalkyl)- and 1-(carboxyalkyl)pyridinones are able to remove iron from the liver. Although 1-(carboxyalkyl)hydroxypyridinones are active, they do not demonstrate any clear advantage over Deferiprone (1,2-dimethyl-3-hydroxypyridin-4-one). Indeed 1-(hydroxyalkyl)hydroxypyridinones which are known to be rapidly converted to 1-(carboxyalkyl)hydroxypyridinones are also marginally superior to Deferiprone. In contrast, 2-ethyl-1-(2'-hydroxyethyl)-3-hydroxypyridin-4-one, which is not metabolized to the corresponding (carboxyalkyl)hydroxypyridinone, was found to be superior to Deferiprone and therefore deserves further consideration as an orally active iron chelator with potential for the treatment of ironoverload associated with transfusion-dependent thalassemia." ], "offsets": [ [ 0, 2281 ] ] } ]

[ { "id": "entity-1-0", "type": "IUPAC", "text": [ "3-hydroxy-4(1H)-pyridinones" ], "offsets": [ [ 28, 55 ] ], "normalized": [] }, { "id": "entity-1-1", "type": "TRIVIAL", "text": [ "iron(III)" ], "offsets": [ [ 92, 101 ] ], "normalized": [] }, { "id": "entity-1-2", "type": "TRIVIAL", "text": [ "iron(III)" ], "offsets": [ [ 190, 199 ] ], "normalized": [] }, { "id": "entity-1-3", "type": "MODIFIER", "text": [ "complexes" ], "offsets": [ [ 200, 209 ] ], "normalized": [] }, { "id": "entity-1-4", "type": "FAMILY", "text": [ " hydroxypyridinones" ], "offsets": [ [ 277, 296 ] ], "normalized": [] }, { "id": "entity-1-5", "type": "TRIVIAL", "text": [ "iron(III)" ], "offsets": [ [ 321, 330 ] ], "normalized": [] }, { "id": "entity-1-6", "type": "MODIFIER", "text": [ "complexes" ], "offsets": [ [ 331, 340 ] ], "normalized": [] }, { "id": "entity-1-7", "type": "TRIVIAL", "text": [ "1-octanol" ], "offsets": [ [ 349, 358 ] ], "normalized": [] }, { "id": "entity-1-8", "type": "TRIVIAL", "text": [ " iron(III)" ], "offsets": [ [ 603, 613 ] ], "normalized": [] }, { "id": "entity-1-9", "type": "MODIFIER", "text": [ "complexes" ], "offsets": [ [ 614, 623 ] ], "normalized": [] }, { "id": "entity-1-10", "type": "FAMILY", "text": [ "hydroxypyridinone" ], "offsets": [ [ 929, 946 ] ], "normalized": [] }, { "id": "entity-1-11", "type": "IUPAC", "text": [ "3-hydroxypyridinones" ], "offsets": [ [ 1087, 1107 ] ], "normalized": [] }, { "id": "entity-1-12", "type": "IUPAC", "text": [ "[59Fe]ferritin" ], "offsets": [ [ 1228, 1242 ] ], "normalized": [] }, { "id": "entity-1-13", "type": "IUPAC", "text": [ "N-(hydroxyalkyl)-3-hydroxypyridin-4-ones" ], "offsets": [ [ 1381, 1421 ] ], "normalized": [] }, { "id": "entity-1-14", "type": "PARTIUPAC", "text": [ "1-(hydroxyalkyl)-" ], "offsets": [ [ 1507, 1524 ] ], "normalized": [] }, { "id": "entity-1-15", "type": "IUPAC", "text": [ "1-(carboxyalkyl)pyridinones" ], "offsets": [ [ 1529, 1556 ] ], "normalized": [] }, { "id": "entity-1-16", "type": "TRIVIAL", "text": [ "iron" ], "offsets": [ [ 1576, 1580 ] ], "normalized": [] }, { "id": "entity-1-17", "type": "IUPAC", "text": [ "1-(carboxyalkyl)hydroxypyridinones" ], "offsets": [ [ 1606, 1640 ] ], "normalized": [] }, { "id": "entity-1-18", "type": "TRIVIAL", "text": [ "Deferiprone" ], "offsets": [ [ 1702, 1713 ] ], "normalized": [] }, { "id": "entity-1-19", "type": "IUPAC", "text": [ "1,2-dimethyl-3-hydroxypyridin-4-one" ], "offsets": [ [ 1715, 1750 ] ], "normalized": [] }, { "id": "entity-1-20", "type": "IUPAC", "text": [ "1-(hydroxyalkyl)hydroxypyridinones" ], "offsets": [ [ 1760, 1794 ] ], "normalized": [] }, { "id": "entity-1-21", "type": "IUPAC", "text": [ "1-(carboxyalkyl)hydroxypyridinones" ], "offsets": [ [ 1838, 1872 ] ], "normalized": [] }, { "id": "entity-1-22", "type": "TRIVIAL", "text": [ "Deferiprone" ], "offsets": [ [ 1905, 1916 ] ], "normalized": [] }, { "id": "entity-1-23", "type": "IUPAC", "text": [ "2-ethyl-1-(2'-hydroxyethyl)-3-hydroxypyridin-4-one" ], "offsets": [ [ 1931, 1981 ] ], "normalized": [] }, { "id": "entity-1-24", "type": "TRIVIAL", "text": [ "(carboxyalkyl)hydroxypyridinone" ], "offsets": [ [ 2029, 2060 ] ], "normalized": [] }, { "id": "entity-1-25", "type": "TRIVIAL", "text": [ "Deferiprone" ], "offsets": [ [ 2090, 2101 ] ], "normalized": [] }, { "id": "entity-1-26", "type": "TRIVIAL", "text": [ "iron" ], "offsets": [ [ 2217, 2221 ] ], "normalized": [] } ]

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[ { "id": "passage-2", "type": "abstract", "text": [ "A series of analogues of the analgesic dipeptide derivative H-Lys-Trp(NPS)-OMe has been designed to determine the influence of the (2-nitrophenyl)sulfenyl (NPS) moiety on the activity. The syntheses and antinociceptive effects of these analogues of general formulaH -Lys-Trp(R)-OMe [R = phenylsulfenyl (PS) (9); R = (2-carbomethyoxyphenyl)sulfenyl (CmPS) ( ); R = (4-nitrophenyl)sulfenyl (pNPS) (11); R = (2,4-dinitrophenyl)sulfenyl (DNPS) (12); R = [2-(acetylamino)-2-carbomethoxyethyl]sulfenyl (AacCmES) (13); R = [2-(acetylamino)phenyl]sulfenyl (AacPS) (17); R = tert-butylsulfenyl (t-BuS) (23); R = (2-carbomethoxyethyl)sulfenyl (CmES) (24)] are described. Reaction of Z-Lys(Z)-Trp-OMe (3) with PS-, CmPS-, pNPS-, DNPS-, and AacCmES-Cl afforded the corresponding 2-(sulfenyl)tryptophan derivatives, which on treatment with boron-tris(trifluoroacetate)/trifluoroacetic acid or trimethylsilyl iodide in acetonitrile (Me3SiI/CH3CN) provided 9-13, respectively. Sulfenylation of 3 with NPS-Cl gave Z-Lys(Z)-Trp(NPS)-OMe, which, on catalytic hydrogenation of the nitro group using Pd/C followed by acetylation of the resulting amino function and removal of the protecting Z groups, gave 17. Condensation of 2-(tert-butylsulfenyl)- and 2-[(2-carbomethoxyethyl)sulfenyl]tryptophan methyl ester, obtained by reaction of methyl 3a-hydroxy-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole-2-carboxyla te with the corresponding thiol, with Z-Lys(Z)-OSu afforded Z-Lys(Z)-Trp(t-BuS)-OMe and Z-Lys(Z)-Trp(CmES)-OMe, which on treatment with Me3SiI/CH3CN provided 23 and 24, respectively. Intracerebroventricular administration of elicited a naloxone-reversible antinociceptive effect in mice similar to that of H-Lys-Trp(NPS)-OMe. No analgesia was however found with the phenylsulfenyl or acyclic sulfenyl substituted dipeptides 9, 11, and 17 or 13, 23, and 24. The Trp(DNPS)-containing analogue was neurotoxic. Structure-activity studies indicate that the role of the NPS and CmPS moietiescould be related to the adoption of a preferential active conformation." ], "offsets": [ [ 0, 2055 ] ] } ]

[ { "id": "entity-2-0", "type": "", "text": [ "H-Lys-Trp(NPS)-OMe" ], "offsets": [ [ 60, 78 ] ], "normalized": [] }, { "id": "entity-2-1", "type": "PARTIUPAC", "text": [ "(2-nitrophenyl)sulfenyl" ], "offsets": [ [ 131, 154 ] ], "normalized": [] }, { "id": "entity-2-2", "type": "ABBREVIATION", "text": [ "NPS" ], "offsets": [ [ 156, 159 ] ], "normalized": [] }, { "id": "entity-2-3", "type": "MODIFIER", "text": [ "moiety" ], "offsets": [ [ 161, 167 ] ], "normalized": [] }, { "id": "entity-2-4", "type": "", "text": [ " H-Lys-Trp(R)-OMe" ], "offsets": [ [ 264, 281 ] ], "normalized": [] }, { "id": "entity-2-5", "type": "PARTIUPAC", "text": [ "phenylsulfenyl" ], "offsets": [ [ 287, 301 ] ], "normalized": [] }, { "id": "entity-2-6", "type": "ABBREVIATION", "text": [ "PS" ], "offsets": [ [ 303, 305 ] ], "normalized": [] }, { "id": "entity-2-7", "type": "PARTIUPAC", "text": [ "2-carbomethyoxyphenyl)sulfenyl" ], "offsets": [ [ 317, 347 ] ], "normalized": [] }, { "id": "entity-2-8", "type": "ABBREVIATION", "text": [ "CmPS" ], "offsets": [ [ 349, 353 ] ], "normalized": [] }, { "id": "entity-2-9", "type": "PARTIUPAC", "text": [ "4-nitrophenyl)sulfenyl" ], "offsets": [ [ 366, 388 ] ], "normalized": [] }, { "id": "entity-2-10", "type": "ABBREVIATION", "text": [ "pNPS" ], "offsets": [ [ 390, 394 ] ], "normalized": [] }, { "id": "entity-2-11", "type": "PARTIUPAC", "text": [ "2,4-dinitrophenyl)sulfenyl" ], "offsets": [ [ 407, 433 ] ], "normalized": [] }, { "id": "entity-2-12", "type": "ABBREVIATION", "text": [ "DNPS" ], "offsets": [ [ 435, 439 ] ], "normalized": [] }, { "id": "entity-2-13", "type": "PARTIUPAC", "text": [ "[2-(acetylamino)-2-carbomethoxyethyl]sulfenyl" ], "offsets": [ [ 451, 496 ] ], "normalized": [] }, { "id": "entity-2-14", "type": "ABBREVIATION", "text": [ "AacCmES" ], "offsets": [ [ 498, 505 ] ], "normalized": [] }, { "id": "entity-2-15", "type": "PARTIUPAC", "text": [ "[2-(acetylamino)phenyl]sulfenyl" ], "offsets": [ [ 517, 548 ] ], "normalized": [] }, { "id": "entity-2-16", "type": "ABBREVIATION", "text": [ "AacPS" ], "offsets": [ [ 550, 555 ] ], "normalized": [] }, { "id": "entity-2-17", "type": "PARTIUPAC", "text": [ "tert-butylsulfenyl" ], "offsets": [ [ 567, 585 ] ], "normalized": [] }, { "id": "entity-2-18", "type": "ABBREVIATION", "text": [ "t-BuS" ], "offsets": [ [ 587, 592 ] ], "normalized": [] }, { "id": "entity-2-19", "type": "PARTIUPAC", "text": [ "(2-carbomethoxyethyl)sulfenyl" ], "offsets": [ [ 604, 633 ] ], "normalized": [] }, { "id": "entity-2-20", "type": "ABBREVIATION", "text": [ "CmES" ], "offsets": [ [ 635, 639 ] ], "normalized": [] }, { "id": "entity-2-21", "type": "", "text": [ "Z-Lys(Z)-Trp-OMe" ], "offsets": [ [ 674, 690 ] ], "normalized": [] }, { "id": "entity-2-22", "type": "ABBREVIATION", "text": [ "PS" ], "offsets": [ [ 700, 702 ] ], "normalized": [] }, { "id": "entity-2-23", "type": "ABBREVIATION", "text": [ "CmPS" ], "offsets": [ [ 705, 709 ] ], "normalized": [] }, { "id": "entity-2-24", "type": "ABBREVIATION", "text": [ "pNPS" ], "offsets": [ [ 712, 716 ] ], "normalized": [] }, { "id": "entity-2-25", "type": "ABBREVIATION", "text": [ "DNPS" ], "offsets": [ [ 719, 723 ] ], "normalized": [] }, { "id": "entity-2-26", "type": "ABBREVIATION", "text": [ "AacCmES-Cl" ], "offsets": [ [ 730, 740 ] ], "normalized": [] }, { "id": "entity-2-27", "type": "IUPAC", "text": [ "2-(sulfenyl)tryptophan" ], "offsets": [ [ 768, 790 ] ], "normalized": [] }, { "id": "entity-2-28", "type": "MODIFIER", "text": [ "derivatives" ], "offsets": [ [ 791, 802 ] ], "normalized": [] }, { "id": "entity-2-29", "type": "IUPAC", "text": [ "boron-tris(trifluoroacetate)" ], "offsets": [ [ 828, 856 ] ], "normalized": [] }, { "id": "entity-2-30", "type": "IUPAC", "text": [ "trifluoroacetic acid" ], "offsets": [ [ 857, 877 ] ], "normalized": [] }, { "id": "entity-2-31", "type": "IUPAC", "text": [ "trimethylsilyl iodide" ], "offsets": [ [ 881, 902 ] ], "normalized": [] }, { "id": "entity-2-32", "type": "TRIVIAL", "text": [ "acetonitrile" ], "offsets": [ [ 906, 918 ] ], "normalized": [] }, { "id": "entity-2-33", "type": "SUM", "text": [ "Me3SiI" ], "offsets": [ [ 920, 926 ] ], "normalized": [] }, { "id": "entity-2-34", "type": "SUM", "text": [ "CH3CN" ], "offsets": [ [ 927, 932 ] ], "normalized": [] }, { "id": "entity-2-35", "type": "ABBREVIATION", "text": [ "NPS-Cl" ], "offsets": [ [ 987, 993 ] ], "normalized": [] }, { "id": "entity-2-36", "type": "", "text": [ "Z-Lys(Z)-Trp(NPS)-OMe" ], "offsets": [ [ 999, 1020 ] ], "normalized": [] }, { "id": "entity-2-37", "type": "PARTIUPAC", "text": [ "2-(tert-butylsulfenyl)-" ], "offsets": [ [ 1211, 1234 ] ], "normalized": [] }, { "id": "entity-2-38", "type": "IUPAC", "text": [ "2-[(2-carbomethoxyethyl)sulfenyl]tryptophan methyl ester" ], "offsets": [ [ 1239, 1295 ] ], "normalized": [] }, { "id": "entity-2-39", "type": "IUPAC", "text": [ "methyl 3a-hydroxy-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole-2-carboxyla te" ], "offsets": [ [ 1321, 1397 ] ], "normalized": [] }, { "id": "entity-2-40", "type": "", "text": [ "Z-Lys(Z)-OSu afforded Z-Lys(Z)-Trp(t-BuS)-OMe" ], "offsets": [ [ 1433, 1478 ] ], "normalized": [] }, { "id": "entity-2-41", "type": "", "text": [ "Z-Lys(Z)-Trp(CmES)-OMe" ], "offsets": [ [ 1483, 1505 ] ], "normalized": [] }, { "id": "entity-2-42", "type": "SUM", "text": [ "Me3SiI" ], "offsets": [ [ 1531, 1537 ] ], "normalized": [] }, { "id": "entity-2-43", "type": "SUM", "text": [ "CH3CN" ], "offsets": [ [ 1538, 1543 ] ], "normalized": [] }, { "id": "entity-2-44", "type": "TRIVIAL", "text": [ "naloxone" ], "offsets": [ [ 1634, 1642 ] ], "normalized": [] }, { "id": "entity-2-45", "type": "", "text": [ "H-Lys-Trp(NPS)-OMe" ], "offsets": [ [ 1704, 1722 ] ], "normalized": [] }, { "id": "entity-2-46", "type": "PARTIUPAC", "text": [ "phenylsulfenyl" ], "offsets": [ [ 1764, 1778 ] ], "normalized": [] }, { "id": "entity-2-47", "type": "IUPAC", "text": [ "acyclic sulfenyl substituted dipeptides" ], "offsets": [ [ 1782, 1821 ] ], "normalized": [] }, { "id": "entity-2-48", "type": "ABBREVIATION", "text": [ "Trp(DNPS)" ], "offsets": [ [ 1859, 1868 ] ], "normalized": [] }, { "id": "entity-2-49", "type": "ABBREVIATION", "text": [ "NPS" ], "offsets": [ [ 1962, 1965 ] ], "normalized": [] }, { "id": "entity-2-50", "type": "ABBREVIATION", "text": [ "CmPS" ], "offsets": [ [ 1970, 1974 ] ], "normalized": [] }, { "id": "entity-2-51", "type": "MODIFIER", "text": [ "moieties" ], "offsets": [ [ 1975, 1983 ] ], "normalized": [] } ]

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[ { "id": "passage-3", "type": "abstract", "text": [ "A series of substituted 1,4-dihydronaphthoquinones, hydroindoloquinones, benzofuran-4,7-dihydroquinones, and benzothiophene-4,7-dihydroquinones were synthesized and evaluated for inhibitory activity against 5-lipoxygenase. These compounds were found to be active in vitro for LTC4/D4 inhibition with the potencies (IC50's) ranging from 0.2 to 85 microM. Active 1,4-dihydronaphthoquinone acetates (IC50 less than microM) were evaluated in an ex vivo LTB4 inhibition assay. The acetates of 1,4-dihydronaphthoquinones containing the alkyl substituent(s) (2-n-butyl, 11, and 2,3-diethyl, 15) exhibited the best activity in LTC4/D4 inhibition (IC50 = 0.2-0.4 microM, in vitro) as well as in LTB4 inhibition ( inhibition)." ], "offsets": [ [ 0, 725 ] ] } ]

[ { "id": "entity-3-0", "type": "IUPAC", "text": [ "1,4-dihydronaphthoquinones" ], "offsets": [ [ 24, 50 ] ], "normalized": [] }, { "id": "entity-3-1", "type": "TRIVIAL", "text": [ "hydroindoloquinones" ], "offsets": [ [ 52, 71 ] ], "normalized": [] }, { "id": "entity-3-2", "type": "IUPAC", "text": [ "benzofuran-4,7-dihydroquinones" ], "offsets": [ [ 73, 103 ] ], "normalized": [] }, { "id": "entity-3-3", "type": "IUPAC", "text": [ "benzothiophene-4,7-dihydroquinones" ], "offsets": [ [ 109, 143 ] ], "normalized": [] }, { "id": "entity-3-4", "type": "IUPAC", "text": [ "1,4-dihydronaphthoquinone acetates" ], "offsets": [ [ 361, 395 ] ], "normalized": [] }, { "id": "entity-3-5", "type": "FAMILY", "text": [ "acetates" ], "offsets": [ [ 479, 487 ] ], "normalized": [] }, { "id": "entity-3-6", "type": "IUPAC", "text": [ "1,4-dihydronaphthoquinones" ], "offsets": [ [ 491, 517 ] ], "normalized": [] }, { "id": "entity-3-7", "type": "PARTIUPAC", "text": [ "alkyl" ], "offsets": [ [ 533, 538 ] ], "normalized": [] }, { "id": "entity-3-8", "type": "MODIFIER", "text": [ "substituent(s)" ], "offsets": [ [ 539, 553 ] ], "normalized": [] }, { "id": "entity-3-9", "type": "PARTIUPAC", "text": [ "2-n-butyl" ], "offsets": [ [ 555, 564 ] ], "normalized": [] }, { "id": "entity-3-10", "type": "PARTIUPAC", "text": [ "2,3-diethyl" ], "offsets": [ [ 574, 585 ] ], "normalized": [] } ]

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[ { "id": "passage-4", "type": "abstract", "text": [ " The regulation of total creatine content in a myoblast cell line. Total cellular creatine content is an important bioenergetic parameter in skeletal muscle. To understand its regulation we investigated creatine transport and accumulation in the G8 cultured skeletal myoblast line. Like other cell types, these contain a creatine transporter, whose activity, measured using a radiolabelling technique, was saturable (Km = +/- 25 microM) and largely dependent on extracellular [Na+]. To study sustained influences on steady state creatine concentration we measured total cellular creatine content using a fluorimetric method in 48 h incubations. We found that the total cellular creatine content was relatively independent of extracellular creatine concentration, consistent with high affinity sodium-dependent uptake balanced by slow passive efflux. Accordingly, in creatine-free incubations net creatine efflux was slow (5 +/- 1% of basal creatine content per day over 6 days), while creatine content in 48 h incubations was reduced by 28 +/- 13% of control by the Na+, K(+)-ATPase inhibitor ouabain. Creatine accumulation after 48 h was stimulated by treatment with the mixed alpha- and beta-adrenergic agonist noradrenaline, the beta-adrenergic agonist isoproterenol, the beta 2-agonist clenbuterol and the cAMP analogue N6,2'-O-dibutyryladenosine 3',5'-cyclic monophosphate, but was unaffected by the alpha 1 adrenergic agonist methoxamine. The noradrenaline enhancement of creatine accumulation at 48 h was inhibited by the mixed alpha- and beta-antagonist labetalol and by the beta-antagonist propranolol, but was unaffected by the alpha 2 antagonist phentolamine; greater inhibition was caused by the beta 2 antagonist butoxamine than the beta 1 antagonist atenolol. Creatine accumulation at 48 h was increased to +/- 6% of control by insulin and by +/- 13% by IGF-I (both at 3 nM). Creatine accumulation at 48 h was also increased to +/- of control by 3,3',5-triiodothyronine (at microM) and to +/- 35% of control by amylin ( nM). As 3,3', 5-triiodothyronine, amylin and isoproterenol all stimulate the Na+, K(+)-ATPase, we suggest that they stimulate Na(+)-creatine cotransport indirectly by increasing the transmembrane [Na+] concentration gradient and membrane potential." ], "offsets": [ [ 0, 2320 ] ] } ]

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[ { "id": "passage-5", "type": "abstract", "text": [ "12742193 Attenuation of cerebral vasospasm in rabbits using clonidine hydrochloride, a central adrenergic agonist. The aim of this study was to assess, firstly, if exclusion of central noradrenergic areas in the hypothalamus and brain stem with the central sympathetic blocker clonidine hydrochloride could prevent the development of chronic vasospasm following experimental subarachnoid haemorrhage in rabbits and, secondly, if, parallel with the effect on cerebral arteries, changes in dopamine beta-hydroxylase concentration in the hypothalamus and brain stem could also be detected.Experimental subarachnoid haemorrhage, in concentrations of 1 ml of autologous arterial blood/1 kg of body weight was carried out on 18 New Zealand rabbits. Histological specimens were obtained by the method of perfusion fixation after the rabbits were sacrificed on day 8 after subarachnoid haemorrhage. The spastic effect of experimentally induced subarachnoid haemorrhage was determined by assessing the intensity of corrugation of the intima of the rabbit basilar artery by the previously developed method of corrugation coefficient and computer image analysis. The concentration and localization of dopamine beta-hydroxylase in noradrenaline-containing neurons was immunohistochemically assessed (semiquantitatively as 0, 1 and 2) with anti-dopamine beta-hydroxylase, at precisely defined sites of the hypothalamus and brain stem of the same rabbit.The results revealed less corrugated and smoother intima in the basilar artery and significantly lower dopamine beta-hydroxylase concentration in the control group of rabbits with sham subarachnoid haemorrhage and without any additional interventions (mean corrugation coefficient=1.123+/-0.024, P=0.35 x (-3); mean dopamine beta-hydroxylase=0.350+/-0.071, P=0.22 x (-3)), and smoother intima in the basilar artery with significantly lower concentration of dopamine beta-hydroxylase in the clonidine group (rabbits with subarachnoid haemorrhage and central alpha(2)-blocker clonidine hydrochloride at a daily dose of 0.03 mg/kg of body weight for 8 days; mean corrugation coefficient=1.177+/-0.058, P=1.7 x (-3); mean dopamine beta-hydroxylase=0.583+/-0.175, P=1.1 x (-3)). In comparison, the haemorrhage only group (rabbits with subarachnoid haemorrhage and without medication; mean corrugation coefficient=1.370+/-0.101; mean dopamine beta-hydroxylase=1.214+/-0.313) displayed intensive corrugation of the intima of the basilar artery and a significantly more intensive accumulation of dopamine beta-hydroxylase than did the control group and the clonidine group.The results of this study demonstrated that the central alpha(2)-blocker clonidine hydrochlorideeffectively prevents vasospasm, and diminishes the concentration of cerebral dopamine beta-hydroxylase in the hypothalamus and brain stem after experimental subarachnoid haemorrhage in rabbits." ], "offsets": [ [ 0, 2905 ] ] } ]

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[ { "id": "passage-6", "type": "abstract", "text": [ "16682228 Heterologous expression of lipoprotein-associated phospholipase A2 in different expression systems. Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is a key enzyme involved in atherosclerosis, and has been considered as a new target for drug discovery. The major difficulty for high-throughput screening of Lp-PLA(2) inhibitors and for functional studies was their fast and efficient production. Purification of native Lp-PLA(2) from human plasma was complicated and produced a very low yield. We herein examined the feasibility of expressing and purifying recombinant Lp-PLA(2) in different heterologous expression systems. The fusion Lp-PLA(2) was expressed at high levels and exhibited strong enzyme activity in insect cell-baculovirus expression system. The functional enzyme could also be produced in Pichia pastoris. The inclusion of a Kozak sequence increased greatly the expression level of recombinant Lp-PLA(2) in insect cells, but had little effect on the expression of recombinant Lp-PLA(2) in P. pastoris and Escherichia coli. P. pastoris-produced Lp-PLA(2) could be purified rapidly and conveniently through a one-step procedure, while baculovirus-produced Lp-PLA(2) could be efficiently purified through a two-step procedure. This ability to readily produce recombinant Lp-PLA(2) could provide a screening model for Lp-PLA(2) inhibitors and will facilitate further studies on this enzyme." ], "offsets": [ [ 0, 1420 ] ] } ]

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[ { "id": "passage-7", "type": "abstract", "text": [ "A series of 2-(diethylamino)thieno1,3?xazin-4-ones was synthesized and evaluated in vitro for inhibitory activity toward human leukocyte elastase (HLE). The Gewald thiophene synthesis was utilized to obtain several ethyl 2-aminothiophene-3-carboxylates. These precursors were subjected to a five-step route to obtain thieno2,3-d1,3?xazin-4-ones bearing various substituents at positions 5 and 6. Both thieno2,3-d and thieno3,2-d fused oxazin-4-ones possess extraordinary chemical stability, which was expressed as rate constants of the alkaline hydrolysis. The kinetic parameters of the HLE inhibition were determined. The most potent compound, 2-(diethylamino)-4H-1benzothieno2,3-d1,3?xazin-4-one, exhibited a K(i) value of 5.8 nM. 2-(Diethylamino)thieno1, 3?xazin-4-ones act as acyl-enzyme inhibitors of HLE, similar to the inhibition of serine proteases by 4H-3,1-benzoxazin-4-ones. The isosteric benzene-thiophenereplacement accounts for an enhanced stability of the acyl-enzyme intermediates." ], "offsets": [ [ 0, 998 ] ] } ]

[ { "id": "entity-7-0", "type": "IUPAC", "text": [ "2-(diethylamino)thieno1,3?xazin-4-ones" ], "offsets": [ [ 12, 50 ] ], "normalized": [] }, { "id": "entity-7-1", "type": "TRIVIAL", "text": [ "thiophene" ], "offsets": [ [ 164, 173 ] ], "normalized": [] }, { "id": "entity-7-2", "type": "IUPAC", "text": [ "ethyl 2-aminothiophene-3-carboxylates" ], "offsets": [ [ 215, 252 ] ], "normalized": [] }, { "id": "entity-7-3", "type": "IUPAC", "text": [ "thieno2,3-d1,3?xazin-4-ones" ], "offsets": [ [ 317, 344 ] ], "normalized": [] }, { "id": "entity-7-4", "type": "PARTIUPAC", "text": [ "thieno2,3-d" ], "offsets": [ [ 401, 412 ] ], "normalized": [] }, { "id": "entity-7-5", "type": "PARTIUPAC", "text": [ "thieno3,2-d" ], "offsets": [ [ 417, 428 ] ], "normalized": [] }, { "id": "entity-7-6", "type": "IUPAC", "text": [ "oxazin-4-ones" ], "offsets": [ [ 435, 448 ] ], "normalized": [] }, { "id": "entity-7-7", "type": "IUPAC", "text": [ "2-(diethylamino)-4H-1benzothieno2,3-d1,3?xazin-4-one" ], "offsets": [ [ 645, 697 ] ], "normalized": [] }, { "id": "entity-7-8", "type": "IUPAC", "text": [ "2-(Diethylamino)thieno1, 3?xazin-4-ones" ], "offsets": [ [ 733, 772 ] ], "normalized": [] }, { "id": "entity-7-9", "type": "IUPAC", "text": [ "4H-3,1-benzoxazin-4-ones" ], "offsets": [ [ 860, 884 ] ], "normalized": [] }, { "id": "entity-7-10", "type": "IUPAC", "text": [ "benzene-thiophene" ], "offsets": [ [ 900, 917 ] ], "normalized": [] } ]

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[ { "id": "passage-8", "type": "abstract", "text": [ "Structure-activity relationships have been investigated for inhibition of DNA-dependent protein kinase (DNA-PK) and ATM kinase by a series of pyran-2-ones, pyran-4-ones, thiopyran-4-ones, and pyridin-4-ones. A wide range of IC50 values were observed for pyranones and thiopyranones substituted at the 6-position, with the 3- and 5-positions proving intolerant to substitution. Related pyran-2-ones, pyran-4-ones, and thiopyran-4-ones showed similar IC50 values against DNA-PK, whereas the pyridin-4-one system proved, in general, ineffective at inhibiting DNA-PK. Extended libraries exploring the 6-position of 2-morpholino-pyran-4-ones and 2-morpholino-thiopyrano-4-ones identified the first highly potent and selective ATM inhibitor 2-morpholin-4-yl-6-thianthren-1-yl-pyran-4-one (151C; ATM; IC50 = 13 nM) and revealed constrained SARs for ATM inhibition compared with DNA-PK. One of the most potent DNA-PK inhibitors identified, 2-(4-methoxyphenyl)-6-(morpholin-4-yl)pyran-4-one (16; DNA-PK; IC50 = nM) effectively sensitized HeLa cells to the topoisomerase II inhibitor etoposidein vitro." ], "offsets": [ [ 0, 1097 ] ] } ]

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[ { "id": "passage-9", "type": "abstract", "text": [ " Differential effects of luteinizing hormone-releasing hormone on follicle-stimulating hormone-dependent responses in rat granulosa cells and Sertoli cells in vitro. The abilities of LHRH and a potent LHRH agonist ([D-Ser-(But),6, des-Gly-NH210]LHRH ethylamide) inhibit FSH responses by rat granulosa cells and Sertoli cells in vitro have been compared. Granulosa cells isolated from 22- or 25-day-old diethylstilbestrol-primed rats and cultured under defined conditions for 48 h with NIH-FSH-S13 ( ng/ml) or cholera toxin (0.1 microgram/ml) showed increased aromatase activity, as determined by the release of 3H2O from [1 beta-3H]testosterone. LHRH ( (-7) M) or th agonist ( (-8) M) added simultaneously with FSH or cholera toxin inhibited the effects on the release of 3H2O without influencing the protein content of the cell cultures. A smaller stimulation of 3H2O production occurred with (Bu)2cAMP (1.0 mM) plus 3-isobutyl-l-methylxanthine (0.1 mM), and this was partially suppressed in the presence of LHRH or the agonist. Parallel studies with Sertoli cells from 15- or -day-old rats demonstrated that culture under appropriate conditions with FSH, cholera toxin, or (Bu)2cAMP (0.5 mM) for 24 h caused an increase in cellular aromatase activity and enhanced secretion into the medium of plasminogen activator. However, no inhibition by LHRH ( (-7) or (-9) M) or the agonist ( (-6) or (-8) M) occurred when the peptides were added either simultaneously or 24 h before the stimulatory agent. Similarly, Sertoli cells from 11-day-old rats treated daily with LHRH agonist for 5 days in culture, showed no inhibition of aromatase activity after a 4-h stimulation with FSH or (Bu)2cAMP. FSH dose-response curves (0-300 ng/ml) for aromatase activity were shown to be similar after 5 days of culture with or without (-8) M LHRH agonist, indicating that the LHRH did not cause a shift in the sensitivity to FSH. The lack of inhibition was seen in Sertoli cell cultures maintained at 37 or 32 C. The enzyme digestion method used to isolated Sertoli cells was not responsible for the lack of effects of LHRH, since cell cultures prepared without the aid of proteolytic enzymes showed similar FSH stimulation of aromatase activity in the presence or absence of (-8) M agonist. Further, there was no evidence of degradation of the LHRH agonist when incubated with Sertoli cell cultures. From these studies, we conclude that 1) granulosa cells and Sertoli cells from immature rats differ in their responses to LHRH, and 2) the immature Sertoli cell is an unlikely target for a direct inhibiting influence of LHRH on spermatogenesis." ], "offsets": [ [ 0, 2652 ] ] } ]

[ { "id": "entity-9-0", "type": "", "text": [ "[D-Ser-(But),6, des-Gly-NH210]LHRH ethylamide" ], "offsets": [ [ 224, 269 ] ], "normalized": [] }, { "id": "entity-9-1", "type": "TRIVIAL", "text": [ "diethylstilbestrol" ], "offsets": [ [ 411, 429 ] ], "normalized": [] }, { "id": "entity-9-2", "type": "TRIVIALVAR", "text": [ "NIH-FSH-S13" ], "offsets": [ [ 494, 505 ] ], "normalized": [] }, { "id": "entity-9-3", "type": "TRIVIAL", "text": [ "cholera toxin" ], "offsets": [ [ 521, 534 ] ], "normalized": [] }, { "id": "entity-9-4", "type": "IUPAC", "text": [ "[1 beta-3H]testosterone" ], "offsets": [ [ 633, 656 ] ], "normalized": [] }, { "id": "entity-9-5", "type": "TRIVIAL", "text": [ "cholera toxin" ], "offsets": [ [ 732, 745 ] ], "normalized": [] }, { "id": "entity-9-6", "type": "SUM", "text": [ "3H2O" ], "offsets": [ [ 786, 790 ] ], "normalized": [] }, { "id": "entity-9-7", "type": "SUM", "text": [ "3H2O" ], "offsets": [ [ 878, 882 ] ], "normalized": [] }, { "id": "entity-9-8", "type": "IUPAC", "text": [ "(Bu)2cAMP" ], "offsets": [ [ 908, 917 ] ], "normalized": [] }, { "id": "entity-9-9", "type": "IUPAC", "text": [ "3-isobutyl-l-methylxanthine" ], "offsets": [ [ 932, 959 ] ], "normalized": [] }, { "id": "entity-9-10", "type": "TRIVIAL", "text": [ "cholera toxin" ], "offsets": [ [ 1173, 1186 ] ], "normalized": [] }, { "id": "entity-9-11", "type": "IUPAC", "text": [ "(Bu)2cAMP" ], "offsets": [ [ 1191, 1200 ] ], "normalized": [] }, { "id": "entity-9-12", "type": "IUPAC", "text": [ "(Bu)2cAMP" ], "offsets": [ [ 1700, 1709 ] ], "normalized": [] } ]

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[ { "id": "passage-10", "type": "abstract", "text": [ "We have previously described (RS)-2-amino-3-(3-hydroxy-7,8-dihydro-6H-cyclohepta[d]isoxazol-4-yl)propionic acid (4-AHCP) as a highly effective agonist at non-N-methyl-d-aspartate (non-NMDA) glutamate (Glu) receptors in vivo, which is more potent than (RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) but inactive at NMDA receptors. However, 4-AHCP was found to be much weaker than AMPA as an inhibitor of [(3)H]AMPA binding and to have limited effect in a [(3)H]kainic acid binding assay using rat cortical membranes. To shed light on the mechanism(s) underlying this quite enigmatic pharmacological profile of 4-AHCP, we have now developed a synthesis of (S)-4-AHCP (6) and (R)-4-AHCP (7). At cloned metabotropic Glu receptors mGluR1alpha (group I), mGluR2 (group II), and mGluR4a (group III), neither 6 nor 7 showed significant agonist or antagonist effects. The stereoisomer 6, but not 7, activated cloned AMPA receptor subunits GluR1o, GluR3o, and GluR4o with EC( ) values in the range 4.5-15 microM and the coexpressed kainate-preferring subunits GluR6 + KA2 (EC( ) = 6.4 microM). Compound 6, but not 7, proved to be a very potent agonist (EC( ) = 0.13 microM) at the kainate-preferring GluR5 subunit, equipotent with (S)-2-amino-3-(5-tert-butyl-3-hydroxyisothiazol-4-yl)propionic acid [(S)-Thio-ATPA, 4] and almost 4 times more potent than (S)-2-amino-3-(5-tert-butyl-3-hydroxyisoxazol-4-yl)propionic acid [(S)-ATPA, 3]. Compound 6 thus represents a new structural class of GluR5 agonists. Molecular modeling and docking to a crystal structure of the extracellular binding domain of the AMPAsubunit GluR2 has enabled identification of the probable active conformation and binding mode of 6. We are able to rationalize the observed selectivities by comparing the docking of 4 and 6 to subtype constructs, i.e., a crystal structure of the extracellular binding domain of GluR2 and a homology model of GluR5." ], "offsets": [ [ 0, 1936 ] ] } ]

[ { "id": "entity-10-0", "type": "IUPAC", "text": [ "(RS)-2-amino-3-(3-hydroxy-7,8-dihydro-6H-cyclohepta[d]isoxazol-4-yl)propionic acid" ], "offsets": [ [ 29, 111 ] ], "normalized": [] }, { "id": "entity-10-1", "type": "ABBREVIATION", "text": [ "4-AHCP" ], "offsets": [ [ 113, 119 ] ], "normalized": [] }, { "id": "entity-10-2", "type": "IUPAC", "text": [ "(RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid" ], "offsets": [ [ 251, 313 ] ], "normalized": [] }, { "id": "entity-10-3", "type": "ABBREVIATION", "text": [ "AMPA" ], "offsets": [ [ 315, 319 ] ], "normalized": [] }, { "id": "entity-10-4", "type": "ABBREVIATION", "text": [ "4-AHCP" ], "offsets": [ [ 362, 368 ] ], "normalized": [] }, { "id": "entity-10-5", "type": "ABBREVIATION", "text": [ "AMPA" ], "offsets": [ [ 402, 406 ] ], "normalized": [] }, { "id": "entity-10-6", "type": "IUPAC", "text": [ "[(3)H]AMPA" ], "offsets": [ [ 426, 436 ] ], "normalized": [] }, { "id": "entity-10-7", "type": "IUPAC", "text": [ "[(3)H]kainic acid" ], "offsets": [ [ 477, 494 ] ], "normalized": [] }, { "id": "entity-10-8", "type": "ABBREVIATION", "text": [ "4-AHCP" ], "offsets": [ [ 632, 638 ] ], "normalized": [] }, { "id": "entity-10-9", "type": "ABBREVIATION", "text": [ "(S)-4-AHCP" ], "offsets": [ [ 677, 687 ] ], "normalized": [] }, { "id": "entity-10-10", "type": "ABBREVIATION", "text": [ "(R)-4-AHCP" ], "offsets": [ [ 696, 706 ] ], "normalized": [] }, { "id": "entity-10-11", "type": "TRIVIAL", "text": [ "kainate" ], "offsets": [ [ 1046, 1053 ] ], "normalized": [] }, { "id": "entity-10-12", "type": "TRIVIAL", "text": [ "kainate" ], "offsets": [ [ 1197, 1204 ] ], "normalized": [] }, { "id": "entity-10-13", "type": "IUPAC", "text": [ "(S)-2-amino-3-(5-tert-butyl-3-hydroxyisothiazol-4-yl)propionic acid" ], "offsets": [ [ 1247, 1314 ] ], "normalized": [] }, { "id": "entity-10-14", "type": "ABBREVIATION", "text": [ "(S)-Thio-ATPA" ], "offsets": [ [ 1316, 1329 ] ], "normalized": [] }, { "id": "entity-10-15", "type": "IUPAC", "text": [ "(S)-2-amino-3-(5-tert-butyl-3-hydroxyisoxazol-4-yl)propionic acid" ], "offsets": [ [ 1370, 1435 ] ], "normalized": [] }, { "id": "entity-10-16", "type": "ABBREVIATION", "text": [ "(S)-ATPA" ], "offsets": [ [ 1437, 1445 ] ], "normalized": [] }, { "id": "entity-10-17", "type": "ABBREVIATION", "text": [ "AMPA" ], "offsets": [ [ 1617, 1621 ] ], "normalized": [] } ]

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[ { "id": "passage-11", "type": "abstract", "text": [ "The synthesis of aminoaceto-2',6'-xylidides substituted on the amide nitrogen with 2-(diethylamino)ethyl, 2-aminoethyl, 2-hydroxyethyl, and 2-ethoxyethyl groups is described. The 2-aminoethyl derivatives were prepared by treatment of N-(2-phthalimidoethyl)-2',6'-xylidine with chloroacetyl chloride, followed by treatment with either potassium phthalmide or diethylamine. Hydrazinolysis of the phthalimides liberated the free amines. The remaining target compounds were produced by alkylation of lidocaine or of 2-phthalimidoaceto-2',6'-xylidide with the appropriate halide and sodium hydride, followed by hydrazinolysis where necessary. All target compounds were evaluated for antiarrhythmic efficacy against chloroform-induced ventricular tachycardia, as well as for acute CNS toxicity in mice. Most of the target compounds were more potent than the corresponding secondary amides and had improved therapeutic margins toward CNS toxicity. The diamines N-(2-aminoethyl)-2-aminoaceto-2',6'-xylidide (13) and N-(2-aminoethyl)--2-(diethylamino)aceto-2',6'-xylidide( 29) are especially promising in this respect. Several compounds were tested as spinal anesthetics." ], "offsets": [ [ 0, 1162 ] ] } ]

[ { "id": "entity-11-0", "type": "IUPAC", "text": [ "aminoaceto-2',6'-xylidides" ], "offsets": [ [ 17, 43 ] ], "normalized": [] }, { "id": "entity-11-1", "type": "MODIFIER", "text": [ "substituted" ], "offsets": [ [ 44, 55 ] ], "normalized": [] }, { "id": "entity-11-2", "type": "FAMILY", "text": [ "amide" ], "offsets": [ [ 63, 68 ] ], "normalized": [] }, { "id": "entity-11-3", "type": "TRIVIAL", "text": [ "nitrogen" ], "offsets": [ [ 69, 77 ] ], "normalized": [] }, { "id": "entity-11-4", "type": "PARTIUPAC", "text": [ "2-(diethylamino)ethyl" ], "offsets": [ [ 83, 104 ] ], "normalized": [] }, { "id": "entity-11-5", "type": "PARTIUPAC", "text": [ "2-aminoethyl" ], "offsets": [ [ 106, 118 ] ], "normalized": [] }, { "id": "entity-11-6", "type": "PARTIUPAC", "text": [ "2-hydroxyethyl" ], "offsets": [ [ 120, 134 ] ], "normalized": [] }, { "id": "entity-11-7", "type": "PARTIUPAC", "text": [ "2-ethoxyethyl" ], "offsets": [ [ 140, 153 ] ], "normalized": [] }, { "id": "entity-11-8", "type": "MODIFIER", "text": [ "groups" ], "offsets": [ [ 154, 160 ] ], "normalized": [] }, { "id": "entity-11-9", "type": "PARTIUPAC", "text": [ "2-aminoethyl" ], "offsets": [ [ 179, 191 ] ], "normalized": [] }, { "id": "entity-11-10", "type": "MODIFIER", "text": [ "derivatives" ], "offsets": [ [ 192, 203 ] ], "normalized": [] }, { "id": "entity-11-11", "type": "IUPAC", "text": [ "N-(2-phthalimidoethyl)-2',6'-xylidine" ], "offsets": [ [ 234, 271 ] ], "normalized": [] }, { "id": "entity-11-12", "type": "IUPAC", "text": [ "chloroacetyl chloride" ], "offsets": [ [ 277, 298 ] ], "normalized": [] }, { "id": "entity-11-13", "type": "IUPAC", "text": [ "potassium phthalmide" ], "offsets": [ [ 334, 354 ] ], "normalized": [] }, { "id": "entity-11-14", "type": "TRIVIAL", "text": [ "diethylamine" ], "offsets": [ [ 358, 370 ] ], "normalized": [] }, { "id": "entity-11-15", "type": "FAMILY", "text": [ "phthalimides" ], "offsets": [ [ 394, 406 ] ], "normalized": [] }, { "id": "entity-11-16", "type": "FAMILY", "text": [ "amines" ], "offsets": [ [ 426, 432 ] ], "normalized": [] }, { "id": "entity-11-17", "type": "TRIVIAL", "text": [ "lidocaine" ], "offsets": [ [ 496, 505 ] ], "normalized": [] }, { "id": "entity-11-18", "type": "IUPAC", "text": [ "2-phthalimidoaceto-2',6'-xylidide" ], "offsets": [ [ 512, 545 ] ], "normalized": [] }, { "id": "entity-11-19", "type": "PARTIUPAC", "text": [ "halide" ], "offsets": [ [ 567, 573 ] ], "normalized": [] }, { "id": "entity-11-20", "type": "IUPAC", "text": [ "sodium hydride" ], "offsets": [ [ 578, 592 ] ], "normalized": [] }, { "id": "entity-11-21", "type": "TRIVIAL", "text": [ "chloroform" ], "offsets": [ [ 710, 720 ] ], "normalized": [] }, { "id": "entity-11-22", "type": "IUPAC", "text": [ "N-(2-aminoethyl)-2-aminoaceto-2',6'-xylidide" ], "offsets": [ [ 954, 998 ] ], "normalized": [] }, { "id": "entity-11-23", "type": "IUPAC", "text": [ "N-(2-aminoethyl)--2-(diethylamino)aceto-2',6'-xylidide" ], "offsets": [ [ 1008, 1062 ] ], "normalized": [] } ]

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[ { "id": "passage-12", "type": "abstract", "text": [ "Some novel 6-fluoro-7-substituted-1,4-dihydro-4-oxoquinoline-3-carboxylic acids have been prepared. At the N-1 position \"standard\" substitution was employed with the ethyl, cyclopropyl, and p-fluorophenyl groups being used. At C-7 the introduction of some novel piperazines was made. Most notably, 2-(fluoromethyl)piperazine ( ) and hexahydro-6-fluoro-1H-1,4-diazepine (16, fluorohomopiperazine) at the quinolone C-7 position produced products with similar in vitro antibacterial activity as the ciprofloxacin reference. The in vivo efficacy of 1-cyclopropyl-6-fluoro-7-[3-(fluoromethyl)piperazinyl]-1,4-dihydro-4- oxoquinoline-3-carboxylic acid ( ) was excellent with better oral absorption than ciprofloxacin( 2)." ], "offsets": [ [ 0, 717 ] ] } ]

[ { "id": "entity-12-0", "type": "IUPAC", "text": [ "6-fluoro-7-substituted-1,4-dihydro-4-oxoquinoline-3-carboxylic acids" ], "offsets": [ [ 11, 79 ] ], "normalized": [] }, { "id": "entity-12-1", "type": "PARTIUPAC", "text": [ "ethyl" ], "offsets": [ [ 166, 171 ] ], "normalized": [] }, { "id": "entity-12-2", "type": "PARTIUPAC", "text": [ "cyclopropyl" ], "offsets": [ [ 173, 184 ] ], "normalized": [] }, { "id": "entity-12-3", "type": "PARTIUPAC", "text": [ "p-fluorophenyl" ], "offsets": [ [ 190, 204 ] ], "normalized": [] }, { "id": "entity-12-4", "type": "MODIFIER", "text": [ "groups" ], "offsets": [ [ 205, 211 ] ], "normalized": [] }, { "id": "entity-12-5", "type": "FAMILY", "text": [ "piperazines" ], "offsets": [ [ 262, 273 ] ], "normalized": [] }, { "id": "entity-12-6", "type": "IUPAC", "text": [ "2-(fluoromethyl)piperazine" ], "offsets": [ [ 298, 324 ] ], "normalized": [] }, { "id": "entity-12-7", "type": "IUPAC", "text": [ "hexahydro-6-fluoro-1H-1,4-diazepine" ], "offsets": [ [ 334, 369 ] ], "normalized": [] }, { "id": "entity-12-8", "type": "TRIVIAL", "text": [ "fluorohomopiperazine" ], "offsets": [ [ 375, 395 ] ], "normalized": [] }, { "id": "entity-12-9", "type": "TRIVIAL", "text": [ "quinolone" ], "offsets": [ [ 404, 413 ] ], "normalized": [] }, { "id": "entity-12-10", "type": "TRIVIAL", "text": [ "ciprofloxacin" ], "offsets": [ [ 497, 510 ] ], "normalized": [] }, { "id": "entity-12-11", "type": "IUPAC", "text": [ "1-cyclopropyl-6-fluoro-7-[3-(fluoromethyl)piperazinyl]-1,4-dihydro-4- oxoquinoline-3-carboxylic acid" ], "offsets": [ [ 546, 646 ] ], "normalized": [] }, { "id": "entity-12-12", "type": "TRIVIAL", "text": [ "ciprofloxacin" ], "offsets": [ [ 699, 712 ] ], "normalized": [] } ]

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[ { "id": "passage-13", "type": "abstract", "text": [ "The thermal Fischer indolization of hydrazones resulting from 4-hydrazino-5-methyl-1H-pyridin-2-one and various beta- and alpha-tetralones led to 4-methyl-6,7-dihydro-2H,5H-pyrido[4,3- b]benzo[e]indol-1-ones and 4-methyl-11-dihydro-2H,5H-pyrido[4,3- b]benzo[g]indol-1-ones, respectively. After aromatization, these compounds were transformed by phosphorus oxychloride, giving 1-chloro-4-methyl-5H-pyrido[4,3- b]benzo[e]- and -benzo[g]indoles which were substituted by [(dialkylamino)alkyl]amines. The resulting 1-[[(dialkylamino)alkyl]amino]-4-methyl-5H-pyrido- [4,3-b]benzo[e]- and -benzo[g]indoles, as well ashydroxy derivatives obtained by demethylation of methoxylated compounds with hydrobromic acid, were tested for antitumor activity in vitro (leukemic and solid tumor cells) and in vivo on various experimental tumor models using the standard NCI protocols. 1-[[3-(Dialkylamino)propyl]-amino]-4-methyl-9-hydroxy-5H-pyrido[4,3- b]benzo[e]indolesappeared as a promising new class of antineoplastic agents." ], "offsets": [ [ 0, 1013 ] ] } ]

[ { "id": "entity-13-0", "type": "FAMILY", "text": [ "hydrazones" ], "offsets": [ [ 36, 46 ] ], "normalized": [] }, { "id": "entity-13-1", "type": "IUPAC", "text": [ "4-hydrazino-5-methyl-1H-pyridin-2-one" ], "offsets": [ [ 62, 99 ] ], "normalized": [] }, { "id": "entity-13-2", "type": "PARTIUPAC", "text": [ "beta-" ], "offsets": [ [ 112, 117 ] ], "normalized": [] }, { "id": "entity-13-3", "type": "IUPAC", "text": [ "alpha-tetralones" ], "offsets": [ [ 122, 138 ] ], "normalized": [] }, { "id": "entity-13-4", "type": "IUPAC", "text": [ "4-methyl-6,7-dihydro-2H,5H-pyrido[4,3- b]benzo[e]indol-1-ones" ], "offsets": [ [ 146, 207 ] ], "normalized": [] }, { "id": "entity-13-5", "type": "IUPAC", "text": [ "4-methyl-11-dihydro-2H,5H-pyrido[4,3- b]benzo[g]indol-1-ones" ], "offsets": [ [ 212, 272 ] ], "normalized": [] }, { "id": "entity-13-6", "type": "IUPAC", "text": [ "phosphorus oxychloride" ], "offsets": [ [ 345, 367 ] ], "normalized": [] }, { "id": "entity-13-7", "type": "PARTIUPAC", "text": [ "1-chloro-4-methyl-5H-pyrido[4,3- b]benzo[e]-" ], "offsets": [ [ 376, 420 ] ], "normalized": [] }, { "id": "entity-13-8", "type": "PARTIUPAC", "text": [ "-benzo[g]indoles" ], "offsets": [ [ 425, 441 ] ], "normalized": [] }, { "id": "entity-13-9", "type": "IUPAC", "text": [ "[(dialkylamino)alkyl]amines" ], "offsets": [ [ 468, 495 ] ], "normalized": [] }, { "id": "entity-13-10", "type": "PARTIUPAC", "text": [ "1-[[(dialkylamino)alkyl]amino]-4-methyl-5H-pyrido- [4,3-b]benzo[e]-" ], "offsets": [ [ 511, 578 ] ], "normalized": [] }, { "id": "entity-13-11", "type": "PARTIUPAC", "text": [ "-benzo[g]indoles" ], "offsets": [ [ 583, 599 ] ], "normalized": [] }, { "id": "entity-13-12", "type": "PARTIUPAC", "text": [ " hydroxy" ], "offsets": [ [ 611, 619 ] ], "normalized": [] }, { "id": "entity-13-13", "type": "MODIFIER", "text": [ "derivatives" ], "offsets": [ [ 620, 631 ] ], "normalized": [] }, { "id": "entity-13-14", "type": "IUPAC", "text": [ "hydrobromic acid" ], "offsets": [ [ 689, 705 ] ], "normalized": [] }, { "id": "entity-13-15", "type": "IUPAC", "text": [ "1-[[3-(Dialkylamino)propyl]-amino]-4-methyl-9-hydroxy-5H-pyrido[4,3- b]benzo[e]indoles" ], "offsets": [ [ 867, 953 ] ], "normalized": [] } ]

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[ { "id": "passage-14", "type": "abstract", "text": [ "596853 [Synthesis and properties of carminomycinone derivatives] The possibility of chemical modification of carminomycinone-aglycone (II) of carminomicin, a side product in the antibiotic production was studied. The methyl group C-14 was functionilized by introducing the bromine atom and performing a number of exchange reactions with the bromine atom. It was found that under definite conditions (1. 1 equiv. Br2in dioxane, degrees, 24 hours) carminomycinone (II) was subjected to selective bromination into the side acetyl group with formation of 14-bromcarminomycinone (III). On interaction with anhydrous potassium acetate 14-bromcarminomycinone (III) yield 14-acetoxycarminomycinone (IV). In its turn the latter compound (IV) easily hydrolized to 14-oxycarminomycinone (V) in treatment with aqueous alkali or acid. 14-oxycarminomycinone (V) was also prepared with a high yield ( per cent) by direct alkaline hydrolysis of 14-bromcarminomycinone (III) in treatment with 0.1N solution of sodium carbonate in a mixture of dioxane and water. The structure of 14-substituted derivatives of carminomycinone was proved by analytical and spectral data and confirmed by their transformation. Thus, according to the data of mass-spectrometry 14-oxycarminomycinone (V) had a molecular weight of c. u. In treatment with an excess of acetic anhydride in pyridine it formed a hexa-acetyl derivative, i.e. 4, 6, 7, 9, 11, 14-hexa-acetyl-14-oxycarminomycinone (VI). The aglycones (III-V) prepared by us may serve a starting material in chemical synthesis, as well as biosynthesis of semi-synthetic preparations of the carminomycin series." ], "offsets": [ [ 0, 1640 ] ] } ]

[ { "id": "entity-14-0", "type": "TRIVIAL", "text": [ "carminomycinone" ], "offsets": [ [ 37, 52 ] ], "normalized": [] }, { "id": "entity-14-1", "type": "MODIFIER", "text": [ "derivatives" ], "offsets": [ [ 53, 64 ] ], "normalized": [] }, { "id": "entity-14-2", "type": "TRIVIAL", "text": [ "carminomycinone-aglycone" ], "offsets": [ [ 111, 135 ] ], "normalized": [] }, { "id": "entity-14-3", "type": "TRIVIAL", "text": [ "carminomicin" ], "offsets": [ [ 144, 156 ] ], "normalized": [] }, { "id": "entity-14-4", "type": "PARTIUPAC", "text": [ "methyl" ], "offsets": [ [ 219, 225 ] ], "normalized": [] }, { "id": "entity-14-5", "type": "MODIFIER", "text": [ "group" ], "offsets": [ [ 226, 231 ] ], "normalized": [] }, { "id": "entity-14-6", "type": "SUM", "text": [ "C-14" ], "offsets": [ [ 232, 236 ] ], "normalized": [] }, { "id": "entity-14-7", "type": "TRIVIAL", "text": [ "bromine" ], "offsets": [ [ 275, 282 ] ], "normalized": [] }, { "id": "entity-14-8", "type": "MODIFIER", "text": [ "atom" ], "offsets": [ [ 283, 287 ] ], "normalized": [] }, { "id": "entity-14-9", "type": "TRIVIAL", "text": [ "bromine" ], "offsets": [ [ 343, 350 ] ], "normalized": [] }, { "id": "entity-14-10", "type": "MODIFIER", "text": [ "atom" ], "offsets": [ [ 351, 355 ] ], "normalized": [] }, { "id": "entity-14-11", "type": "SUM", "text": [ "Br2" ], "offsets": [ [ 414, 417 ] ], "normalized": [] }, { "id": "entity-14-12", "type": "TRIVIAL", "text": [ "dioxane" ], "offsets": [ [ 420, 427 ] ], "normalized": [] }, { "id": "entity-14-13", "type": "TRIVIAL", "text": [ "carminomycinone" ], "offsets": [ [ 451, 466 ] ], "normalized": [] }, { "id": "entity-14-14", "type": "TRIVIAL", "text": [ "acetyl" ], "offsets": [ [ 525, 531 ] ], "normalized": [] }, { "id": "entity-14-15", "type": "MODIFIER", "text": [ "group" ], "offsets": [ [ 532, 537 ] ], "normalized": [] }, { "id": "entity-14-16", "type": "IUPAC", "text": [ "14-bromcarminomycinone" ], "offsets": [ [ 556, 578 ] ], "normalized": [] }, { "id": "entity-14-17", "type": "IUPAC", "text": [ "potassium acetate 14-bromcarminomycinone" ], "offsets": [ [ 616, 656 ] ], "normalized": [] }, { "id": "entity-14-18", "type": "IUPAC", "text": [ "14-acetoxycarminomycinone" ], "offsets": [ [ 669, 694 ] ], "normalized": [] }, { "id": "entity-14-19", "type": "IUPAC", "text": [ "14-oxycarminomycinone" ], "offsets": [ [ 759, 780 ] ], "normalized": [] }, { "id": "entity-14-20", "type": "IUPAC", "text": [ "14-oxycarminomycinone" ], "offsets": [ [ 827, 848 ] ], "normalized": [] }, { "id": "entity-14-21", "type": "IUPAC", "text": [ "14-bromcarminomycinone" ], "offsets": [ [ 936, 958 ] ], "normalized": [] }, { "id": "entity-14-22", "type": "IUPAC", "text": [ "sodium carbonate" ], "offsets": [ [ 1000, 1016 ] ], "normalized": [] }, { "id": "entity-14-23", "type": "TRIVIAL", "text": [ "dioxane" ], "offsets": [ [ 1033, 1040 ] ], "normalized": [] }, { "id": "entity-14-24", "type": "MODIFIER", "text": [ "derivatives" ], "offsets": [ [ 1084, 1095 ] ], "normalized": [] }, { "id": "entity-14-25", "type": "TRIVIAL", "text": [ "carminomycinone" ], "offsets": [ [ 1099, 1114 ] ], "normalized": [] }, { "id": "entity-14-26", "type": "IUPAC", "text": [ "14-oxycarminomycinone" ], "offsets": [ [ 1246, 1267 ] ], "normalized": [] }, { "id": "entity-14-27", "type": "IUPAC", "text": [ "acetic anhydride" ], "offsets": [ [ 1339, 1355 ] ], "normalized": [] }, { "id": "entity-14-28", "type": "TRIVIAL", "text": [ "pyridine" ], "offsets": [ [ 1359, 1367 ] ], "normalized": [] }, { "id": "entity-14-29", "type": "IUPAC", "text": [ "hexa-acetyl" ], "offsets": [ [ 1380, 1391 ] ], "normalized": [] }, { "id": "entity-14-30", "type": "MODIFIER", "text": [ "derivative" ], "offsets": [ [ 1392, 1402 ] ], "normalized": [] }, { "id": "entity-14-31", "type": "IUPAC", "text": [ "4, 6, 7, 9, 11, 14-hexa-acetyl-14-oxycarminomycinone" ], "offsets": [ [ 1409, 1461 ] ], "normalized": [] }, { "id": "entity-14-32", "type": "FAMILY", "text": [ "aglycones" ], "offsets": [ [ 1472, 1481 ] ], "normalized": [] }, { "id": "entity-14-33", "type": "TRIVIAL", "text": [ "carminomycin" ], "offsets": [ [ 1620, 1632 ] ], "normalized": [] }, { "id": "entity-14-34", "type": "MODIFIER", "text": [ "series" ], "offsets": [ [ 1633, 1639 ] ], "normalized": [] } ]

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[ { "id": "passage-15", "type": "abstract", "text": [ "Adenosine 5'-triphosphate (ATP) derivatives of the types N6-R-ATP [R = (CH2)nNHCOCH2I, (CH2)nNHCO-(CH2)mNHCOCH2I, or (CH2)nCON(Me)(CH2)mN(Me)CO(CH2)nNHCOCH2I], N6-Me-N6-R-ATP [R = (CH2)nN-(Me)CO(CH2)mNHCOCH2I], and 8-R-ATP [R = NM(CH2)nNHCOCH2I] with 5--19 spacer atoms between N6 or C-8 and iodine have been evaluated as potential exo-ATP-site-directed reagents for phosphokinases. Substrate and inhibitor properties indicated that the compounds possessed affinity for the ATP sites of the muscle (M), kidney (K), and liver (L) isozymes of rat pyruvate kinase (PK), of E. coli thymidine kinase (TK), and of yeast hexokinase (HK) and rat KH I, II, and III isozymes. Tests for time-dependent loss of enzyme activity (inactivation) were performed under conditions in which a large proportion of each phosphokinase was present as an enzyme-inhibitor complex. No ATP-site-directed inactivations resulted when the M, L, or K isozymes of PK were exposed for 8 h, 22 degrees C, to 5 mM levels of 18 ATP derivatives or 6 analogous ADP derivatives or when yeast HK or rat KH I, II, or III was exposed for 6 h, 22 degrees C, to 5 mM levels of 28 ATP derivatives. Escherichia coli TK was inactivated by 6 of 25 ATP derivatives tested at mM, 6 h, 0 degrees C; inactivation was slowed by MgATP in the case of N6-CH3-N6-R-ATP [R = (CH2)4N(CH3)CO(CH2)5NHCOCH2I]. Only 1% of 298 enzyme-inhibitor combinations exhibited ATP-site-directed inactivation, signifying that few suitably positioned and sufficiently reactive nucleophilic groups were present near the enzymic ATPsites . Studies have now shown that exo-active-site-directed reagents can act as isozyme- or species-selective enzyme inhibitors. The present survey indicates that in many cases such reagents may be difficult of access when data are not available regarding structural or physicochemical features of the target enzyme adjacent to its catalytic site." ], "offsets": [ [ 0, 1905 ] ] } ]

[ { "id": "entity-15-0", "type": "ABBREVIATION", "text": [ "ATP" ], "offsets": [ [ 27, 30 ] ], "normalized": [] }, { "id": "entity-15-1", "type": "MODIFIER", "text": [ "derivatives" ], "offsets": [ [ 32, 43 ] ], "normalized": [] }, { "id": "entity-15-2", "type": "ABBREVIATION", "text": [ "N6-R-ATP" ], "offsets": [ [ 57, 65 ] ], "normalized": [] }, { "id": "entity-15-3", "type": "SUM", "text": [ "(CH2)nNHCOCH2I" ], "offsets": [ [ 71, 85 ] ], "normalized": [] }, { "id": "entity-15-4", "type": "SUM", "text": [ "(CH2)nNHCO-(CH2)mNHCOCH2I" ], "offsets": [ [ 87, 112 ] ], "normalized": [] }, { "id": "entity-15-5", "type": "SUM", "text": [ "(CH2)nCON(Me)(CH2)mN(Me)CO(CH2)nNHCOCH2I" ], "offsets": [ [ 117, 157 ] ], "normalized": [] }, { "id": "entity-15-6", "type": "ABBREVIATION", "text": [ "N6-Me-N6-R-ATP" ], "offsets": [ [ 160, 174 ] ], "normalized": [] }, { "id": "entity-15-7", "type": "SUM", "text": [ "(CH2)nN-(Me)CO(CH2)mNHCOCH2I" ], "offsets": [ [ 180, 208 ] ], "normalized": [] }, { "id": "entity-15-8", "type": "ABBREVIATION", "text": [ "8-R-ATP" ], "offsets": [ [ 215, 222 ] ], "normalized": [] }, { "id": "entity-15-9", "type": "SUM", "text": [ "NM(CH2)nNHCOCH2I" ], "offsets": [ [ 228, 244 ] ], "normalized": [] }, { "id": "entity-15-10", "type": "TRIVIAL", "text": [ "iodine" ], "offsets": [ [ 292, 298 ] ], "normalized": [] }, { "id": "entity-15-11", "type": "ABBREVIATION", "text": [ "ATP" ], "offsets": [ [ 336, 339 ] ], "normalized": [] }, { "id": "entity-15-12", "type": "ABBREVIATION", "text": [ "ATP" ], "offsets": [ [ 474, 477 ] ], "normalized": [] }, { "id": "entity-15-13", "type": "ABBREVIATION", "text": [ "ATP" ], "offsets": [ [ 859, 862 ] ], "normalized": [] }, { "id": "entity-15-14", "type": "ABBREVIATION", "text": [ "ATP" ], "offsets": [ [ 992, 995 ] ], "normalized": [] }, { "id": "entity-15-15", "type": "MODIFIER", "text": [ "derivatives" ], "offsets": [ [ 996, 1007 ] ], "normalized": [] }, { "id": "entity-15-16", "type": "ABBREVIATION", "text": [ "ADP" ], "offsets": [ [ 1023, 1026 ] ], "normalized": [] }, { "id": "entity-15-17", "type": "MODIFIER", "text": [ "derivatives" ], "offsets": [ [ 1027, 1038 ] ], "normalized": [] }, { "id": "entity-15-18", "type": "ABBREVIATION", "text": [ "ATP" ], "offsets": [ [ 1136, 1139 ] ], "normalized": [] }, { "id": "entity-15-19", "type": "MODIFIER", "text": [ "derivatives" ], "offsets": [ [ 1140, 1151 ] ], "normalized": [] }, { "id": "entity-15-20", "type": "ABBREVIATION", "text": [ "MgATP" ], "offsets": [ [ 1278, 1283 ] ], "normalized": [] }, { "id": "entity-15-21", "type": "ABBREVIATION", "text": [ "N6-CH3-N6-R-ATP" ], "offsets": [ [ 1299, 1314 ] ], "normalized": [] }, { "id": "entity-15-22", "type": "SUM", "text": [ "(CH2)4N(CH3)CO(CH2)5NHCOCH2I" ], "offsets": [ [ 1320, 1348 ] ], "normalized": [] }, { "id": "entity-15-23", "type": "ABBREVIATION", "text": [ "ATP" ], "offsets": [ [ 1406, 1409 ] ], "normalized": [] }, { "id": "entity-15-24", "type": "ABBREVIATION", "text": [ "ATP" ], "offsets": [ [ 1554, 1557 ] ], "normalized": [] } ]

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[ { "id": "passage-16", "type": "abstract", "text": [ "2944474 Effect of recombinant human fibroblast interferon and mezerein on growth, differentiation, immune interferon binding and tumor associated antigen expression in human melanoma cells. The combination of recombinant human fibroblast interferon (INF-delta) and the antileukemic compound mezerein (MEZ) results in a synergistic suppression in the growth of human melanoma cells and a concomitant increase in melanin synthesis. In the present study we have further analyzed this synergistic interaction and have also evaluated the effect of IFN-delta and MEZ, alone and in combination, on recombinant human gamma interferon (IFN-gamma) binding and Class I HLA and melanoma associated antigen (MAA) expression in the HO-1 human melanoma cell line. Single cell clones isolated from the HO-1 cell line varied in their sensitivity to the antiproliferative effects of IFN-delta and MEZ. With all twelve clones, however, the combination of IFN-delta plus MEZ was more growth inhibitory than either agent used alone, even in HO-1 subclones displaying relative resistance to IFN-delta. By continuous growth in gradually increasing concentrations of IFN-delta, a variant population of HO-1 cells, HO-1 delta R-D, was generated which was more resistant to the antigrowth effects of IFN-delta than the original HO-1 parental cell line. In the IFN delta R-D cell line the combination of IFN-delta plus MEZ synergistically suppressed growth. Exposure of HO-1 cells to units/ml IFN-delta or ng/ml MEZ for 96 hr resulted in no change or an increase in the binding of labelled IFN-gamma to surface receptors, whereas the combination of IFN-delta plus MEZ increased IFN-gamma binding 2-to-4-fold in HO-1 cells. This increase was the result of an increase in the number of receptors on treated cells coupled with a protection against a decrease in receptors observed for confluent untreated cells. Changes in IFN-gamma binding resulting from treatment with IFN-delta plus MEZ were not associated with alterations in the binding affinity of INF-gamma to its receptor. Changes were also observed in the expression of HLA Class I antigens and MAAs following treatment of HO-1 cells with IFN-delta, MEZ or IFN-delta plus MEZ. IFN-delta and MEZincreased the expression of HLA Class I antigens a 96 kd MAA defined by MoAb CL203, a kd MAA defined by MoAb 376.96 and a 115 kd MAA defined by MoAb 345.134 but decreased the expression of a high molecular weight-melanoma associated antigen (HMW-MAA) defined by MoAb 325.28S.(ABSTRACT TRUNCATED AT WORDS)" ], "offsets": [ [ 0, 2546 ] ] } ]

[ { "id": "entity-16-0", "type": "TRIVIAL", "text": [ "mezerein" ], "offsets": [ [ 63, 71 ] ], "normalized": [] }, { "id": "entity-16-1", "type": "TRIVIAL", "text": [ "mezerein" ], "offsets": [ [ 293, 301 ] ], "normalized": [] }, { "id": "entity-16-2", "type": "ABBREVIATION", "text": [ "MEZ" ], "offsets": [ [ 303, 306 ] ], "normalized": [] }, { "id": "entity-16-3", "type": "TRIVIAL", "text": [ "melanin" ], "offsets": [ [ 413, 420 ] ], "normalized": [] }, { "id": "entity-16-4", "type": "ABBREVIATION", "text": [ "MEZ" ], "offsets": [ [ 559, 562 ] ], "normalized": [] }, { "id": "entity-16-5", "type": "ABBREVIATION", "text": [ "MEZ" ], "offsets": [ [ 881, 884 ] ], "normalized": [] }, { "id": "entity-16-6", "type": "ABBREVIATION", "text": [ "MEZ" ], "offsets": [ [ 953, 956 ] ], "normalized": [] }, { "id": "entity-16-7", "type": "ABBREVIATION", "text": [ "MEZ" ], "offsets": [ [ 1394, 1397 ] ], "normalized": [] }, { "id": "entity-16-8", "type": "ABBREVIATION", "text": [ "MEZ" ], "offsets": [ [ 1495, 1498 ] ], "normalized": [] }, { "id": "entity-16-9", "type": "ABBREVIATION", "text": [ "MEZ" ], "offsets": [ [ 1647, 1650 ] ], "normalized": [] }, { "id": "entity-16-10", "type": "ABBREVIATION", "text": [ "MEZ" ], "offsets": [ [ 1966, 1969 ] ], "normalized": [] }, { "id": "entity-16-11", "type": "ABBREVIATION", "text": [ "MEZ" ], "offsets": [ [ 2189, 2192 ] ], "normalized": [] }, { "id": "entity-16-12", "type": "ABBREVIATION", "text": [ "MEZ" ], "offsets": [ [ 2211, 2214 ] ], "normalized": [] }, { "id": "entity-16-13", "type": "ABBREVIATION", "text": [ "MEZ" ], "offsets": [ [ 2230, 2233 ] ], "normalized": [] } ]

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[ { "id": "passage-17", "type": "abstract", "text": [ "Degarelix (FE200486, Ac-d-2Nal(1)-d-4Cpa(2)-d-3Pal(3)-Ser(4)-4Aph(l-Hor)(5)-d-4Aph(Cbm)(6)-Leu(7)-ILys(8)-Pro(9)-d-Ala( )-NH(2)) is a potent and very long acting antagonist of gonadotropin-releasing hormone (GnRH) after subcutaneous administration in mammals including humans. Analogues of degarelix were synthesized, characterized, and screened for the antagonism of GnRH-induced response in a reporter gene assay in HEK-293 cells expressing the human GnRH receptor. The duration of action was also determined in the castrated male rat assay to measure the extent (efficacy and duration of action) of inhibition of luteinizing hormone (LH) release. Structurally, this series of analogues has novel substitutions at positions 3, 7, and 8 and N(alpha)-methylation at positions 6, 7, and 8 in the structure of degarelix. These substitutions were designed to probe the spatial limitations of the receptor's cavity and to map the steric and ionic boundaries. Some functional groups were introduced that were hypothesized to influence the phamacokinetic properties of the analogues such as bioavailability, solubility, intra- or intermolecular hydrogen bond forming capacity, and ability to bind carrier proteins. Substitutions at positions 3 ([N(beta)-(2-pyridyl-methyl)d-Dap(3)]degarelix, IC( ) = 2.71 nM) (5), 7 ([Pra(7)]degarelix, IC( ) = 2.11 nM) (16), and 8 ([N(delta)-(IGly)Orn(8)]degarelix, IC( ) = 1.38 nM) ( ) and N-methylation ([N(alpha)-methyl-Leu(7)]degarelix, IC( ) = 1.47 nM) (32) yielded analogues that were equipotent to degarelix (2) in vitro (IC( ) = 1.64 nM) but shorter acting in vivo. Out of the 33 novel analogues tested for the duration of action in this series, two analogues ([N(epsilon)-cyclohexyl-Lys(8)]degarelix, IC( ) = 1.50 nM) (23) and ([N(beta)-(IbetaAla)Dap(8)]degarelix, IC( ) = 1.98 nM) (26) had antagonist potencies and duration of action similar to that of azaline B {inhibited LH (> ) release for >72 h after sc injection to castrated male rats at a standard dose of mug/rat in 5% mannitol}. Under similar conditions analogues ([N(gamma)-(IGly)Dab(8)]degarelix, IC( ) = 1.56 nM) (21) and ([IOrn(8)]degarelix, IC( ) = 1.72 nM) (18) had a longer duration of action {inhibited LH (>96 h) release} than azaline B; however they were shorter acting than degarelix. Hydrophilicity of these analogues, a potential measure of their ability to be formulated for sustained release, was determined using RP-HPLC at neutral pH yielding analogues with shorter as well as longer retention times. No correlation was found between retention times and antagonist potency or duration of action." ], "offsets": [ [ 0, 2635 ] ] } ]

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[ { "id": "passage-18", "type": "abstract", "text": [ " [Method of determination of biogenic amines in wines by high-performance liquid chromatography with fluorescence detector and ultraviolet detector] OBJECTIVE: A pre-column derivation reversed-phase high-performance liquid chromatography method was developed for the determination of biogenic amines (tryptamine, phenylethyamine, putrescine, cadaverine, histamine, tyramine, spermidine, and spermine) in wines with fluorescecse detector (FLD) and ultraviolet detector (UVD). METHODS: Liqiud-liqiud extraction (LLE) was used to clean up wine samples with chloroform/butanol prior to derivatization with dansyl chloride, biogenic amines were separated using gradient elution. Mobile phase A was methanol and mobile phase B was water with the flow rate 1.5 ml/min. The column used was a CAPCELL PAK C18 MG (4.6 mm I.D. x mm, 5 microm) and gradient elution at constant column tempereture with degrees C under fluorescence detector with Ex and Em , The method and ultraviolet detector with 254nm. 1,7-Diaminoheptane was used as the internal standard (IS). RESULTS: was linear for the amines studied at concentration ranging from 0.05 to 25 mg/L, except for spermidine and spermine, which ranging from 0.05 to 15 mg/L. The average recoveries ranged from 79.2% to 127.5% for all amines, The RSDs were less than . With this method, 5 wine samples were determined, the results were favorable. CONCLUTION: method can be applied for determination of biogenic amines in wines." ], "offsets": [ [ 0, 1495 ] ] } ]

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[ { "id": "passage-19", "type": "abstract", "text": [ "The isomeric 4-(3-chloro-4-hydroxyphenyl)- and 4-(4-chloro-3-hydroxyphenyl)-1,2,3,4-tetrahydroisoquinolines, the N-methyl derivative of the 4-(4-chloro-3-hydroxyphenyl) isomer, and 4-(3-hydroxyphenyl)-1,2,3,4-tetrahydroisoquinoline were synthesized and evaluated for dopamine D-1 antagonist activity. The 4-(3-chloro-4-hydroxyphenyl) and the 4-(3-hydroxyphenyl) isomer possessed similar potencies as D-1 antagonists. Introduction of the N-methyl group enhanced potency about twofold. The \"pharmacophore\" for selective dopamine D-1 antagonist activity appears to be a tertiary 2-(3-hydroxyphenyl)-2-phenethylamine." ], "offsets": [ [ 0, 613 ] ] } ]

[ { "id": "entity-19-0", "type": "PARTIUPAC", "text": [ "4-(3-chloro-4-hydroxyphenyl)-" ], "offsets": [ [ 13, 42 ] ], "normalized": [] }, { "id": "entity-19-1", "type": "IUPAC", "text": [ "4-(4-chloro-3-hydroxyphenyl)-1,2,3,4-tetrahydroisoquinolines" ], "offsets": [ [ 47, 107 ] ], "normalized": [] }, { "id": "entity-19-2", "type": "PARTIUPAC", "text": [ "N-methyl" ], "offsets": [ [ 113, 121 ] ], "normalized": [] }, { "id": "entity-19-3", "type": "MODIFIER", "text": [ "derivative" ], "offsets": [ [ 122, 132 ] ], "normalized": [] }, { "id": "entity-19-4", "type": "IUPAC", "text": [ "4-(4-chloro-3-hydroxyphenyl)" ], "offsets": [ [ 140, 168 ] ], "normalized": [] }, { "id": "entity-19-5", "type": "MODIFIER", "text": [ "isomer" ], "offsets": [ [ 169, 175 ] ], "normalized": [] }, { "id": "entity-19-6", "type": "IUPAC", "text": [ "4-(3-hydroxyphenyl)-1,2,3,4-tetrahydroisoquinoline" ], "offsets": [ [ 181, 231 ] ], "normalized": [] }, { "id": "entity-19-7", "type": "IUPAC", "text": [ "4-(3-chloro-4-hydroxyphenyl)" ], "offsets": [ [ 305, 333 ] ], "normalized": [] }, { "id": "entity-19-8", "type": "IUPAC", "text": [ "4-(3-hydroxyphenyl)" ], "offsets": [ [ 342, 361 ] ], "normalized": [] }, { "id": "entity-19-9", "type": "MODIFIER", "text": [ "isomer" ], "offsets": [ [ 362, 368 ] ], "normalized": [] }, { "id": "entity-19-10", "type": "PARTIUPAC", "text": [ "N-methyl" ], "offsets": [ [ 437, 445 ] ], "normalized": [] }, { "id": "entity-19-11", "type": "MODIFIER", "text": [ "group" ], "offsets": [ [ 446, 451 ] ], "normalized": [] }, { "id": "entity-19-12", "type": "IUPAC", "text": [ "2-(3-hydroxyphenyl)-2-phenethylamine" ], "offsets": [ [ 576, 612 ] ], "normalized": [] } ]

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[ { "id": "passage-20", "type": "abstract", "text": [ "In a continuing effort to design small-molecule inhibitors of dihydrofolate reductase (DHFR) that combine the enzyme-binding selectivity of 2,4-diamino-5-(3',4',5'-trimethoxybenzyl)pyrimidine (trimethoprim, TMP) with the potency of 2,4-diamino-5-methyl-6-(2',5'-dimethoxybenzyl)pyrido[2,3-d]pyrimidine (piritrexim, PTX), seven previously undescribed 2,4-diamino-5-[2'-methoxy-5'-(substituted benzyl)]pyrimidines were synthesized in which the substituent at the 5'-position was a carboxyphenyl group linked to the benzyl moiety by a bridge of two or four atoms in length. The new analogues were all obtained from 2,4-diamino-5-(5'-iodo-2'-methoxybenzyl)pyrimidine via a Sonogashira reaction, followed, where appropriate, by catalytic hydrogenation. The new analogues were tested as inhibitors of DHFR from Pneumocystis carinii (Pc), Toxoplasma gondii (Tg), and Mycobacterium avium (Ma), three life-threatening pathogens often found in AIDS patients and individuals whose immune system is impaired as a result of treatment with immunosuppressive chemotherapy or radiation. The selectivity index (SI) of each compound was obtained by dividing its inhibitory concentration (IC( )) against Pc, Tg, or Ma DHFR by its IC( ) against rat DHFR. 2,4-Diamino-[2'-methoxy-5'-(3-carboxyphenyl)ethynylbenzyl]pyrimidine (28), with an IC( ) of 23 nM and an SI of 28 in the Pc DHFR assay, had about the same potency as PTX and was times more potent than TMP. As an inhibitor of Tg DHFR, 28 had an IC( ) of 5.5 nM ( -fold lower than that of TMP and similar to that of PTX) and an SI value of (2-fold better than TMP and vastly superior to PTX). Against Ma DHFR, 28 had IC( ) and SI values of 1.5 nM and , respectively, compared with nM and for TMP. Although it had 2.5-fold lower potency than 28 against Ma DHFR (IC( ) = 3.7 nM) and was substantially weaker against Pc and Tg DHFR, 2,4-diamino-[2'-methoxy-5'-(4-carboxyphenyl)ethynylbenzyl]pyrimidine (29), with the carboxy group at the para rather than the meta position, displayed -fold selectivity against the Ma enzyme and was the most selective 2,4-diamino-5-(5'-substituted benzyl)pyrimidineinhibitor of this enzyme we have encountered to date. Additional bioassay data for these compounds are also reported." ], "offsets": [ [ 0, 2281 ] ] } ]

[ { "id": "entity-20-0", "type": "IUPAC", "text": [ "2,4-diamino-5-(3',4',5'-trimethoxybenzyl)pyrimidine" ], "offsets": [ [ 140, 191 ] ], "normalized": [] }, { "id": "entity-20-1", "type": "TRIVIAL", "text": [ "trimethoprim" ], "offsets": [ [ 193, 205 ] ], "normalized": [] }, { "id": "entity-20-2", "type": "ABBREVIATION", "text": [ "TMP" ], "offsets": [ [ 207, 210 ] ], "normalized": [] }, { "id": "entity-20-3", "type": "IUPAC", "text": [ "2,4-diamino-5-methyl-6-(2',5'-dimethoxybenzyl)pyrido[2,3-d]pyrimidine" ], "offsets": [ [ 232, 301 ] ], "normalized": [] }, { "id": "entity-20-4", "type": "TRIVIAL", "text": [ "piritrexim" ], "offsets": [ [ 303, 313 ] ], "normalized": [] }, { "id": "entity-20-5", "type": "ABBREVIATION", "text": [ "PTX" ], "offsets": [ [ 315, 318 ] ], "normalized": [] }, { "id": "entity-20-6", "type": "IUPAC", "text": [ "2,4-diamino-5-[2'-methoxy-5'-(substituted benzyl)]pyrimidines" ], "offsets": [ [ 350, 411 ] ], "normalized": [] }, { "id": "entity-20-7", "type": "PARTIUPAC", "text": [ "carboxyphenyl" ], "offsets": [ [ 479, 492 ] ], "normalized": [] }, { "id": "entity-20-8", "type": "MODIFIER", "text": [ "group" ], "offsets": [ [ 493, 498 ] ], "normalized": [] }, { "id": "entity-20-9", "type": "PARTIUPAC", "text": [ "benzyl" ], "offsets": [ [ 513, 519 ] ], "normalized": [] }, { "id": "entity-20-10", "type": "MODIFIER", "text": [ "moiety" ], "offsets": [ [ 520, 526 ] ], "normalized": [] }, { "id": "entity-20-11", "type": "IUPAC", "text": [ "2,4-diamino-5-(5'-iodo-2'-methoxybenzyl)pyrimidine" ], "offsets": [ [ 612, 662 ] ], "normalized": [] }, { "id": "entity-20-12", "type": "IUPAC", "text": [ "2,4-Diamino-[2'-methoxy-5'-(3-carboxyphenyl)ethynylbenzyl]pyrimidine" ], "offsets": [ [ 1241, 1309 ] ], "normalized": [] }, { "id": "entity-20-13", "type": "ABBREVIATION", "text": [ "PTX" ], "offsets": [ [ 1408, 1411 ] ], "normalized": [] }, { "id": "entity-20-14", "type": "ABBREVIATION", "text": [ "TMP" ], "offsets": [ [ 1447, 1450 ] ], "normalized": [] }, { "id": "entity-20-15", "type": "ABBREVIATION", "text": [ "TMP" ], "offsets": [ [ 1536, 1539 ] ], "normalized": [] }, { "id": "entity-20-16", "type": "ABBREVIATION", "text": [ "PTX" ], "offsets": [ [ 1563, 1566 ] ], "normalized": [] }, { "id": "entity-20-17", "type": "ABBREVIATION", "text": [ "TMP" ], "offsets": [ [ 1611, 1614 ] ], "normalized": [] }, { "id": "entity-20-18", "type": "ABBREVIATION", "text": [ "PTX" ], "offsets": [ [ 1638, 1641 ] ], "normalized": [] }, { "id": "entity-20-19", "type": "ABBREVIATION", "text": [ "TMP" ], "offsets": [ [ 1755, 1758 ] ], "normalized": [] }, { "id": "entity-20-20", "type": "IUPAC", "text": [ "2,4-diamino-[2'-methoxy-5'-(4-carboxyphenyl)ethynylbenzyl]pyrimidine" ], "offsets": [ [ 1894, 1962 ] ], "normalized": [] }, { "id": "entity-20-21", "type": "TRIVIAL", "text": [ "carboxy" ], "offsets": [ [ 1978, 1985 ] ], "normalized": [] }, { "id": "entity-20-22", "type": "MODIFIER", "text": [ "group" ], "offsets": [ [ 1986, 1991 ] ], "normalized": [] }, { "id": "entity-20-23", "type": "IUPAC", "text": [ "2,4-diamino-5-(5'-substituted benzyl)pyrimidine" ], "offsets": [ [ 2116, 2163 ] ], "normalized": [] } ]

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[ { "id": "passage-21", "type": "abstract", "text": [ " Parenteral hydroxypropyl cyclodextrins: intravenous and intracerebral administration of lipophiles. Hydroxypropyl cyclodextrins are nontoxic carbohydrate derivatives of moderate molecular weight ( Da) which form water-soluble complexes with many lipophiles. The fate of hydroxypropyl beta-cyclodextrin alone and in complex with testosterone or cholesterol injected intravenously or intracerebrally into rats was followed. More than of intravenously administered hydroxypropyl beta-cyclodextrin was cleared into urine in 4 h, as previously described (Monbaliu, J.; Van Beijsterveld, L.; Meuldermans, W.; Szathmary, S.; Haykants, J. Abstracts, 5th International Symposium on Cyclodextrins, Paris, ; Abstract 65). After the injection of steroids in complex with hydroxypropyl beta-cyclodextrin into the tail vein of rats, the steroid component was released from the complex, before it reached the kidneys; the release occurred mainly into the proteins and lipoproteins of serum. Hydroxypropyl beta-cyclodextrins injected alone into the brain were cleared within less than 24 h, presumably via the flow of interstitial and cerebrospinal fluids, and eventually were excreted in urine. Testosterone, incorporated in a hydroxypropyl beta-cyclodextrin complex, after intracerebral injection was cleared from the brain even more rapidly than hydroxypropyl beta-cyclodextrin, presumably by crossing the blood-brain barrier and later removal to the liver by the specific carrier proteins in serum. Complexed cholesterol, in a similar experiment, was largely retained in the brain and its distribution there was uneven and remained that way for at least 3 days. It is clear that lipophilic agents, after their incorporation into hydroxypropyl beta-cyclodextrin complexes and subsequent in vivo administration, are rapidly released and exchanged into the plasma. In absence of plasma they enter tissues surrounding the injection site and thus are also promptly transferred into the organism's lipid systems. The manner in which different lipophilic agents are transported in vivo appears not to be greatly affected by their previous complexation; rather hydroxypropyl cyclodextrinsjust enable their entry in a larger amount and in an exchangeable, nonaggregated form." ], "offsets": [ [ 0, 2282 ] ] } ]

[ { "id": "entity-21-0", "type": "IUPAC", "text": [ "hydroxypropyl cyclodextrins" ], "offsets": [ [ 20, 47 ] ], "normalized": [] }, { "id": "entity-21-1", "type": "IUPAC", "text": [ "Hydroxypropyl cyclodextrins" ], "offsets": [ [ 110, 137 ] ], "normalized": [] }, { "id": "entity-21-2", "type": "FAMILY", "text": [ "carbohydrate" ], "offsets": [ [ 151, 163 ] ], "normalized": [] }, { "id": "entity-21-3", "type": "MODIFIER", "text": [ "derivatives" ], "offsets": [ [ 164, 175 ] ], "normalized": [] }, { "id": "entity-21-4", "type": "IUPAC", "text": [ "hydroxypropyl beta-cyclodextrin" ], "offsets": [ [ 289, 320 ] ], "normalized": [] }, { "id": "entity-21-5", "type": "TRIVIAL", "text": [ "testosterone" ], "offsets": [ [ 347, 359 ] ], "normalized": [] }, { "id": "entity-21-6", "type": "TRIVIAL", "text": [ "cholesterol" ], "offsets": [ [ 363, 374 ] ], "normalized": [] }, { "id": "entity-21-7", "type": "IUPAC", "text": [ "hydroxypropyl beta-cyclodextrin" ], "offsets": [ [ 485, 516 ] ], "normalized": [] }, { "id": "entity-21-8", "type": "TRIVIAL", "text": [ "Cyclodextrins" ], "offsets": [ [ 696, 709 ] ], "normalized": [] }, { "id": "entity-21-9", "type": "IUPAC", "text": [ "hydroxypropyl beta-cyclodextrin" ], "offsets": [ [ 786, 817 ] ], "normalized": [] }, { "id": "entity-21-10", "type": "IUPAC", "text": [ "Hydroxypropyl beta-cyclodextrins" ], "offsets": [ [ 1003, 1035 ] ], "normalized": [] }, { "id": "entity-21-11", "type": "TRIVIAL", "text": [ "Testosterone" ], "offsets": [ [ 1207, 1219 ] ], "normalized": [] }, { "id": "entity-21-12", "type": "IUPAC", "text": [ "hydroxypropyl beta-cyclodextrin" ], "offsets": [ [ 1239, 1270 ] ], "normalized": [] }, { "id": "entity-21-13", "type": "MODIFIER", "text": [ "complex" ], "offsets": [ [ 1271, 1278 ] ], "normalized": [] }, { "id": "entity-21-14", "type": "IUPAC", "text": [ "hydroxypropyl beta-cyclodextrin" ], "offsets": [ [ 1360, 1391 ] ], "normalized": [] }, { "id": "entity-21-15", "type": "TRIVIAL", "text": [ "cholesterol" ], "offsets": [ [ 1524, 1535 ] ], "normalized": [] }, { "id": "entity-21-16", "type": "IUPAC", "text": [ "hydroxypropyl beta-cyclodextrin" ], "offsets": [ [ 1744, 1775 ] ], "normalized": [] }, { "id": "entity-21-17", "type": "MODIFIER", "text": [ "complexes" ], "offsets": [ [ 1776, 1785 ] ], "normalized": [] }, { "id": "entity-21-18", "type": "FAMILY", "text": [ "lipid" ], "offsets": [ [ 2007, 2012 ] ], "normalized": [] }, { "id": "entity-21-19", "type": "IUPAC", "text": [ "hydroxypropyl cyclodextrins" ], "offsets": [ [ 2168, 2195 ] ], "normalized": [] } ]

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[ { "id": "passage-22", "type": "abstract", "text": [ "6264792 Inhibition of renin secretion by intrarenal alpha-adrenoceptor blockade. This study was designed to determine whether renal alpha-adrenoceptors can mediate tonic neural stimulation of renin secretion. The effect of alpha-adrenoceptor blockade by phenoxybenzamine (POB) or prazosin on renin secretion rate (RSR) was studied in pentobarbital-anesthetized dogs in which renal perfusion pressure was held constant with an adjustable aortic clamp. POB alone ( micrograms.kg-1.min-1 iv) did not change arterial plasma renin activity (PRA). However, when beta-adrenoceptors were blocked by intravenous propranolol, intravenous POB infusion ( micrograms.kg-1.min-1) decreased PRA and RSR to 48 +/- 8 and 21 +/- 9% of previous levels within min. This effect was abolished by acute bilateral renal denervation. Direct intrarenal POB infusion ( or 3.3 micrograms.kg-1.min-1) decreased RSR, whereas intravenous POB (3.3 micrograms.kg-1.min-1) had no effect on either RSR or PRA in propranolol-pretreated dogs. Prazosin (1 microgram.kg-1.min-1 iv) also significantly decreased PRA. These data indicate that when beta-adrenoceptors are blocked by propranolol, tonic neural stimulation of renin secretion is mediated by renal alpha-adrenoceptors." ], "offsets": [ [ 0, 1252 ] ] } ]

[ { "id": "entity-22-0", "type": "TRIVIAL", "text": [ "phenoxybenzamine" ], "offsets": [ [ 256, 272 ] ], "normalized": [] }, { "id": "entity-22-1", "type": "ABBREVIATION", "text": [ "POB" ], "offsets": [ [ 274, 277 ] ], "normalized": [] }, { "id": "entity-22-2", "type": "TRIVIAL", "text": [ "prazosin" ], "offsets": [ [ 282, 290 ] ], "normalized": [] }, { "id": "entity-22-3", "type": "TRIVIAL", "text": [ "pentobarbital" ], "offsets": [ [ 336, 349 ] ], "normalized": [] }, { "id": "entity-22-4", "type": "ABBREVIATION", "text": [ "POB" ], "offsets": [ [ 453, 456 ] ], "normalized": [] }, { "id": "entity-22-5", "type": "TRIVIAL", "text": [ "propranolol" ], "offsets": [ [ 608, 619 ] ], "normalized": [] }, { "id": "entity-22-6", "type": "ABBREVIATION", "text": [ "POB" ], "offsets": [ [ 633, 636 ] ], "normalized": [] }, { "id": "entity-22-7", "type": "ABBREVIATION", "text": [ "POB" ], "offsets": [ [ 838, 841 ] ], "normalized": [] }, { "id": "entity-22-8", "type": "ABBREVIATION", "text": [ "POB" ], "offsets": [ [ 920, 923 ] ], "normalized": [] }, { "id": "entity-22-9", "type": "TRIVIAL", "text": [ "propranolol" ], "offsets": [ [ 990, 1001 ] ], "normalized": [] }, { "id": "entity-22-10", "type": "TRIVIAL", "text": [ "Prazosin" ], "offsets": [ [ 1019, 1027 ] ], "normalized": [] }, { "id": "entity-22-11", "type": "TRIVIAL", "text": [ "propranolol" ], "offsets": [ [ 1154, 1165 ] ], "normalized": [] } ]

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[ { "id": "passage-23", "type": "abstract", "text": [ " Metabolism of D- and L-glyceraldehyde in adipose tissue: a stereochemical probe for glycerokinase activity. Distributions of (14)C have been determined in free glycerol, in glycerol from triglycerides, in glucose from glycogen, and in lactate after incubation of d-glyceraldehyde-3-(14)C andl -glyceraldehyde-3-(14)C with rat adipose tissue. The distributions are interpreted in terms of presently accepted possible reactions for the initial metabolism of glyceraldehyde. Formation of glycerol-1-(14)C fromd -glyceraldehyde-3-(14)C indicates that in adipose tissue glyceraldehyde is reduced to glycerol. Incorporation of (14)C from d-glyceraldehyde-3-(14)C into carbon 3 of the glycerol of triglyceride indicates thatd -glyceraldehyde is either phosphorylated or oxidized to d-glyceric acid, or both, in its initial metabolism. Incorporation of (14)C froml -glyceraldehyde-3-(14)C into carbon 3 of glycerol indicates that l-glyceraldehyde is reduced to glycerol, which is phosphorylated and (or) converted to d-glyceric acid via l-glyceric acid. Some (14)C from l-glyceraldehyde-3-(14)C is incorporated into carbon 1 of glycerol of triglycerides and carbon 4 of glycogen; the explanation for this incorporation is uncertain." ], "offsets": [ [ 0, 1234 ] ] } ]

[ { "id": "entity-23-0", "type": "IUPAC", "text": [ "D-" ], "offsets": [ [ 23, 25 ] ], "normalized": [] }, { "id": "entity-23-1", "type": "IUPAC", "text": [ "L-glyceraldehyde" ], "offsets": [ [ 30, 46 ] ], "normalized": [] }, { "id": "entity-23-2", "type": "SUM", "text": [ "(14)C" ], "offsets": [ [ 135, 140 ] ], "normalized": [] }, { "id": "entity-23-3", "type": "TRIVIAL", "text": [ "glycerol" ], "offsets": [ [ 170, 178 ] ], "normalized": [] }, { "id": "entity-23-4", "type": "TRIVIAL", "text": [ "glycerol" ], "offsets": [ [ 183, 191 ] ], "normalized": [] }, { "id": "entity-23-5", "type": "FAMILY", "text": [ "triglycerides" ], "offsets": [ [ 197, 210 ] ], "normalized": [] }, { "id": "entity-23-6", "type": "TRIVIAL", "text": [ "glucose" ], "offsets": [ [ 215, 222 ] ], "normalized": [] }, { "id": "entity-23-7", "type": "TRIVIAL", "text": [ "glycogen" ], "offsets": [ [ 228, 236 ] ], "normalized": [] }, { "id": "entity-23-8", "type": "IUPAC", "text": [ "d-glyceraldehyde-3-(14)C" ], "offsets": [ [ 273, 297 ] ], "normalized": [] }, { "id": "entity-23-9", "type": "IUPAC", "text": [ " l-glyceraldehyde-3-(14)C" ], "offsets": [ [ 301, 326 ] ], "normalized": [] }, { "id": "entity-23-10", "type": "TRIVIAL", "text": [ "glyceraldehyde" ], "offsets": [ [ 466, 480 ] ], "normalized": [] }, { "id": "entity-23-11", "type": "IUPAC", "text": [ "glycerol-1-(14)C" ], "offsets": [ [ 495, 511 ] ], "normalized": [] }, { "id": "entity-23-12", "type": "IUPAC", "text": [ " d-glyceraldehyde-3-(14)C" ], "offsets": [ [ 516, 541 ] ], "normalized": [] }, { "id": "entity-23-13", "type": "TRIVIAL", "text": [ "glyceraldehyde" ], "offsets": [ [ 575, 589 ] ], "normalized": [] }, { "id": "entity-23-14", "type": "TRIVIAL", "text": [ "glycerol" ], "offsets": [ [ 604, 612 ] ], "normalized": [] }, { "id": "entity-23-15", "type": "SUM", "text": [ "(14)C" ], "offsets": [ [ 631, 636 ] ], "normalized": [] }, { "id": "entity-23-16", "type": "IUPAC", "text": [ "d-glyceraldehyde-3-(14)C" ], "offsets": [ [ 642, 666 ] ], "normalized": [] }, { "id": "entity-23-17", "type": "TRIVIAL", "text": [ "carbon" ], "offsets": [ [ 672, 678 ] ], "normalized": [] }, { "id": "entity-23-18", "type": "TRIVIAL", "text": [ "glycerol" ], "offsets": [ [ 688, 696 ] ], "normalized": [] }, { "id": "entity-23-19", "type": "FAMILY", "text": [ "triglyceride" ], "offsets": [ [ 700, 712 ] ], "normalized": [] }, { "id": "entity-23-20", "type": "IUPAC", "text": [ " d-glyceraldehyde" ], "offsets": [ [ 727, 744 ] ], "normalized": [] }, { "id": "entity-23-21", "type": "IUPAC", "text": [ "d-glyceric acid" ], "offsets": [ [ 785, 800 ] ], "normalized": [] }, { "id": "entity-23-22", "type": "SUM", "text": [ "(14)C" ], "offsets": [ [ 855, 860 ] ], "normalized": [] }, { "id": "entity-23-23", "type": "IUPAC", "text": [ " l-glyceraldehyde-3-(14)C" ], "offsets": [ [ 865, 890 ] ], "normalized": [] }, { "id": "entity-23-24", "type": "TRIVIAL", "text": [ "carbon" ], "offsets": [ [ 896, 902 ] ], "normalized": [] }, { "id": "entity-23-25", "type": "TRIVIAL", "text": [ "glycerol" ], "offsets": [ [ 908, 916 ] ], "normalized": [] }, { "id": "entity-23-26", "type": "IUPAC", "text": [ "l-glyceraldehyde" ], "offsets": [ [ 932, 948 ] ], "normalized": [] }, { "id": "entity-23-27", "type": "TRIVIAL", "text": [ "glycerol" ], "offsets": [ [ 963, 971 ] ], "normalized": [] }, { "id": "entity-23-28", "type": "IUPAC", "text": [ "d-glyceric acid" ], "offsets": [ [ 1019, 1034 ] ], "normalized": [] }, { "id": "entity-23-29", "type": "IUPAC", "text": [ "l-glyceric acid" ], "offsets": [ [ 1039, 1054 ] ], "normalized": [] }, { "id": "entity-23-30", "type": "SUM", "text": [ "(14)C" ], "offsets": [ [ 1061, 1066 ] ], "normalized": [] }, { "id": "entity-23-31", "type": "IUPAC", "text": [ "l-glyceraldehyde-3-(14)C" ], "offsets": [ [ 1072, 1096 ] ], "normalized": [] }, { "id": "entity-23-32", "type": "TRIVIAL", "text": [ "carbon" ], "offsets": [ [ 1118, 1124 ] ], "normalized": [] }, { "id": "entity-23-33", "type": "TRIVIAL", "text": [ "glycerol" ], "offsets": [ [ 1130, 1138 ] ], "normalized": [] }, { "id": "entity-23-34", "type": "FAMILY", "text": [ "triglycerides" ], "offsets": [ [ 1142, 1155 ] ], "normalized": [] }, { "id": "entity-23-35", "type": "TRIVIAL", "text": [ "carbon" ], "offsets": [ [ 1160, 1166 ] ], "normalized": [] }, { "id": "entity-23-36", "type": "TRIVIAL", "text": [ "glycogen" ], "offsets": [ [ 1172, 1180 ] ], "normalized": [] } ]

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[ { "id": "passage-24", "type": "abstract", "text": [ " Attenuation of glucocorticoid functions in an Anx-A1-/- cell line. The Ca(2+)- and phospholipid-binding protein Anx-A1 (annexin 1; lipocortin 1) has been described both as an inhibitor of phospholipase A(2) (PLA(2)) activity and as a mediator of glucocorticoid-regulated cell growth and eicosanoid generation. Here we show that, when compared with Anx-A1(+/+) cells, lung fibroblast cell lines derived from the Anx-A1(-/-) mouse exhibit an altered morphology characterized by a spindle-shaped appearance and an accumulation of intracellular organelles. Unlike their wild-type counterparts, Anx-A1(-/-) cells also overexpress cyclo-oxygenase 2 (COX 2), cytosolic PLA(2) and secretory PLA(2) and in response to fetal calf serum, exhibit an exaggerated release of eicosanoids, which is insensitive to dexamethasone ( (-8)- (-6) M) inhibition. Proliferation and serum-induced progression of Anx-A1(+/+) cells from G(0)/G(1) into S phase, and the associated expression of extracellular signal-regulated kinase 2 (ERK2), cyclin-dependent kinase 4 (cdk4) and COX 2, is strongly inhibited by dexamethasone, whereas Anx-A1(-/-) cells are refractory to the drug. Loss of the response to dexamethasone in Anx-A1(-/-) cells occurs against a background of no apparent change in glucocorticoid receptor expression or sensitivity to non-steroidal anti-inflammatory drugs. Taken together, these observations suggest strongly that Anx-A1 functions as an inhibitor of signal-transduction pathways that lead to cell proliferation and may help to explain how glucocorticoidsregulate these processes." ], "offsets": [ [ 0, 1594 ] ] } ]

[ { "id": "entity-24-0", "type": "FAMILY", "text": [ "glucocorticoid" ], "offsets": [ [ 25, 39 ] ], "normalized": [] }, { "id": "entity-24-1", "type": "FAMILY", "text": [ "glucocorticoid" ], "offsets": [ [ 257, 271 ] ], "normalized": [] }, { "id": "entity-24-2", "type": "TRIVIAL", "text": [ "eicosanoid" ], "offsets": [ [ 298, 308 ] ], "normalized": [] }, { "id": "entity-24-3", "type": "TRIVIAL", "text": [ "eicosanoids" ], "offsets": [ [ 772, 783 ] ], "normalized": [] }, { "id": "entity-24-4", "type": "TRIVIAL", "text": [ "dexamethasone" ], "offsets": [ [ 809, 822 ] ], "normalized": [] }, { "id": "entity-24-5", "type": "TRIVIAL", "text": [ "dexamethasone" ], "offsets": [ [ 1191, 1204 ] ], "normalized": [] }, { "id": "entity-24-6", "type": "FAMILY", "text": [ "glucocorticoids" ], "offsets": [ [ 1553, 1568 ] ], "normalized": [] } ]

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[ { "id": "passage-25", "type": "abstract", "text": [ "14591846 Cognitive assessment of geriatric schizophrenic patients with severe impairment. There is evidence that some elderly patients with chronic schizophrenia experience marked impairments in cognitive functioning. Assessment of these patients may be difficult with traditional neuropsychological measures. The purpose of the present study was to determine if cognitive functioning could be validly assessed with the Alzheimer's Disease Assessment Scale-Late Version Cognitive factor score (ADAS-L Cog) in patients whose scores on the Mini-Mental State Examination (MMSE) reflect profound cognitive impairment. Patients with MMSE scores from 0 to were selected from a larger database. Neuropsychological instruments designed for the assessment of mild to moderate dementia were found to be inadequate in this profoundly impaired population, due to floor effects. In contrast, there was a significant relationship between ADAS-L scores and several criterion measures, including the MMSE (R=-.71, P<.001), the Social Adaptive Functions Evaluation (SAFE) social functions scale (R=.47, P<.001), and the negative symptom total score of the Positive and Negative Syndrome Scale (PANSS) (R=.412, P<.001). The MMSE was somewhat less strongly correlated with both social functions (R=-.401, P<.001) and the negative symptom total score of the PANSS (R=-.366, P<.001). These results suggest that cognition can be reliably and validly assessed with instruments such as the ADAS-L that are designed for the assessment of severely impaired patients." ], "offsets": [ [ 0, 1545 ] ] } ]

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[ { "id": "passage-26", "type": "abstract", "text": [ " Evidence for messenger ribonucleic acid of an ammonium-inducible glutamate dehydrogenase and synthesis, covalent modification, and degradation of enzyme subunits in uninduced Chlorella sorokiniana cells. The cells of Chlorella sorokiniana cultured in nitrate medium contain no detectable catalytic activity of an ammonium-inducible nicotinamide adenine dinucleotide phosphate-specific glutamate dehydrogenase (NADP-GDH). However, several lines of experimental evidence indicated that the NADP-GDH messenger ribonucleic acid was present at high levels and was being translated in uninduced cells. First, binding studies with 125I-labeled anti-NADP-GDH immunoglobulin G and total polysomes isolated from uninduced and induced cells showed that NADP-GDH subunits were being synthesized on polysomes from both types of cells. Second, when polyadenylic acid-containing ribonucleic acid was extracted from polysomes from uninduced and induced cells and placed into a messenger ribonucleic acid-dependent in vitro translation system, NADP-GDH subunits were synthesized from the ribonucleic acid from both sources. Third, when ammonia was added to uninduced cells, NADP-GDH antigen accumulated without an apparent induction lag. Fourth, by use of a specific immunoprecipitation procedure coupled to pulse-chase studies with [35S]sulfate, it was shown that the NADP-GDH subunits are rapidly synthesized, covalently modified, and then degraded in uninduced cells." ], "offsets": [ [ 0, 1463 ] ] } ]

[ { "id": "entity-26-0", "type": "TRIVIAL", "text": [ "nitrate" ], "offsets": [ [ 261, 268 ] ], "normalized": [] }, { "id": "entity-26-1", "type": "IUPAC", "text": [ "polyadenylic acid" ], "offsets": [ [ 845, 862 ] ], "normalized": [] }, { "id": "entity-26-2", "type": "FAMILY", "text": [ "ammonia" ], "offsets": [ [ 1129, 1136 ] ], "normalized": [] }, { "id": "entity-26-3", "type": "IUPAC", "text": [ "[35S]sulfate" ], "offsets": [ [ 1326, 1338 ] ], "normalized": [] } ]

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[ { "id": "passage-27", "type": "abstract", "text": [ " Nucleotide regulation of heat-stable enterotoxin receptor binding and of guanylate cyclase activation. Certain nucleotides were found to regulate the binding of the Escherichia coli heat-stable enterotoxin (STa) to its receptor in pig intestinal brush border membranes. ATP and adenine nucleotide analogues inhibited 125I-STa binding, while guanine nucleotide analogues stimulated binding, with maximal effects at 0.5-1.0 mM. The strongest inhibitors were adenosine 5'-[beta gamma-imido]triphosphate (App[NH]p) (36%) and adenosine 5'-[beta-thio]diphosphate (ADP[S]) (41%). Inhibition did not require Mg2+, and was blocked by p-chloromercuribenzenesulphonate (PCMBS). Stimulation of binding required Mg2+, was not prevented by PCMBS and was maximal with GDP[S] (41%). While App[NH]p and MgGDP[S] appeared to be acting at different sites, they also interfered with each other. These nucleotides exerted only inhibitory effects on STa-stimulated guanylate cyclase activity, in contrast with the stimulatory effects of adenine nucleotides on atrial natriuretic peptide (ANP)-stimulated guanylate cyclase. Inhibition by low concentrations ofMgApp [NH]p and MgATP was weaker above 0.1 mM, while MgGDP[S] and magnesium guanosine 5'-[gamma-thio]triphosphate (MgGTP[S]) inhibited in a single phase. Inhibition by MgApp[NH]p, at all concentrations, was competitive with the substrate (MgGTP), as was that by MgGDP[S] and MgGTP[S]. Whereas membrane guanylate cyclases usually show positively co-operative kinetics with respect to the substrate, STa-stimulated activity exhibited Michaelis-Menten kinetics with respect to MgGTP. This changed to positive co-operativity when Lubrol PX was the activator, or when the substrate was MnGTP. These results suggest the presence of both a regulatory and a catalytic nucleotide-binding site, which do not interact co-operatively with STa activation." ], "offsets": [ [ 0, 1888 ] ] } ]

[ { "id": "entity-27-0", "type": "FAMILY", "text": [ "Nucleotide" ], "offsets": [ [ 9, 19 ] ], "normalized": [] }, { "id": "entity-27-1", "type": "FAMILY", "text": [ "nucleotides" ], "offsets": [ [ 121, 132 ] ], "normalized": [] }, { "id": "entity-27-2", "type": "ABBREVIATION", "text": [ "ATP" ], "offsets": [ [ 280, 283 ] ], "normalized": [] }, { "id": "entity-27-3", "type": "TRIVIAL", "text": [ "adenine" ], "offsets": [ [ 288, 295 ] ], "normalized": [] }, { "id": "entity-27-4", "type": "FAMILY", "text": [ "nucleotide" ], "offsets": [ [ 296, 306 ] ], "normalized": [] }, { "id": "entity-27-5", "type": "MODIFIER", "text": [ "analogues" ], "offsets": [ [ 307, 316 ] ], "normalized": [] }, { "id": "entity-27-6", "type": "TRIVIAL", "text": [ "guanine" ], "offsets": [ [ 351, 358 ] ], "normalized": [] }, { "id": "entity-27-7", "type": "FAMILY", "text": [ "nucleotide" ], "offsets": [ [ 359, 369 ] ], "normalized": [] }, { "id": "entity-27-8", "type": "MODIFIER", "text": [ "analogues" ], "offsets": [ [ 370, 379 ] ], "normalized": [] }, { "id": "entity-27-9", "type": "IUPAC", "text": [ "adenosine 5'-[beta gamma-imido]triphosphate" ], "offsets": [ [ 466, 509 ] ], "normalized": [] }, { "id": "entity-27-10", "type": "ABBREVIATION", "text": [ "App[NH]p" ], "offsets": [ [ 511, 519 ] ], "normalized": [] }, { "id": "entity-27-11", "type": "IUPAC", "text": [ "adenosine 5'-[beta-thio]diphosphate" ], "offsets": [ [ 531, 566 ] ], "normalized": [] }, { "id": "entity-27-12", "type": "ABBREVIATION", "text": [ "ADP[S]" ], "offsets": [ [ 568, 574 ] ], "normalized": [] }, { "id": "entity-27-13", "type": "SUM", "text": [ "Mg2+" ], "offsets": [ [ 610, 614 ] ], "normalized": [] }, { "id": "entity-27-14", "type": "IUPAC", "text": [ "p-chloromercuribenzenesulphonate" ], "offsets": [ [ 635, 667 ] ], "normalized": [] }, { "id": "entity-27-15", "type": "ABBREVIATION", "text": [ "PCMBS" ], "offsets": [ [ 669, 674 ] ], "normalized": [] }, { "id": "entity-27-16", "type": "SUM", "text": [ "Mg2+" ], "offsets": [ [ 709, 713 ] ], "normalized": [] }, { "id": "entity-27-17", "type": "ABBREVIATION", "text": [ "PCMBS" ], "offsets": [ [ 736, 741 ] ], "normalized": [] }, { "id": "entity-27-18", "type": "ABBREVIATION", "text": [ "GDP[S]" ], "offsets": [ [ 763, 769 ] ], "normalized": [] }, { "id": "entity-27-19", "type": "ABBREVIATION", "text": [ "App[NH]p" ], "offsets": [ [ 783, 791 ] ], "normalized": [] }, { "id": "entity-27-20", "type": "ABBREVIATION", "text": [ "MgGDP[S]" ], "offsets": [ [ 796, 804 ] ], "normalized": [] }, { "id": "entity-27-21", "type": "FAMILY", "text": [ "nucleotides" ], "offsets": [ [ 891, 902 ] ], "normalized": [] }, { "id": "entity-27-22", "type": "TRIVIAL", "text": [ "adenine" ], "offsets": [ [ 1025, 1032 ] ], "normalized": [] }, { "id": "entity-27-23", "type": "ABBREVIATION", "text": [ " MgApp[NH]p" ], "offsets": [ [ 1146, 1157 ] ], "normalized": [] }, { "id": "entity-27-24", "type": "ABBREVIATION", "text": [ "MgATP" ], "offsets": [ [ 1162, 1167 ] ], "normalized": [] }, { "id": "entity-27-25", "type": "ABBREVIATION", "text": [ "MgGDP[S]" ], "offsets": [ [ 1199, 1207 ] ], "normalized": [] }, { "id": "entity-27-26", "type": "IUPAC", "text": [ "magnesium guanosine 5'-[gamma-thio]triphosphate" ], "offsets": [ [ 1212, 1259 ] ], "normalized": [] }, { "id": "entity-27-27", "type": "ABBREVIATION", "text": [ "MgGTP[S]" ], "offsets": [ [ 1261, 1269 ] ], "normalized": [] }, { "id": "entity-27-28", "type": "ABBREVIATION", "text": [ "MgApp[NH]p" ], "offsets": [ [ 1314, 1324 ] ], "normalized": [] }, { "id": "entity-27-29", "type": "ABBREVIATION", "text": [ "MgGTP" ], "offsets": [ [ 1385, 1390 ] ], "normalized": [] }, { "id": "entity-27-30", "type": "ABBREVIATION", "text": [ "MgGDP[S]" ], "offsets": [ [ 1408, 1416 ] ], "normalized": [] }, { "id": "entity-27-31", "type": "ABBREVIATION", "text": [ "MgGTP[S]" ], "offsets": [ [ 1421, 1429 ] ], "normalized": [] }, { "id": "entity-27-32", "type": "ABBREVIATION", "text": [ "MgGTP" ], "offsets": [ [ 1620, 1625 ] ], "normalized": [] }, { "id": "entity-27-33", "type": "TRIVIAL", "text": [ "Lubrol PX" ], "offsets": [ [ 1672, 1681 ] ], "normalized": [] }, { "id": "entity-27-34", "type": "ABBREVIATION", "text": [ "MnGTP" ], "offsets": [ [ 1727, 1732 ] ], "normalized": [] } ]

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[ { "id": "passage-28", "type": "abstract", "text": [ "The syntheses of (3RS,4RS)-4-hydroxypiperidine-3-carboxylic acid (4), (3RS,5SR)-5-hydroxypiperidine-3-carboxylic acid ( ), (3RS,4SR)-4-acetamidopiperidine-3-carboxylic acid ( ), and (3RS,5SR)-5-acetamidopiperidine-3-carboxylic acid (18), related to the specific gamma-aminobutyric acid (GABA) uptake inhibitors (RS)-piperidine-3-carboxylic acid (nipecotic acid) and (3RS,4SR)-4-hydroxypiperidine-3-carboxylic acid (21), are described. Furthermore, (3RS,4SR)-3-hydroxypiperidine-4-carboxylic acid (14), related to the specific GABA agonist piperidine-4-carboxylic acid (isonipecotic acid), has been synthesized. The structures of 4, , 14, 18, and have been established by -MHz 1H NMR spectroscopic analyses. The affinity of the compounds for the GABA receptors and for the neuronal (synaptosomal) GABA uptake system in vitro has been measured. Compound 14 interacts selectively with the GABA receptors but less effectively than isonipecotic acid and the cis-isomer 22. Compounds 4, 18, and are inhibitors of the GABA uptake system, although much weaker than nipecotic acid and (3RS,4SR)-4-hydroxypiperidine-3-carboxylic acid( 21). Compound is inactive in both test systems." ], "offsets": [ [ 0, 1188 ] ] } ]

[ { "id": "entity-28-0", "type": "IUPAC", "text": [ "(3RS,4RS)-4-hydroxypiperidine-3-carboxylic acid" ], "offsets": [ [ 17, 64 ] ], "normalized": [] }, { "id": "entity-28-1", "type": "IUPAC", "text": [ "(3RS,5SR)-5-hydroxypiperidine-3-carboxylic acid" ], "offsets": [ [ 70, 117 ] ], "normalized": [] }, { "id": "entity-28-2", "type": "IUPAC", "text": [ "(3RS,4SR)-4-acetamidopiperidine-3-carboxylic acid" ], "offsets": [ [ 124, 173 ] ], "normalized": [] }, { "id": "entity-28-3", "type": "IUPAC", "text": [ "(3RS,5SR)-5-acetamidopiperidine-3-carboxylic acid" ], "offsets": [ [ 184, 233 ] ], "normalized": [] }, { "id": "entity-28-4", "type": "IUPAC", "text": [ "gamma-aminobutyric acid" ], "offsets": [ [ 264, 287 ] ], "normalized": [] }, { "id": "entity-28-5", "type": "ABBREVIATION", "text": [ "GABA" ], "offsets": [ [ 289, 293 ] ], "normalized": [] }, { "id": "entity-28-6", "type": "IUPAC", "text": [ "(RS)-piperidine-3-carboxylic acid" ], "offsets": [ [ 313, 346 ] ], "normalized": [] }, { "id": "entity-28-7", "type": "IUPAC", "text": [ "nipecotic acid" ], "offsets": [ [ 348, 362 ] ], "normalized": [] }, { "id": "entity-28-8", "type": "IUPAC", "text": [ "(3RS,4SR)-4-hydroxypiperidine-3-carboxylic acid" ], "offsets": [ [ 368, 415 ] ], "normalized": [] }, { "id": "entity-28-9", "type": "IUPAC", "text": [ "(3RS,4SR)-3-hydroxypiperidine-4-carboxylic acid" ], "offsets": [ [ 450, 497 ] ], "normalized": [] }, { "id": "entity-28-10", "type": "ABBREVIATION", "text": [ "GABA" ], "offsets": [ [ 528, 532 ] ], "normalized": [] }, { "id": "entity-28-11", "type": "IUPAC", "text": [ "piperidine-4-carboxylic acid" ], "offsets": [ [ 541, 569 ] ], "normalized": [] }, { "id": "entity-28-12", "type": "IUPAC", "text": [ "isonipecotic acid" ], "offsets": [ [ 571, 588 ] ], "normalized": [] }, { "id": "entity-28-13", "type": "ABBREVIATION", "text": [ "GABA" ], "offsets": [ [ 806, 810 ] ], "normalized": [] }, { "id": "entity-28-14", "type": "IUPAC", "text": [ "isonipecotic acid" ], "offsets": [ [ 937, 954 ] ], "normalized": [] }, { "id": "entity-28-15", "type": "ABBREVIATION", "text": [ "GABA" ], "offsets": [ [ 1024, 1028 ] ], "normalized": [] }, { "id": "entity-28-16", "type": "IUPAC", "text": [ "nipecotic acid" ], "offsets": [ [ 1070, 1084 ] ], "normalized": [] }, { "id": "entity-28-17", "type": "IUPAC", "text": [ "(3RS,4SR)-4-hydroxypiperidine-3-carboxylic acid" ], "offsets": [ [ 1089, 1136 ] ], "normalized": [] } ]

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[ { "id": "passage-29", "type": "abstract", "text": [ "16946562 Novel genetic variations and haplotypes of hepatocyte nuclear factor 4alpha (HNF4A) found in Japanese type II diabetic patients. Thirty-nine single nucleotide variations, including 16 novel ones, were found in the 5' promoter region, all of the exons and their surrounding introns of HNF4A in 74 Japanese type II diabetic patients. The following novel variations were identified (based on the amino acid numbering of splicing variant 2): - >C in the 5' promoter region; 1154C>T (A385V) and 1193T>C (M398T) in the coding exons; >A, 1852G>T, >T, >A, and 2362_2380delAAGAATGGTGTGGGAGAGG in the 3'-untranslated region, and IVS1+231G>A, IVS2-83C>T, IVS3+ >T, IVS3-54delC, IVS5+173_176delTTAG, IVS5-181_- , IVS8- >G, and IVS9-151A>C in the introns. The allele frequencies were 0.311 for 2362_2380delAAGAATGGTGTGGGAGAGG, 0.054 for >A, 0.047 for 1852G>T, 0.020 for IVS1+231G>A, 0.014 for IVS9-151A>C, and 0.007 for the other 11 variations. In addition, one known nonsynonymous single nucleotide polymorphism, 416C>T (T139I), was detected at a 0.007 frequency. Based on the linkage disequilibrium profiles, the region analyzed was divided into three blocks. Haplotype analysis determined/inferred , 16, and 12 haplotypes for block 1, 2, and 3, respectively. Our results on HNF4A variations and haplotypes would be useful for pharmacogenetic studies in Japanese." ], "offsets": [ [ 0, 1400 ] ] } ]

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[ { "id": "passage-30", "type": "abstract", "text": [ " Predictive clinical parameters for therapeutic efficacy of rosiglitazone in Korean type 2 diabetes mellitus. This study evaluated the efficacy of rosiglitazone in non-obese and obese Korean type 2 diabetic patients of long duration. A total of 125 patients (M:F=44:81, mean age: 58.4+/-9.1 years, BMI: 24.2+/-2.7 kg/m2, duration of diabetes: 11.0+/-6.4 years) were randomly allocated to 12 weeks of rosiglitazone treatment (4 mg per day) or a control group. Responders were defined as patients who experienced fasting plasma glucose (FPG) reduction of > or HbA1c reduction of >1 (%). Rosiglitazone significantly improved glycemic control by reducing FPG and HbA1c (-3.4 mmol/l and -1.1%, P<0.001, respectively). It also significantly increased HOMA(beta-cell function) (+9.7, P<0.01) and QUICKI (+0.029, P<0.001), and decreased HOMA(IR) (-1.73, P<0.001). Females and those with higher waist-hip ratio made up a greater portion of rosiglitazone-responders. Responders (45 patients, 75%) also showed significantly higher FPG, HbA1c, systolic blood pressures, fasting insulin levels and HOMA(IR), and lower QUICKI than nonresponders. Among these parameters of responders, waist-hip ratio of non-obese subgroup, initial glycemic control of obese subgroup, and systolic blood pressure of both subgroups lost their significance after subdivision analysis. However, the baseline HOMA(IR) and QUICKI were significantly correlated with the response rate to rosiglitazone. Moreover, in multiple logistic regression analysis, HOMA(IR) and QUICKI retained their significance as the independent predictors. Even in Korean type 2 diabetic patients of long duration but with relatively preserved beta-cell function, rosiglitazone improved glycemic control, insulin sensitivity, and beta-cell function. In this ethnic group, female gender, central obesity, and especially severe insulin resistance were identified as predictive clinical parameters of rosiglitazone-responders." ], "offsets": [ [ 0, 1974 ] ] } ]

[ { "id": "entity-30-0", "type": "TRIVIAL", "text": [ "rosiglitazone" ], "offsets": [ [ 69, 82 ] ], "normalized": [] }, { "id": "entity-30-1", "type": "TRIVIAL", "text": [ "rosiglitazone" ], "offsets": [ [ 157, 170 ] ], "normalized": [] }, { "id": "entity-30-2", "type": "TRIVIAL", "text": [ "rosiglitazone" ], "offsets": [ [ 410, 423 ] ], "normalized": [] }, { "id": "entity-30-3", "type": "TRIVIAL", "text": [ "glucose" ], "offsets": [ [ 536, 543 ] ], "normalized": [] }, { "id": "entity-30-4", "type": "TRIVIAL", "text": [ "Rosiglitazone" ], "offsets": [ [ 598, 611 ] ], "normalized": [] }, { "id": "entity-30-5", "type": "TRIVIAL", "text": [ "rosiglitazone" ], "offsets": [ [ 1462, 1475 ] ], "normalized": [] }, { "id": "entity-30-6", "type": "TRIVIAL", "text": [ "rosiglitazone" ], "offsets": [ [ 1949, 1962 ] ], "normalized": [] } ]

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[ { "id": "passage-31", "type": "abstract", "text": [ "The synthesis of 2'-fluoro- -propargyl-5,8-dideazafolic acid and its 2-desamino, 2-desamino-2-hydroxymethyl, and 2-desamino-2-methoxy analogues is described. In general the synthetic route involved the coupling of diethyl N-[2-fluoro-4-(prop-2-ynylamino)benzoyl]-L-glutamate with the appropriate 6-(bromomethyl)quinazoline followed by deprotection with mild alkali. These four compounds together with the 2-desamino-2-methyl analogue were tested for their activity against L1210 thymidylate synthase (TS). They were also examined for their inhibition of the growth of the L1210 cell line and of two mutant L1210 cell lines, the L1210:R7A that overproduces dihydrofolate reductase (DHFR) and the L1210:1565 that has impaired uptake of reduced folates. Compared with their non-fluorinated parent compounds, the 2'-fluoro analogueswere all approximately 2-fold more potent as TS inhibitors. Similarly, they also showed improved inhibition of L1210 cell growth (1.5-5-fold), and this activity was prevented by co-incubation with thymidine. All had retained or improved activity against both the L1210:R7A and L1210:1565 cell lines." ], "offsets": [ [ 0, 1129 ] ] } ]

[ { "id": "entity-31-0", "type": "IUPAC", "text": [ "2'-fluoro-10-propargyl-5,8-dideazafolic acid" ], "offsets": [ [ 17, 61 ] ], "normalized": [] }, { "id": "entity-31-1", "type": "PARTIUPAC", "text": [ "2-desamino" ], "offsets": [ [ 70, 80 ] ], "normalized": [] }, { "id": "entity-31-2", "type": "PARTIUPAC", "text": [ "2-desamino-2-hydroxymethyl" ], "offsets": [ [ 82, 108 ] ], "normalized": [] }, { "id": "entity-31-3", "type": "PARTIUPAC", "text": [ "2-desamino-2-methoxy" ], "offsets": [ [ 114, 134 ] ], "normalized": [] }, { "id": "entity-31-4", "type": "MODIFIER", "text": [ "analogues" ], "offsets": [ [ 135, 144 ] ], "normalized": [] }, { "id": "entity-31-5", "type": "IUPAC", "text": [ "diethyl N-[2-fluoro-4-(prop-2-ynylamino)benzoyl]-L-glutamate" ], "offsets": [ [ 215, 275 ] ], "normalized": [] }, { "id": "entity-31-6", "type": "IUPAC", "text": [ "6-(bromomethyl)quinazoline" ], "offsets": [ [ 297, 323 ] ], "normalized": [] }, { "id": "entity-31-7", "type": "PARTIUPAC", "text": [ "2-desamino-2-methyl" ], "offsets": [ [ 406, 425 ] ], "normalized": [] }, { "id": "entity-31-8", "type": "MODIFIER", "text": [ "analogue" ], "offsets": [ [ 426, 434 ] ], "normalized": [] }, { "id": "entity-31-9", "type": "PARTIUPAC", "text": [ "2'-fluoro" ], "offsets": [ [ 810, 819 ] ], "normalized": [] }, { "id": "entity-31-10", "type": "MODIFIER", "text": [ "analogues" ], "offsets": [ [ 820, 829 ] ], "normalized": [] } ]

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[ { "id": "passage-32", "type": "abstract", "text": [ "A novel class of 5-substituted acyclic pyrimidine nucleosides, 1-[(2-hydroxyethoxy)methyl]-5-(1-azidovinyl)uracil (9a), 1-[(2-hydroxy-1-(hydroxymethyl)ethoxy)methyl]-5-(1-azidovinyl)uracil (9b), and 1-[4-hydroxy-3-(hydroxymethyl)-1-butyl]-5-(1-azidovinyl)uracil (9c), were synthesized by regiospecific addition of bromine azide to the 5-vinyl substituent of the respective 5-vinyluracils (2a-c) followed by treatment of the obtained 5-(1-azido-2-bromoethyl) compounds (3a-c) with t-BuOK, to affect the base-catalyzed elimination of HBr. Thermal decomposition of 9b and 9c at degrees C in dioxane yielded corresponding 5-[2-(1-azirinyl)]uracil analogues ( ,c). The 5-(1-azidovinyl)uracil derivatives 9a-c were found to exhibit potent and selective in vitro anti-HBV activity against duck hepatitis B virus (DHBV) infected primary duck hepatocytes at low concentrations (EC( ) = 0.01-0.1 microg/mL range). The most active anti-DHBV agent (9c), possessing a [4-hydroxy-3-(hydroxymethyl)-1-butyl] substituent at N-1, exhibited an activity (EC( ) of 0.01-0.05 microg/mL) comparable to that of reference compound (-)-beta-L-2',3'-dideoxy-3'-thiacytidine (3-TC) (EC( ) = 0.01-0.05 microg/mL). In contrast, related 5-[2-(1-azirinyl)]uracil analogues ( ,c) were devoid of anti-DHBV activity, indicating that an acyclic side chain at C-5 position of the pyrimidine ring is essential for anti-HBV activity. The pyrimidine nucleosides( 9a-c, ,c) exhibited no cytotoxic activity against a panel of human cancer cell lines. All of the compounds investigated did not show any detectable toxicity to several stationary and proliferating host cell lines or to mitogen stimulated proliferating human T lymphocytes, up to the highest concentration tested." ], "offsets": [ [ 0, 1753 ] ] } ]

[ { "id": "entity-32-0", "type": "IUPAC", "text": [ "5-substituted acyclic pyrimidine nucleosides" ], "offsets": [ [ 17, 61 ] ], "normalized": [] }, { "id": "entity-32-1", "type": "IUPAC", "text": [ "1-[(2-hydroxyethoxy)methyl]-5-(1-azidovinyl)uracil" ], "offsets": [ [ 63, 113 ] ], "normalized": [] }, { "id": "entity-32-2", "type": "IUPAC", "text": [ "1-[(2-hydroxy-1-(hydroxymethyl)ethoxy)methyl]-5-(1-azidovinyl)uracil" ], "offsets": [ [ 120, 188 ] ], "normalized": [] }, { "id": "entity-32-3", "type": "IUPAC", "text": [ "1-[4-hydroxy-3-(hydroxymethyl)-1-butyl]-5-(1-azidovinyl)uracil" ], "offsets": [ [ 199, 261 ] ], "normalized": [] }, { "id": "entity-32-4", "type": "IUPAC", "text": [ "bromine azide" ], "offsets": [ [ 314, 327 ] ], "normalized": [] }, { "id": "entity-32-5", "type": "PARTIUPAC", "text": [ "5-vinyl" ], "offsets": [ [ 335, 342 ] ], "normalized": [] }, { "id": "entity-32-6", "type": "MODIFIER", "text": [ "substituent" ], "offsets": [ [ 343, 354 ] ], "normalized": [] }, { "id": "entity-32-7", "type": "IUPAC", "text": [ "5-vinyluracils" ], "offsets": [ [ 373, 387 ] ], "normalized": [] }, { "id": "entity-32-8", "type": "IUPAC", "text": [ "5-(1-azido-2-bromoethyl)" ], "offsets": [ [ 433, 457 ] ], "normalized": [] }, { "id": "entity-32-9", "type": "MODIFIER", "text": [ "compounds" ], "offsets": [ [ 458, 467 ] ], "normalized": [] }, { "id": "entity-32-10", "type": "TRIVIAL", "text": [ "t-BuOK" ], "offsets": [ [ 480, 486 ] ], "normalized": [] }, { "id": "entity-32-11", "type": "SUM", "text": [ "HBr" ], "offsets": [ [ 532, 535 ] ], "normalized": [] }, { "id": "entity-32-12", "type": "TRIVIAL", "text": [ "dioxane" ], "offsets": [ [ 592, 599 ] ], "normalized": [] }, { "id": "entity-32-13", "type": "IUPAC", "text": [ "5-[2-(1-azirinyl)]uracil" ], "offsets": [ [ 622, 646 ] ], "normalized": [] }, { "id": "entity-32-14", "type": "MODIFIER", "text": [ "analogues" ], "offsets": [ [ 647, 656 ] ], "normalized": [] }, { "id": "entity-32-15", "type": "IUPAC", "text": [ "5-(1-azidovinyl)uracil" ], "offsets": [ [ 670, 692 ] ], "normalized": [] }, { "id": "entity-32-16", "type": "MODIFIER", "text": [ "derivatives" ], "offsets": [ [ 693, 704 ] ], "normalized": [] }, { "id": "entity-32-17", "type": "PARTIUPAC", "text": [ "[4-hydroxy-3-(hydroxymethyl)-1-butyl]" ], "offsets": [ [ 962, 999 ] ], "normalized": [] }, { "id": "entity-32-18", "type": "MODIFIER", "text": [ "substituent" ], "offsets": [ [ 1000, 1011 ] ], "normalized": [] }, { "id": "entity-32-19", "type": "IUPAC", "text": [ "(-)-beta-L-2',3'-dideoxy-3'-thiacytidine" ], "offsets": [ [ 1115, 1155 ] ], "normalized": [] }, { "id": "entity-32-20", "type": "IUPAC", "text": [ "5-[2-(1-azirinyl)]uracil" ], "offsets": [ [ 1216, 1240 ] ], "normalized": [] }, { "id": "entity-32-21", "type": "MODIFIER", "text": [ "analogues" ], "offsets": [ [ 1241, 1250 ] ], "normalized": [] }, { "id": "entity-32-22", "type": "FAMILY", "text": [ "pyrimidine" ], "offsets": [ [ 1355, 1365 ] ], "normalized": [] }, { "id": "entity-32-23", "type": "FAMILY", "text": [ "pyrimidine" ], "offsets": [ [ 1411, 1421 ] ], "normalized": [] }, { "id": "entity-32-24", "type": "MODIFIER", "text": [ "nucleosides" ], "offsets": [ [ 1422, 1433 ] ], "normalized": [] } ]

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[ { "id": "passage-33", "type": "abstract", "text": [ " Antiestrogens reduce plasma levels of endothelin-1 without affecting nitrate levels in breast cancer patients. Tamoxifen protects against myocardial infarction through mechanisms that are poorly understood. We studied the effects of tamoxifen and another antiestrogen, toremifene, on the production of vasoconstrictive endothelin-1 and of vasodilatory nitric oxide in 44 postmenopausal patients with breast cancer. These started treatment, in randomized order, with either tamoxifen ( mg/day; n = 25) or toremifene ( mg/day; n = 19). Plasma samples collected before treatment and after 6 and 12 months of both regimens were assayed for endothelin-1 with a specific radioimmunoassay and for nitrite/nitrate with a method based on the Griess reaction. The antiestrogen group as a whole showed a fall in endothelin-1 at 6 months (5.9 +/- 3.3%; p = 0.06) (mean +/- SE) and at 12 months (7.1 +/- 5.5%; p = 0.03). This fall was solely due to toremifene, the use of which was associated with falls in endothelin-1 at 6 months (12.9 +/- 4.7%; p = 0.01) and 12 months (9.2 +/- 6.2%; p = 0.06). The antiestrogen regimen failed to affect plasma nitric oxide significantly but nevertheless the ratio between nitric oxide and endothelin-1 rose by 31.6 +/- 13.3% at 6 months and by 35.6 +/- 15.3% at 12 months in the antiestrogen users, an effect similar in the tamoxifen and toremifene groups. We conclude that antiestrogens may protect against myocardial infarction by preventing the release of endothelin-1 and by shifting the balance between nitric oxide and endothelin-1 to the dominance of the former. Our data predict that toremifene and tamoxifenat the doses studied here will provide similar cardiovascular protection." ], "offsets": [ [ 0, 1729 ] ] } ]

[ { "id": "entity-33-0", "type": "IUPAC", "text": [ "nitrate" ], "offsets": [ [ 79, 86 ] ], "normalized": [] }, { "id": "entity-33-1", "type": "TRIVIAL", "text": [ "Tamoxifen" ], "offsets": [ [ 122, 131 ] ], "normalized": [] }, { "id": "entity-33-2", "type": "TRIVIAL", "text": [ "tamoxifen" ], "offsets": [ [ 244, 253 ] ], "normalized": [] }, { "id": "entity-33-3", "type": "TRIVIAL", "text": [ "toremifene" ], "offsets": [ [ 280, 290 ] ], "normalized": [] }, { "id": "entity-33-4", "type": "IUPAC", "text": [ "nitric oxide" ], "offsets": [ [ 363, 375 ] ], "normalized": [] }, { "id": "entity-33-5", "type": "TRIVIAL", "text": [ "tamoxifen" ], "offsets": [ [ 484, 493 ] ], "normalized": [] }, { "id": "entity-33-6", "type": "TRIVIAL", "text": [ "nitrite" ], "offsets": [ [ 705, 712 ] ], "normalized": [] }, { "id": "entity-33-7", "type": "TRIVIAL", "text": [ "nitrate" ], "offsets": [ [ 713, 720 ] ], "normalized": [] }, { "id": "entity-33-8", "type": "TRIVIAL", "text": [ "toremifene" ], "offsets": [ [ 951, 961 ] ], "normalized": [] }, { "id": "entity-33-9", "type": "IUPAC", "text": [ "nitric oxide" ], "offsets": [ [ 1149, 1161 ] ], "normalized": [] }, { "id": "entity-33-10", "type": "IUPAC", "text": [ "nitric oxide" ], "offsets": [ [ 1211, 1223 ] ], "normalized": [] }, { "id": "entity-33-11", "type": "TRIVIAL", "text": [ "tamoxifen" ], "offsets": [ [ 1363, 1372 ] ], "normalized": [] }, { "id": "entity-33-12", "type": "TRIVIAL", "text": [ "toremifene" ], "offsets": [ [ 1377, 1387 ] ], "normalized": [] }, { "id": "entity-33-13", "type": "IUPAC", "text": [ "nitric oxide" ], "offsets": [ [ 1547, 1559 ] ], "normalized": [] }, { "id": "entity-33-14", "type": "TRIVIAL", "text": [ "toremifene" ], "offsets": [ [ 1631, 1641 ] ], "normalized": [] }, { "id": "entity-33-15", "type": "TRIVIAL", "text": [ "tamoxifen" ], "offsets": [ [ 1646, 1655 ] ], "normalized": [] } ]

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[ { "id": "passage-34", "type": "abstract", "text": [ "A series of new 5-(1-hydroxy-2-iodoethyl)-2'-deoxyuridine and uridine compounds (11, 16) was synthesized by the regiospecific addition of HOI to the vinyl substituent of 5-vinyl-2'-deoxyuridine ( ), 5-vinyl-2'-fluoro-2'-deoxyuridine ( ), 5-vinyluridine ( ), and (E)-5-(2-iodovinyl)-2'-deoxyuridine (4b). Treatment of the iodohydrins 11a-c with methanolic sulfuric acid afforded the corresponding 5-(1-methoxy-2-iodoethyl) derivatives (12a-c). In contrast, reaction of 5-(1-hydroxy-2-iodoethyl)-2'-deoxyuridine (11a) with sodium carbonate in methanol afforded a mixture of 5-(1-hydroxy-2-methoxyethyl)-2'-deoxyuridine (13) and 2,3-dihydro-3-hydroxy-5-(2'-deoxy-beta-D-ribofuranosyl)- furano[2,3-d]pyrimidin-6(5H)-one (14). The most active compound, 5-(1-methoxy-2-iodoethyl)-2'-deoxyuridine (12a, ID50 = 0.1 micrograms/mL), which exhibited antiviral activity (HSV-1) -fold higher than that of the 5-(1-hydroxy-2-iodoethyl) analogue (11a), was less active than IVDU or acyclovir (ID50 = 0.01-0.1 micrograms/mL range). The C-5 substituent in the 2'-deoxyuridine series was a determinant of cytotoxic activity, as determined in the in vitro L1210 screen, where the relative activity order was CH(OH)CHI2 (16) greater than CH(OMe)CH2I (12a) greater than CH(OH)CH2I (11a) congruent to CH(OH)CH2OMe (13). The 2'-substituent was also a determinant of cytotoxic activity in the 5-(1-hydroxy-2-iodoethyl) (11a-c) and 5-(1-methoxy-2-iodoethyl) series of compounds, where the relative activity profile was 2'-deoxyuridine greater than 2'-fluoro-2'-deoxyuridine greater than uridine (11a greater than 11b greater than or equal to 11c; 12a greater than 12b greater than 12c). The most active cytotoxic agent (16), possessing a 5-(1-hydroxy-2,2-diiodoethyl) substituent (ED50 = 0.77 micrograms/mL), exhibited an activity approaching that of melphalan (ED50 = 0.15 micrograms/mL). All compounds tested, except for 13 and 14, exhibited high affinity (Ki = 0.035-0.22 mM range relative to deoxyuridine, Ki = 0.125) for the murine NBMPR-sensitive erythrocyte nucleoside transport system, suggesting that these iodohydrinsare good permeants of cell membranes." ], "offsets": [ [ 0, 2149 ] ] } ]

[ { "id": "entity-34-0", "type": "IUPAC", "text": [ "5-(1-hydroxy-2-iodoethyl)-2'-deoxyuridine" ], "offsets": [ [ 16, 57 ] ], "normalized": [] }, { "id": "entity-34-1", "type": "TRIVIAL", "text": [ "uridine" ], "offsets": [ [ 62, 69 ] ], "normalized": [] }, { "id": "entity-34-2", "type": "MODIFIER", "text": [ "compounds" ], "offsets": [ [ 70, 79 ] ], "normalized": [] }, { "id": "entity-34-3", "type": "SUM", "text": [ "HOI" ], "offsets": [ [ 138, 141 ] ], "normalized": [] }, { "id": "entity-34-4", "type": "TRIVIAL", "text": [ "vinyl" ], "offsets": [ [ 149, 154 ] ], "normalized": [] }, { "id": "entity-34-5", "type": "MODIFIER", "text": [ "substituent" ], "offsets": [ [ 155, 166 ] ], "normalized": [] }, { "id": "entity-34-6", "type": "IUPAC", "text": [ "5-vinyl-2'-deoxyuridine" ], "offsets": [ [ 170, 193 ] ], "normalized": [] }, { "id": "entity-34-7", "type": "IUPAC", "text": [ "5-vinyl-2'-fluoro-2'-deoxyuridine" ], "offsets": [ [ 201, 234 ] ], "normalized": [] }, { "id": "entity-34-8", "type": "IUPAC", "text": [ "5-vinyluridine" ], "offsets": [ [ 242, 256 ] ], "normalized": [] }, { "id": "entity-34-9", "type": "IUPAC", "text": [ "(E)-5-(2-iodovinyl)-2'-deoxyuridine" ], "offsets": [ [ 268, 303 ] ], "normalized": [] }, { "id": "entity-34-10", "type": "FAMILY", "text": [ "iodohydrins" ], "offsets": [ [ 327, 338 ] ], "normalized": [] }, { "id": "entity-34-11", "type": "IUPAC", "text": [ "methanolic sulfuric acid" ], "offsets": [ [ 350, 374 ] ], "normalized": [] }, { "id": "entity-34-12", "type": "IUPAC", "text": [ "5-(1-methoxy-2-iodoethyl)" ], "offsets": [ [ 402, 427 ] ], "normalized": [] }, { "id": "entity-34-13", "type": "MODIFIER", "text": [ "derivatives" ], "offsets": [ [ 428, 439 ] ], "normalized": [] }, { "id": "entity-34-14", "type": "IUPAC", "text": [ "5-(1-hydroxy-2-iodoethyl)-2'-deoxyuridine" ], "offsets": [ [ 474, 515 ] ], "normalized": [] }, { "id": "entity-34-15", "type": "IUPAC", "text": [ "sodium carbonate" ], "offsets": [ [ 527, 543 ] ], "normalized": [] }, { "id": "entity-34-16", "type": "TRIVIAL", "text": [ "methanol" ], "offsets": [ [ 547, 555 ] ], "normalized": [] }, { "id": "entity-34-17", "type": "IUPAC", "text": [ "5-(1-hydroxy-2-methoxyethyl)-2'-deoxyuridine" ], "offsets": [ [ 578, 622 ] ], "normalized": [] }, { "id": "entity-34-18", "type": "IUPAC", "text": [ "2,3-dihydro-3-hydroxy-5-(2'-deoxy-beta-D-ribofuranosyl)- furano[2,3-d]pyrimidin-6(5H)-one" ], "offsets": [ [ 632, 721 ] ], "normalized": [] }, { "id": "entity-34-19", "type": "IUPAC", "text": [ "5-(1-methoxy-2-iodoethyl)-2'-deoxyuridine" ], "offsets": [ [ 754, 795 ] ], "normalized": [] }, { "id": "entity-34-20", "type": "IUPAC", "text": [ "5-(1-hydroxy-2-iodoethyl)" ], "offsets": [ [ 905, 930 ] ], "normalized": [] }, { "id": "entity-34-21", "type": "MODIFIER", "text": [ "analogue" ], "offsets": [ [ 931, 939 ] ], "normalized": [] }, { "id": "entity-34-22", "type": "ABBREVIATION", "text": [ "IVDU" ], "offsets": [ [ 968, 972 ] ], "normalized": [] }, { "id": "entity-34-23", "type": "TRIVIAL", "text": [ "acyclovir" ], "offsets": [ [ 976, 985 ] ], "normalized": [] }, { "id": "entity-34-24", "type": "PARTIUPAC", "text": [ "C-5" ], "offsets": [ [ 1029, 1032 ] ], "normalized": [] }, { "id": "entity-34-25", "type": "MODIFIER", "text": [ "substituent" ], "offsets": [ [ 1033, 1044 ] ], "normalized": [] }, { "id": "entity-34-26", "type": "IUPAC", "text": [ "2'-deoxyuridine" ], "offsets": [ [ 1052, 1067 ] ], "normalized": [] }, { "id": "entity-34-27", "type": "MODIFIER", "text": [ "series" ], "offsets": [ [ 1068, 1074 ] ], "normalized": [] }, { "id": "entity-34-28", "type": "SUM", "text": [ "CH(OH)CHI2" ], "offsets": [ [ 1198, 1208 ] ], "normalized": [] }, { "id": "entity-34-29", "type": "SUM", "text": [ "CH(OMe)CH2I" ], "offsets": [ [ 1227, 1238 ] ], "normalized": [] }, { "id": "entity-34-30", "type": "SUM", "text": [ "CH(OH)CH2I" ], "offsets": [ [ 1258, 1268 ] ], "normalized": [] }, { "id": "entity-34-31", "type": "SUM", "text": [ "CH(OH)CH2OMe" ], "offsets": [ [ 1288, 1300 ] ], "normalized": [] }, { "id": "entity-34-32", "type": "PARTIUPAC", "text": [ "2'-" ], "offsets": [ [ 1311, 1314 ] ], "normalized": [] }, { "id": "entity-34-33", "type": "IUPAC", "text": [ "5-(1-hydroxy-2-iodoethyl)" ], "offsets": [ [ 1378, 1403 ] ], "normalized": [] }, { "id": "entity-34-34", "type": "IUPAC", "text": [ "5-(1-methoxy-2-iodoethyl)" ], "offsets": [ [ 1416, 1441 ] ], "normalized": [] }, { "id": "entity-34-35", "type": "MODIFIER", "text": [ "series" ], "offsets": [ [ 1442, 1448 ] ], "normalized": [] }, { "id": "entity-34-36", "type": "IUPAC", "text": [ "2'-deoxyuridine" ], "offsets": [ [ 1503, 1518 ] ], "normalized": [] }, { "id": "entity-34-37", "type": "IUPAC", "text": [ "2'-fluoro-2'-deoxyuridine" ], "offsets": [ [ 1532, 1557 ] ], "normalized": [] }, { "id": "entity-34-38", "type": "TRIVIAL", "text": [ "uridine" ], "offsets": [ [ 1571, 1578 ] ], "normalized": [] }, { "id": "entity-34-39", "type": "PARTIUPAC", "text": [ "5-(1-hydroxy-2,2-diiodoethyl)" ], "offsets": [ [ 1722, 1751 ] ], "normalized": [] }, { "id": "entity-34-40", "type": "MODIFIER", "text": [ "substituent" ], "offsets": [ [ 1752, 1763 ] ], "normalized": [] }, { "id": "entity-34-41", "type": "TRIVIAL", "text": [ "melphalan" ], "offsets": [ [ 1835, 1844 ] ], "normalized": [] }, { "id": "entity-34-42", "type": "TRIVIAL", "text": [ "deoxyuridine" ], "offsets": [ [ 1980, 1992 ] ], "normalized": [] }, { "id": "entity-34-43", "type": "FAMILY", "text": [ "iodohydrins" ], "offsets": [ [ 2100, 2111 ] ], "normalized": [] } ]

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[ { "id": "passage-35", "type": "abstract", "text": [ "N-Methylacetazolamide was shown to be active topically in reducing intraocular pressure (IOP) to a small but statistically significant level in the normotensive rabbit eye. In vivo experiments with N-methylacetazolamide suggest that ocular metabolism to acetazolamide was responsible for the observed topical activity. Examination of initial rate kinetics of carbonic anhydrase catalyzed p-nitrophenyl acetate hydrolysis showed that N-methylacetazolamide was a competitive inhibitor, in contrast to noncompetitive inhibition seen with acetazolamide and other primary sulfonamide inhibitors. N-Substituted and unsubstituted 4-chlorobenzene- and 4-nitrobenzenesulfonamides were also synthesized, and their biochemical characteristics and in vivo ability to lower IOP when applied topically were determined. The primary sulfonamides were reversible noncompetitive inhibitors of carbonic anhydrase, with no effect on IOP after topical administration. 4-Nitrobenzene- and 4-chlorobenzenesulfonamides containing both N-hydroxy and N-methyl substituents were model irreversible inhibitors of carbonic anhydrase and exhibited a trend toward topical activity in reducing IOP in normotensive rabbit eyes. Therefore, this paper describes the synthesis and characterization of two types of carbonic anhydrase inhibitors; the N-methyl-substituted sulfonamides are reversible competitive inhibitors of carbonic anhydrase, while the N-hydroxy-N-methyl-substituted sulfonamidesare irreversible inhibitors." ], "offsets": [ [ 0, 1490 ] ] } ]

[ { "id": "entity-35-0", "type": "IUPAC", "text": [ "N-methylacetazolamide" ], "offsets": [ [ 198, 219 ] ], "normalized": [] }, { "id": "entity-35-1", "type": "TRIVIAL", "text": [ "acetazolamide" ], "offsets": [ [ 254, 267 ] ], "normalized": [] }, { "id": "entity-35-2", "type": "IUPAC", "text": [ "p-nitrophenyl acetate" ], "offsets": [ [ 388, 409 ] ], "normalized": [] }, { "id": "entity-35-3", "type": "IUPAC", "text": [ "N-methylacetazolamide" ], "offsets": [ [ 433, 454 ] ], "normalized": [] }, { "id": "entity-35-4", "type": "TRIVIAL", "text": [ "acetazolamide" ], "offsets": [ [ 535, 548 ] ], "normalized": [] }, { "id": "entity-35-5", "type": "TRIVIAL", "text": [ "sulfonamide" ], "offsets": [ [ 567, 578 ] ], "normalized": [] }, { "id": "entity-35-6", "type": "PARTIUPAC", "text": [ "N-Substituted" ], "offsets": [ [ 591, 604 ] ], "normalized": [] }, { "id": "entity-35-7", "type": "PARTIUPAC", "text": [ "unsubstituted 4-chlorobenzene-" ], "offsets": [ [ 609, 639 ] ], "normalized": [] }, { "id": "entity-35-8", "type": "IUPAC", "text": [ "4-nitrobenzenesulfonamides" ], "offsets": [ [ 644, 670 ] ], "normalized": [] }, { "id": "entity-35-9", "type": "FAMILY", "text": [ "sulfonamides" ], "offsets": [ [ 817, 829 ] ], "normalized": [] }, { "id": "entity-35-10", "type": "PARTIUPAC", "text": [ "4-Nitrobenzene-" ], "offsets": [ [ 947, 962 ] ], "normalized": [] }, { "id": "entity-35-11", "type": "IUPAC", "text": [ "4-chlorobenzenesulfonamides" ], "offsets": [ [ 967, 994 ] ], "normalized": [] }, { "id": "entity-35-12", "type": "PARTIUPAC", "text": [ "N-hydroxy" ], "offsets": [ [ 1011, 1020 ] ], "normalized": [] }, { "id": "entity-35-13", "type": "PARTIUPAC", "text": [ "N-methyl" ], "offsets": [ [ 1025, 1033 ] ], "normalized": [] }, { "id": "entity-35-14", "type": "MODIFIER", "text": [ "substituents" ], "offsets": [ [ 1034, 1046 ] ], "normalized": [] }, { "id": "entity-35-15", "type": "IUPAC", "text": [ "N-methyl-substituted sulfonamides" ], "offsets": [ [ 1313, 1346 ] ], "normalized": [] }, { "id": "entity-35-16", "type": "IUPAC", "text": [ "N-hydroxy-N-methyl-substituted sulfonamides" ], "offsets": [ [ 1418, 1461 ] ], "normalized": [] } ]

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[ { "id": "passage-36", "type": "abstract", "text": [ "Condensation of 14-bromodaunorubicin with thiols in methanol, in the presence of potassium carbonate, resulted in the formation of 14-thia analogues of the antitumor antibiotic adriamycin. However, similar condensation of N-(trifluoroacetyl)-14-iododaunorubicin with thiols invariably led to a redox reaction, with the formation of N-(trifluoroacetyl)daunorubicin and disulfides. Accordingly, N-(trifluoroacetyl)-14-bromodaunorubicin was used for reaction with thiols to yield thia analogues of the clinically active but non-DNA-binding adriamycin analogue N-(trifluoroacetyl)adriamycin 14-valerate (AD 32). Reaction of 14-bromoadunorubicin with alpha, omega-alkanedithiols gave bis(thiaadriamycin) analogues as potential difunctional intercalating agents. The aforementioned products, plus two related phenylselena derivatives, were examined for in vitro growth inhibition, in vivo antitumor activity, and, where appropriate, DNA binding. A number of agents, most notably 14-(carbethoxymethyl)-14-thiaadriamycin and N-(trifluoroacetyl)-14-phenyl-14-selenaadriamycin, were active against murine L1210 leukemia in vivo. Several of the amino glycoside unsubstituted 14-thiaadriamycin analogues exhibited DNA-binding properties equivalent to those of adriamycin." ], "offsets": [ [ 0, 1259 ] ] } ]

[ { "id": "entity-36-0", "type": "IUPAC", "text": [ "14-bromodaunorubicin" ], "offsets": [ [ 16, 36 ] ], "normalized": [] }, { "id": "entity-36-1", "type": "FAMILY", "text": [ "thiols" ], "offsets": [ [ 42, 48 ] ], "normalized": [] }, { "id": "entity-36-2", "type": "TRIVIAL", "text": [ "methanol" ], "offsets": [ [ 52, 60 ] ], "normalized": [] }, { "id": "entity-36-3", "type": "TRIVIAL", "text": [ "potassium carbonate" ], "offsets": [ [ 81, 100 ] ], "normalized": [] }, { "id": "entity-36-4", "type": "PARTIUPAC", "text": [ "14-thia" ], "offsets": [ [ 131, 138 ] ], "normalized": [] }, { "id": "entity-36-5", "type": "MODIFIER", "text": [ "analogues" ], "offsets": [ [ 139, 148 ] ], "normalized": [] }, { "id": "entity-36-6", "type": "TRIVIAL", "text": [ "adriamycin" ], "offsets": [ [ 177, 187 ] ], "normalized": [] }, { "id": "entity-36-7", "type": "IUPAC", "text": [ "N-(trifluoroacetyl)-14-iododaunorubicin" ], "offsets": [ [ 222, 261 ] ], "normalized": [] }, { "id": "entity-36-8", "type": "IUPAC", "text": [ "N-(trifluoroacetyl)daunorubicin" ], "offsets": [ [ 332, 363 ] ], "normalized": [] }, { "id": "entity-36-9", "type": "FAMILY", "text": [ "disulfides" ], "offsets": [ [ 368, 378 ] ], "normalized": [] }, { "id": "entity-36-10", "type": "IUPAC", "text": [ "N-(trifluoroacetyl)-14-bromodaunorubicin" ], "offsets": [ [ 393, 433 ] ], "normalized": [] }, { "id": "entity-36-11", "type": "FAMILY", "text": [ "thiols" ], "offsets": [ [ 461, 467 ] ], "normalized": [] }, { "id": "entity-36-12", "type": "TRIVIAL", "text": [ "adriamycin" ], "offsets": [ [ 537, 547 ] ], "normalized": [] }, { "id": "entity-36-13", "type": "MODIFIER", "text": [ "analogue" ], "offsets": [ [ 548, 556 ] ], "normalized": [] }, { "id": "entity-36-14", "type": "IUPAC", "text": [ "N-(trifluoroacetyl)adriamycin 14-valerate" ], "offsets": [ [ 557, 598 ] ], "normalized": [] }, { "id": "entity-36-15", "type": "IUPAC", "text": [ "14-bromoadunorubicin" ], "offsets": [ [ 620, 640 ] ], "normalized": [] }, { "id": "entity-36-16", "type": "IUPAC", "text": [ "alpha, omega-alkanedithiols" ], "offsets": [ [ 646, 673 ] ], "normalized": [] }, { "id": "entity-36-17", "type": "TRIVIAL", "text": [ "bis(thiaadriamycin)" ], "offsets": [ [ 679, 698 ] ], "normalized": [] }, { "id": "entity-36-18", "type": "MODIFIER", "text": [ "analogues" ], "offsets": [ [ 699, 708 ] ], "normalized": [] }, { "id": "entity-36-19", "type": "TRIVIAL", "text": [ "phenylselena" ], "offsets": [ [ 803, 815 ] ], "normalized": [] }, { "id": "entity-36-20", "type": "MODIFIER", "text": [ "derivatives" ], "offsets": [ [ 816, 827 ] ], "normalized": [] }, { "id": "entity-36-21", "type": "IUPAC", "text": [ "14-(carbethoxymethyl)-14-thiaadriamycin" ], "offsets": [ [ 973, 1012 ] ], "normalized": [] }, { "id": "entity-36-22", "type": "IUPAC", "text": [ "N-(trifluoroacetyl)-14-phenyl-14-selenaadriamycin" ], "offsets": [ [ 1017, 1066 ] ], "normalized": [] }, { "id": "entity-36-23", "type": "IUPAC", "text": [ "amino glycoside unsubstituted 14-thiaadriamycin" ], "offsets": [ [ 1134, 1181 ] ], "normalized": [] }, { "id": "entity-36-24", "type": "MODIFIER", "text": [ "analogues" ], "offsets": [ [ 1182, 1191 ] ], "normalized": [] }, { "id": "entity-36-25", "type": "TRIVIAL", "text": [ "adriamycin" ], "offsets": [ [ 1248, 1258 ] ], "normalized": [] } ]

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[ { "id": "passage-37", "type": "abstract", "text": [ " Enalapril in subantihypertensive dosage attenuates kidney proliferation and functional recovery in normotensive ablation nephropathy of the rat. Most studies on the antiproliferative action of angiotensin converting enzyme inhibitors (ACEI) were performed in a rat hypertensive remnant kidney model with 5/6 kidney ablation which raised objections about the antihypertensive effect of ACEI and the influence of other antihypertensive drugs administered to remnant kidney control rats. To prevent these objections, a normotensive 4/6 remnant kidney model was elaborated and a subantihypertensive dosage of enalapril was used to evaluate its antiproliferative action. Subtotally nephrectomized rats (Nx) markedly increased the remnant kidney weight during a 4-week period and this rise was prevented by the treatment with enalapril (NxE) (Nx +297+/-35 mg vs. sham-operated +145+/-32 mg, p<0.001; NxE +154+/-35 mg vs. Nx p<0.001). While collagen concentration in the kidney cortex was not increased in sham-operated rats (Sham) in comparison with the control group (Ctrl) at the beginning of the study, the subsequent increase was significant in the Nx group and enalapril did not attenuate this increase (Sham 148+/-5 mg/ g w.w. vs. Nx 164+/-2 mg/ g w.w., p<0.01; NxE 161+/-4 mg/ g w.w. vs. Sham p<0.05). The tubular protein/DNA ratio increase, which was significant in the Nx group, was inhibited by enalapril (Nx 26.2+/- vs. NxE 15.3+/-2.6, p<0.05). The protein/DNA ratio was much lower in glomeruli, with no significant changes in either the Nx or NxE groups. Serum urea concentrations were slightly higher in the Nx group than in the sham-operated group, but markedly elevated in the NxE group (Nx +/-0.76 mmol/l vs. Sham 6.10+/-0.33 mmol/l, p<0.001; NxE 28.9+/-2.6 mmol/l vs. Sham p<0.001). Creatinine concentrations in the Nx group were increased in comparison with the sham-operated group and markedly increased in the NxE group (Nx 63.7+/-3.56 micromol/l vs. Sham 37.2+/-2.84 micromol/l, p<0.001; NxE +/-5.2 micromol/l vs. Sham p<0.001). The clearance of creatinine was lower in the Nx group than in the sham-operated group and was markedly reduced in the NxE group (Nx 0.89+/-0.06 ml/min.g kidney wt. vs. Sham 1.05+/-0.16 ml/min x g kidney wt., p<0.01; NxE 0.58+/-0.029 ml/min x g kidney wt. vs. Sham, p<0.001). Enalapril improved proteinuria in comparison with the Nx group (NxE 5.6+/-0.6 mg/24 h vs. Nx 16.1+/-3.4 mg/24 h, p<0.05). Thus remnant kidney proliferation is substantial even in normotensive rats. It includes both proliferation and collagen accumulation with partial recovery of kidney weight and function, but is accompanied by enhanced proteinuria. Enalaprilattenuates the proliferation and decreases proteinuria but prolongs kidney function recovery." ], "offsets": [ [ 0, 2808 ] ] } ]

[ { "id": "entity-37-0", "type": "TRIVIAL", "text": [ "Enalapril" ], "offsets": [ [ 10, 19 ] ], "normalized": [] }, { "id": "entity-37-1", "type": "TRIVIAL", "text": [ "enalapril" ], "offsets": [ [ 616, 625 ] ], "normalized": [] }, { "id": "entity-37-2", "type": "TRIVIAL", "text": [ "enalapril" ], "offsets": [ [ 831, 840 ] ], "normalized": [] }, { "id": "entity-37-3", "type": "TRIVIAL", "text": [ "enalapril" ], "offsets": [ [ 1171, 1180 ] ], "normalized": [] }, { "id": "entity-37-4", "type": "TRIVIAL", "text": [ "enalapril" ], "offsets": [ [ 1419, 1428 ] ], "normalized": [] }, { "id": "entity-37-5", "type": "TRIVIAL", "text": [ "urea" ], "offsets": [ [ 1591, 1595 ] ], "normalized": [] }, { "id": "entity-37-6", "type": "TRIVIAL", "text": [ "Creatinine" ], "offsets": [ [ 1823, 1833 ] ], "normalized": [] }, { "id": "entity-37-7", "type": "TRIVIAL", "text": [ "creatinine" ], "offsets": [ [ 2095, 2105 ] ], "normalized": [] }, { "id": "entity-37-8", "type": "TRIVIAL", "text": [ "Enalapril" ], "offsets": [ [ 2353, 2362 ] ], "normalized": [] }, { "id": "entity-37-9", "type": "TRIVIAL", "text": [ "Enalapril" ], "offsets": [ [ 2705, 2714 ] ], "normalized": [] } ]

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[ { "id": "passage-38", "type": "abstract", "text": [ " Replacing dietary palmitic acid with elaidic acid (t-C18:1 delta9) depresses HDL and increases CETP activity in cebus monkeys. The question whether dietary trans fatty acids affect lipoprotein metabolism similarly to specific saturated fatty acids was investigated in 11 normolipemic cebus monkeys by exchanging 5% dietary energy (%en) between elaidic (t-C18:1 delta9) and palmitic acid (16:0) in two test diets ( en fat + mg cholesterol/ kcal diet) conforming to the American Heart Association (AHA) Step 1 guidelines. These were compared with a normal control diet rich in saturated fat and cholesterol (38%en fat + mg cholesterol/ kcal diet). The control diet was fed initially for 14 wk, followed by each of the the two test diets in a crossover design. Plasma lipid concentrations were determined four times between the 6th and 14th wk. Turnover studies (using 125I-HDL and 131I-LDL) were conducted after 9 wk in each dietary period. Relative to the control diet, both test diets significantly reduced plasma total cholesterol (TC), HDL cholesterol (HDL-C) and VLDL plus LDL cholesterol (LDL-C) concentrations; triglyceride (TG) concentrations tended to be lower. However, the trans diet resulted in a significantly greater reduction in HDL-C than the palmitate diet (124 +/- 17, 117 +/- 18 and +/- 13 mg/dL for the control, palmitate and trans diets, respectively). The palmitate diet significantly decreased the TC/HDL-C ratio by 11% when compared with the control diet (1.68 +/- 0.17 vs. 1.89 +/- 0.30), whereas the trans diet had no effect (1.81 +/- 0.20 vs. 1.89 +/- 0.30). Kinetic studies revealed that, relative to the control diet, both test diets significantly lowered the LDL apolipoprotein B (apoB) pool size, principally reflecting an increase in the LDL apoB fractional catabolic rate (FCR) related to the reduced cholesterol intake. Between the two test diets, no significant differences in LDL kinetic parameters were observed. Both test diets significantly decreased HDL apoA1 concentrations in comparison with the control diet, which was partly explained by an increase in the fractional catabolic rate of HDL. Of the two test diets, the trans diet was associated with a 9.5% greater HDL FCR than the palmitate diet (P < 0.08) and a significant increase in plasma cholesteryl ester transfer protein (CETP) activity (% transfer 114 +/- 7 vs. 91 +/- 7; P < 0.03). Thus, palmitic acid- and elaidic acid-rich diets produced identical effects on LDL metabolism in normocholesterolemic cebus monkeys fed diets with low levels of cholesterol, whereas elaidic aciddepressed HDL-C, attributable to both increased CETP activity and HDL clearance." ], "offsets": [ [ 0, 2691 ] ] } ]

[ { "id": "entity-38-0", "type": "IUPAC", "text": [ "palmitic acid" ], "offsets": [ [ 27, 40 ] ], "normalized": [] }, { "id": "entity-38-1", "type": "IUPAC", "text": [ "elaidic acid" ], "offsets": [ [ 46, 58 ] ], "normalized": [] }, { "id": "entity-38-2", "type": "FAMILY", "text": [ "saturated fatty acids" ], "offsets": [ [ 236, 257 ] ], "normalized": [] }, { "id": "entity-38-3", "type": "PARTIUPAC", "text": [ "elaidic" ], "offsets": [ [ 354, 361 ] ], "normalized": [] }, { "id": "entity-38-4", "type": "IUPAC", "text": [ "palmitic acid" ], "offsets": [ [ 383, 396 ] ], "normalized": [] }, { "id": "entity-38-5", "type": "TRIVIAL", "text": [ "cholesterol" ], "offsets": [ [ 442, 453 ] ], "normalized": [] }, { "id": "entity-38-6", "type": "TRIVIAL", "text": [ "cholesterol" ], "offsets": [ [ 613, 624 ] ], "normalized": [] }, { "id": "entity-38-7", "type": "TRIVIAL", "text": [ "cholesterol" ], "offsets": [ [ 645, 656 ] ], "normalized": [] }, { "id": "entity-38-8", "type": "FAMILY", "text": [ "lipid" ], "offsets": [ [ 793, 798 ] ], "normalized": [] }, { "id": "entity-38-9", "type": "TRIVIAL", "text": [ "cholesterol" ], "offsets": [ [ 1048, 1059 ] ], "normalized": [] }, { "id": "entity-38-10", "type": "TRIVIAL", "text": [ "cholesterol" ], "offsets": [ [ 1070, 1081 ] ], "normalized": [] }, { "id": "entity-38-11", "type": "TRIVIAL", "text": [ "cholesterol" ], "offsets": [ [ 1108, 1119 ] ], "normalized": [] }, { "id": "entity-38-12", "type": "FAMILY", "text": [ "triglyceride" ], "offsets": [ [ 1144, 1156 ] ], "normalized": [] }, { "id": "entity-38-13", "type": "ABBREVIATION", "text": [ "TG" ], "offsets": [ [ 1158, 1160 ] ], "normalized": [] }, { "id": "entity-38-14", "type": "TRIVIAL", "text": [ "palmitate" ], "offsets": [ [ 1408, 1417 ] ], "normalized": [] }, { "id": "entity-38-15", "type": "TRIVIAL", "text": [ "palmitate" ], "offsets": [ [ 2255, 2264 ] ], "normalized": [] }, { "id": "entity-38-16", "type": "IUPAC", "text": [ "palmitic acid" ], "offsets": [ [ 2422, 2435 ] ], "normalized": [] }, { "id": "entity-38-17", "type": "IUPAC", "text": [ "elaidic acid" ], "offsets": [ [ 2441, 2453 ] ], "normalized": [] }, { "id": "entity-38-18", "type": "TRIVIAL", "text": [ "cholesterol" ], "offsets": [ [ 2577, 2588 ] ], "normalized": [] }, { "id": "entity-38-19", "type": "IUPAC", "text": [ "elaidic acid" ], "offsets": [ [ 2598, 2610 ] ], "normalized": [] } ]

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[ { "id": "passage-39", "type": "abstract", "text": [ "Radiolabeled m-iodobenzylguanidine (MIBG) is a tumor-seeking radioactive drug used in the diagnosis and treatment of pheochromocytomas and neuroblastomas. It is transported into the tumor cells by the neuronal norepinephrine (NE) transporter (NET) which is expressed in almost all neuroblastoma cells. Here, we describe the synthesis and some pharmacological properties of a series of fluorescent compounds structurally related to the NET substrate, MIBG, or to the NET inhibitors, (-)-(2R,3S)-cocaine and nisoxetine. Three of synthesized fluorescent compounds, 1-(1-naphthylmethyl)guanidinium sulfate (1), 1-[2-(dibenz[b, f]azepin-5-yl)ethyl]guanidinium sulfate (2), and (2R, 3S)-2beta-ethoxycarbonyl-3beta-tropanyl 5-(dimethylamino)naphthalene-1-sulfonate (6), exhibited high affinity (IC( ) about nM) for the NET. Thenisoxetine derivatives 8 (rac-N-[(3-methylamino-1-phenyl)propyl]-5-(dimethylamino)-1-naphthale nesulfonamide) and 9 (rac-4-[(3-methylamino-1-phenyl)propyl]amino-7-nitro-2,1, 3-benzoxadiazole) and especially the guanidine derivative 4 (1-[4-(4-phenyl-1,3-butadienyl)benzyl]guanidinium sulfate) which are characterized by intermediate affinity for the NET (IC( ) nM) caused significant and nisoxetine-sensitive cell fluorescence. At least the guanidine derivative4 might represent a potentially useful agent for imaging of neuroblastoma cells." ], "offsets": [ [ 0, 1379 ] ] } ]

[ { "id": "entity-39-0", "type": "IUPAC", "text": [ "m-iodobenzylguanidine" ], "offsets": [ [ 13, 34 ] ], "normalized": [] }, { "id": "entity-39-1", "type": "ABBREVIATION", "text": [ "MIBG" ], "offsets": [ [ 36, 40 ] ], "normalized": [] }, { "id": "entity-39-2", "type": "TRIVIAL", "text": [ "norepinephrine" ], "offsets": [ [ 210, 224 ] ], "normalized": [] }, { "id": "entity-39-3", "type": "ABBREVIATION", "text": [ "NE" ], "offsets": [ [ 226, 228 ] ], "normalized": [] }, { "id": "entity-39-4", "type": "ABBREVIATION", "text": [ "MIBG" ], "offsets": [ [ 450, 454 ] ], "normalized": [] }, { "id": "entity-39-5", "type": "IUPAC", "text": [ "(-)-(2R,3S)-cocaine" ], "offsets": [ [ 482, 501 ] ], "normalized": [] }, { "id": "entity-39-6", "type": "TRIVIAL", "text": [ "nisoxetine" ], "offsets": [ [ 506, 516 ] ], "normalized": [] }, { "id": "entity-39-7", "type": "IUPAC", "text": [ "1-(1-naphthylmethyl)guanidinium sulfate" ], "offsets": [ [ 565, 604 ] ], "normalized": [] }, { "id": "entity-39-8", "type": "IUPAC", "text": [ "1-[2-(dibenz[b, f]azepin-5-yl)ethyl]guanidinium sulfate" ], "offsets": [ [ 610, 665 ] ], "normalized": [] }, { "id": "entity-39-9", "type": "IUPAC", "text": [ "(2R, 3S)-2beta-ethoxycarbonyl-3beta-tropanyl 5-(dimethylamino)naphthalene-1-sulfonate" ], "offsets": [ [ 675, 760 ] ], "normalized": [] }, { "id": "entity-39-10", "type": "TRIVIAL", "text": [ " nisoxetine" ], "offsets": [ [ 827, 838 ] ], "normalized": [] }, { "id": "entity-39-11", "type": "MODIFIER", "text": [ "derivatives" ], "offsets": [ [ 839, 850 ] ], "normalized": [] }, { "id": "entity-39-12", "type": "IUPAC", "text": [ "rac-N-[(3-methylamino-1-phenyl)propyl]-5-(dimethylamino)-1-naphthale nesulfonamide" ], "offsets": [ [ 854, 936 ] ], "normalized": [] }, { "id": "entity-39-13", "type": "IUPAC", "text": [ "rac-4-[(3-methylamino-1-phenyl)propyl]amino-7-nitro-2,1, 3-benzoxadiazole" ], "offsets": [ [ 945, 1018 ] ], "normalized": [] }, { "id": "entity-39-14", "type": "TRIVIAL", "text": [ "guanidine" ], "offsets": [ [ 1039, 1048 ] ], "normalized": [] }, { "id": "entity-39-15", "type": "MODIFIER", "text": [ "derivative" ], "offsets": [ [ 1049, 1059 ] ], "normalized": [] }, { "id": "entity-39-16", "type": "IUPAC", "text": [ "1-[4-(4-phenyl-1,3-butadienyl)benzyl]guanidinium sulfate" ], "offsets": [ [ 1063, 1119 ] ], "normalized": [] }, { "id": "entity-39-17", "type": "TRIVIAL", "text": [ "nisoxetine" ], "offsets": [ [ 1225, 1235 ] ], "normalized": [] }, { "id": "entity-39-18", "type": "TRIVIAL", "text": [ "guanidine" ], "offsets": [ [ 1278, 1287 ] ], "normalized": [] }, { "id": "entity-39-19", "type": "MODIFIER", "text": [ "derivative" ], "offsets": [ [ 1288, 1298 ] ], "normalized": [] } ]

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[ { "id": "passage-40", "type": "abstract", "text": [ "11358723 Influence of estrogens on the androgen metabolism in different subunits of human hair follicles. The molecular pathways involved in estrogen-mediated induction of hair growth in androgenetic alopecia are unknown. Some authors found that estradiol (E) inhibited 5alpha-reductase (5alpha-R) activity and therefore we addressed the question whether 17alpha- or 17beta-E are able to modulate the activity of 5alpha-R, 3beta-hydroxysteroid dehydrogenase (3beta-HSD) or 17beta-hydroxysteroid dehydrogenase (17beta-HSD) in isolated compartments of human hair follicles. For this purpose, scalp biopsies from volunteers were taken and from each biopsy root sheaths, connective tissue sheaths and dermal papillae (DP) were dissected and incubated in the presence of 3H-testosterone (T) and, in addition, either 17alpha-E, 17beta-E, progesterone orfinasteride for up to 48 hrs. Thereafter high-performance liquid chromatography analysis of culture supernatants was performed to detect T-metabolites. At the tested concentrations, finasteride was found to be a major inhibitor of dihydrotestosterone (DHT) formation. Even 1 nM finasteride inhibited DHT synthesis in DP by 86% and 1 nM progesterone by 75%. Estrogens were less able to inhibit the synthesis of DHT in DP (e.g. nM 17alpha-E: ; nM 17beta-E: ). Whether E directly inhibits 5alpha-R in DP's or whether the effect of estrogens might be explained by an increased conversion of T to the weaker androgens such as androstendione (via 17beta-HSD), androstenediol (via 3beta-HSD) or 17beta-E (via aromatase), thereby diminishing the amount of T available for the conversion to DHT, remains to be shown." ], "offsets": [ [ 0, 1671 ] ] } ]

[ { "id": "entity-40-0", "type": "FAMILY", "text": [ "estrogens" ], "offsets": [ [ 23, 32 ] ], "normalized": [] }, { "id": "entity-40-1", "type": "FAMILY", "text": [ "androgen" ], "offsets": [ [ 40, 48 ] ], "normalized": [] }, { "id": "entity-40-2", "type": "FAMILY", "text": [ "estrogen" ], "offsets": [ [ 143, 151 ] ], "normalized": [] }, { "id": "entity-40-3", "type": "TRIVIAL", "text": [ "estradiol" ], "offsets": [ [ 248, 257 ] ], "normalized": [] }, { "id": "entity-40-4", "type": "ABBREVIATION", "text": [ "E" ], "offsets": [ [ 259, 260 ] ], "normalized": [] }, { "id": "entity-40-5", "type": "PARTIUPAC", "text": [ "17alpha-" ], "offsets": [ [ 357, 365 ] ], "normalized": [] }, { "id": "entity-40-6", "type": "IUPAC", "text": [ "17beta-E" ], "offsets": [ [ 369, 377 ] ], "normalized": [] }, { "id": "entity-40-7", "type": "IUPAC", "text": [ "3H-testosterone" ], "offsets": [ [ 768, 783 ] ], "normalized": [] }, { "id": "entity-40-8", "type": "ABBREVIATION", "text": [ "T" ], "offsets": [ [ 785, 786 ] ], "normalized": [] }, { "id": "entity-40-9", "type": "IUPAC", "text": [ "17alpha-E" ], "offsets": [ [ 813, 822 ] ], "normalized": [] }, { "id": "entity-40-10", "type": "IUPAC", "text": [ "17beta-E" ], "offsets": [ [ 824, 832 ] ], "normalized": [] }, { "id": "entity-40-11", "type": "TRIVIAL", "text": [ "progesterone" ], "offsets": [ [ 834, 846 ] ], "normalized": [] }, { "id": "entity-40-12", "type": "TRIVIAL", "text": [ " finasteride" ], "offsets": [ [ 849, 861 ] ], "normalized": [] }, { "id": "entity-40-13", "type": "TRIVIAL", "text": [ "finasteride" ], "offsets": [ [ 1032, 1043 ] ], "normalized": [] }, { "id": "entity-40-14", "type": "TRIVIAL", "text": [ "dihydrotestosterone" ], "offsets": [ [ 1081, 1100 ] ], "normalized": [] }, { "id": "entity-40-15", "type": "ABBREVIATION", "text": [ "DHT" ], "offsets": [ [ 1102, 1105 ] ], "normalized": [] }, { "id": "entity-40-16", "type": "TRIVIAL", "text": [ "finasteride" ], "offsets": [ [ 1128, 1139 ] ], "normalized": [] }, { "id": "entity-40-17", "type": "ABBREVIATION", "text": [ "DHT" ], "offsets": [ [ 1150, 1153 ] ], "normalized": [] }, { "id": "entity-40-18", "type": "FAMILY", "text": [ "Estrogens" ], "offsets": [ [ 1207, 1216 ] ], "normalized": [] }, { "id": "entity-40-19", "type": "ABBREVIATION", "text": [ "DHT" ], "offsets": [ [ 1260, 1263 ] ], "normalized": [] }, { "id": "entity-40-20", "type": "IUPAC", "text": [ "17alpha-E" ], "offsets": [ [ 1283, 1292 ] ], "normalized": [] }, { "id": "entity-40-21", "type": "IUPAC", "text": [ "17beta-E" ], "offsets": [ [ 1306, 1314 ] ], "normalized": [] }, { "id": "entity-40-22", "type": "ABBREVIATION", "text": [ "E" ], "offsets": [ [ 1330, 1331 ] ], "normalized": [] }, { "id": "entity-40-23", "type": "FAMILY", "text": [ "estrogens" ], "offsets": [ [ 1392, 1401 ] ], "normalized": [] }, { "id": "entity-40-24", "type": "ABBREVIATION", "text": [ "T" ], "offsets": [ [ 1451, 1452 ] ], "normalized": [] }, { "id": "entity-40-25", "type": "FAMILY", "text": [ "androgens" ], "offsets": [ [ 1467, 1476 ] ], "normalized": [] }, { "id": "entity-40-26", "type": "TRIVIAL", "text": [ "androstendione" ], "offsets": [ [ 1485, 1499 ] ], "normalized": [] }, { "id": "entity-40-27", "type": "TRIVIAL", "text": [ "androstenediol" ], "offsets": [ [ 1518, 1532 ] ], "normalized": [] }, { "id": "entity-40-28", "type": "IUPAC", "text": [ "17beta-E" ], "offsets": [ [ 1552, 1560 ] ], "normalized": [] }, { "id": "entity-40-29", "type": "ABBREVIATION", "text": [ "T" ], "offsets": [ [ 1612, 1613 ] ], "normalized": [] }, { "id": "entity-40-30", "type": "ABBREVIATION", "text": [ "DHT" ], "offsets": [ [ 1646, 1649 ] ], "normalized": [] } ]

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[ { "id": "passage-41", "type": "abstract", "text": [ " Involvement of phospholipase D2 in lysophosphatidate-induced transactivation of platelet-derived growth factor receptor-beta in human bronchial epithelial cells. Lysophosphatidate (LPA) mediates multiple cellular responses via heterotrimeric G protein coupled LPA-1, LPA-2, and LPA-3 receptors. Many G protein-coupled receptors stimulate ERK following tyrosine phosphorylation of growth factor receptors; however, the mechanism(s) of transactivation of receptor tyrosine kinases are not well defined. Here, we provide evidence for the involvement of phospholipase D (PLD) in LPA-mediated transactivation of platelet-derived growth factor receptor-beta (PDGF-R beta). In primary cultures of human bronchial epithelial cells (HBEpCs), LPA stimulated tyrosine phosphorylation of PDGF-R beta and threonine/tyrosine phosphorylation of ERK1/2. The LPA-mediated activation of ERK and tyrosine phosphorylation of PDGF-R beta was attenuated by tyrphostin AG 1296, an inhibitor of PDGF-R kinase, suggesting transactivation of PDGF-R by LPA. Furthermore, LPA-, but not PDGF beta-chain homodimer-induced tyrosine phosphorylation of PDGF-R beta was partially blocked by pertussis toxin, indicating coupling of LPA-R(s) to Gi. Exposure of HBEpCs to LPA activated PLD. Butan-1-ol, which acts as an acceptor of phosphatidate generated by the PLD pathway, blocked LPA-mediated transactivation of PDGF-R beta. This effect was not seen with butan-3-ol, suggesting PLD involvement. The role of PLD1 and PLD2 in the PDGF-R beta transactivation by LPA was investigated by infection of cells with adenoviral constructs of wild type and catalytically inactive mutants of PLD. LPA activated both PLD1 and PLD2 in HBEpCs; however, infection of cells with cDNA for wild type PLD2, but not PLD1, increased the tyrosine phosphorylation of PDGF-R beta in response to LPA. Also, the LPA-mediated tyrosine phosphorylation of PDGF-R beta was attenuated by the catalytically inactive mutant mPLD2-K758R. Infection of HBEpCs with adenoviral constructs of wild type hPLD1, mPLD2, and the inactive mutants of hPLD1 and mPLD2 resulted in association of PLD2 wild type and inactive mutant proteins with the PDGF-R beta compared with PLD1. These results show for the first time that transactivation of PDGF-R beta by LPAin HBEpCs is regulated by PLD2." ], "offsets": [ [ 0, 2323 ] ] } ]

[ { "id": "entity-41-0", "type": "TRIVIAL", "text": [ "lysophosphatidate" ], "offsets": [ [ 45, 62 ] ], "normalized": [] }, { "id": "entity-41-1", "type": "TRIVIAL", "text": [ "Lysophosphatidate" ], "offsets": [ [ 173, 190 ] ], "normalized": [] }, { "id": "entity-41-2", "type": "ABBREVIATION", "text": [ "LPA" ], "offsets": [ [ 192, 195 ] ], "normalized": [] }, { "id": "entity-41-3", "type": "TRIVIAL", "text": [ "tyrosine" ], "offsets": [ [ 363, 371 ] ], "normalized": [] }, { "id": "entity-41-4", "type": "ABBREVIATION", "text": [ "LPA" ], "offsets": [ [ 586, 589 ] ], "normalized": [] }, { "id": "entity-41-5", "type": "ABBREVIATION", "text": [ "LPA" ], "offsets": [ [ 744, 747 ] ], "normalized": [] }, { "id": "entity-41-6", "type": "TRIVIAL", "text": [ "tyrosine" ], "offsets": [ [ 759, 767 ] ], "normalized": [] }, { "id": "entity-41-7", "type": "TRIVIAL", "text": [ "threonine" ], "offsets": [ [ 803, 812 ] ], "normalized": [] }, { "id": "entity-41-8", "type": "TRIVIAL", "text": [ "tyrosine" ], "offsets": [ [ 813, 821 ] ], "normalized": [] }, { "id": "entity-41-9", "type": "ABBREVIATION", "text": [ "LPA" ], "offsets": [ [ 853, 856 ] ], "normalized": [] }, { "id": "entity-41-10", "type": "TRIVIAL", "text": [ "tyrosine" ], "offsets": [ [ 888, 896 ] ], "normalized": [] }, { "id": "entity-41-11", "type": "TRIVIAL", "text": [ "tyrphostin" ], "offsets": [ [ 946, 956 ] ], "normalized": [] }, { "id": "entity-41-12", "type": "TRIVIALVAR", "text": [ "AG 1296" ], "offsets": [ [ 957, 964 ] ], "normalized": [] }, { "id": "entity-41-13", "type": "ABBREVIATION", "text": [ "LPA" ], "offsets": [ [ 1037, 1040 ] ], "normalized": [] }, { "id": "entity-41-14", "type": "ABBREVIATION", "text": [ "LPA" ], "offsets": [ [ 1055, 1058 ] ], "normalized": [] }, { "id": "entity-41-15", "type": "ABBREVIATION", "text": [ "LPA" ], "offsets": [ [ 1208, 1211 ] ], "normalized": [] }, { "id": "entity-41-16", "type": "IUPAC", "text": [ "Butan-1-ol" ], "offsets": [ [ 1265, 1275 ] ], "normalized": [] }, { "id": "entity-41-17", "type": "TRIVIAL", "text": [ "phosphatidate" ], "offsets": [ [ 1306, 1319 ] ], "normalized": [] }, { "id": "entity-41-18", "type": "ABBREVIATION", "text": [ "LPA" ], "offsets": [ [ 1358, 1361 ] ], "normalized": [] }, { "id": "entity-41-19", "type": "IUPAC", "text": [ "butan-3-ol" ], "offsets": [ [ 1433, 1443 ] ], "normalized": [] }, { "id": "entity-41-20", "type": "ABBREVIATION", "text": [ "LPA" ], "offsets": [ [ 1537, 1540 ] ], "normalized": [] }, { "id": "entity-41-21", "type": "ABBREVIATION", "text": [ "LPA" ], "offsets": [ [ 1663, 1666 ] ], "normalized": [] }, { "id": "entity-41-22", "type": "ABBREVIATION", "text": [ "LPA" ], "offsets": [ [ 1848, 1851 ] ], "normalized": [] }, { "id": "entity-41-23", "type": "ABBREVIATION", "text": [ "LPA" ], "offsets": [ [ 1863, 1866 ] ], "normalized": [] }, { "id": "entity-41-24", "type": "TRIVIAL", "text": [ "tyrosine" ], "offsets": [ [ 1876, 1884 ] ], "normalized": [] }, { "id": "entity-41-25", "type": "ABBREVIATION", "text": [ "LPA" ], "offsets": [ [ 2288, 2291 ] ], "normalized": [] } ]

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[ { "id": "passage-42", "type": "abstract", "text": [ " Thyrotropin modulates low density lipoprotein binding activity in FRTL-5 thyroid cells. FRTL-5 cells possess high affinity low density lipoprotein (LDL) receptors which bind, internalize, and degrade LDL. When FRTL-5 cells are deprived of thyrotropin (TSH) the binding of LDL increases more than 2-fold. Upon addition of TSH, at a concentration of 1 x (- ) M or greater, LDL binding decreases rapidly and within 24 h reaches the level which is typical of FRTL-5 cells chronically stimulated by TSH. The data available suggest that TSH-dependent down-regulation of LDL receptor activity is exerted through a reduction of the number of active LDL receptors, with no change in affinity. It is unlikely that the synthesis of LDL receptors is impaired, since LDL receptor messenger RNA is not decreased by TSH. The effect of the hormone on LDL receptor activity can be mimicked by 8-Br-cAMP and is completely abolished by the protein synthesis inhibitor cycloheximide but not by actinomycin D. TSH regulation of LDL receptor activity is lost in v-ras Ki-transformed FRTL-5 cells (Ki Mol) which also have lost TSH dependence for adenylate cyclase activation and growth. However, 8-Br-cAMP decreases LDL binding in Ki Mol FRTL-5 cells. The reduced availability of LDL receptor in TSH-stimulated FRTL-5 cells may be related to the increased membrane fluidity (Beguinot, F., Beguinot, L., Tramontano, D., Duilio, C., Formisano, S., Bifulco, M., Ambesi-Impiombato, F. S., and Aloj, S. M. (1987) J. Biol. Chem. 262, 1575-1582) or may reflect increased degradation of LDL receptors. We propose that a lower cholesterol uptake is needed in an actively proliferating cell population, to increase the production of isoprenoids whether it be for cholesterolbiosynthesis or for the synthesis of other compounds requiring isoprenoid precursors." ], "offsets": [ [ 0, 1840 ] ] } ]

[ { "id": "entity-42-0", "type": "IUPAC", "text": [ "8-Br-cAMP" ], "offsets": [ [ 889, 898 ] ], "normalized": [] }, { "id": "entity-42-1", "type": "TRIVIAL", "text": [ "cycloheximide" ], "offsets": [ [ 962, 975 ] ], "normalized": [] }, { "id": "entity-42-2", "type": "TRIVIAL", "text": [ "actinomycin D" ], "offsets": [ [ 987, 1000 ] ], "normalized": [] }, { "id": "entity-42-3", "type": "IUPAC", "text": [ "8-Br-cAMP" ], "offsets": [ [ 1186, 1195 ] ], "normalized": [] }, { "id": "entity-42-4", "type": "FAMILY", "text": [ "isoprenoids" ], "offsets": [ [ 1713, 1724 ] ], "normalized": [] }, { "id": "entity-42-5", "type": "TRIVIAL", "text": [ "cholesterol" ], "offsets": [ [ 1743, 1754 ] ], "normalized": [] } ]

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[ { "id": "passage-43", "type": "abstract", "text": [ "In order to develop tracers with higher specific activity to supplant the currently used [3H]-8-OH-DPAT [8-hydroxy-2-(N,N-di-n-propylamino)tetralin] for in vitro and in vivo evaluation of 5-HT1A receptors, a new radioiodinated ligand was prepared. (R,S)-trans-8- Hydroxy-2-[N-n-propyl-N-(3'-iodo-2'-propenyl)amino]tetralin (trans-8-OH-PIPAT), 8, was synthesized by a -step reaction. Binding studies with rat hippocampal membrane homogenates showed that 8 exhibited a Ki value of 0.92 nM against (R,S)-[3H]-8-OH-DPAT. Radiolabeled [125I]-8 was prepared from the corresponding tri-n-butyltin precursor via an oxidative iododestannylation reaction with sodium [125I]iodide. Binding studies in the hippocampal homogenates revealed that [125I]-8 bound to a single high-affinity site (Kd = 0.38 +/- 0.03 nM,Bmax = +/- fmol/mg of protein). Competition binding experiments clearly indicated that the new ligand displayed the expected 5-HT1A receptor binding profile. The rank order of potency was (R,S)-trans-8-OH-PIPAT &gt; (R,S)- 8-OH-DPAT &gt; WB4101 &gt; 5-HT &gt; (R,S)-trans-7-OH-PIPAT &gt; (R,S)-7-OH-DPAT &gt; (R,S)-propranolol &gt; spiperone &gt;&gt; ketanserin &gt;&gt; dopamine &gt; atropine. This new ligand offers several unique advantages, including high specific activity, high binding affinity, and low nonspecific binding, all of which make it an excellent probe for the investigation and characterization of 5-HT1A receptors." ], "offsets": [ [ 0, 1444 ] ] } ]

[ { "id": "entity-43-0", "type": "IUPAC", "text": [ "[3H]-8-OH-DPAT" ], "offsets": [ [ 89, 103 ] ], "normalized": [] }, { "id": "entity-43-1", "type": "IUPAC", "text": [ "8-hydroxy-2-(N,N-di-n-propylamino)tetralin" ], "offsets": [ [ 105, 147 ] ], "normalized": [] }, { "id": "entity-43-2", "type": "IUPAC", "text": [ "(R,S)-trans-8- Hydroxy-2-[N-n-propyl-N-(3'-iodo-2'-propenyl)amino]tetralin" ], "offsets": [ [ 248, 322 ] ], "normalized": [] }, { "id": "entity-43-3", "type": "IUPAC", "text": [ "trans-8-OH-PIPAT" ], "offsets": [ [ 324, 340 ] ], "normalized": [] }, { "id": "entity-43-4", "type": "IUPAC", "text": [ "(R,S)-[3H]-8-OH-DPAT" ], "offsets": [ [ 497, 517 ] ], "normalized": [] }, { "id": "entity-43-5", "type": "PARTIUPAC", "text": [ "[125I]-" ], "offsets": [ [ 532, 539 ] ], "normalized": [] }, { "id": "entity-43-6", "type": "IUPAC", "text": [ "tri-n-butyltin" ], "offsets": [ [ 577, 591 ] ], "normalized": [] }, { "id": "entity-43-7", "type": "IUPAC", "text": [ "[125I]iodide" ], "offsets": [ [ 659, 671 ] ], "normalized": [] }, { "id": "entity-43-8", "type": "PARTIUPAC", "text": [ "[125I]-" ], "offsets": [ [ 734, 741 ] ], "normalized": [] }, { "id": "entity-43-9", "type": "IUPAC", "text": [ "(R,S)-trans-8-OH-PIPAT" ], "offsets": [ [ 998, 1020 ] ], "normalized": [] }, { "id": "entity-43-10", "type": "IUPAC", "text": [ "(R,S)- 8-OH-DPAT" ], "offsets": [ [ 1026, 1042 ] ], "normalized": [] }, { "id": "entity-43-11", "type": "TRIVIAL", "text": [ "WB4101" ], "offsets": [ [ 1048, 1054 ] ], "normalized": [] }, { "id": "entity-43-12", "type": "IUPAC", "text": [ "(R,S)-trans-7-OH-PIPAT" ], "offsets": [ [ 1070, 1092 ] ], "normalized": [] }, { "id": "entity-43-13", "type": "IUPAC", "text": [ "(R,S)-7-OH-DPAT" ], "offsets": [ [ 1098, 1113 ] ], "normalized": [] }, { "id": "entity-43-14", "type": "IUPAC", "text": [ "(R,S)-propranolol" ], "offsets": [ [ 1119, 1136 ] ], "normalized": [] }, { "id": "entity-43-15", "type": "TRIVIAL", "text": [ "spiperone" ], "offsets": [ [ 1142, 1151 ] ], "normalized": [] }, { "id": "entity-43-16", "type": "TRIVIAL", "text": [ "ketanserin" ], "offsets": [ [ 1161, 1171 ] ], "normalized": [] }, { "id": "entity-43-17", "type": "TRIVIAL", "text": [ "dopamine" ], "offsets": [ [ 1181, 1189 ] ], "normalized": [] }, { "id": "entity-43-18", "type": "TRIVIAL", "text": [ "atropine" ], "offsets": [ [ 1195, 1203 ] ], "normalized": [] } ]

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[ { "id": "passage-44", "type": "abstract", "text": [ "The synthesis and pharmacological profile of a series of neuroprotective adenosine agonists are described. Novel A(1) agonists with potent central nervous system effects and diminished influence on the cardiovascular system are reported and compared to selected reference adenosine agonists. The novel compounds featured are derived structurally from two key lead structures: 2-chloro-N-(1-phenoxy-2-propyl)adenosine (NNC 21-0041, 9) and 2-chloro-N-(1-piperidinyl)adenosine (NNC , 4). The agonists are characterized in terms of their in vitro profiles, both binding and functional, and in vivo activity in relevant animal models. Neuroprotective properties assessed after postischemic dosing in a Mongolian gerbil severe temporary forebrain ischemia paradigm, using hippocampal CA1 damage endpoints, and the efficacy of these agonists in an A(1) functional assay show similarities to some reference adenosine agonists. However, the new compounds we describe exhibit diminished cardiovascular effects in both anesthetized and awake rats when compared to reference A(1) agonists such as (R)-phenylisopropyladenosine (R-PIA, 5), N-cyclopentyladenosine (CPA, 2), 4, N-[(1S,trans)-2-hydroxycyclopentyl]adenosine (GR 79236, 26), N-cyclohexyl-2'-O-methyladenosine (SDZ WAG 994, 27), and N-[(2-methylphenyl)methyl]adenosine (Metrifudil, 28). In mouse permanent middle cerebral artery occlusion focal ischemia, 2-chloro-N-[(R)-[(2-benzothiazolyl)thio]-2-propyl]adenosine (NNC 21-0136, 12) exhibited significant neuroprotection at the remarkably low total intraperitoneal dose of 0.1 mg/kg, a dose at which no cardiovascular effects are observed in conscious rats. The novel agonists described inhibit 6, 7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate-induced seizures, and in mouse locomotor activity higher doses are required to reach ED( ) values than for reference A(1) agonists. We conclude that two of the novel adenosine derivatives revealed herein, 12 and 5'-deoxy-5'-chloro-N-[4-(phenylthio)-1-piperidinyl]adenosine (NNC 21-0147, 13), representatives of a new series of P(1) ligands, reinforce the fact that novel selective adenosine A(1) agonists have potential in the treatment of cerebral ischemia in humans." ], "offsets": [ [ 0, 2220 ] ] } ]

[ { "id": "entity-44-0", "type": "IUPAC", "text": [ "2-chloro-N-(1-phenoxy-2-propyl)adenosine" ], "offsets": [ [ 376, 416 ] ], "normalized": [] }, { "id": "entity-44-1", "type": "TRIVIALVAR", "text": [ "NNC 21-0041" ], "offsets": [ [ 418, 429 ] ], "normalized": [] }, { "id": "entity-44-2", "type": "IUPAC", "text": [ "2-chloro-N-(1-piperidinyl)adenosine" ], "offsets": [ [ 438, 473 ] ], "normalized": [] }, { "id": "entity-44-3", "type": "TRIVIALVAR", "text": [ "NNC 90-1515" ], "offsets": [ [ 475, 486 ] ], "normalized": [] }, { "id": "entity-44-4", "type": "IUPAC", "text": [ "(R)-phenylisopropyladenosine" ], "offsets": [ [ 1092, 1120 ] ], "normalized": [] }, { "id": "entity-44-5", "type": "ABBREVIATION", "text": [ "R-PIA" ], "offsets": [ [ 1122, 1127 ] ], "normalized": [] }, { "id": "entity-44-6", "type": "IUPAC", "text": [ "N-cyclopentyladenosine" ], "offsets": [ [ 1133, 1155 ] ], "normalized": [] }, { "id": "entity-44-7", "type": "ABBREVIATION", "text": [ "CPA" ], "offsets": [ [ 1157, 1160 ] ], "normalized": [] }, { "id": "entity-44-8", "type": "IUPAC", "text": [ "N-[(1S,trans)-2-hydroxycyclopentyl]adenosine" ], "offsets": [ [ 1169, 1213 ] ], "normalized": [] }, { "id": "entity-44-9", "type": "TRIVIALVAR", "text": [ "GR 79236" ], "offsets": [ [ 1215, 1223 ] ], "normalized": [] }, { "id": "entity-44-10", "type": "IUPAC", "text": [ "N-cyclohexyl-2'-O-methyladenosine" ], "offsets": [ [ 1230, 1263 ] ], "normalized": [] }, { "id": "entity-44-11", "type": "TRIVIALVAR", "text": [ "SDZ WAG 994" ], "offsets": [ [ 1265, 1276 ] ], "normalized": [] }, { "id": "entity-44-12", "type": "IUPAC", "text": [ "N-[(2-methylphenyl)methyl]adenosine" ], "offsets": [ [ 1287, 1322 ] ], "normalized": [] }, { "id": "entity-44-13", "type": "TRIVIAL", "text": [ "Metrifudil" ], "offsets": [ [ 1324, 1334 ] ], "normalized": [] }, { "id": "entity-44-14", "type": "IUPAC", "text": [ "2-chloro-N-[(R)-[(2-benzothiazolyl)thio]-2-propyl]adenosine" ], "offsets": [ [ 1409, 1468 ] ], "normalized": [] }, { "id": "entity-44-15", "type": "TRIVIALVAR", "text": [ "NNC 21-0136" ], "offsets": [ [ 1470, 1481 ] ], "normalized": [] }, { "id": "entity-44-16", "type": "IUPAC", "text": [ "6, 7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate" ], "offsets": [ [ 1699, 1750 ] ], "normalized": [] }, { "id": "entity-44-17", "type": "IUPAC", "text": [ "5'-deoxy-5'-chloro-N-[4-(phenylthio)-1-piperidinyl]adenosine" ], "offsets": [ [ 1964, 2024 ] ], "normalized": [] }, { "id": "entity-44-18", "type": "TRIVIALVAR", "text": [ "NNC 21-0147" ], "offsets": [ [ 2026, 2037 ] ], "normalized": [] } ]

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[ { "id": "passage-45", "type": "abstract", "text": [ "A series of 8-(trifluoromethyl)-substituted quinolones has been prepared and evaluated for in vitro and in vivo antibacterial activity, and phototolerance in a mouse phototolerance assay. These analogues were compared to the corresponding series of 6,8-difluoro- and 6-fluoro-8H-quinolones (ciprofloxacin type). Although their in vitro antibacterial activities are less than the 6,8-difluoro analogues, the 8-(trifluoromethyl)quinolones are generally equivalent to their 8H analogues. In vivo, they are comparable to the 6,8-difluoro series and show up to -fold improvement in efficacy when compared to their ciprofloxacin counterparts vs Streptococcus pyogenes and Streptococcus pneumonia. In the phototolerance model, the 8-(trifluoromethyl)quinolones are comparable to the 8H-quinolones. Both of these series display much higher no effect doses (greater tolerance) than the corresponding 6,8-difluoroquinolones." ], "offsets": [ [ 0, 916 ] ] } ]

[ { "id": "entity-45-0", "type": "IUPAC", "text": [ "8-(trifluoromethyl)-substituted quinolones" ], "offsets": [ [ 12, 54 ] ], "normalized": [] }, { "id": "entity-45-1", "type": "PARTIUPAC", "text": [ "6,8-difluoro-" ], "offsets": [ [ 249, 262 ] ], "normalized": [] }, { "id": "entity-45-2", "type": "IUPAC", "text": [ "6-fluoro-8H-quinolones" ], "offsets": [ [ 267, 289 ] ], "normalized": [] }, { "id": "entity-45-3", "type": "TRIVIAL", "text": [ "ciprofloxacin" ], "offsets": [ [ 291, 304 ] ], "normalized": [] }, { "id": "entity-45-4", "type": "PARTIUPAC", "text": [ "6,8-difluoro" ], "offsets": [ [ 379, 391 ] ], "normalized": [] }, { "id": "entity-45-5", "type": "MODIFIER", "text": [ "analogues" ], "offsets": [ [ 392, 401 ] ], "normalized": [] }, { "id": "entity-45-6", "type": "IUPAC", "text": [ "8-(trifluoromethyl)quinolones" ], "offsets": [ [ 407, 436 ] ], "normalized": [] }, { "id": "entity-45-7", "type": "PARTIUPAC", "text": [ "8H" ], "offsets": [ [ 471, 473 ] ], "normalized": [] }, { "id": "entity-45-8", "type": "MODIFIER", "text": [ "analogues" ], "offsets": [ [ 474, 483 ] ], "normalized": [] }, { "id": "entity-45-9", "type": "PARTIUPAC", "text": [ "6,8-difluoro" ], "offsets": [ [ 521, 533 ] ], "normalized": [] }, { "id": "entity-45-10", "type": "MODIFIER", "text": [ "series" ], "offsets": [ [ 534, 540 ] ], "normalized": [] }, { "id": "entity-45-11", "type": "TRIVIAL", "text": [ "ciprofloxacin" ], "offsets": [ [ 611, 624 ] ], "normalized": [] }, { "id": "entity-45-12", "type": "IUPAC", "text": [ "8-(trifluoromethyl)quinolones" ], "offsets": [ [ 726, 755 ] ], "normalized": [] }, { "id": "entity-45-13", "type": "IUPAC", "text": [ "8H-quinolones" ], "offsets": [ [ 778, 791 ] ], "normalized": [] }, { "id": "entity-45-14", "type": "IUPAC", "text": [ "6,8-difluoroquinolones" ], "offsets": [ [ 893, 915 ] ], "normalized": [] } ]

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[ { "id": "passage-46", "type": "abstract", "text": [ "This study emphasizes the importance of the metabolic conversion of the enantiomers of 3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP) into their catechol analogues, the enantiomers of 3-(3,4-dihydroxyphenyl)-N-n-propylpiperidine. These isomers are both shown to be excellent substrates for COMT, with a slight preference for the S-(-) enantiomer. Assessment of the dopaminergic activity of these catechols and the results from the determination of brain levels of the enantiomers of 3-PPP and their metabolites indicate that the metabolites probably do not alter the pharmacological profiles established for (R)-(+)- and (S)-(-)-3-PPP. The conversion of the monophenols into catecholic metabolites is only 1-5%, and the further conversion of these catecholic metabolites into methoxylated analogues is very rapid. However, the very interesting observation was made that, when inhibiting COMT by means of tropolone and subsequently treating the rats with high doses of (S)-(-)-3-PPP (ip), postsynaptic dopaminergic activity was elicited. This has never been seen for (S)-(-)-3-PPP without tropolone pretreatment and might indicate that, in this special case, the catecholic metabolite affects the in vivo pharmacological profile of (S)-(-)-3-PPP." ], "offsets": [ [ 0, 1247 ] ] } ]

[ { "id": "entity-46-0", "type": "IUPAC", "text": [ "3-(3-hydroxyphenyl)-N-n-propylpiperidine" ], "offsets": [ [ 87, 127 ] ], "normalized": [] }, { "id": "entity-46-1", "type": "ABBREVIATION", "text": [ "3-PPP" ], "offsets": [ [ 129, 134 ] ], "normalized": [] }, { "id": "entity-46-2", "type": "TRIVIAL", "text": [ "catechol" ], "offsets": [ [ 147, 155 ] ], "normalized": [] }, { "id": "entity-46-3", "type": "MODIFIER", "text": [ "analogues" ], "offsets": [ [ 156, 165 ] ], "normalized": [] }, { "id": "entity-46-4", "type": "IUPAC", "text": [ "3-(3,4-dihydroxyphenyl)-N-n-propylpiperidine" ], "offsets": [ [ 186, 230 ] ], "normalized": [] }, { "id": "entity-46-5", "type": "ABBREVIATION", "text": [ "3-PPP" ], "offsets": [ [ 485, 490 ] ], "normalized": [] }, { "id": "entity-46-6", "type": "PARTIUPAC", "text": [ "(R)-(+)-" ], "offsets": [ [ 610, 618 ] ], "normalized": [] }, { "id": "entity-46-7", "type": "IUPAC", "text": [ "(S)-(-)-3-PPP" ], "offsets": [ [ 623, 636 ] ], "normalized": [] }, { "id": "entity-46-8", "type": "FAMILY", "text": [ "monophenols" ], "offsets": [ [ 660, 671 ] ], "normalized": [] }, { "id": "entity-46-9", "type": "TRIVIAL", "text": [ "tropolone" ], "offsets": [ [ 906, 915 ] ], "normalized": [] }, { "id": "entity-46-10", "type": "IUPAC", "text": [ "(S)-(-)-3-PPP" ], "offsets": [ [ 970, 983 ] ], "normalized": [] }, { "id": "entity-46-11", "type": "IUPAC", "text": [ "(S)-(-)-3-PPP" ], "offsets": [ [ 1068, 1081 ] ], "normalized": [] }, { "id": "entity-46-12", "type": "TRIVIAL", "text": [ "tropolone" ], "offsets": [ [ 1090, 1099 ] ], "normalized": [] }, { "id": "entity-46-13", "type": "IUPAC", "text": [ "(S)-(-)-3-PPP" ], "offsets": [ [ 1233, 1246 ] ], "normalized": [] } ]

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[ { "id": "passage-47", "type": "abstract", "text": [ "1512594 Genetic absence epilepsy in rats from Strasbourg--a review. We have selected a strain of rats and designated it the Genetic Absence Epilepsy Rat from Strasbourg (GAERS). In this strain, of the animals present recurrent generalized non-convulsive seizures characterized by bilateral and synchronous spike-and-wave discharges accompanied with behavioural arrest, staring and sometimes twitching of the vibrissae. Spontaneous SWD (7-11 cps, microV, 0.5-75 sec) start and end abruptly on a normal background EEG. They usually occur at a mean frequency of 1.5 per min when the animals are in a state of quiet wakefulness. Drugs effective against absence seizures in humans (ethosuccimide, trimethadione, valproate, benzodiazepines) suppress the SWD dose-dependently, whereas drugs specific for convulsive or focal seizures (carbamazepine, phenytoin) are ineffective. SWD are increased by epileptogenic drugs inducing petit mal-like seizures, such as pentylenetetrazol, gamma-hydroxybutyrate, THIP and penicillin. Depth EEG recordings and lesion experiments show that SWD in GAERs depend on cortical and thalamic structures with a possible rhythmic triggering by the lateral thalamus. Most neurotransmitters are involved in the control of SWD (dopamine, noradrenaline, NMDA, acetylcholine), but GABA and gamma-hydroxybutyrate (GHB) seem to play a critical role. SWD are genetically determined with an autosomal dominant inheritance. The variable expression of SWD in offsprings from GAERS x control reciprocal crosses may be due to the existence of multiple genes. Neurophysiological, behavioural, pharmacological and genetic studies demonstrate that spontaneous SWD in GAERS fulfill all the requirements for an experimental model of absence epilepsy. As the mechanisms underlying absence epilepsy in humans are still unknown, the analysis of the genetic thalamocortical dysfunction in GAERS may be fruitful in investigations of the pathogenesis of generalized non-convulsive seizures." ], "offsets": [ [ 0, 2004 ] ] } ]

[ { "id": "entity-47-0", "type": "TRIVIAL", "text": [ "ethosuccimide" ], "offsets": [ [ 694, 707 ] ], "normalized": [] }, { "id": "entity-47-1", "type": "TRIVIAL", "text": [ "trimethadione" ], "offsets": [ [ 709, 722 ] ], "normalized": [] }, { "id": "entity-47-2", "type": "TRIVIAL", "text": [ "valproate" ], "offsets": [ [ 724, 733 ] ], "normalized": [] }, { "id": "entity-47-3", "type": "TRIVIAL", "text": [ "benzodiazepines" ], "offsets": [ [ 735, 750 ] ], "normalized": [] }, { "id": "entity-47-4", "type": "TRIVIAL", "text": [ "carbamazepine" ], "offsets": [ [ 844, 857 ] ], "normalized": [] }, { "id": "entity-47-5", "type": "TRIVIAL", "text": [ "phenytoin" ], "offsets": [ [ 859, 868 ] ], "normalized": [] }, { "id": "entity-47-6", "type": "TRIVIAL", "text": [ "pentylenetetrazol" ], "offsets": [ [ 970, 987 ] ], "normalized": [] }, { "id": "entity-47-7", "type": "IUPAC", "text": [ "gamma-hydroxybutyrate" ], "offsets": [ [ 989, 1010 ] ], "normalized": [] }, { "id": "entity-47-8", "type": "ABBREVIATION", "text": [ "THIP" ], "offsets": [ [ 1012, 1016 ] ], "normalized": [] }, { "id": "entity-47-9", "type": "TRIVIAL", "text": [ "penicillin" ], "offsets": [ [ 1021, 1031 ] ], "normalized": [] }, { "id": "entity-47-10", "type": "TRIVIAL", "text": [ "dopamine" ], "offsets": [ [ 1263, 1271 ] ], "normalized": [] }, { "id": "entity-47-11", "type": "TRIVIAL", "text": [ "noradrenaline" ], "offsets": [ [ 1273, 1286 ] ], "normalized": [] }, { "id": "entity-47-12", "type": "ABBREVIATION", "text": [ "NMDA" ], "offsets": [ [ 1288, 1292 ] ], "normalized": [] }, { "id": "entity-47-13", "type": "TRIVIAL", "text": [ "acetylcholine" ], "offsets": [ [ 1294, 1307 ] ], "normalized": [] }, { "id": "entity-47-14", "type": "ABBREVIATION", "text": [ "GABA " ], "offsets": [ [ 1314, 1319 ] ], "normalized": [] }, { "id": "entity-47-15", "type": "IUPAC", "text": [ "gamma-hydroxybutyrate" ], "offsets": [ [ 1323, 1344 ] ], "normalized": [] }, { "id": "entity-47-16", "type": "ABBREVIATION", "text": [ "GHB" ], "offsets": [ [ 1346, 1349 ] ], "normalized": [] } ]

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[ { "id": "passage-48", "type": "abstract", "text": [ " Diphenol activation of the monophenolase and diphenolase activities of field bean (Dolichos lablab) polyphenol oxidase. This paper reports a study on the hydroxylation of ferulic acid and tyrosine by field bean (Dolichos lablab) polyphenol oxidase, a reaction that does not take place without the addition of catechol. A lag period similar to the characteristic lag of tyrosinase activity was observed, the length of which decreased with increasing catechol concentration and increased with increasing ferulic acid concentration. The activation constant K(a) of catechol for ferulic acid hydroxylation reaction was 5 mM. The kinetic parameters of field bean polyphenol oxidase toward ferulic acid and tyrosine were evaluated in the presence of catechol. 4-Methyl catechol, L-dihydroxyphenylalanine, pyrogallol, and 2,3,4-trihydroxybenzoic acid, substrates with high binding affinity to field bean polyphenol oxidase, could stimulate this hydroxylation reaction. In contrast, diphenols such as protocatechuic acid, gallic acid, chlorogenic acid, and caffeic acid, which were not substrates for the oxidation reaction, were unable to bring about this activation. It is most likely that only o-diphenols that are substrates for the diphenolase serve as cosubstrates by donating electrons at the active site for the monophenolase activity. The reaction mechanism for this activation is consistent with that proposed for tyrosinase (Sanchez-Ferrer, A.; Rodriguez-Lopez, J. N.; Garcia-Canovas, F.; Garcia-Carmona, F. Biochim. Biophys. Acta 1995, 1247, 1-11). The presence of o-diphenols, viz. catechol, L-dihydroxyphenylalanine, and 4-methyl catechol, is also necessary for the oxidation of the diphenols, caffeic acid, and catechin to their quinones by the field bean polyphenol oxidase. This oxidation reaction occurs immediately with no lag period and does not occur without the addition of diphenol. The kinetic parameters for caffeic acid (K(m) = 0.08 mM, V(max) = u/mg) in the presence of catechol and the activation constant K(a) of catechol (4.6 mM) for this reaction were enumerated. The absence of a lag period for this reaction indicates that the diphenol mechanism of diphenolase activation differs from the way in which the same o-diphenolsactivate the monophenolase activity." ], "offsets": [ [ 0, 2301 ] ] } ]

[ { "id": "entity-48-0", "type": "FAMILY", "text": [ "Diphenol" ], "offsets": [ [ 10, 18 ] ], "normalized": [] }, { "id": "entity-48-1", "type": "IUPAC", "text": [ "ferulic acid" ], "offsets": [ [ 182, 194 ] ], "normalized": [] }, { "id": "entity-48-2", "type": "TRIVIAL", "text": [ "tyrosine" ], "offsets": [ [ 199, 207 ] ], "normalized": [] }, { "id": "entity-48-3", "type": "TRIVIAL", "text": [ "catechol" ], "offsets": [ [ 320, 328 ] ], "normalized": [] }, { "id": "entity-48-4", "type": "TRIVIAL", "text": [ "catechol" ], "offsets": [ [ 460, 468 ] ], "normalized": [] }, { "id": "entity-48-5", "type": "IUPAC", "text": [ "ferulic acid" ], "offsets": [ [ 513, 525 ] ], "normalized": [] }, { "id": "entity-48-6", "type": "TRIVIAL", "text": [ "catechol" ], "offsets": [ [ 573, 581 ] ], "normalized": [] }, { "id": "entity-48-7", "type": "IUPAC", "text": [ "ferulic acid" ], "offsets": [ [ 586, 598 ] ], "normalized": [] }, { "id": "entity-48-8", "type": "IUPAC", "text": [ "ferulic acid" ], "offsets": [ [ 695, 707 ] ], "normalized": [] }, { "id": "entity-48-9", "type": "TRIVIAL", "text": [ "tyrosine" ], "offsets": [ [ 712, 720 ] ], "normalized": [] }, { "id": "entity-48-10", "type": "TRIVIAL", "text": [ "catechol" ], "offsets": [ [ 755, 763 ] ], "normalized": [] }, { "id": "entity-48-11", "type": "IUPAC", "text": [ "4-Methyl catechol" ], "offsets": [ [ 765, 782 ] ], "normalized": [] }, { "id": "entity-48-12", "type": "IUPAC", "text": [ "L-dihydroxyphenylalanine" ], "offsets": [ [ 784, 808 ] ], "normalized": [] }, { "id": "entity-48-13", "type": "TRIVIAL", "text": [ "pyrogallol" ], "offsets": [ [ 810, 820 ] ], "normalized": [] }, { "id": "entity-48-14", "type": "IUPAC", "text": [ "2,3,4-trihydroxybenzoic acid" ], "offsets": [ [ 826, 854 ] ], "normalized": [] }, { "id": "entity-48-15", "type": "FAMILY", "text": [ "diphenols" ], "offsets": [ [ 986, 995 ] ], "normalized": [] }, { "id": "entity-48-16", "type": "IUPAC", "text": [ "protocatechuic acid" ], "offsets": [ [ 1004, 1023 ] ], "normalized": [] }, { "id": "entity-48-17", "type": "IUPAC", "text": [ "gallic acid" ], "offsets": [ [ 1025, 1036 ] ], "normalized": [] }, { "id": "entity-48-18", "type": "IUPAC", "text": [ "chlorogenic acid" ], "offsets": [ [ 1038, 1054 ] ], "normalized": [] }, { "id": "entity-48-19", "type": "IUPAC", "text": [ "caffeic acid" ], "offsets": [ [ 1060, 1072 ] ], "normalized": [] }, { "id": "entity-48-20", "type": "FAMILY", "text": [ "o-diphenols" ], "offsets": [ [ 1200, 1211 ] ], "normalized": [] }, { "id": "entity-48-21", "type": "FAMILY", "text": [ "o-diphenols" ], "offsets": [ [ 1580, 1591 ] ], "normalized": [] }, { "id": "entity-48-22", "type": "TRIVIAL", "text": [ "catechol" ], "offsets": [ [ 1598, 1606 ] ], "normalized": [] }, { "id": "entity-48-23", "type": "IUPAC", "text": [ "L-dihydroxyphenylalanine" ], "offsets": [ [ 1608, 1632 ] ], "normalized": [] }, { "id": "entity-48-24", "type": "IUPAC", "text": [ "4-methyl catechol" ], "offsets": [ [ 1638, 1655 ] ], "normalized": [] }, { "id": "entity-48-25", "type": "FAMILY", "text": [ "diphenols" ], "offsets": [ [ 1700, 1709 ] ], "normalized": [] }, { "id": "entity-48-26", "type": "TRIVIAL", "text": [ "caffeic acid" ], "offsets": [ [ 1711, 1723 ] ], "normalized": [] }, { "id": "entity-48-27", "type": "TRIVIAL", "text": [ "catechin" ], "offsets": [ [ 1729, 1737 ] ], "normalized": [] }, { "id": "entity-48-28", "type": "FAMILY", "text": [ "quinones" ], "offsets": [ [ 1747, 1755 ] ], "normalized": [] }, { "id": "entity-48-29", "type": "FAMILY", "text": [ "diphenol" ], "offsets": [ [ 1899, 1907 ] ], "normalized": [] }, { "id": "entity-48-30", "type": "TRIVIAL", "text": [ "caffeic acid" ], "offsets": [ [ 1936, 1948 ] ], "normalized": [] }, { "id": "entity-48-31", "type": "TRIVIAL", "text": [ "catechol" ], "offsets": [ [ 2006, 2014 ] ], "normalized": [] }, { "id": "entity-48-32", "type": "TRIVIAL", "text": [ "catechol" ], "offsets": [ [ 2051, 2059 ] ], "normalized": [] }, { "id": "entity-48-33", "type": "FAMILY", "text": [ "diphenol" ], "offsets": [ [ 2169, 2177 ] ], "normalized": [] }, { "id": "entity-48-34", "type": "FAMILY", "text": [ "o-diphenols" ], "offsets": [ [ 2253, 2264 ] ], "normalized": [] } ]

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[ { "id": "passage-49", "type": "abstract", "text": [ "In the present investigation, the last two possible modes of generating conformationally semirigid diacylglycerol (DAG) analogues embedded into five-membered ring lactones as templates III and IV are investigated. The first two templates studied in previous investigations corresponded to 2-deoxyribonolactone (template I) and 4,4-disubstituted gamma-butyrolactone (template II), with the latter producing potent protein kinase C (PK-C) ligands with low nanomolar binding affinities. The templates reported in this work correspond to 2,3-dideoxy-L-erythro- or -threo-hexono-1,4-lactone (template III) and 2-deoxyapiolactone (template IV). Compounds constructed with the dideoxy-L-erythro- or -threo-hexono-1,4-lactone template were synthesized stereospecifically from tri-O-acetyl-L-glucal and L-galactono-1,4-lactone, respectively. Compounds constructed with the 2-deoxyapiolactone template were synthesized stereoselectively from di-O-isopropylidene-alpha-D-apiose. Inhibition of the binding of [3H]phorbol-12,13-dibutyrate to PK-C alpha showed that only the threo-isomer, 5-O-tetradecanoyl-2,3-dideoxy-L-threo-hexono-1,4-lactone (2) was a good PK-C ligand (Ki = 1 microM). The rest of the ligands had poorer affinities with Ki values between and 28 microM. With these results, the order of importance of five-membered ring lactones as competent templates for the construction of semirigid DAGsurrogates with effective PK-C binding affinity can be established as II &gt;&gt; I approximately III &gt; IV." ], "offsets": [ [ 0, 1509 ] ] } ]

[ { "id": "entity-49-0", "type": "TRIVIAL", "text": [ "diacylglycerol" ], "offsets": [ [ 99, 113 ] ], "normalized": [] }, { "id": "entity-49-1", "type": "ABBREVIATION", "text": [ "DAG" ], "offsets": [ [ 115, 118 ] ], "normalized": [] }, { "id": "entity-49-2", "type": "MODIFIER", "text": [ "analogues" ], "offsets": [ [ 120, 129 ] ], "normalized": [] }, { "id": "entity-49-3", "type": "FAMILY", "text": [ "lactones" ], "offsets": [ [ 163, 171 ] ], "normalized": [] }, { "id": "entity-49-4", "type": "IUPAC", "text": [ "2-deoxyribonolactone" ], "offsets": [ [ 289, 309 ] ], "normalized": [] }, { "id": "entity-49-5", "type": "IUPAC", "text": [ "4,4-disubstituted gamma-butyrolactone" ], "offsets": [ [ 327, 364 ] ], "normalized": [] }, { "id": "entity-49-6", "type": "PARTIUPAC", "text": [ "2,3-dideoxy-L-erythro-" ], "offsets": [ [ 534, 556 ] ], "normalized": [] }, { "id": "entity-49-7", "type": "IUPAC", "text": [ "-threo-hexono-1,4-lactone" ], "offsets": [ [ 560, 585 ] ], "normalized": [] }, { "id": "entity-49-8", "type": "IUPAC", "text": [ "2-deoxyapiolactone" ], "offsets": [ [ 605, 623 ] ], "normalized": [] }, { "id": "entity-49-9", "type": "PARTIUPAC", "text": [ "dideoxy-L-erythro-" ], "offsets": [ [ 670, 688 ] ], "normalized": [] }, { "id": "entity-49-10", "type": "IUPAC", "text": [ "-threo-hexono-1,4-lactone" ], "offsets": [ [ 692, 717 ] ], "normalized": [] }, { "id": "entity-49-11", "type": "IUPAC", "text": [ "tri-O-acetyl-L-glucal" ], "offsets": [ [ 768, 789 ] ], "normalized": [] }, { "id": "entity-49-12", "type": "IUPAC", "text": [ "L-galactono-1,4-lactone" ], "offsets": [ [ 794, 817 ] ], "normalized": [] }, { "id": "entity-49-13", "type": "IUPAC", "text": [ "2-deoxyapiolactone" ], "offsets": [ [ 864, 882 ] ], "normalized": [] }, { "id": "entity-49-14", "type": "IUPAC", "text": [ "di-O-isopropylidene-alpha-D-apiose" ], "offsets": [ [ 932, 966 ] ], "normalized": [] }, { "id": "entity-49-15", "type": "IUPAC", "text": [ "[3H]phorbol-12,13-dibutyrate" ], "offsets": [ [ 997, 1025 ] ], "normalized": [] }, { "id": "entity-49-16", "type": "FAMILY", "text": [ "threo-isomer" ], "offsets": [ [ 1061, 1073 ] ], "normalized": [] }, { "id": "entity-49-17", "type": "IUPAC", "text": [ "5-O-tetradecanoyl-2,3-dideoxy-L-threo-hexono-1,4-lactone" ], "offsets": [ [ 1075, 1131 ] ], "normalized": [] }, { "id": "entity-49-18", "type": "FAMILY", "text": [ "lactones" ], "offsets": [ [ 1329, 1337 ] ], "normalized": [] }, { "id": "entity-49-19", "type": "ABBREVIATION", "text": [ "DAG" ], "offsets": [ [ 1395, 1398 ] ], "normalized": [] } ]

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[ { "id": "passage-50", "type": "abstract", "text": [ "Hypoxic cells are an important target for antitumor therapy because tumors are typically characterized by such cells. Virtually all tumors which are present as solid masses contain hypoxic cells, while normal cells generally have an adequate supply of oxygen. Accordingly, antitumor agents can be made selective for tumors by virtue of high activity under hypoxic conditions. The initial purpose of this work was to determine the influence of different groups in position 3. Thus, the synthesis of some 3-NH-substituted derivatives (2a, 3a, 4a) starting from 3-amino-2-quinoxalinecarbonitrile 1,4-di-N-oxide (1a) is described. Reductive deamination of compounds 1a-k provides the 2-quinoxalinecarbonitriles 5a-k, which are more potent, while selectivity is maintained or increased in some derivatives. The compound 7-(4-nitrophenyl)-2-quinoxalinecarbonitrile 1,4-di-N-oxide (5k) is -fold more potent than tirapazamine (3-amino-1,2,4- benzotriazine 1,4-di-N-oxide), which has been used as a standard. Three derivatives (5g,i,k) show a hypoxic cytotoxicity ratio (HCR) &gt; or = , better than that of tirapazamine (HCR = 75) in V79 cells. Replacement of the 3-amino group by chlorine affords the potent but nonselective 3-chloro derivatives 6a-k showing similar toxicities under both aerobic and hypoxic conditions. These compounds were used as intermediates for the synthesis of a new series of water-soluble compounds derived from 3-[[(N,N- dialkylamino)alkyl[amino]-2-quinoxalinecarbonitrile 1,4-di-N-oxides -i and 11a-i. The 7-chloro and the 7-trifluoromethyl derivatives ,f have demonstrated high potency (0.4 and 0.3 microM) and excellent selectivity (HCR = and ). Several 7-chloro analogues, 12b, 13b.1,b.2, and 14b, and the dimer 16b have been prepared and evaluated in order to determine the optimum lateral chain in position 3, which appears to be the [(N,N-dimethylamino)propyl]amino moiety." ], "offsets": [ [ 0, 1919 ] ] } ]

[ { "id": "entity-50-0", "type": "PARTIUPAC", "text": [ "3-NH-substituted" ], "offsets": [ [ 503, 519 ] ], "normalized": [] }, { "id": "entity-50-1", "type": "MODIFIER", "text": [ "derivatives" ], "offsets": [ [ 520, 531 ] ], "normalized": [] }, { "id": "entity-50-2", "type": "IUPAC", "text": [ "3-amino-2-quinoxalinecarbonitrile 1,4-di-N-oxide" ], "offsets": [ [ 559, 607 ] ], "normalized": [] }, { "id": "entity-50-3", "type": "IUPAC", "text": [ "2-quinoxalinecarbonitriles" ], "offsets": [ [ 680, 706 ] ], "normalized": [] }, { "id": "entity-50-4", "type": "IUPAC", "text": [ "7-(4-nitrophenyl)-2-quinoxalinecarbonitrile 1,4-di-N-oxide" ], "offsets": [ [ 815, 873 ] ], "normalized": [] }, { "id": "entity-50-5", "type": "TRIVIAL", "text": [ "tirapazamine" ], "offsets": [ [ 908, 920 ] ], "normalized": [] }, { "id": "entity-50-6", "type": "IUPAC", "text": [ "3-amino-1,2,4- benzotriazine 1,4-di-N-oxide" ], "offsets": [ [ 922, 965 ] ], "normalized": [] }, { "id": "entity-50-7", "type": "TRIVIAL", "text": [ "tirapazamine" ], "offsets": [ [ 1105, 1117 ] ], "normalized": [] }, { "id": "entity-50-8", "type": "PARTIUPAC", "text": [ "3-amino" ], "offsets": [ [ 1162, 1169 ] ], "normalized": [] }, { "id": "entity-50-9", "type": "MODIFIER", "text": [ "group" ], "offsets": [ [ 1170, 1175 ] ], "normalized": [] }, { "id": "entity-50-10", "type": "TRIVIAL", "text": [ "chlorine" ], "offsets": [ [ 1179, 1187 ] ], "normalized": [] }, { "id": "entity-50-11", "type": "PARTIUPAC", "text": [ "3-chloro" ], "offsets": [ [ 1224, 1232 ] ], "normalized": [] }, { "id": "entity-50-12", "type": "MODIFIER", "text": [ "derivatives" ], "offsets": [ [ 1233, 1244 ] ], "normalized": [] }, { "id": "entity-50-13", "type": "IUPAC", "text": [ "3-[[(N,N- dialkylamino)alkyl[amino]-2-quinoxalinecarbonitrile 1,4-di-N-oxides" ], "offsets": [ [ 1437, 1514 ] ], "normalized": [] }, { "id": "entity-50-14", "type": "PARTIUPAC", "text": [ "7-chloro" ], "offsets": [ [ 1536, 1544 ] ], "normalized": [] }, { "id": "entity-50-15", "type": "PARTIUPAC", "text": [ "7-trifluoromethyl" ], "offsets": [ [ 1553, 1570 ] ], "normalized": [] }, { "id": "entity-50-16", "type": "MODIFIER", "text": [ "derivatives" ], "offsets": [ [ 1571, 1582 ] ], "normalized": [] }, { "id": "entity-50-17", "type": "PARTIUPAC", "text": [ "7-chloro" ], "offsets": [ [ 1696, 1704 ] ], "normalized": [] }, { "id": "entity-50-18", "type": "MODIFIER", "text": [ "analogues" ], "offsets": [ [ 1705, 1714 ] ], "normalized": [] }, { "id": "entity-50-19", "type": "PARTIUPAC", "text": [ "(N,N-dimethylamino)propyl]amino" ], "offsets": [ [ 1880, 1911 ] ], "normalized": [] }, { "id": "entity-50-20", "type": "MODIFIER", "text": [ "moiety" ], "offsets": [ [ 1912, 1918 ] ], "normalized": [] } ]

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[ { "id": "passage-51", "type": "abstract", "text": [ "8654448 Activity of beta-lactamase inhibitor combinations on Escherichia coli isolates exhibiting various patterns of resistance to beta-lactam agents. The efficacy of the clinically available beta-lactam/beta-lactamase inhibitor combinations (amoxicillin/clavulanic acid (CA), ticarcillin/CA, amoxicillin/sulbactam, and piperacillin/tazobactam) was evaluated on amoxicillin-resistant Escherichia coli isolates having the main patterns of beta-lactam resistance. The patterns, which reflect the production of various beta-lactamase enzymes, were analyzed by a principal component analysis of susceptibility to 11 beta-lactam antibiotics or beta-lactam/beta-lactamase inhibitor combinations. Sixty-two percent of strains were not very susceptible to penicillins, cephalothin, or any beta-lactam/beta-lactamase inhibitor combinations except for piperacillin/tazobactam; these strains may represent high-level broad-spectrum beta-lactamase (so-called penicillinase) production phenotype or inhibitor-resistant TEM-like enzyme production phenotype. Of the strains, 14.7% were resistant to amoxicillin andticarcillin compatible with low-level broad-spectrum beta-lactamase production phenotype; 5.7% were cefoxitin resistant and were postulated to present a high-level cephalosporinase production phenotype; and 2.6% were resistant to cephalothin only, attributable to a low-level cephalosporinase production phenotype. Three percent of strains were intermediate or resistant to cefotaxime and may produce an extended-spectrum beta-lactamase, and the remaining strains (12 %), resistant to all tested antibiotics except for cefotaxime and piperacillin/tazobactam, were hypothesized to produce both broad-spectrum beta-lactamase plus cephalosporinase. The minimal inhibitory concentration (MIC) for these phenotype patterns indicated that combinations of CA plus amoxicillin or ticarcillin, or sulbactam plus amoxicillin, restored the activity of penicillins against phenotype 1 strains, whereas these combinations remained inactive against the other phenotype strains. Piperacillin plus tazobactamshowed the best in vitro effect against the strains of all resistance phenotypes." ], "offsets": [ [ 0, 2181 ] ] } ]

[ { "id": "entity-51-0", "type": "FAMILY", "text": [ "beta-lactam" ], "offsets": [ [ 133, 144 ] ], "normalized": [] }, { "id": "entity-51-1", "type": "TRIVIAL", "text": [ "amoxicillin" ], "offsets": [ [ 246, 257 ] ], "normalized": [] }, { "id": "entity-51-2", "type": "TRIVIAL", "text": [ "clavulanic acid" ], "offsets": [ [ 258, 273 ] ], "normalized": [] }, { "id": "entity-51-3", "type": "ABBREVIATION", "text": [ "CA" ], "offsets": [ [ 275, 277 ] ], "normalized": [] }, { "id": "entity-51-4", "type": "TRIVIAL", "text": [ "ticarcillin" ], "offsets": [ [ 280, 291 ] ], "normalized": [] }, { "id": "entity-51-5", "type": "ABBREVIATION", "text": [ "CA" ], "offsets": [ [ 292, 294 ] ], "normalized": [] }, { "id": "entity-51-6", "type": "TRIVIAL", "text": [ "amoxicillin" ], "offsets": [ [ 296, 307 ] ], "normalized": [] }, { "id": "entity-51-7", "type": "TRIVIAL", "text": [ "sulbactam" ], "offsets": [ [ 308, 317 ] ], "normalized": [] }, { "id": "entity-51-8", "type": "TRIVIAL", "text": [ "piperacillin" ], "offsets": [ [ 323, 335 ] ], "normalized": [] }, { "id": "entity-51-9", "type": "TRIVIAL", "text": [ "tazobactam" ], "offsets": [ [ 336, 346 ] ], "normalized": [] }, { "id": "entity-51-10", "type": "TRIVIAL", "text": [ "amoxicillin" ], "offsets": [ [ 369, 380 ] ], "normalized": [] }, { "id": "entity-51-11", "type": "FAMILY", "text": [ "beta-lactam" ], "offsets": [ [ 445, 456 ] ], "normalized": [] }, { "id": "entity-51-12", "type": "FAMILY", "text": [ "beta-lactam" ], "offsets": [ [ 619, 630 ] ], "normalized": [] }, { "id": "entity-51-13", "type": "FAMILY", "text": [ "beta-lactam" ], "offsets": [ [ 646, 657 ] ], "normalized": [] }, { "id": "entity-51-14", "type": "TRIVIAL", "text": [ "penicillins" ], "offsets": [ [ 755, 766 ] ], "normalized": [] }, { "id": "entity-51-15", "type": "TRIVIAL", "text": [ "cephalothin" ], "offsets": [ [ 768, 779 ] ], "normalized": [] }, { "id": "entity-51-16", "type": "FAMILY", "text": [ "beta-lactam" ], "offsets": [ [ 788, 799 ] ], "normalized": [] }, { "id": "entity-51-17", "type": "TRIVIAL", "text": [ "piperacillin" ], "offsets": [ [ 849, 861 ] ], "normalized": [] }, { "id": "entity-51-18", "type": "TRIVIAL", "text": [ "tazobactam" ], "offsets": [ [ 862, 872 ] ], "normalized": [] }, { "id": "entity-51-19", "type": "TRIVIAL", "text": [ "amoxicillin" ], "offsets": [ [ 1091, 1102 ] ], "normalized": [] }, { "id": "entity-51-20", "type": "TRIVIAL", "text": [ " ticarcillin" ], "offsets": [ [ 1106, 1118 ] ], "normalized": [] }, { "id": "entity-51-21", "type": "TRIVIAL", "text": [ "cefoxitin" ], "offsets": [ [ 1207, 1216 ] ], "normalized": [] }, { "id": "entity-51-22", "type": "TRIVIAL", "text": [ "cephalothin" ], "offsets": [ [ 1337, 1348 ] ], "normalized": [] }, { "id": "entity-51-23", "type": "TRIVIAL", "text": [ "cefotaxime" ], "offsets": [ [ 1481, 1491 ] ], "normalized": [] }, { "id": "entity-51-24", "type": "TRIVIAL", "text": [ "cefotaxime" ], "offsets": [ [ 1626, 1636 ] ], "normalized": [] }, { "id": "entity-51-25", "type": "TRIVIAL", "text": [ "piperacillin" ], "offsets": [ [ 1641, 1653 ] ], "normalized": [] }, { "id": "entity-51-26", "type": "TRIVIAL", "text": [ "tazobactam" ], "offsets": [ [ 1654, 1664 ] ], "normalized": [] }, { "id": "entity-51-27", "type": "ABBREVIATION", "text": [ "CA" ], "offsets": [ [ 1856, 1858 ] ], "normalized": [] }, { "id": "entity-51-28", "type": "TRIVIAL", "text": [ "amoxicillin" ], "offsets": [ [ 1864, 1875 ] ], "normalized": [] }, { "id": "entity-51-29", "type": "TRIVIAL", "text": [ "ticarcillin" ], "offsets": [ [ 1879, 1890 ] ], "normalized": [] }, { "id": "entity-51-30", "type": "TRIVIAL", "text": [ "sulbactam" ], "offsets": [ [ 1895, 1904 ] ], "normalized": [] }, { "id": "entity-51-31", "type": "TRIVIAL", "text": [ "amoxicillin" ], "offsets": [ [ 1910, 1921 ] ], "normalized": [] }, { "id": "entity-51-32", "type": "TRIVIAL", "text": [ "penicillins" ], "offsets": [ [ 1948, 1959 ] ], "normalized": [] }, { "id": "entity-51-33", "type": "TRIVIAL", "text": [ "Piperacillin" ], "offsets": [ [ 2071, 2083 ] ], "normalized": [] }, { "id": "entity-51-34", "type": "TRIVIAL", "text": [ "tazobactam" ], "offsets": [ [ 2089, 2099 ] ], "normalized": [] } ]

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[ { "id": "passage-52", "type": "abstract", "text": [ "The syntheses and anthelmintic activities of 31 3- and 5-(isothiocyanatophenyl)-1,2,4-oxadiazoles are reported. In the primary anthelmintic screen, 3-(4-isothiocyanatophenyl)-1,2,4-oxadiazole (39) showed nematocidal activity and 3-(2-furanyl)-5-(4-isothiocyanatophenyl)-1,2,4-oxadiazole (63), 3-(2-furanyl)-5-(2-chloro-4-isothiocyanatophenyl)-1,2,4-oxadiazole (64), and 3-(2-furanyl)-5-(4-chloro-3-isothiocyanatophenyl)-1,2,4-oxadiazole( 66) showed taeniacidal activity when administered orally to mice. The two most active members of this series, 39 and 63, were active against the gastrointestinal nematodes of sheep at mg/kg. In addition, 39 was also found to be active against hookworms in dogs at a single, oral dose of mg/kg." ], "offsets": [ [ 0, 749 ] ] } ]

[ { "id": "entity-52-0", "type": "PARTIUPAC", "text": [ "3-" ], "offsets": [ [ 48, 50 ] ], "normalized": [] }, { "id": "entity-52-1", "type": "IUPAC", "text": [ "5-(isothiocyanatophenyl)-1,2,4-oxadiazoles" ], "offsets": [ [ 55, 97 ] ], "normalized": [] }, { "id": "entity-52-2", "type": "IUPAC", "text": [ "3-(4-isothiocyanatophenyl)-1,2,4-oxadiazole" ], "offsets": [ [ 148, 191 ] ], "normalized": [] }, { "id": "entity-52-3", "type": "IUPAC", "text": [ "3-(2-furanyl)-5-(4-isothiocyanatophenyl)-1,2,4-oxadiazole" ], "offsets": [ [ 234, 291 ] ], "normalized": [] }, { "id": "entity-52-4", "type": "IUPAC", "text": [ "3-(2-furanyl)-5-(2-chloro-4-isothiocyanatophenyl)-1,2,4-oxadiazole" ], "offsets": [ [ 298, 364 ] ], "normalized": [] }, { "id": "entity-52-5", "type": "IUPAC", "text": [ "3-(2-furanyl)-5-(4-chloro-3-isothiocyanatophenyl)-1,2,4-oxadiazole" ], "offsets": [ [ 375, 441 ] ], "normalized": [] } ]

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[ { "id": "passage-53", "type": "abstract", "text": [ " Allopurinol induces renal toxicity by impairing pyrimidine metabolism in mice. We investigated the relationship between the toxic effect of allopurinol and pyrimidine metabolism in mice. Allopurinol-induced increases in plasma transaminase levels in dinitrofluorobenzene (DNFB)-sensitized mice were not affected by uridine. In contrast, plasma creatinine and BUN tended to decrease 18 hr after the last injection of uridine. Both plasma and urinary orotidine (OD) were detected in DNFB-sensitized mice after administration of a single dose of allopurinol. In contrast, TEI- , a newly synthesized xanthine oxidase/xanthine dehydrogenase inhibitor, caused neither pyrimidine metabolism abnormality nor renal impairment in DNFB-sensitized mice. Also, normal mice administered high doses of allopurinol showed abnormal pyrimidine metabolism together with renal toxicity which could be ameliorated by uridine, indicating that allopurinol essentially causes pyrimidine metabolism abnormality leading to renal impairment. In DNFB-sensitized mice, allopurinol increased urinary OD excretion to an extent similar to that in normal mice administered the same dose of allopurinol. However, renal impairment by allopurinol was more striking in DNFB-sensitized mice than in normal mice. Histopathological observations showed that allopurinol induced calculus formation in the collecting tubules and papillary duct. Calculus formation was increased by DNFB and decreased by uridine. These observations indicate that the enhancement of the renal toxicity of allopurinol by DNFB-sensitization may be due to some biological interactions between DNFB and allopurinol. In humans, it is possible that there are some biological interactions which serve to enhance the toxicity of allopurinol, resulting in the development of allopurinol hypersensitivity syndrome (AHS). In contrast, TEI- , had no effect on pyrimidinemetabolism and showed no toxic effect." ], "offsets": [ [ 0, 1952 ] ] } ]

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[ { "id": "passage-54", "type": "abstract", "text": [ "The determination of the structure and function of the sigma receptor subtypes and their physiological role(s) has been impeded by the unavailability of selective ligands. We have developed a new class of sigma subtype selective receptor ligands that are (E)-8-benzylidene derivatives of the synthetic opioid (+/-)-, (+)-, and (-)-2-methyl-5-(3-hydroxyphenyl)morphan-7-one (1). The derivatives can be prepared by reaction of 1, (+)-1, and (-)-1 with the appropriate benzaldehyde under Claisen-Schmidt conditions. Incorporation of substituted (E)-8-benzylidene moieties onto the 7-keto precursor of (+)-2-methyl-5-(3-hydroxyphenyl)morphan, (+)-1, produces compounds (-)-2 through (-)-7 (5.8-32.0 nM, sigma 1), which have between a 25- and 131-fold increase in affinity for the sigma 1 receptor subtype relative to the keto precursor (+)-1 (Ki = 762 nM, sigma 1). Compound (-)-2 is the most selective of this group (16-fold) for the sigma 1 subtype versus sigma 2. Substitution of an (E)-8-benzylidenemoiety onto the 7-keto precursor of (-)-2-methyl-5-(3-hydroxyphenyl)morphan, (-)-1, produces compounds (+)-2-(+)-9 (6.4-52.6 nM, sigma 2), which have at least a 475-3906-fold increase in affinity for the sigma 2 receptor subtype relative to the keto precursor (-)-1 (Ki = 25 x (3) nM). This enhancement of sigma 2 receptor affinity is accompanied by substantial selectivity of all of these dextrorotatory products for the sigma 2 relative to the sigma 1 subtype (32-238-fold), and thus, they are among the most sigma 2 selective compounds currently known. Furthermore, the sigma 1 subtype is highly enantioselective for the levorotatory isomers, (-)-2-(-)-7 (41-1034-fold), whereas the sigma 2 subtype is only somewhat enantioselective for the dextrorotatory isomers, (+)-2-(+)-7 (2.6-9.3-fold). All of these derivatives retain substantial affinity for the mu opioid receptor. Despite the high affinity of the dextrorotatory derivatives for the mu opioid receptor, the high affinity and selectivity for sigma 2 over sigma 1 sites will surely prove beneficial as tools for the delineation of the function and physiological role of sigma 2 receptors." ], "offsets": [ [ 0, 2150 ] ] } ]

[ { "id": "entity-54-0", "type": "IUPAC", "text": [ "(E)-8-benzylidene" ], "offsets": [ [ 255, 272 ] ], "normalized": [] }, { "id": "entity-54-1", "type": "MODIFIER", "text": [ "derivatives" ], "offsets": [ [ 273, 284 ] ], "normalized": [] }, { "id": "entity-54-2", "type": "PARTIUPAC", "text": [ "(+/-)-" ], "offsets": [ [ 309, 315 ] ], "normalized": [] }, { "id": "entity-54-3", "type": "PARTIUPAC", "text": [ "(+)-" ], "offsets": [ [ 317, 321 ] ], "normalized": [] }, { "id": "entity-54-4", "type": "IUPAC", "text": [ "(-)-2-methyl-5-(3-hydroxyphenyl)morphan-7-one" ], "offsets": [ [ 327, 372 ] ], "normalized": [] }, { "id": "entity-54-5", "type": "TRIVIAL", "text": [ "benzaldehyde" ], "offsets": [ [ 466, 478 ] ], "normalized": [] }, { "id": "entity-54-6", "type": "IUPAC", "text": [ "(E)-8-benzylidene" ], "offsets": [ [ 542, 559 ] ], "normalized": [] }, { "id": "entity-54-7", "type": "MODIFIER", "text": [ "moieties" ], "offsets": [ [ 560, 568 ] ], "normalized": [] }, { "id": "entity-54-8", "type": "IUPAC", "text": [ "(+)-2-methyl-5-(3-hydroxyphenyl)morphan" ], "offsets": [ [ 598, 637 ] ], "normalized": [] }, { "id": "entity-54-9", "type": "IUPAC", "text": [ "(E)-8-benzylidene" ], "offsets": [ [ 982, 999 ] ], "normalized": [] } ]

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[ { "id": "passage-55", "type": "abstract", "text": [ "The design, synthesis, and biological evaluation of several unsaturated acyclonucleosides related to augustmycin A are described. The (propargyloxy)methyl acyclonucleoside analogues of 6-chloropurine, adenine, 6-methoxypurine, hypoxanthine, 6-mercaptopurine, and azathioprine have been prepared. The 9-[(propargyloxy)methyl]adenine (5) and 9-[(propargyloxy)methyl]hypoxanthine (12) analogues were converted to the corresponding 5'-tributylstannyl intermediates (9 and 13), respectively, which gave 9-[[[(Z)-5-iodo-5-propenyl]oxy]methyl]adenine ( ) and 9-[[[(Z)-5-iodo-5-propenyl]oxy]methyl]hypoxanthine (14), respectively, after iododestannylation. The [125I]-radiolabeled congeners of and 14 were prepared as potential metabolic markers. Among the unsaturated acyclonucleosides tested, 9-[(propargyloxy)methyl]-6-chloropurine (3), 9-[(propargyloxy)methyl]-6-mercaptopurine (15), 9-[(propargyloxy)methyl]azathioprine (17), and angustmycin Aanalogue showed inhibition of cancer cell growth, but only at a minimal level, and 17 also showed 14% cancer cell death in vitro. Compound provided approximately protection against HIV at (-4) M concentrations. Biodistribution results of [125I]- in mice indicate that compound is readily metabolized via deiodination in vivo, possibly by serving as a substrate for the enzyme S-adenosyl-L-homocysteine hydrolase." ], "offsets": [ [ 0, 1374 ] ] } ]

[ { "id": "entity-55-0", "type": "FAMILY", "text": [ "unsaturated acyclonucleosides" ], "offsets": [ [ 60, 89 ] ], "normalized": [] }, { "id": "entity-55-1", "type": "TRIVIAL", "text": [ "augustmycin A" ], "offsets": [ [ 101, 114 ] ], "normalized": [] }, { "id": "entity-55-2", "type": "IUPAC", "text": [ "(propargyloxy)methyl acyclonucleoside" ], "offsets": [ [ 134, 171 ] ], "normalized": [] }, { "id": "entity-55-3", "type": "MODIFIER", "text": [ "analogues" ], "offsets": [ [ 172, 181 ] ], "normalized": [] }, { "id": "entity-55-4", "type": "IUPAC", "text": [ "6-chloropurine" ], "offsets": [ [ 185, 199 ] ], "normalized": [] }, { "id": "entity-55-5", "type": "TRIVIAL", "text": [ "adenine" ], "offsets": [ [ 201, 208 ] ], "normalized": [] }, { "id": "entity-55-6", "type": "IUPAC", "text": [ "6-methoxypurine" ], "offsets": [ [ 210, 225 ] ], "normalized": [] }, { "id": "entity-55-7", "type": "TRIVIAL", "text": [ "hypoxanthine" ], "offsets": [ [ 227, 239 ] ], "normalized": [] }, { "id": "entity-55-8", "type": "IUPAC", "text": [ "6-mercaptopurine" ], "offsets": [ [ 241, 257 ] ], "normalized": [] }, { "id": "entity-55-9", "type": "TRIVIAL", "text": [ "azathioprine" ], "offsets": [ [ 263, 275 ] ], "normalized": [] }, { "id": "entity-55-10", "type": "IUPAC", "text": [ "9-[(propargyloxy)methyl]adenine" ], "offsets": [ [ 300, 331 ] ], "normalized": [] }, { "id": "entity-55-11", "type": "IUPAC", "text": [ "9-[(propargyloxy)methyl]hypoxanthine" ], "offsets": [ [ 340, 376 ] ], "normalized": [] }, { "id": "entity-55-12", "type": "MODIFIER", "text": [ "analogues" ], "offsets": [ [ 382, 391 ] ], "normalized": [] }, { "id": "entity-55-13", "type": "PARTIUPAC", "text": [ "5'-tributylstannyl" ], "offsets": [ [ 428, 446 ] ], "normalized": [] }, { "id": "entity-55-14", "type": "MODIFIER", "text": [ "intermediates" ], "offsets": [ [ 447, 460 ] ], "normalized": [] }, { "id": "entity-55-15", "type": "IUPAC", "text": [ "9-[[[(Z)-5-iodo-5-propenyl]oxy]methyl]adenine" ], "offsets": [ [ 498, 543 ] ], "normalized": [] }, { "id": "entity-55-16", "type": "IUPAC", "text": [ "9-[[[(Z)-5-iodo-5-propenyl]oxy]methyl]hypoxanthine" ], "offsets": [ [ 553, 603 ] ], "normalized": [] }, { "id": "entity-55-17", "type": "FAMILY", "text": [ "unsaturated acyclonucleosides" ], "offsets": [ [ 753, 782 ] ], "normalized": [] }, { "id": "entity-55-18", "type": "IUPAC", "text": [ "9-[(propargyloxy)methyl]-6-chloropurine" ], "offsets": [ [ 791, 830 ] ], "normalized": [] }, { "id": "entity-55-19", "type": "IUPAC", "text": [ "9-[(propargyloxy)methyl]-6-mercaptopurine" ], "offsets": [ [ 836, 877 ] ], "normalized": [] }, { "id": "entity-55-20", "type": "IUPAC", "text": [ "9-[(propargyloxy)methyl]azathioprine" ], "offsets": [ [ 884, 920 ] ], "normalized": [] }, { "id": "entity-55-21", "type": "TRIVIAL", "text": [ "angustmycin A" ], "offsets": [ [ 931, 944 ] ], "normalized": [] } ]

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[ { "id": "passage-56", "type": "abstract", "text": [ "In an attempt to increase the combined toxicity of the metabolic end-products [acrolein (4) and phosphoramide mustard (3)] from cyclophosphamide (1), the analog 2-[bis(2-chloroethyl)amino]tetrahydro-6-trifluoromethyl-2H-1,3,2-oxazaphosphorine 2-oxide (2, 6-trifluoromethylcyclophosphamide) was synthesized and its metabolism and antitumor activity studied. Following metabolism of 2 by rat liver microsomes the predicted formation of 4,4,4-trifluorocrotonaldehyde (5) was confirmed by isolation and identification, by mass spectrometry, of its dinitrophenylhydrazone. The therapeutic indices (LD50-/ID90) for 2 against the ADJ/PC6 mouse tumor and the Walker 256 tumor in the rat were 28.6 and 7.7, respectively, and were lower than the corresponding values for 1 (91.8 and 33.2, respectively) although the toxicities toward Walker cells in a bioassay system of 1 and 2 following microsomal metabolism were similar. In order to study the toxicities of 4 and 5 released under drug metabolizing conditions independently of the production of a toxic mustard the analogs 18 [2-(diethylamino)tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide] and 6 [2-(diethylamino)tetrahydro-6-trifluoromethyl-2H-1,3,2-oxazaphosphorine 2-oxide] were also synthesized. The release of 5 from 6 following metabolism was confirmed and shown by use of the bioassay system to be an event of similar toxicity to release of 4 from 18; in vivo, however, 6 (LD50 mg/kg) was more toxic to mice than 18 (LD50 greater than mg/kg)." ], "offsets": [ [ 0, 1499 ] ] } ]

[ { "id": "entity-56-0", "type": "TRIVIAL", "text": [ "acrolein" ], "offsets": [ [ 79, 87 ] ], "normalized": [] }, { "id": "entity-56-1", "type": "TRIVIAL", "text": [ "cyclophosphamide" ], "offsets": [ [ 128, 144 ] ], "normalized": [] }, { "id": "entity-56-2", "type": "MODIFIER", "text": [ "analog" ], "offsets": [ [ 154, 160 ] ], "normalized": [] }, { "id": "entity-56-3", "type": "IUPAC", "text": [ "2-[bis(2-chloroethyl)amino]tetrahydro-6-trifluoromethyl-2H-1,3,2-oxazaphosphorine 2-oxide" ], "offsets": [ [ 161, 250 ] ], "normalized": [] }, { "id": "entity-56-4", "type": "IUPAC", "text": [ "2, 6-trifluoromethylcyclophosphamide" ], "offsets": [ [ 252, 288 ] ], "normalized": [] }, { "id": "entity-56-5", "type": "IUPAC", "text": [ "4,4,4-trifluorocrotonaldehyde" ], "offsets": [ [ 434, 463 ] ], "normalized": [] }, { "id": "entity-56-6", "type": "TRIVIAL", "text": [ "dinitrophenylhydrazone" ], "offsets": [ [ 544, 566 ] ], "normalized": [] }, { "id": "entity-56-7", "type": "FAMILY", "text": [ "mustard" ], "offsets": [ [ 1046, 1053 ] ], "normalized": [] }, { "id": "entity-56-8", "type": "MODIFIER", "text": [ "analogs" ], "offsets": [ [ 1058, 1065 ] ], "normalized": [] }, { "id": "entity-56-9", "type": "IUPAC", "text": [ "2-(diethylamino)tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide" ], "offsets": [ [ 1070, 1130 ] ], "normalized": [] }, { "id": "entity-56-10", "type": "IUPAC", "text": [ "2-(diethylamino)tetrahydro-6-trifluoromethyl-2H-1,3,2-oxazaphosphorine 2-oxide" ], "offsets": [ [ 1139, 1217 ] ], "normalized": [] } ]

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[ { "id": "passage-57", "type": "abstract", "text": [ "There is reported the first four members of heteroarotinoids, the names of which are ethyl (E)-p-[2-(4,4-dimethylthiochroman-6-yl)propenyl]benzoate (1b), ethyl (E)-p-[2-(4,4-dimethylchroman-6-yl)propenyl]benzoate (1c), ethyl (E)-p-[2-(4,4-dimethyl-1-oxothiochroman-6-yl)propenyl]benzoate (1d), and (E)-p-[2-(4,4-dimethylchroman-6-yl)propenyl]benzoic acid (1e). IR, 1H NMR and 13C NMR data have been recorded for each compound and support the structural assignments. To provide a firm basis for comparison purposes of future analogues, an X-ray analysis was performed on a single crystal of ethyl (E)-p-[2-(4,4-dimethylthiochroman-6-yl)propenyl]benzoate (1b) and a precursor 4,4-dimethylthiochroman-6-yl methyl ketone 1,1-dioxide (18). These data for the heteroarotinoid 1b revealed that the two aryl ring systems were nearly perpendicular in each of the two molecules present in the unit cell (86.37 degrees and 84.17 degrees, respectively). The space group for both molecules was P1 in triclinic systems. Unit cell dimensions (at 15 degrees C) are as follows: for 1b, a = (6) A, b = 14.760 (3) A, c = 7.679 (2) A, alpha = 113.33 (2) degrees, beta = 79.45 (2) degrees, gamma = 79.98 (2) degrees, Z = 4; for 18, a = 9.292 (5) A, b = 9.291 (5) A, c = 7.951 (3) A, alpha = (3) degrees, beta = 77.49 (3) degrees, gamma = 79.60 (4) degrees, Z = 2. The sulfur-containing ring is in a distorted half-chair in 1b and the methyl carbon C(12) is shown to be trans to H(13) at the C(11)-C(13) bond. The biological activity of these arotinoids was determined in the tracheal organ culture assay and compared with trans-retinoic acid for ability to reverse keratinization in vitamin A deficient hamsters. The ester 1b displayed activity about one-half log unit less than that of the reference while 1c and 1e had activity nearly one log until less than trans-retinoic acid. The sulfoxide was the least active of the heteroretinoids." ], "offsets": [ [ 0, 1933 ] ] } ]

[ { "id": "entity-57-0", "type": "FAMILY", "text": [ "heteroarotinoids" ], "offsets": [ [ 44, 60 ] ], "normalized": [] }, { "id": "entity-57-1", "type": "IUPAC", "text": [ "ethyl (E)-p-[2-(4,4-dimethylthiochroman-6-yl)propenyl]benzoate" ], "offsets": [ [ 85, 147 ] ], "normalized": [] }, { "id": "entity-57-2", "type": "IUPAC", "text": [ "ethyl (E)-p-[2-(4,4-dimethylchroman-6-yl)propenyl]benzoate" ], "offsets": [ [ 154, 212 ] ], "normalized": [] }, { "id": "entity-57-3", "type": "IUPAC", "text": [ "ethyl (E)-p-[2-(4,4-dimethyl-1-oxothiochroman-6-yl)propenyl]benzoate" ], "offsets": [ [ 219, 287 ] ], "normalized": [] }, { "id": "entity-57-4", "type": "IUPAC", "text": [ "(E)-p-[2-(4,4-dimethylchroman-6-yl)propenyl]benzoic acid" ], "offsets": [ [ 298, 354 ] ], "normalized": [] }, { "id": "entity-57-5", "type": "IUPAC", "text": [ "ethyl (E)-p-[2-(4,4-dimethylthiochroman-6-yl)propenyl]benzoate" ], "offsets": [ [ 590, 652 ] ], "normalized": [] }, { "id": "entity-57-6", "type": "IUPAC", "text": [ "4,4-dimethylthiochroman-6-yl methyl ketone 1,1-dioxide" ], "offsets": [ [ 674, 728 ] ], "normalized": [] }, { "id": "entity-57-7", "type": "FAMILY", "text": [ "heteroarotinoid" ], "offsets": [ [ 754, 769 ] ], "normalized": [] }, { "id": "entity-57-8", "type": "TRIVIAL", "text": [ "sulfur" ], "offsets": [ [ 1361, 1367 ] ], "normalized": [] }, { "id": "entity-57-9", "type": "PARTIUPAC", "text": [ "methyl" ], "offsets": [ [ 1427, 1433 ] ], "normalized": [] }, { "id": "entity-57-10", "type": "TRIVIAL", "text": [ "carbon" ], "offsets": [ [ 1434, 1440 ] ], "normalized": [] }, { "id": "entity-57-11", "type": "FAMILY", "text": [ "arotinoids" ], "offsets": [ [ 1535, 1545 ] ], "normalized": [] }, { "id": "entity-57-12", "type": "TRIVIAL", "text": [ "trans-retinoic acid" ], "offsets": [ [ 1615, 1634 ] ], "normalized": [] }, { "id": "entity-57-13", "type": "TRIVIAL", "text": [ "vitamin A" ], "offsets": [ [ 1676, 1685 ] ], "normalized": [] }, { "id": "entity-57-14", "type": "TRIVIAL", "text": [ "trans-retinoic acid" ], "offsets": [ [ 1854, 1873 ] ], "normalized": [] }, { "id": "entity-57-15", "type": "FAMILY", "text": [ "sulfoxide" ], "offsets": [ [ 1879, 1888 ] ], "normalized": [] }, { "id": "entity-57-16", "type": "FAMILY", "text": [ "heteroretinoids" ], "offsets": [ [ 1917, 1932 ] ], "normalized": [] } ]

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[ { "id": "passage-58", "type": "abstract", "text": [ "15652357 Identification of MAGI-3 as a transforming growth factor-alpha tail binding protein. The cytoplasmic domain of the transforming growth factor-alpha precursor (proTGFalpha) contains a C-terminal PSD-95/SAP90, Discs Large, and Zona Occludens-1 (PDZ) recognition motif (TVV). By yeast two-hybrid screening of a mouse embryo library, we have found that a third member of a family of PDZ-containing proteins, membrane associated guanylate kinase inverted-3 (MAGI-3), binds to TGFalpha's TVV. MAGI-3 is widely expressed in multiple mouse tissues, including brain. Immunolocalization showed that MAGI-3 and TGFalpha were colocalized in neurons in the cortex and dentate gyrus, as well as in ependymal cells and some astrocytes. In vitro, proTGFalpha bound the PDZ-1 domain of MAGI-3 and MAGI-2, but not MAGI-1. MAGI-3 and the 17-kDa cell surface form of proTGFalpha interact transiently in MDCK cells stably transfected with both MAGI-3 and human proTGFalpha cDNAs. MAGI-3 and wild-type proTGFalpha colocalize at the cell surface. In contrast, MAGI-3 forms a stable complex with membrane-fixed TGFalpha early in the secretory pathway and interacts with immature and cell surface forms of membrane-fixed TGFalpha. Overexpression of MAGI-3 resulted in increased levels of TGFalpha in the basolateral medium of polarized MDCK cells, suggesting that MAGI-3 has a role in efficient trafficking of TGFalpha to the cell surface in polarized epithelial cells." ], "offsets": [ [ 0, 1455 ] ] } ]

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[ { "id": "passage-59", "type": "abstract", "text": [ "A series of 22-hydroxycholesterol derivatives with a modified side chain terminus was prepared. These agents were evaluated in vitro and in vivo for their ability to suppress HMG CoA reductase, the rate-limiting enzyme of cholesterol biosynthesis. In tissue culture assays, 22-hydroxycholesterol as well as the side chain modified analogues were potent inhibitors of HMG CoA reductase. However, only those sterols with a modified side chain terminus were effective suppressors of liver reductase when administered ig to rats. 22-Hydroxy-25-methylcholesterol (4a) and 25-fluoro-22-hydroxycholesterol (15a) significantly lowered serum cholesterol levels when administered ig to primates; 25-chloro-22-hydroxycholesterol (15b) and the analogue with a cyclopropyl terminus, , were ineffective. The cholesterol-lowering sterolsdid not significantly alter lipoprotein levels; however, the two compounds have been shown to inhibit acyl-coenzyme A:cholesterol acyl-transferase (ACAT) in tissue culture studies." ], "offsets": [ [ 0, 1006 ] ] } ]

[ { "id": "entity-59-0", "type": "IUPAC", "text": [ "22-hydroxycholesterol" ], "offsets": [ [ 12, 33 ] ], "normalized": [] }, { "id": "entity-59-1", "type": "MODIFIER", "text": [ "derivatives" ], "offsets": [ [ 34, 45 ] ], "normalized": [] }, { "id": "entity-59-2", "type": "TRIVIAL", "text": [ "cholesterol" ], "offsets": [ [ 222, 233 ] ], "normalized": [] }, { "id": "entity-59-3", "type": "IUPAC", "text": [ "22-hydroxycholesterol" ], "offsets": [ [ 274, 295 ] ], "normalized": [] }, { "id": "entity-59-4", "type": "IUPAC", "text": [ "22-Hydroxy-25-methylcholesterol" ], "offsets": [ [ 526, 557 ] ], "normalized": [] }, { "id": "entity-59-5", "type": "IUPAC", "text": [ "25-fluoro-22-hydroxycholesterol" ], "offsets": [ [ 567, 598 ] ], "normalized": [] }, { "id": "entity-59-6", "type": "IUPAC", "text": [ "25-chloro-22-hydroxycholesterol" ], "offsets": [ [ 686, 717 ] ], "normalized": [] }, { "id": "entity-59-7", "type": "TRIVIAL", "text": [ "cyclopropyl" ], "offsets": [ [ 748, 759 ] ], "normalized": [] }, { "id": "entity-59-8", "type": "TRIVIAL", "text": [ "cholesterol" ], "offsets": [ [ 797, 808 ] ], "normalized": [] }, { "id": "entity-59-9", "type": "FAMILY", "text": [ "sterols" ], "offsets": [ [ 818, 825 ] ], "normalized": [] } ]

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[ { "id": "passage-60", "type": "abstract", "text": [ "11597479 Synthesis of pyridino[2,3-f]indole-4,9-dione and 6,7-disubstituted quinoline-5,8-dione derivatives and evaluation on their cytotoxic activity. We report upon the synthesis of the following derivatives: N-substituted-pyridino[2,3-f]indole-4,9-dione, and 6-(alpha-diethoxycarbonyl-methyl)-7-substituted-amino-quinoline-5,8-dione, which contain the active quinoline-5,8-dione (VII) moiety. The cytotoxic activities of these compounds have been tested in SRB (SulfoRhodamine B) assays against the cancer cell lines of A-549 (human lung cancer), SK-MEL-2 (human melanoma cancer), SK-OV-3 (human ovarian cancer), XF-498 (human brain cancer) and HCT 15 (human colon cancer). The compound, N-benzyl-3-ethoxycarbonyl-2-hydroxy-pyridino[2,3-f]indole-4,9-dione (A-9), also showed higher activity than cis-platin. The highest level of cytotoxic activity in these human tumor cell lines was observed in the compound 6-(alpha-diethoxycarbonyl-methyl)-7-(2-methyl-phenylamino)-quinoline-5,8-dione( B-3)." ], "offsets": [ [ 0, 999 ] ] } ]

[ { "id": "entity-60-0", "type": "IUPAC", "text": [ "pyridino[2,3-f]indole-4,9-dione" ], "offsets": [ [ 23, 54 ] ], "normalized": [] }, { "id": "entity-60-1", "type": "IUPAC", "text": [ "6,7-disubstituted quinoline-5,8-dione" ], "offsets": [ [ 59, 96 ] ], "normalized": [] }, { "id": "entity-60-2", "type": "MODIFIER", "text": [ "derivatives" ], "offsets": [ [ 97, 108 ] ], "normalized": [] }, { "id": "entity-60-3", "type": "IUPAC", "text": [ "N-substituted-pyridino[2,3-f]indole-4,9-dione" ], "offsets": [ [ 213, 258 ] ], "normalized": [] }, { "id": "entity-60-4", "type": "IUPAC", "text": [ "6-(alpha-diethoxycarbonyl-methyl)-7-substituted-amino-quinoline-5,8-dione" ], "offsets": [ [ 264, 337 ] ], "normalized": [] }, { "id": "entity-60-5", "type": "IUPAC", "text": [ "quinoline-5,8-dione" ], "offsets": [ [ 364, 383 ] ], "normalized": [] }, { "id": "entity-60-6", "type": "MODIFIER", "text": [ "moiety" ], "offsets": [ [ 390, 396 ] ], "normalized": [] }, { "id": "entity-60-7", "type": "IUPAC", "text": [ "N-benzyl-3-ethoxycarbonyl-2-hydroxy-pyridino[2,3-f]indole-4,9-dione" ], "offsets": [ [ 693, 760 ] ], "normalized": [] }, { "id": "entity-60-8", "type": "TRIVIAL", "text": [ "cis-platin" ], "offsets": [ [ 801, 811 ] ], "normalized": [] }, { "id": "entity-60-9", "type": "IUPAC", "text": [ "6-(alpha-diethoxycarbonyl-methyl)-7-(2-methyl-phenylamino)-quinoline-5,8-dione" ], "offsets": [ [ 914, 992 ] ], "normalized": [] } ]

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[ { "id": "passage-61", "type": "abstract", "text": [ "Two 2,3-dihydrobenzofuran analogues of hallucinogenic amphetamines were prepared and evaluated for activity in the two-lever drug-discrimination paradigm in rats trained to discriminate saline from LSD tartrate (0.08 mg/kg) and for the ability to displace [125I]-(R)-DOI [( 125I]-(R)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane) from rat cortical homogenate 5-HT2 receptors. The compounds, 1-(5-methoxy-2,3-dihydrobenzofuran-4-yl)-2-aminopropane (6a) and its 7-brominated analogue 6b, possessed activity comparable to their conformationally flexible counterparts 1-(2,5-dimethoxyphenyl)-2-aminopropane (3) and its 4-bromo derivative DOB (5), respectively. The results suggest that the dihydrofuran ring in 6a and 6b models the active conformation of the 5-methoxy groups in 3 and 5. Free energy of binding, derived from radioligand displacement KA values, indicated that addition of the bromine in either series contributes 2.4-3.2 kcal/mol of binding energy. On the basis of surface area of the bromine atom, this value is 2-3 times higher than would be expected on the basis of hydrophobic binding. Thus, hydrophobicity of the para substituent alone cannot account for the dramatic enhancement of hallucinogenic activity. Although this substituent may play a minor role in orienting the conformation of the 5-methoxy groupin derivatives such as 4 and 5, there appears to be some other, as yet unknown, critical receptor interaction." ], "offsets": [ [ 0, 1437 ] ] } ]

[ { "id": "entity-61-0", "type": "IUPAC", "text": [ "2,3-dihydrobenzofuran" ], "offsets": [ [ 4, 25 ] ], "normalized": [] }, { "id": "entity-61-1", "type": "MODIFIER", "text": [ "analogues" ], "offsets": [ [ 26, 35 ] ], "normalized": [] }, { "id": "entity-61-2", "type": "FAMILY", "text": [ "amphetamines" ], "offsets": [ [ 54, 66 ] ], "normalized": [] }, { "id": "entity-61-3", "type": "IUPAC", "text": [ "LSD tartrate" ], "offsets": [ [ 198, 210 ] ], "normalized": [] }, { "id": "entity-61-4", "type": "IUPAC", "text": [ "[125I]-(R)-DOI" ], "offsets": [ [ 256, 270 ] ], "normalized": [] }, { "id": "entity-61-5", "type": "IUPAC", "text": [ "( 125I]-(R)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane)" ], "offsets": [ [ 272, 330 ] ], "normalized": [] }, { "id": "entity-61-6", "type": "IUPAC", "text": [ "1-(5-methoxy-2,3-dihydrobenzofuran-4-yl)-2-aminopropane" ], "offsets": [ [ 392, 447 ] ], "normalized": [] }, { "id": "entity-61-7", "type": "PARTIUPAC", "text": [ "7-brominated" ], "offsets": [ [ 461, 473 ] ], "normalized": [] }, { "id": "entity-61-8", "type": "MODIFIER", "text": [ "analogue" ], "offsets": [ [ 474, 482 ] ], "normalized": [] }, { "id": "entity-61-9", "type": "IUPAC", "text": [ "1-(2,5-dimethoxyphenyl)-2-aminopropane" ], "offsets": [ [ 565, 603 ] ], "normalized": [] }, { "id": "entity-61-10", "type": "PARTIUPAC", "text": [ "4-bromo" ], "offsets": [ [ 616, 623 ] ], "normalized": [] }, { "id": "entity-61-11", "type": "MODIFIER", "text": [ "derivative" ], "offsets": [ [ 624, 634 ] ], "normalized": [] }, { "id": "entity-61-12", "type": "ABBREVIATION", "text": [ "DOB" ], "offsets": [ [ 635, 638 ] ], "normalized": [] }, { "id": "entity-61-13", "type": "TRIVIAL", "text": [ "dihydrofuran" ], "offsets": [ [ 687, 699 ] ], "normalized": [] }, { "id": "entity-61-14", "type": "PARTIUPAC", "text": [ "5-methoxy" ], "offsets": [ [ 756, 765 ] ], "normalized": [] }, { "id": "entity-61-15", "type": "MODIFIER", "text": [ "groups" ], "offsets": [ [ 766, 772 ] ], "normalized": [] }, { "id": "entity-61-16", "type": "TRIVIAL", "text": [ "bromine" ], "offsets": [ [ 889, 896 ] ], "normalized": [] }, { "id": "entity-61-17", "type": "TRIVIAL", "text": [ "bromine" ], "offsets": [ [ 998, 1005 ] ], "normalized": [] }, { "id": "entity-61-18", "type": "MODIFIER", "text": [ "atom" ], "offsets": [ [ 1006, 1010 ] ], "normalized": [] }, { "id": "entity-61-19", "type": "PARTIUPAC", "text": [ "5-methoxy" ], "offsets": [ [ 1311, 1320 ] ], "normalized": [] }, { "id": "entity-61-20", "type": "MODIFIER", "text": [ "group" ], "offsets": [ [ 1321, 1326 ] ], "normalized": [] } ]

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[ { "id": "passage-62", "type": "abstract", "text": [ "Sulfur-bridged pregnanes 6,19-epithioprogesterone, 21-hydroxy-6,19-epithioprogesterone, and the corresponding sulfoxides and sulfones were synthesized and tested as blockers of the immunosuppresive activity of dexamethasone in rat thymocytes. A new one-pot procedure is described for the preparation of 6,19-epithioprogesterone and related compounds by iodocyclization of a 19-sulfanylpregn-5-ene. Antiimmunosuppresive activity was evaluated by the ability of the different steroids to block dexamethasone-mediated apoptosis in thymocytes and dexamethasone-mediated inhibition of the NFkappa-B transcription factor activity. DNA fragmentation and annexin V-FITC positive cells were taken as parameters of apoptosis whereas NFkappa-B activity was tested by the expression of the reporter vector kappaB-luciferase by TNF-alpha in Hela cells. 21-Hydroxy-6,19-epithioprogesterone S,S-dioxide had improved activity in both parameters, while 21-hydroxy-6,19-epithioprogesterone had improved activity only in blocking dexamethasone-induced programmed cell death." ], "offsets": [ [ 0, 1055 ] ] } ]

[ { "id": "entity-62-0", "type": "IUPAC", "text": [ "6,19-epithioprogesterone" ], "offsets": [ [ 25, 49 ] ], "normalized": [] }, { "id": "entity-62-1", "type": "IUPAC", "text": [ "21-hydroxy-6,19-epithioprogesterone" ], "offsets": [ [ 51, 86 ] ], "normalized": [] }, { "id": "entity-62-2", "type": "FAMILY", "text": [ "sulfoxides" ], "offsets": [ [ 110, 120 ] ], "normalized": [] }, { "id": "entity-62-3", "type": "FAMILY", "text": [ "sulfones" ], "offsets": [ [ 125, 133 ] ], "normalized": [] }, { "id": "entity-62-4", "type": "TRIVIAL", "text": [ "dexamethasone" ], "offsets": [ [ 210, 223 ] ], "normalized": [] }, { "id": "entity-62-5", "type": "IUPAC", "text": [ "6,19-epithioprogesterone" ], "offsets": [ [ 303, 327 ] ], "normalized": [] }, { "id": "entity-62-6", "type": "IUPAC", "text": [ "19-sulfanylpregn-5-ene" ], "offsets": [ [ 374, 396 ] ], "normalized": [] }, { "id": "entity-62-7", "type": "TRIVIAL", "text": [ "dexamethasone" ], "offsets": [ [ 492, 505 ] ], "normalized": [] }, { "id": "entity-62-8", "type": "TRIVIAL", "text": [ "dexamethasone" ], "offsets": [ [ 543, 556 ] ], "normalized": [] }, { "id": "entity-62-9", "type": "IUPAC", "text": [ "21-Hydroxy-6,19-epithioprogesterone S,S-dioxide" ], "offsets": [ [ 840, 887 ] ], "normalized": [] }, { "id": "entity-62-10", "type": "IUPAC", "text": [ "21-hydroxy-6,19-epithioprogesterone" ], "offsets": [ [ 936, 971 ] ], "normalized": [] }, { "id": "entity-62-11", "type": "TRIVIAL", "text": [ "dexamethasone" ], "offsets": [ [ 1011, 1024 ] ], "normalized": [] } ]

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[ { "id": "passage-63", "type": "abstract", "text": [ "A number of derivatives structurally related to cirazoline (1) were synthesized and studied with the purpose of modulating alpha2-adrenoreceptors selectivity versus both alpha1-adrenoreceptors and I2 imidazoline binding sites. The most potent alpha2-agonist was 2-[1-(biphenyl-2-yloxy)ethyl]-4,5-dihydro-1H-imidazole (7), whose key pharmacophoric features closely matched those found in the alpha2-agonist 2-(3-exo-(3-phenylprop-1-yl)-2-exo-norbornyl)amino-2-oxazoline (15). (S)-(-)-7 was the most potent of the two enantiomers, confirming the stereospecificity of the interaction with alpha2-adrenoreceptors. This eutomer was tested on two algesiometric paradigms and, because of the interaction with alpha2-adrenoreceptors, showed a potent and long-lasting antinociceptive activity, since it was abolished by the selective alpha2-antagonist RX821002." ], "offsets": [ [ 0, 852 ] ] } ]

[ { "id": "entity-63-0", "type": "TRIVIAL", "text": [ "cirazoline" ], "offsets": [ [ 48, 58 ] ], "normalized": [] }, { "id": "entity-63-1", "type": "TRIVIAL", "text": [ "imidazoline" ], "offsets": [ [ 200, 211 ] ], "normalized": [] }, { "id": "entity-63-2", "type": "IUPAC", "text": [ "2-[1-(biphenyl-2-yloxy)ethyl]-4,5-dihydro-1H-imidazole" ], "offsets": [ [ 262, 316 ] ], "normalized": [] }, { "id": "entity-63-3", "type": "IUPAC", "text": [ "2-(3-exo-(3-phenylprop-1-yl)-2-exo-norbornyl)amino-2-oxazoline" ], "offsets": [ [ 406, 468 ] ], "normalized": [] }, { "id": "entity-63-4", "type": "", "text": [ "(S)-(-)-7" ], "offsets": [ [ 475, 484 ] ], "normalized": [] }, { "id": "entity-63-5", "type": "TRIVIALVAR", "text": [ "RX821002" ], "offsets": [ [ 843, 851 ] ], "normalized": [] } ]

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[ { "id": "passage-64", "type": "abstract", "text": [ "17368496 Tissue and serum levels of principal androgens in benign prostatic hyperplasia and prostate cancer. Androgens are considered to play a substantial role in pathogenesis of both benign prostatic hyperplasia (BPH) and prostate cancer. The importance of determination of androgen levels in tissue and serum for cancer progression and prognosis has been poorly understood. The aim of study was to find out hormonal differences in both diseases, their correlations between intraprostatic and serum levels and predicted value of their investigation. Testosterone, dihydrotestosterone, androstenedione and also epitestosterone were determined in prostate tissue from 57 patients who underwent transvesical prostatectomy for BPH and 121 patients after radical prostatectomy for prostate cancer. In 75 subjects with cancer and 51 with BPH the serum samples were analyzed for testosterone, dihydrotestosterone and SHBG. Significantly higher intraprostatic androgen concentrations, i.e. 8.85+/-6.77 versus 6.44+/-6.43 pmol/g, p<0.01 for dihydrotestosterone, and 4.61+/-7.02 versus 3.44+/-4.53 pmol/g, p<0.05 for testosterone, respectively, were found in patients with prostate cancer than in BPH. Higher levels in cancer tissue were found also for epitestosterone. However, no differences were found in serum levels. Highly significant correlations occurred between all pairs of intraprostatic androgens and also epitestosterone as well as between serum testosterone and dihydrotestosterone (p<0.001) in both BPH and cancer groups. Correlation was not found between corresponding tissue and serum testosterone and dihydrotestosterone, either in benign or cancer samples. The results point to importance of intraprostatic hormone levels for evaluation of androgen status of patients, contrasting to a low value of serum hormone measurement." ], "offsets": [ [ 0, 1838 ] ] } ]

[ { "id": "entity-64-0", "type": "FAMILY", "text": [ "androgens" ], "offsets": [ [ 47, 56 ] ], "normalized": [] }, { "id": "entity-64-1", "type": "FAMILY", "text": [ "Androgens" ], "offsets": [ [ 111, 120 ] ], "normalized": [] }, { "id": "entity-64-2", "type": "FAMILY", "text": [ "androgen" ], "offsets": [ [ 278, 286 ] ], "normalized": [] }, { "id": "entity-64-3", "type": "TRIVIAL", "text": [ "Testosterone" ], "offsets": [ [ 554, 566 ] ], "normalized": [] }, { "id": "entity-64-4", "type": "TRIVIAL", "text": [ "dihydrotestosterone" ], "offsets": [ [ 568, 587 ] ], "normalized": [] }, { "id": "entity-64-5", "type": "TRIVIAL", "text": [ "androstenedione" ], "offsets": [ [ 589, 604 ] ], "normalized": [] }, { "id": "entity-64-6", "type": "TRIVIAL", "text": [ "epitestosterone" ], "offsets": [ [ 614, 629 ] ], "normalized": [] }, { "id": "entity-64-7", "type": "TRIVIAL", "text": [ "testosterone" ], "offsets": [ [ 876, 888 ] ], "normalized": [] }, { "id": "entity-64-8", "type": "TRIVIAL", "text": [ "dihydrotestosterone" ], "offsets": [ [ 890, 909 ] ], "normalized": [] }, { "id": "entity-64-9", "type": "TRIVIAL", "text": [ "androgen" ], "offsets": [ [ 956, 964 ] ], "normalized": [] }, { "id": "entity-64-10", "type": "TRIVIAL", "text": [ "dihydrotestosterone" ], "offsets": [ [ 1036, 1055 ] ], "normalized": [] }, { "id": "entity-64-11", "type": "TRIVIAL", "text": [ "testosterone" ], "offsets": [ [ 1111, 1123 ] ], "normalized": [] }, { "id": "entity-64-12", "type": "TRIVIAL", "text": [ "epitestosterone" ], "offsets": [ [ 1247, 1262 ] ], "normalized": [] }, { "id": "entity-64-13", "type": "FAMILY", "text": [ "androgens" ], "offsets": [ [ 1393, 1402 ] ], "normalized": [] }, { "id": "entity-64-14", "type": "TRIVIAL", "text": [ "epitestosterone" ], "offsets": [ [ 1412, 1427 ] ], "normalized": [] }, { "id": "entity-64-15", "type": "TRIVIAL", "text": [ "testosterone" ], "offsets": [ [ 1453, 1465 ] ], "normalized": [] }, { "id": "entity-64-16", "type": "TRIVIAL", "text": [ "dihydrotestosterone" ], "offsets": [ [ 1470, 1489 ] ], "normalized": [] }, { "id": "entity-64-17", "type": "TRIVIAL", "text": [ "testosterone" ], "offsets": [ [ 1596, 1608 ] ], "normalized": [] }, { "id": "entity-64-18", "type": "TRIVIAL", "text": [ "dihydrotestosterone" ], "offsets": [ [ 1613, 1632 ] ], "normalized": [] } ]

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[ { "id": "passage-65", "type": "abstract", "text": [ " XBMP-1B (Xtld), a Xenopus homolog of dorso-ventral polarity gene in Drosophila, modifies tissue phenotypes of ventral explants. Previously we have isolated a Xenopus cDNA homolog of bone morphogenetic protein-1 (XBMP-1A). In the present report we describe a new cDNA clone called XBMP-1B (or Xtld) from a Xenopus embryonic library. Sequence analysis indicates that these two clones share an indentical N-terminal sequence, including a region of metalloprotease domain, three copies of a repeat first found in complement proteins C1r/s and an epidermal growth factor (EGF)-like sequence. XBMP-1B protein has an additional copy of an EGF-like sequence followed by two copies of complement 1 r/s repeat in the C-terminus. The overall protein structure predicted from the XBMP-1B sequence reveals that it encodes a protein homologous to Drosophila tolloid. Three XBMP-1 transcripts (2.9, 5.2 and 6.6 kb) were detected by northern blot analysis. However, the 2.9 kb transcript hybridized specifically with XBMP-1A and the 5.2 and 6.6 kb transcripts hybridized with XBMP-1B. In Drosophila, a major function of tolloid is to augment the activity of the decapentaplegic gene product, a close relative of tumor growth factor (TGF)-beta superfamily members, BMP-2/4. Although XBMP-1 and XBMP-4 are detected in various adult tissues of Xenopus, the expression pattern of these two genes was not tightly correlated. In the embryo, the expression of XBMP-1 increased gradually from the morula to the swimming tadpole stages. Injection of XBMP-1B RNA into the ventral blastomeres at the 4-cell stage caused an elongation of the ventral marginal zone explants and converted globin-positive blood cells to mesenchymal and muscle tissues at later stages. It was shown that XBMP-1A was less active and a 1A mutant lacking the signal sequence was inactive. Further studies revealed that injection of XBMP-1B RNA into the ventral marginal zone induced up-regulation of dorsal marginal zone markers, such as goosecoid and chordin, at the gastrulation stage. These data indicate that XBMP-1 may have a role in determining dorso-ventral patterning in Xenopus, but in a different way from the dpp/tolloid system demonstrated in Drosophila." ], "offsets": [ [ 0, 2225 ] ] } ]

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[ { "id": "passage-66", "type": "abstract", "text": [ "Spiro[isobenzofuran-1(3H),4'-piperidines] and the corresponding benzofuran and benzopyran derivatives have been synthesized and evaluated as sigma ligands. The compounds are related to Lu 28-179 (1'-[4-[1-(4-fluorophenyl)-1H-indol-3-yl]-1- butyl]spiro[isobenzofuran-1(3H),4'-piperidine]) that has been demonstrated to be a selective sigma 2 ligand with affinity in the subnanomolar range. The object of the study was to determine the structural factors governing sigma 1/sigma 2 affinity and selectivity within this class of compounds. TheN -substituent in spiro[isobenzofuran-1(3H),4'-piperidines] is highly important, both for affinity and selectivity. Spiropiperidines with no or small N-substituents (H, Me, Et) exert very low affinity for both sigma 1 and sigma 2 binding sites (IC50(sigma 1, sigma 2) &gt; nM), whereas medium-sized substituents (e.g., Pr, Bu, Ph(CH2)2) result in potent, but unselective compounds (IC50(sigma 1, sigma 2) = 2-5 nM). Increasing the chain length and the lipophilicity of the N-substituent result in compounds in which high affinity for sigma 2 binding sites is retained and with selectivity for sigma 2 vs sigma 1 binding sites (e.g., 4-cyclohexyl-1-butyl: IC50-(sigma 1) = 1.5 nM, IC50(sigma 2) = 0.07 nM). Introduction of substituents in the benzene ring of the spiro[isobenzofuran-1(3H),4'-piperidine] ring system of Lu 28-179 mainly affects affinity for sigma 1 binding sites. Compounds with substituents (F, CF3) in the 4- or 7-position of the isobenzofuran display high affinity for sigma 2 binding sites (IC50(sigma 2) = 0.5-2 nM) and very low affinity for sigma 1 binding sites (IC50(sigma 1) &gt; nM). Compounds with substituents (F, CF3, Me) in the 5- or 6-position of the isobenzofuran exert increased affinity for sigma 1 binding sites (IC50(sigma 1) = 5-30 nM, IC50(sigma 2) = 0.3-7 nM), thus rendering unselective compounds. Exchanging the isobenzofuran moiety of Lu 28-179 with thioisobenzofuran, benzofuran, or benzopyran also has a pronounced effect on both affinity and selectivity for sigma binding sites. The position of the oxygen atom and the position of the spiroconnection with the 4-position of the piperidine ring were varied, and only compounds in which both the benzene ring and the heteroatom are attached directly to the piperidine ring retain high affinity and selectivity for sigma 2 binding sites (e.g., 3,4-dihydro-1'-[4-[1-(4-fluorophenyl)-1H-indol-3-yl]-1- butyl]spiro[1H-2-benzopyran-1,4'-piperidine]: IC50(sigma 1) = 53 nM, IC50(sigma 2) = 0.9 nM).(ABSTRACT TRUNCATED AT WORDS)" ], "offsets": [ [ 0, 2564 ] ] } ]

[ { "id": "entity-66-0", "type": "TRIVIAL", "text": [ "benzofuran" ], "offsets": [ [ 64, 74 ] ], "normalized": [] }, { "id": "entity-66-1", "type": "TRIVIAL", "text": [ "benzopyran" ], "offsets": [ [ 79, 89 ] ], "normalized": [] }, { "id": "entity-66-2", "type": "MODIFIER", "text": [ "derivatives" ], "offsets": [ [ 90, 101 ] ], "normalized": [] }, { "id": "entity-66-3", "type": "TRIVIALVAR", "text": [ "Lu 28-179" ], "offsets": [ [ 185, 194 ] ], "normalized": [] }, { "id": "entity-66-4", "type": "IUPAC", "text": [ "1'-[4-[1-(4-fluorophenyl)-1H-indol-3-yl]-1- butyl]spiro[isobenzofuran-1(3H),4'-piperidine]" ], "offsets": [ [ 196, 286 ] ], "normalized": [] }, { "id": "entity-66-5", "type": "PARTIUPAC", "text": [ " N-substituent" ], "offsets": [ [ 539, 553 ] ], "normalized": [] }, { "id": "entity-66-6", "type": "IUPAC", "text": [ "spiro[isobenzofuran-1(3H),4'-piperidines]" ], "offsets": [ [ 557, 598 ] ], "normalized": [] }, { "id": "entity-66-7", "type": "TRIVIAL", "text": [ "Spiropiperidines" ], "offsets": [ [ 655, 671 ] ], "normalized": [] }, { "id": "entity-66-8", "type": "PARTIUPAC", "text": [ "N-substituents" ], "offsets": [ [ 689, 703 ] ], "normalized": [] }, { "id": "entity-66-9", "type": "SUM", "text": [ "H" ], "offsets": [ [ 705, 706 ] ], "normalized": [] }, { "id": "entity-66-10", "type": "ABBREVIATION", "text": [ "Me" ], "offsets": [ [ 708, 710 ] ], "normalized": [] }, { "id": "entity-66-11", "type": "ABBREVIATION", "text": [ "Et" ], "offsets": [ [ 712, 714 ] ], "normalized": [] }, { "id": "entity-66-12", "type": "ABBREVIATION", "text": [ "Pr" ], "offsets": [ [ 862, 864 ] ], "normalized": [] }, { "id": "entity-66-13", "type": "ABBREVIATION", "text": [ "Bu" ], "offsets": [ [ 866, 868 ] ], "normalized": [] }, { "id": "entity-66-14", "type": "SUM", "text": [ "Ph(CH2)2" ], "offsets": [ [ 870, 878 ] ], "normalized": [] }, { "id": "entity-66-15", "type": "PARTIUPAC", "text": [ "N-substituent" ], "offsets": [ [ 1016, 1029 ] ], "normalized": [] }, { "id": "entity-66-16", "type": "IUPAC", "text": [ "4-cyclohexyl-1-butyl" ], "offsets": [ [ 1176, 1196 ] ], "normalized": [] }, { "id": "entity-66-17", "type": "TRIVIAL", "text": [ "benzene" ], "offsets": [ [ 1285, 1292 ] ], "normalized": [] }, { "id": "entity-66-18", "type": "IUPAC", "text": [ "spiro[isobenzofuran-1(3H),4'-piperidine]" ], "offsets": [ [ 1305, 1345 ] ], "normalized": [] }, { "id": "entity-66-19", "type": "TRIVIAL", "text": [ "Lu 28-179" ], "offsets": [ [ 1361, 1370 ] ], "normalized": [] }, { "id": "entity-66-20", "type": "SUM", "text": [ "F" ], "offsets": [ [ 1451, 1452 ] ], "normalized": [] }, { "id": "entity-66-21", "type": "SUM", "text": [ "CF3" ], "offsets": [ [ 1454, 1457 ] ], "normalized": [] }, { "id": "entity-66-22", "type": "TRIVIAL", "text": [ "isobenzofuran" ], "offsets": [ [ 1490, 1503 ] ], "normalized": [] }, { "id": "entity-66-23", "type": "ABBREVIATION", "text": [ "F" ], "offsets": [ [ 1685, 1686 ] ], "normalized": [] }, { "id": "entity-66-24", "type": "ABBREVIATION", "text": [ "CF3" ], "offsets": [ [ 1688, 1691 ] ], "normalized": [] }, { "id": "entity-66-25", "type": "ABBREVIATION", "text": [ "Me" ], "offsets": [ [ 1693, 1695 ] ], "normalized": [] }, { "id": "entity-66-26", "type": "TRIVIAL", "text": [ "isobenzofuran" ], "offsets": [ [ 1728, 1741 ] ], "normalized": [] }, { "id": "entity-66-27", "type": "TRIVIAL", "text": [ "isobenzofuran" ], "offsets": [ [ 1899, 1912 ] ], "normalized": [] }, { "id": "entity-66-28", "type": "TRIVIALVAR", "text": [ "Lu 28-179" ], "offsets": [ [ 1923, 1932 ] ], "normalized": [] }, { "id": "entity-66-29", "type": "TRIVIAL", "text": [ "thioisobenzofuran" ], "offsets": [ [ 1938, 1955 ] ], "normalized": [] }, { "id": "entity-66-30", "type": "IUPAC", "text": [ "benzofuran" ], "offsets": [ [ 1957, 1967 ] ], "normalized": [] }, { "id": "entity-66-31", "type": "TRIVIAL", "text": [ "benzopyran" ], "offsets": [ [ 1972, 1982 ] ], "normalized": [] }, { "id": "entity-66-32", "type": "TRIVIAL", "text": [ "piperidine" ], "offsets": [ [ 2169, 2179 ] ], "normalized": [] }, { "id": "entity-66-33", "type": "TRIVIAL", "text": [ "benzene" ], "offsets": [ [ 2235, 2242 ] ], "normalized": [] }, { "id": "entity-66-34", "type": "TRIVIAL", "text": [ "piperidine" ], "offsets": [ [ 2296, 2306 ] ], "normalized": [] }, { "id": "entity-66-35", "type": "IUPAC", "text": [ "3,4-dihydro-1'-[4-[1-(4-fluorophenyl)-1H-indol-3-yl]-1- butyl]spiro[1H-2-benzopyran-1,4'-piperidine]" ], "offsets": [ [ 2382, 2482 ] ], "normalized": [] } ]

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[ { "id": "passage-67", "type": "abstract", "text": [ " Maitotoxin-induced calcium entry in human lymphocytes: modulation by yessotoxin, Ca(2+) channel blockers and kinases. We have studied the effect of the ciguatera-related toxin maitotoxin (MTX) on the cytosolic free calcium concentration ([Ca(2+)]i) of human peripheral blood lymphocytes loaded with the fluorescent probe Fura2 and the regulation of MTX action by different drugs known to interfere in cellular Ca(2+) signalling mechanisms and by the marine phycotoxin yessotoxin (YTX). MTX produced a concentration-dependent elevation of [Ca(2+)]i in a Ca(2+)-containing medium. This effect was stimulated by pretreatment with YTX 1 microM and NiCl(2) 15 microM. The voltage-independent Ca(2+) channel antagonist 1-[beta-[3-(4-methoxyphenyl)propoxyl]-4-methoxyphenyl]-1H-imidazole hydrochloride (SKF96365) blocked the MTX-induced [Ca(2+)]i elevation, while the L-type channel blocker nifedipine had no effect. Pretreatment with NiCl(2) or nifedipine did not modify YTX-induced potentiation of MTX effect, and SKF96365-induced inhibition was reduced in the presence of YTX, which suggest different pathways to act on [Ca(2+)]i. Preincubation with N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide.2HCl (H-89) or genistein ( microM) also had no effect on the MTX-induced [Ca(2+)]i increment. In contrast, the PKC inhibitor bisindolilmaleimide I (GF109203X 1 microM) potentiated the MTX effect, whereas phosphatidylinositol (PI) 3-kinase inhibition with wortmannin ( nM) reduced the MTX-elicited Ca(2+) entry. In summary, MTX produced Ca(2+) influx into human lymphocytes through a SKF96365-sensitive, nifedipine-insensitive pathway. The MTX-induced [Ca(2+)]i elevation was stimulated by the marine toxin YTX through a mechanism insensitive to SKF96365, nifedipine or NiCl(2). It was also stimulated by the divalent cation Ni(2+)and PKC inhibition and was partially inhibited by PI 3-kinase inhibition." ], "offsets": [ [ 0, 1925 ] ] } ]

[ { "id": "entity-67-0", "type": "TRIVIAL", "text": [ "Maitotoxin" ], "offsets": [ [ 10, 20 ] ], "normalized": [] }, { "id": "entity-67-1", "type": "TRIVIAL", "text": [ "yessotoxin" ], "offsets": [ [ 79, 89 ] ], "normalized": [] }, { "id": "entity-67-2", "type": "SUM", "text": [ "Ca(2+)" ], "offsets": [ [ 91, 97 ] ], "normalized": [] }, { "id": "entity-67-3", "type": "TRIVIAL", "text": [ "maitotoxin" ], "offsets": [ [ 187, 197 ] ], "normalized": [] }, { "id": "entity-67-4", "type": "ABBREVIATION", "text": [ "MTX" ], "offsets": [ [ 199, 202 ] ], "normalized": [] }, { "id": "entity-67-5", "type": "TRIVIAL", "text": [ "calcium" ], "offsets": [ [ 226, 233 ] ], "normalized": [] }, { "id": "entity-67-6", "type": "SUM", "text": [ "Ca(2+)" ], "offsets": [ [ 250, 256 ] ], "normalized": [] }, { "id": "entity-67-7", "type": "ABBREVIATION", "text": [ "MTX" ], "offsets": [ [ 360, 363 ] ], "normalized": [] }, { "id": "entity-67-8", "type": "SUM", "text": [ "Ca(2+)" ], "offsets": [ [ 421, 427 ] ], "normalized": [] }, { "id": "entity-67-9", "type": "TRIVIAL", "text": [ "yessotoxin" ], "offsets": [ [ 479, 489 ] ], "normalized": [] }, { "id": "entity-67-10", "type": "ABBREVIATION", "text": [ "YTX" ], "offsets": [ [ 491, 494 ] ], "normalized": [] }, { "id": "entity-67-11", "type": "ABBREVIATION", "text": [ "MTX" ], "offsets": [ [ 497, 500 ] ], "normalized": [] }, { "id": "entity-67-12", "type": "SUM", "text": [ "Ca(2+)" ], "offsets": [ [ 550, 556 ] ], "normalized": [] }, { "id": "entity-67-13", "type": "SUM", "text": [ "Ca(2+)" ], "offsets": [ [ 564, 570 ] ], "normalized": [] }, { "id": "entity-67-14", "type": "ABBREVIATION", "text": [ "YTX" ], "offsets": [ [ 638, 641 ] ], "normalized": [] }, { "id": "entity-67-15", "type": "SUM", "text": [ "NiCl(2)" ], "offsets": [ [ 655, 662 ] ], "normalized": [] }, { "id": "entity-67-16", "type": "SUM", "text": [ "Ca(2+)" ], "offsets": [ [ 698, 704 ] ], "normalized": [] }, { "id": "entity-67-17", "type": "IUPAC", "text": [ "1-[beta-[3-(4-methoxyphenyl)propoxyl]-4-methoxyphenyl]-1H-imidazole hydrochloride" ], "offsets": [ [ 724, 805 ] ], "normalized": [] }, { "id": "entity-67-18", "type": "TRIVIALVAR", "text": [ "SKF96365" ], "offsets": [ [ 807, 815 ] ], "normalized": [] }, { "id": "entity-67-19", "type": "ABBREVIATION", "text": [ "MTX" ], "offsets": [ [ 829, 832 ] ], "normalized": [] }, { "id": "entity-67-20", "type": "SUM", "text": [ "Ca(2+)" ], "offsets": [ [ 842, 848 ] ], "normalized": [] }, { "id": "entity-67-21", "type": "TRIVIAL", "text": [ "nifedipine" ], "offsets": [ [ 895, 905 ] ], "normalized": [] }, { "id": "entity-67-22", "type": "SUM", "text": [ "NiCl(2)" ], "offsets": [ [ 939, 946 ] ], "normalized": [] }, { "id": "entity-67-23", "type": "TRIVIAL", "text": [ "nifedipine" ], "offsets": [ [ 950, 960 ] ], "normalized": [] }, { "id": "entity-67-24", "type": "ABBREVIATION", "text": [ "YTX" ], "offsets": [ [ 976, 979 ] ], "normalized": [] }, { "id": "entity-67-25", "type": "ABBREVIATION", "text": [ "MTX" ], "offsets": [ [ 1004, 1007 ] ], "normalized": [] }, { "id": "entity-67-26", "type": "TRIVIAL", "text": [ "SKF96365" ], "offsets": [ [ 1020, 1028 ] ], "normalized": [] }, { "id": "entity-67-27", "type": "ABBREVIATION", "text": [ "YTX" ], "offsets": [ [ 1079, 1082 ] ], "normalized": [] }, { "id": "entity-67-28", "type": "SUM", "text": [ "Ca(2+)" ], "offsets": [ [ 1128, 1134 ] ], "normalized": [] }, { "id": "entity-67-29", "type": "IUPAC", "text": [ "N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide" ], "offsets": [ [ 1157, 1216 ] ], "normalized": [] }, { "id": "entity-67-30", "type": "SUM", "text": [ "2HCl" ], "offsets": [ [ 1217, 1221 ] ], "normalized": [] }, { "id": "entity-67-31", "type": "TRIVIALVAR", "text": [ "H-89" ], "offsets": [ [ 1223, 1227 ] ], "normalized": [] }, { "id": "entity-67-32", "type": "TRIVIAL", "text": [ "genistein" ], "offsets": [ [ 1232, 1241 ] ], "normalized": [] }, { "id": "entity-67-33", "type": "ABBREVIATION", "text": [ "MTX" ], "offsets": [ [ 1280, 1283 ] ], "normalized": [] }, { "id": "entity-67-34", "type": "SUM", "text": [ "Ca(2+)" ], "offsets": [ [ 1293, 1299 ] ], "normalized": [] }, { "id": "entity-67-35", "type": "TRIVIAL", "text": [ "bisindolilmaleimide I" ], "offsets": [ [ 1344, 1365 ] ], "normalized": [] }, { "id": "entity-67-36", "type": "TRIVIALVAR", "text": [ "GF109203X" ], "offsets": [ [ 1367, 1376 ] ], "normalized": [] }, { "id": "entity-67-37", "type": "ABBREVIATION", "text": [ "MTX" ], "offsets": [ [ 1403, 1406 ] ], "normalized": [] }, { "id": "entity-67-38", "type": "TRIVIAL", "text": [ "wortmannin" ], "offsets": [ [ 1474, 1484 ] ], "normalized": [] }, { "id": "entity-67-39", "type": "ABBREVIATION", "text": [ "MTX" ], "offsets": [ [ 1505, 1508 ] ], "normalized": [] }, { "id": "entity-67-40", "type": "SUM", "text": [ "Ca(2+)" ], "offsets": [ [ 1518, 1524 ] ], "normalized": [] }, { "id": "entity-67-41", "type": "ABBREVIATION", "text": [ "MTX" ], "offsets": [ [ 1544, 1547 ] ], "normalized": [] }, { "id": "entity-67-42", "type": "ABBREVIATION", "text": [ "Ca(2+)" ], "offsets": [ [ 1557, 1563 ] ], "normalized": [] }, { "id": "entity-67-43", "type": "TRIVIALVAR", "text": [ "SKF96365" ], "offsets": [ [ 1604, 1612 ] ], "normalized": [] }, { "id": "entity-67-44", "type": "TRIVIAL", "text": [ "nifedipine" ], "offsets": [ [ 1624, 1634 ] ], "normalized": [] }, { "id": "entity-67-45", "type": "ABBREVIATION", "text": [ "MTX" ], "offsets": [ [ 1660, 1663 ] ], "normalized": [] }, { "id": "entity-67-46", "type": "SUM", "text": [ "Ca(2+)" ], "offsets": [ [ 1673, 1679 ] ], "normalized": [] }, { "id": "entity-67-47", "type": "ABBREVIATION", "text": [ "YTX" ], "offsets": [ [ 1727, 1730 ] ], "normalized": [] }, { "id": "entity-67-48", "type": "TRIVIALVAR", "text": [ "SKF96365" ], "offsets": [ [ 1766, 1774 ] ], "normalized": [] }, { "id": "entity-67-49", "type": "TRIVIAL", "text": [ "nifedipine" ], "offsets": [ [ 1776, 1786 ] ], "normalized": [] }, { "id": "entity-67-50", "type": "SUM", "text": [ "NiCl(2)" ], "offsets": [ [ 1790, 1797 ] ], "normalized": [] }, { "id": "entity-67-51", "type": "SUM", "text": [ "Ni(2+)" ], "offsets": [ [ 1845, 1851 ] ], "normalized": [] } ]

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[ { "id": "passage-68", "type": "abstract", "text": [ "Selective protection of (9R)-9-amino-9-deoxoerythromycin A allowed for elimination of the 12-hydroxyl group to afford a versatile 12,21-olefin intermediate. Further modifications of the intermediate led to the syntheses of (9R)-9-deoxo-9-(N,N-dimethylamino)-12,21-epoxyerythromycin B, (9R)-9-deoxo-9-(N,N-dimethylamino)-21-hydroxyerythromycin A, and (9R)-9-deoxo-9-(N,N-dimethylamino)-21-hydroxyerythromycin B. All three compounds retained antibacterial activity against several organisms normally susceptible to (9R)-9-deoxo-9-(N,N-dimethylamino)erythromycin A. However, the 21-hydroxylated erythromycin A analogue was weaker in potency than the corresponding erythromycin B congener and much weaker than the epoxy derivative. This suggests that while substitution of a polar functionality at C-21 does not abolish antibacterial activity, introduction of vicinal polar groups at both C-12 and C-21 may lead to reduction in potency. Nevertheless, these 21-functionalized derivatives of (9R)-erythromycylamine provide an entry into novel analogues of the important macrolide antibiotic erythromycin." ], "offsets": [ [ 0, 1098 ] ] } ]

[ { "id": "entity-68-0", "type": "IUPAC", "text": [ "(9R)-9-amino-9-deoxoerythromycin A" ], "offsets": [ [ 24, 58 ] ], "normalized": [] }, { "id": "entity-68-1", "type": "PARTIUPAC", "text": [ "12-hydroxyl" ], "offsets": [ [ 90, 101 ] ], "normalized": [] }, { "id": "entity-68-2", "type": "MODIFIER", "text": [ "group" ], "offsets": [ [ 102, 107 ] ], "normalized": [] }, { "id": "entity-68-3", "type": "IUPAC", "text": [ "12,21-olefin" ], "offsets": [ [ 130, 142 ] ], "normalized": [] }, { "id": "entity-68-4", "type": "MODIFIER", "text": [ "intermediate" ], "offsets": [ [ 143, 155 ] ], "normalized": [] }, { "id": "entity-68-5", "type": "IUPAC", "text": [ "(9R)-9-deoxo-9-(N,N-dimethylamino)-12,21-epoxyerythromycin B" ], "offsets": [ [ 223, 283 ] ], "normalized": [] }, { "id": "entity-68-6", "type": "IUPAC", "text": [ "(9R)-9-deoxo-9-(N,N-dimethylamino)-21-hydroxyerythromycin A" ], "offsets": [ [ 285, 344 ] ], "normalized": [] }, { "id": "entity-68-7", "type": "IUPAC", "text": [ "(9R)-9-deoxo-9-(N,N-dimethylamino)-21-hydroxyerythromycin B" ], "offsets": [ [ 350, 409 ] ], "normalized": [] }, { "id": "entity-68-8", "type": "IUPAC", "text": [ "(9R)-9-deoxo-9-(N,N-dimethylamino)erythromycin A" ], "offsets": [ [ 513, 561 ] ], "normalized": [] }, { "id": "entity-68-9", "type": "IUPAC", "text": [ "21-hydroxylated erythromycin A" ], "offsets": [ [ 576, 606 ] ], "normalized": [] }, { "id": "entity-68-10", "type": "MODIFIER", "text": [ "analogue" ], "offsets": [ [ 607, 615 ] ], "normalized": [] }, { "id": "entity-68-11", "type": "TRIVIAL", "text": [ "erythromycin B congener" ], "offsets": [ [ 661, 684 ] ], "normalized": [] }, { "id": "entity-68-12", "type": "TRIVIAL", "text": [ "epoxy" ], "offsets": [ [ 710, 715 ] ], "normalized": [] }, { "id": "entity-68-13", "type": "MODIFIER", "text": [ "derivative" ], "offsets": [ [ 716, 726 ] ], "normalized": [] }, { "id": "entity-68-14", "type": "IUPAC", "text": [ "(9R)-erythromycylamine" ], "offsets": [ [ 986, 1008 ] ], "normalized": [] }, { "id": "entity-68-15", "type": "TRIVIAL", "text": [ "erythromycin" ], "offsets": [ [ 1085, 1097 ] ], "normalized": [] } ]

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[ { "id": "passage-69", "type": "abstract", "text": [ " Serum lipid and leptin concentrations in hypopituitary patients with growth hormone deficiency. OBJECTIVE: To investigate the effects of growth hormone (GH) deficiency on serum lipid and leptin concentrations in hypopituitary patients taking conventional replacement therapy and to determine the relations between leptin and gender and anthropometric and metabolic variables. SUBJECTS: Twenty-one GH deficient adult hypopituitary patients (15 women, six men) and 21 (14 women, seven men) age, sex and body mass index (BMI) matched healthy controls. MEASUREMENTS: After an overnight fast, anthropometric parameters were measured and body composition was determined by a bioelectrical impedance analyser. Venous blood samples were obtained for the measurements of glucose, total cholesterol, high density lipoprotein (HDL) cholesterol, triglyceride, intact insulin, insulin-like growth factor 1 (IGF-1) and leptin concentrations. Serum leptin and hormones were analysed by radioimmunoassay. RESULTS: Hypopituitary patients with GH deficiency showed significantly higher triglyceride, total and low density lipoprotein (LDL) cholesterol and lower HDL cholesterol concentrations on conventional replacement therapy. The unfavourable lipid profile was particularly evident in women. Significantly higher leptin concentrations were found in patients compared with healthy controls with similar body fat content (23. 5+/-11.8 ng/ml vs 11.7+/-6.9 ng/ml, P=0.01). This difference remained significant even when leptin values were expressed in relation to fat mass percentage (0.79+/-0.40 vs. 0.42+/-0.17 ng/ml%, P<0.05) and fat mass kg (1.32+/-0.81 vs 0.66+/-0.30 ng/ml kg, P<0. 05). Significant positive correlations were observed between leptin concentrations and body fat percentage and age in the control group. In patients the sole significant relation between leptin and study parameters was the positive correlation observed between leptin and total cholesterol concentrations. Serum leptin concentrations were significantly higher in women than men in the control group, but not in the patients. No significant gender difference was observed when leptin concentrations were expressed in relation to fat mass (percentage and kg). CONCLUSION: Growth hormone deficient hypopituitary patients (particularly women) on conventional replacement therapy have a more atherogenic lipidprofile . Leptin concentrations are increased in GH deficient adults even after adjustment for percentage body fat and body fat mass (kg). Although the nature of our data does not allow us to draw any conclusions on the mechanism(s) of increased leptin concentrations in GH deficiency, decreased central sensitivity to leptin and increased leptin production from per unit fat mass, or alterations in leptin clearance, might be operative." ], "offsets": [ [ 0, 2822 ] ] } ]

[ { "id": "entity-69-0", "type": "FAMILY", "text": [ "lipid" ], "offsets": [ [ 16, 21 ] ], "normalized": [] }, { "id": "entity-69-1", "type": "FAMILY", "text": [ "lipid" ], "offsets": [ [ 188, 193 ] ], "normalized": [] }, { "id": "entity-69-2", "type": "TRIVIAL", "text": [ "glucose" ], "offsets": [ [ 773, 780 ] ], "normalized": [] }, { "id": "entity-69-3", "type": "TRIVIAL", "text": [ "cholesterol" ], "offsets": [ [ 788, 799 ] ], "normalized": [] }, { "id": "entity-69-4", "type": "TRIVIAL", "text": [ "cholesterol" ], "offsets": [ [ 832, 843 ] ], "normalized": [] }, { "id": "entity-69-5", "type": "FAMILY", "text": [ "triglyceride" ], "offsets": [ [ 845, 857 ] ], "normalized": [] }, { "id": "entity-69-6", "type": "FAMILY", "text": [ "triglyceride" ], "offsets": [ [ 1079, 1091 ] ], "normalized": [] }, { "id": "entity-69-7", "type": "TRIVIAL", "text": [ "cholesterol" ], "offsets": [ [ 1133, 1144 ] ], "normalized": [] }, { "id": "entity-69-8", "type": "TRIVIAL", "text": [ "cholesterol" ], "offsets": [ [ 1159, 1170 ] ], "normalized": [] }, { "id": "entity-69-9", "type": "FAMILY", "text": [ "lipid" ], "offsets": [ [ 1240, 1245 ] ], "normalized": [] }, { "id": "entity-69-10", "type": "TRIVIAL", "text": [ "cholesterol" ], "offsets": [ [ 1959, 1970 ] ], "normalized": [] }, { "id": "entity-69-11", "type": "FAMILY", "text": [ "lipid" ], "offsets": [ [ 2380, 2385 ] ], "normalized": [] } ]

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[ { "id": "passage-70", "type": "abstract", "text": [ "Conversion of the 8-phenolic 1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocines to the corresponding 8-thiophenolic analogues was achieved by three different routes. Diazotization of 8-amino-2,6-methano-3-benzazocine (2) followed by the reaction with CH3SNa afforded 8-(methylthio)-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine (3). Another route using Grewe cyclization was also examined for the synthesis of 3. As the most effective route, Newman-Kwart rearrangement of benzazocines was selected and closely investigated. 8-(N,N-Dimethylthiocarbamoyl)oxy derivatives (6a-e) rearranged to 8-(N,N-dimethylcarbamoyl)thio derivatives (7a-e) in good yields. Reductive cleavage of 7a-e and subsequent methylation or acylations gave the title compounds (3, 8-24). Although analgesic activities of sulfur-containing benzazocines decreased compared to the corresponding hydroxy compounds, the N-methyl derivative (S-metazocine, 8) showed potent analgesic activity." ], "offsets": [ [ 0, 957 ] ] } ]

[ { "id": "entity-70-0", "type": "IUPAC", "text": [ "8-phenolic 1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocines" ], "offsets": [ [ 18, 77 ] ], "normalized": [] }, { "id": "entity-70-1", "type": "PARTIUPAC", "text": [ "8-thiophenolic" ], "offsets": [ [ 99, 113 ] ], "normalized": [] }, { "id": "entity-70-2", "type": "MODIFIER", "text": [ "analogues" ], "offsets": [ [ 114, 123 ] ], "normalized": [] }, { "id": "entity-70-3", "type": "IUPAC", "text": [ "8-amino-2,6-methano-3-benzazocine" ], "offsets": [ [ 181, 214 ] ], "normalized": [] }, { "id": "entity-70-4", "type": "SUM", "text": [ "CH3SNa" ], "offsets": [ [ 249, 255 ] ], "normalized": [] }, { "id": "entity-70-5", "type": "IUPAC", "text": [ "8-(methylthio)-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine" ], "offsets": [ [ 265, 327 ] ], "normalized": [] }, { "id": "entity-70-6", "type": "PARTIUPAC", "text": [ "8-(N,N-Dimethylthiocarbamoyl)oxy" ], "offsets": [ [ 524, 556 ] ], "normalized": [] }, { "id": "entity-70-7", "type": "MODIFIER", "text": [ "derivatives" ], "offsets": [ [ 557, 568 ] ], "normalized": [] }, { "id": "entity-70-8", "type": "PARTIUPAC", "text": [ "8-(N,N-dimethylcarbamoyl)thio" ], "offsets": [ [ 590, 619 ] ], "normalized": [] }, { "id": "entity-70-9", "type": "MODIFIER", "text": [ "derivatives" ], "offsets": [ [ 620, 631 ] ], "normalized": [] }, { "id": "entity-70-10", "type": "FAMILY", "text": [ "benzazocines" ], "offsets": [ [ 810, 822 ] ], "normalized": [] }, { "id": "entity-70-11", "type": "PARTIUPAC", "text": [ "hydroxy" ], "offsets": [ [ 863, 870 ] ], "normalized": [] }, { "id": "entity-70-12", "type": "MODIFIER", "text": [ "compounds" ], "offsets": [ [ 871, 880 ] ], "normalized": [] }, { "id": "entity-70-13", "type": "PARTIUPAC", "text": [ "N-methyl" ], "offsets": [ [ 886, 894 ] ], "normalized": [] }, { "id": "entity-70-14", "type": "MODIFIER", "text": [ "derivative" ], "offsets": [ [ 895, 905 ] ], "normalized": [] }, { "id": "entity-70-15", "type": "IUPAC", "text": [ "S-metazocine" ], "offsets": [ [ 907, 919 ] ], "normalized": [] } ]

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[ { "id": "passage-71", "type": "abstract", "text": [ "N,O-Dicarbethoxy-4-chlorobenzenesulfohydroxamate (1c) and O-carbethoxy-N-hydroxysaccharin (6), both potential carbethoxylating agents, inhibited yeast aldehyde dehydrogenase (AlDH) with IC50's of 24 and 56 microM, respectively. The esterase activity of the enzyme was commensurably inhibited. AlDH activity was only partially restored on incubation with mercaptoethanol ( mM) for 1 h. On incubation with rat plasma, 1c liberated nitroxyl, a potent inhibitor of AlDH. Under the same conditions, nitroxyl generation from 6 was minimal, a result compatible with a previous observation that nitroxyl generation from N-hydroxysaccharin (7), the product of the hydrolysis of the carbethoxy group of 6, was minimal at physiological pH. Since chemical carbethoxylating agents represented by the O-carbethoxylated N-hydroxyphthalimide, 1-hydroxybenzotriazole, and N-hydroxysuccinimide( 8, 9, and , respectively) likewise inhibited yeast AlDH, albeit with IC50's 1 order of magnitude higher, we postulate that 1c and 6 act as irreversible inhibitors of AlDH by carbethoxylating the active site of the enzyme." ], "offsets": [ [ 0, 1102 ] ] } ]

[ { "id": "entity-71-0", "type": "IUPAC", "text": [ "O-carbethoxy-N-hydroxysaccharin" ], "offsets": [ [ 58, 89 ] ], "normalized": [] }, { "id": "entity-71-1", "type": "TRIVIAL", "text": [ "mercaptoethanol" ], "offsets": [ [ 354, 369 ] ], "normalized": [] }, { "id": "entity-71-2", "type": "TRIVIAL", "text": [ "nitroxyl" ], "offsets": [ [ 431, 439 ] ], "normalized": [] }, { "id": "entity-71-3", "type": "TRIVIAL", "text": [ "nitroxyl" ], "offsets": [ [ 496, 504 ] ], "normalized": [] }, { "id": "entity-71-4", "type": "TRIVIAL", "text": [ "nitroxyl" ], "offsets": [ [ 589, 597 ] ], "normalized": [] }, { "id": "entity-71-5", "type": "IUPAC", "text": [ "N-hydroxysaccharin" ], "offsets": [ [ 614, 632 ] ], "normalized": [] }, { "id": "entity-71-6", "type": "PARTIUPAC", "text": [ "carbethoxy" ], "offsets": [ [ 675, 685 ] ], "normalized": [] }, { "id": "entity-71-7", "type": "MODIFIER", "text": [ "group" ], "offsets": [ [ 686, 691 ] ], "normalized": [] }, { "id": "entity-71-8", "type": "IUPAC", "text": [ "O-carbethoxylated N-hydroxyphthalimide" ], "offsets": [ [ 789, 827 ] ], "normalized": [] }, { "id": "entity-71-9", "type": "IUPAC", "text": [ "1-hydroxybenzotriazole" ], "offsets": [ [ 829, 851 ] ], "normalized": [] }, { "id": "entity-71-10", "type": "IUPAC", "text": [ "N-hydroxysuccinimide" ], "offsets": [ [ 857, 877 ] ], "normalized": [] } ]

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[ { "id": "passage-72", "type": "abstract", "text": [ "At physiological pH, the spatial arrangement of the three charges of DL-tetrazol-5-ylglycine (5) could be viewed as similar to those found in certain conformations of the two excitatory amino acids (EAAs)--aspartic and glutamic acids. Given significant binding to one or more EAA receptors, 5 would offer unique modeling and perhaps biological opportunities. We have previously shown it to be the most potent NMDA agonist known, with a unique and marked in vitro neutrotoxicity at depolarizing concentrations. Now we report the details required for its synthesis, together with its potency and efficacy in two assays of functional activation of the NMDA receptor, namely agonist-influenced [3H]MK801 binding and agonist-induced release of the neurotransmitter [3H]-norepinephrine from brain slices. In both these assays DL-tetrazol-5-ylglycine proved to be more potent and efficacious than NMDA and cis-methanoglutamate. It was more potent than, and equally efficacious to, L-glutamate in [3H]MK801 binding. The structural features of 5 may well reflect optimal agonist interaction at the NMDA receptor site. (We considered the possibility that some decarboxylation of DL-tetrazol-5-ylglycine may have occurred during testing. This would give 5-(aminomethyl)tetrazole (13), the tetrazole acid analog of glycine; and glycine is involved in NMDA receptor activation. Compound 13 does not affect [3H]glycine binding at the strychnine-insensitive glycine binding site, and [3H]MK801 binding studies showed that the (aminomethyl)-tetrazole, even if is formed, would probably have no effect on the activity of tetrazol-5-ylglycineat the NMDA receptor." ], "offsets": [ [ 0, 1646 ] ] } ]

[ { "id": "entity-72-0", "type": "IUPAC", "text": [ "DL-tetrazol-5-ylglycine" ], "offsets": [ [ 69, 92 ] ], "normalized": [] }, { "id": "entity-72-1", "type": "PARTIUPAC", "text": [ "aspartic" ], "offsets": [ [ 206, 214 ] ], "normalized": [] }, { "id": "entity-72-2", "type": "IUPAC", "text": [ "glutamic acids" ], "offsets": [ [ 219, 233 ] ], "normalized": [] }, { "id": "entity-72-3", "type": "ABBREVIATION", "text": [ "NMDA" ], "offsets": [ [ 409, 413 ] ], "normalized": [] }, { "id": "entity-72-4", "type": "IUPAC", "text": [ "[3H]MK801" ], "offsets": [ [ 690, 699 ] ], "normalized": [] }, { "id": "entity-72-5", "type": "IUPAC", "text": [ "[3H]-norepinephrine" ], "offsets": [ [ 760, 779 ] ], "normalized": [] }, { "id": "entity-72-6", "type": "IUPAC", "text": [ "DL-tetrazol-5-ylglycine" ], "offsets": [ [ 820, 843 ] ], "normalized": [] }, { "id": "entity-72-7", "type": "ABBREVIATION", "text": [ "NMDA" ], "offsets": [ [ 890, 894 ] ], "normalized": [] }, { "id": "entity-72-8", "type": "IUPAC", "text": [ "cis-methanoglutamate" ], "offsets": [ [ 899, 919 ] ], "normalized": [] }, { "id": "entity-72-9", "type": "IUPAC", "text": [ "L-glutamate" ], "offsets": [ [ 974, 985 ] ], "normalized": [] }, { "id": "entity-72-10", "type": "IUPAC", "text": [ "[3H]MK801" ], "offsets": [ [ 989, 998 ] ], "normalized": [] }, { "id": "entity-72-11", "type": "IUPAC", "text": [ "DL-tetrazol-5-ylglycine" ], "offsets": [ [ 1169, 1192 ] ], "normalized": [] }, { "id": "entity-72-12", "type": "IUPAC", "text": [ "5-(aminomethyl)tetrazole" ], "offsets": [ [ 1243, 1267 ] ], "normalized": [] }, { "id": "entity-72-13", "type": "IUPAC", "text": [ "tetrazole acid" ], "offsets": [ [ 1278, 1292 ] ], "normalized": [] }, { "id": "entity-72-14", "type": "MODIFIER", "text": [ "analog" ], "offsets": [ [ 1293, 1299 ] ], "normalized": [] }, { "id": "entity-72-15", "type": "TRIVIAL", "text": [ "glycine" ], "offsets": [ [ 1303, 1310 ] ], "normalized": [] }, { "id": "entity-72-16", "type": "TRIVIAL", "text": [ "glycine" ], "offsets": [ [ 1316, 1323 ] ], "normalized": [] }, { "id": "entity-72-17", "type": "IUPAC", "text": [ "[3H]glycine" ], "offsets": [ [ 1393, 1404 ] ], "normalized": [] }, { "id": "entity-72-18", "type": "TRIVIAL", "text": [ "strychnine" ], "offsets": [ [ 1420, 1430 ] ], "normalized": [] }, { "id": "entity-72-19", "type": "TRIVIAL", "text": [ "glycine" ], "offsets": [ [ 1443, 1450 ] ], "normalized": [] }, { "id": "entity-72-20", "type": "IUPAC", "text": [ "[3H]MK801" ], "offsets": [ [ 1469, 1478 ] ], "normalized": [] }, { "id": "entity-72-21", "type": "IUPAC", "text": [ "(aminomethyl)-tetrazole" ], "offsets": [ [ 1511, 1534 ] ], "normalized": [] }, { "id": "entity-72-22", "type": "IUPAC", "text": [ "tetrazol-5-ylglycine" ], "offsets": [ [ 1604, 1624 ] ], "normalized": [] } ]

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[ { "id": "passage-73", "type": "abstract", "text": [ " Oribatid Mite Communities in the Canopy of Montane Abies amabilis and Tsuga heterophylla Trees on Vancouver Island, British Columbia. To study the oribatid mite community inhabiting microhabitats in the canopy of montane Abies amabilis [(Douglas ex D. Don) Lindl.] and Tsuga heterophylla [(Raf.) Sarg] tree species across five elevational sites, we collected branch tips and foliose/crustose lichen samples over three time periods. Thirty-three species of oribatid mites were identified from the study area. Mite species richness and abundance was significantly affected by microhabitat, and this association was independent of sampling time. At the microhabitat scale, distinct species assemblages were associated with lichen and branch tip habitats, and to a lesser degree, tree species. Conifer specificity was most apparent in the closely related species of Jugatala, where Jugatala tuberosa Ewing was only found on branch tips from A. amabilis and Jugatala sp. was primarily found on branch tips from T. heterophylla. Microhabitat specificity was most pronounced in Dendrozetes sp. where most individuals were found on branch tips and Anachiperia geminus Lindo et al. that occurred primarily on lichens. Principal components analysis of oribatid mite community composition further showed a high degree of association with microhabitat and tree species. Habitat profiles are difficult to discern for many species because tree, microhabitat, and elevation preferences confound distribution patterns. Given the significant tree-microhabitat associations in species composition in this montane canopy study, we suggest that sampling multiple microhabitats across elevations to look for patterns in community structure offers opportunities to explicitly test organizing principles in community ecology." ], "offsets": [ [ 0, 1821 ] ] } ]

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[ { "id": "passage-74", "type": "abstract", "text": [ " Tinnitus and brain MRI findings in Japanese elderly. Conclusion. There is evidence of an inverse association between cerebral infarction and tinnitus in this study. The effects of cerebral infarction on tinnitus could be explained by a neurophysiological model of tinnitus. Objectives. We examined the relationship between tinnitus and brain MRI findings including cerebral infarction, brain atrophy, ventricular dilatation, and white matter lesions. Subjects and methods. This was a cross-sectional population-based study of 2193 subjects aged 41-82 years living in Aichi prefecture, Japan. Detailed questionnaires, pure tone audiometry, and brain MRI were performed. Results. After adjusting for potential confounders in a multiple logistic analysis, cerebral infarction was inversely associated with tinnitus (odds ratio (OR)=0.649, 95% confidence interval (CI)=0.477-0.884). Cerebral infarctions of the basal ganglia (OR=0.542), thalamus (OR=0.441), and pons (OR=0.319) were especially associated with tinnitus. Brain atrophy, ventricular dilatation, and white matter lesions had no significant effects on the prevalence of tinnitus." ], "offsets": [ [ 0, 1148 ] ] } ]

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[ { "id": "passage-75", "type": "abstract", "text": [ " A neural network-based method for risk factor analysis of West Nile virus. There is a lack of knowledge about which risk factors are more important in West Nile virus (WNV) transmission and risk magnitude. A better understanding of the risk factors is of great help in developing effective new technologies and appropriate prevention strategies for WNV infection. A contribution analysis of all risk factors in WNV infection would identify those major risk factors. Based on the identified major risk factors, measures to control WNV proliferation could be directed toward those significant risk factors, thus improving the effectiveness and efficiency in developing WNV control and prevention strategies. Neural networks have many generally accepted advantages over conventional analytical techniques, for instance, ability to automatically learn the relationship between the inputs and outputs from training data, powerful generalization ability, and capability of handling nonlinear interactions. In this article, a neural network model was developed for analysis of risk factors in WNV infection. To reveal the relative contribution of the input variables, the neural network was trained using an algorithm called structural learning with forgetting. During the learning, weak neural connections are forced to fade away while a skeletal network with strong connections emerges. The significant risk factors can be identified by analyzing this skeletal network. The proposed approach is tested with the dead bird surveillance data in Ontario, Canada. The results demonstrate the effectiveness of the proposed approach." ], "offsets": [ [ 0, 1632 ] ] } ]

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[ { "id": "passage-76", "type": "abstract", "text": [ " Involvement of the incudostapedial joint anomaly in conductive deafness. Conclusion. The outcome of surgery depends on complexities of middle ear anomalies and definite diagnosis can only be achieved during exploratory tympanotomy. We must be aware that the pathology of the congenital ossicular anomalies is variable and careful surgery is needed for hearing improvement. Objective. This study aimed to investigate congenital ossicular malformation. Subjects and methods. Fifteen cases of ossicular anomalies without external ear malformation were studied. The anomaly of the incus-stapes complex was the most frequent. There were two cases of fused incudostapedial (IS) joint, which is an extremely rare occurrence. Case 1 was a 33-year-old man, in whom otosclerosis was suspected and exploratory tympanotomy was performed. The IS joint was fused, and the stapes was immobile. Small fenestra stapedectomy was performed. In case 2, a 52-year-old woman, otosclerosis was also suspected and exploratory tympanotomy was performed. The IS joint was fused and the incus was fixed. After the long process of the incus was cut, the stapes became mobile. However, since the incus remained immobile, it was removed and was placed on the stapes. In both cases, the hearing improved after surgery. The averaged hearing gain of 15 cases was 28.8 dB." ], "offsets": [ [ 0, 1349 ] ] } ]

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[ { "id": "passage-77", "type": "abstract", "text": [ " Combination of Bernouilli effect producing maneuver-induced pharyngeal narrowing rate with body mass index as predictive tool for obstructive sleep apnea syndrome. Conclusions. It is suggested that the combination of the pharyngeal narrowing rate during the Bernouilli effect producing maneuver (BEPM) with the body mass index (BMI) might be a promising predictive method for obstructive sleep apnea syndrome (OSAS). Objectives. An attempt was made to clarify the possibility that the dynamic narrowing of the pharynx evaluated by nasopharyngoscopy with BEPM, a forced inspiration through the nose with the mouth closed, might be a reliable clinical daytime predictor for identifying patients at risk of developing OSAS. Subjects and methods. Subjects were 57 patients complaining of snoring and sleepiness during daytime. Endoscopic images of the retropalatal pharynx were obtained and their area was measured by NIH imaging. The pharyngeal narrowing rate during quiet nasal breathing and that during BEPM were compared to assess pharyngeal dynamics. To increase the sensitivity of this method, BMI was added to the pharyngeal narrowing rate during BEPM. Results. The criterion of BEPM at a cut-off value of with BMI at a cut-off value of 25 kg/m(2) achieved a sensitivity of 93%, while the specificity was 67% in differentiating simple snorers from OSAS patients (apnea index >5). In addition, the likelihood ratio of the method was found to be 2.81." ], "offsets": [ [ 0, 1467 ] ] } ]

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[ { "id": "passage-78", "type": "abstract", "text": [ " Frequency and bases of abnormal performance by healthy adults on neuropsychological testing. The frequency and determinants of abnormal test performance by normal individuals are critically important to clinical inference. Here we compare two approaches to predicting rates of abnormal test performance among healthy individuals with the rates actually shown by 327 neurologically normal adults aged 18-92 years. We counted how many participants produced abnormal scores, defined by three different cutoffs with test batteries of varied length, and the number of abnormal scores they produced. Observed rates generally were closer to predictions based on a series of Monte Carlo simulations than on the binomial model. They increased with the number of tests administered, decreased as more stringent cutoffs were used to identify abnormality, varied with the degree of correlation among test scores, and depended on individual differences in age, education, race, sex, and estimated premorbid IQ. Adjusting scores for demographic variables and premorbid IQ did not reduce rates of abnormal performance. However, it eliminated the contribution of these variables to rates of abnormal test performance. These findings raise fundamental questions about the nature and interpretation of abnormal test performance by normal, healthy adults." ], "offsets": [ [ 0, 1347 ] ] } ]

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[ { "id": "passage-79", "type": "abstract", "text": [ " Is laparoscopy dying for radical prostatectomy? Training in laparoscopic urology, extensive experimental work, and dedicated surgical performance constitute the foundation of advanced laparoscopic urology, which is currently a reasonable surgical option in pediatrics, reconstructive surgery, and oncology. This article discusses topics related to laparoscopic approaches for radical prostatectomy, focusing on their introduction, development, accomplishments, and current standards and future goals for the minimally invasive treatment of urologic diseases. We highlight the dynamic status of the laparoscopic approach for radical prostatectomy (pure or robotic-assisted) that constitutes one of the most rapidly evolving fields in urology." ], "offsets": [ [ 0, 752 ] ] } ]

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[ { "id": "passage-80", "type": "abstract", "text": [ " Quantitative magnetic resonance image analysis of the cerebellum in macrocephalic and normocephalic children and adults with autism. A detailed morphometric analysis of the cerebellum in autism with and without macrocephaly. Four subject groups (N = 65; male; IQs > or = 65; age 7 to 26 years) were studied with quantitative MRI; normocephalic and macrocephalic individuals with autism without mental retardation were compared to normocephalic and benign macrocephalic typically developing individuals. Total cerebellum volumes and surface areas of four lobular midsagittal groups were measured. Independent t-tests between autism and control subjects matched for head size revealed no significant differences. Multivariate analyses of variance were also performed, using the diagnostic group as the fixed factor, cerebellar measures as the dependent variables and total intracranial volume, total brain volume, age, verbal IQ, and performance IQ as covariates. No significant differences were found; however, a trend was noted in which macrocephalic individuals with autism consistently exhibited slightly smaller cerebellar volume or surface area when compared to individuals with benign macrocephaly. In autism, with and without macrocephaly, cerebellar structures were found to be proportional to head size and did not differ from typically developing subjects." ], "offsets": [ [ 0, 1376 ] ] } ]

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[ { "id": "passage-81", "type": "abstract", "text": [ " Worker size in the formosan subterranean termite in relation to colony breeding structure as inferred from molecular markers. The Formosan subterranean termite, Coptotermes formosanus Shiraki, is an invasive species that originated in China and has been introduced to Hawaii and the U.S. mainland. Colonies are headed either by a pair of reproductives (simple families) or by varying numbers of inbreeding reproductives (extended families), and therefore have variable degrees of inbreeding. Worker size also varies among colonies of Formosan termites. We tested whether variation in worker size can be explained by the breeding system. Workers were collected from colonies from three geographically separated populations (China, Hawaii, and Louisiana), and body weight and head size were measured. Microsatellite genotyping was used to establish whether colonies were simple or extended families and to determine the heterozygosity of workers and their degree of inbreeding relative to their colony (F (IC), sensitive to the number of reproductives). All Chinese colonies contained multiple inbreeding neotenics. In Hawaii, 37% of the colonies were simple families and 63% were extended families, both having considerable degrees of inbreeding. In Louisiana, 57% of the colonies were simple families, which were mostly headed by unrelated pairs, and 43% were extended families. In simple families, size and body weight of workers were not associated with F (IC) or heterozygosity. In extended families of two populations, both size parameters were negatively correlated with F (IC); however, heterozygosity was not associated with worker size in any of the populations. This suggests that the number of reproductives within colonies has a stronger influence on worker size than the individuals' genetic diversity in Formosan subterranean termite colonies." ], "offsets": [ [ 0, 1867 ] ] } ]

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[ { "id": "passage-82", "type": "abstract", "text": [ " Protease production by different thermophilic fungi. A comparative study was carried out to evaluate protease production in solid-state fermentation (SSF) and submerged fermentation (SmF) by nine different thermophilic fungi - Thermoascus aurantiacus Miehe, Thermomyces lanuginosus, T. lanuginosus TO.03, Aspergillus flavus 1.2, Aspergillus sp. 13.33, Aspergillus sp. 13.34, Aspergillus sp. 13.35, Rhizomucor pusillus 13.36 and Rhizomucor sp. 13.37 - using substrates containing proteins to induce enzyme secretion. Soybean extract (soybean milk), soybean flour, milk powder, rice, and wheat bran were tested. The most satisfactory results were obtained when using wheat bran in SSF. The fungi that stood out in SSF were T. lanuginosus, T. lanuginosus TO.03, Aspergillus sp. 13.34, Aspergillus sp. 13.35, and Rhizomucor sp. 13.37, and those in SmF were T. aurantiacus, T. lanuginosus TO.03, and 13.37. In both fermentation systems, A. flavus 1.2 and R. pusillus 13.36 presented the lowest levels of proteolytic activity." ], "offsets": [ [ 0, 1031 ] ] } ]

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[ { "id": "passage-83", "type": "abstract", "text": [ " Inhomogeneity of Fecal Flora in Separately Reared Laboratory Mice, as Detected by Denaturing Gradient Gel Electrophoresis (DGGE). Laboratory mice were divided into 2 groups and introduced to different rooms immediately after being transferred from a mouse farm. Polymerase chain reaction followed by denaturing gradient gel electrophoresis were performed on the V6-V8 regions of bacterial 16S rDNA obtained from fecal samples at 0, 1, 2, 3, 4 and 8 weeks after the introduction. Binary data were obtained from banding patterns, and Euclidean distances for each week were calculated and analyzed by cluster analysis and non-metric multidimensional scaling. Euclidean distances were significantly higher at weeks 1 and 2 than at week 0 in both groups, although the distances between the 2 groups were significantly higher after week 1 than week 0. The distances between the 2 groups were significantly higher than those within each group at weeks 4 and 8. Mice in the 2 groups formed clusters at weeks 2 and 3 respectively, and mice were divided into 2 clusters by their respective groups at weeks 4 and 8. Mice in the 2 groups were distributed on opposite sides of the origin on the 2-dimensional plane after week 2. These results suggest that mouse fecal flora changed characteristically, according to the local environment after introduction." ], "offsets": [ [ 0, 1354 ] ] } ]

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[ { "id": "passage-84", "type": "abstract", "text": [ " Mail-in data collection at SPring-8 protein crystallography beamlines. A mail-in data collection system makes it possible for beamline users to collect diffraction data without visiting a synchrotron facility. In the mail-in data collection system at SPring-8, users pack crystals into sample trays and send the trays to SPring-8 via a courier service as the first step. Next, the user specifies measurement conditions and checks the diffraction images via the Internet. The user can also collect diffraction data using an automated sample changer robot and beamline control software. For distant users there is a newly developed data management system, D-Cha. D-Cha provides a graphical user interface that enables the user to specify the experimental conditions for samples and to check and download the diffraction images using a web browser. This system is now in routine operation and is contributing to high-throughput beamline operation." ], "offsets": [ [ 0, 955 ] ] } ]

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[ { "id": "passage-85", "type": "abstract", "text": [ " Implied preference for seismic design level and earthquake insurance. Seismic risk can be reduced by implementing newly developed seismic provisions in design codes. Furthermore, financial protection or enhanced utility and happiness for stakeholders could be gained through the purchase of earthquake insurance. If this is not so, there would be no market for such insurance. However, perceived benefit associated with insurance is not universally shared by stakeholders partly due to their diverse risk attitudes. This study investigates the implied seismic design preference with insurance options for decisionmakers of bounded rationality whose preferences could be adequately represented by the cumulative prospect theory (CPT). The investigation is focused on assessing the sensitivity of the implied seismic design preference with insurance options to model parameters of the CPT and to fair and unfair insurance arrangements. Numerical results suggest that human cognitive limitation and risk perception can affect the implied seismic design preference by the CPT significantly. The mandatory purchase of fair insurance will lead the implied seismic design preference to the optimum design level that is dictated by the minimum expected lifecycle cost rule. Unfair insurance decreases the expected gain as well as its associated variability, which is preferred by risk-averse decisionmakers. The obtained results of the implied preference for the combination of the seismic design level and insurance option suggest that property owners, financial institutions, and municipalities can take advantage of affordable insurance to establish successful seismic risk management strategies." ], "offsets": [ [ 0, 1702 ] ] } ]

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[ { "id": "passage-86", "type": "abstract", "text": [ " X-ray beam stabilization at BL-17A, the protein microcrystallography beamline of the Photon Factory. BL-17A is a new structural biology beamline at the Photon Factory, Japan. The high-brilliance beam, derived from the new short-gap undulator (SGU#17), allows for unique protein crystallographic experiments such as data collection from microcrystals and structural determination using softer X-rays. However, microcrystal experiments require robust beam stability during data collection and minor fluctuations could not be ignored. Initially, significant beam instability was observed at BL-17A. The causes of the beam instability were investigated and its various sources identified. Subsequently, several effective countermeasures have been implemented, and the fluctuation of the beam intensity successfully suppressed to within 1%. Here the instability reduction techniques used at BL-17A are presented." ], "offsets": [ [ 0, 918 ] ] } ]

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[ { "id": "passage-87", "type": "abstract", "text": [ " Neonatal pulmonary tuberculosis evolving to a destroyed lung. Tuberculosis (TB) in the newborn is infrequent, difficult to diagnose and often devastating. Congenital TB is rare, with most neonates and young infants becoming infected after birth. The incidence of neonatal TB might increase in industrialised countries as a result of immigration from countries with higher TB incidence among women of childbearing age. We report two cases of post-natally acquired pulmonary TB in newborns who developed marked lung destruction, a complication of TB which has seldom been described in the first month of life. A high index of clinical suspicion is required when evaluating pregnant women at risk for TB and their ill children, as early identification and treatment can prevent the devastating consequences of TB." ], "offsets": [ [ 0, 821 ] ] } ]

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[ { "id": "passage-88", "type": "abstract", "text": [ " Visual perception in prediagnostic and early stage Huntington's disease. Disturbances of visual perception frequently accompany neurodegenerative disorders but have been little studied in Huntington's disease (HD) gene carriers. We used psychophysical tests to assess visual perception among individuals in the prediagnostic and early stages of HD. The sample comprised four groups, which included nongene carriers (NG), 32 prediagnostic gene carriers with minimal neurological abnormalities (PD1); prediagnostic gene carriers with moderate neurological abnormalities (PD2), and 36 gene carriers with diagnosed HD. Contrast sensitivity for stationary and moving sinusoidal gratings, and tests of form and motion discrimination, were used to probe different visual pathways. Patients with HD showed impaired contrast sensitivity for moving gratings. For one of the three contrast sensitivity tests, the prediagnostic gene carriers with greater neurological abnormality (PD2) also had impaired performance as compared with NG. These findings suggest that early stage HD disrupts visual functions associated with the magnocellular pathway. However, these changes are only observed in individuals diagnosed with HD or who are in the more symptomatic stages of prediagnostic HD." ], "offsets": [ [ 0, 1291 ] ] } ]

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[ { "id": "passage-89", "type": "abstract", "text": [ " Prospects for the use of differentiation-modulating agents as adjuvant of photodynamic therapy for proliferative dermatoses. Current interest in photodynamic therapy (PDT) in dermatology stems from its recognized success in dermatological oncology, straightforward approach, easy accessibility and low cost. PDT is a photochemistry-based modality in which a light-activated photosensitizer (PS) destroys tissue through oxygen-dependent and -independent mechanisms. Although PDT has been used in dermatology for several decades, its application has still not extended significantly into the routine management of neoplastic and proliferative dermatoses because of continuing issues with the selectivity of the PS for affected tissues. This review analyzes prospects for optimization of PDT for the management of dermatoses with defects in keratinocyte proliferation/differentiation, and discusses the use of differentiating agents that redirect metabolic utilization within cells and lead to high levels of PS accumulation." ], "offsets": [ [ 0, 1033 ] ] } ]

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[ { "id": "passage-90", "type": "abstract", "text": [ " Photodynamic diagnostics of bladder tumors. Approximately 18,000 new cases of urothelial cancer of the bladder occur annually, making it the most frequent urogenital neoplasia representing nearly 4% of all malignomas. Tumor stage defines two subgroups requiring specific therapeutic approaches and implying distinct prognoses. Non-muscle-invasive urothelial cancer recurs frequently and occasionally progresses to muscle-invasive stages. Remnant tumor after initial resection is seen as one major factor in high recurrence rates. Although photodynamic diagnostics improving detection and increasing recurrence-free survival has been introduced to broad application, it has yet not been established as standard procedure. This article reviews the current literature and discusses controversial aspects." ], "offsets": [ [ 0, 812 ] ] } ]

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[ { "id": "passage-91", "type": "abstract", "text": [ " Thalamic atrophy and cognition in unilateral temporal lobe epilepsy. This study examined quantitative magnetic resonance volumes of the thalamus and hippocampus and determined their relationship with cognitive function and clinical seizure characteristics in a sample of 46 unilateral temporal lobe epilepsy (TLE) subjects ( left and 26 right) and 29 controls. The hippocampus and thalamus exhibited different patterns of volume abnormality, different associations with clinical seizure characteristics, and different patterns of relationship with cognitive measures. Hippocampal volume reduction was primarily ipsilateral to the seizure focus, and thalamic volume reduction was bilateral. Ipsilateral hippocampal volume was significantly correlated with both early neurodevelopmental features (age of seizure onset) and disease characteristics (duration of epilepsy), whereas thalamus integrity was related only to disease variables. Hippocampal volume showed a selective association with verbal memory performance. In contrast, both left and right thalamic volumes were significantly correlated with performance on both memory and nonmemory cognitive domains. These findings underscore the importance of thalamic atrophy in chronic TLE and its potential implications for cognition." ], "offsets": [ [ 0, 1296 ] ] } ]

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[ { "id": "passage-92", "type": "abstract", "text": [ " Unilateral hearing disturbance could be an isolated manifestation prior to ipsilateral anterior inferior cerebellar artery infarction. A -year-old man presented with a sudden onset of right-sided hearing disturbance. His hearing disturbance improved gradually, however, dysarthria, right-sided facial weakness and dysesthesia, and gait disturbance was developed 11 days after the onset of hearing disturbance. MR imaging revealed fresh infarctions of the right dorsolateral pons and middle cerebellar peduncle localized in the territory of anterior inferior cerebellar artery. Unilateral hearing disturbance could be an isolated manifestation prior to ipsilateral anterior inferior cerebellar artery infarction." ], "offsets": [ [ 0, 724 ] ] } ]

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[ { "id": "passage-93", "type": "abstract", "text": [ " An OLETF Allele of Hyperglycemic QTL Nidd3/of Is Dominant. The OLETF rat is a well-established model for the study of type 2 diabetes associated with obesity and has been shown to possess multiple hyperglycemic alleles in its genome. Here we focused on and carefully characterized one of the previously reported congenic strains, F.O-Nidd3/of that carries the OLETF allele of the Nidd3/of locus (also known as Niddm21 in the Rat Genome Database) in the normoglycemic F344 genetic background. A prominent finding was that the F1 progeny between the congenic and the F344 stain, whose genotype is heterozygote at the Nidd3/of locus, showed mild hyperglycemia equal to the parental congenic rat, suggesting that the OLETF allele is dominant. To our knowledge, this is the first study in which a diabetic QTL has been directly demonstrated to be dominant by using congenic strains." ], "offsets": [ [ 0, 888 ] ] } ]

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[ { "id": "passage-94", "type": "abstract", "text": [ " Implementation of remote monitoring and diffraction evaluation systems at the Photon Factory macromolecular crystallography beamlines. Owing to recent advances in high-throughput technology in macromolecular crystallography beamlines, such as high-brilliant X-ray sources, high-speed readout detectors and robotics, the number of samples that can be examined in a single visit to the beamline has increased dramatically. In order to make these experiments more efficient, two functions, remote monitoring and diffraction image evaluation, have been implemented in the macromolecular crystallography beamlines at the Photon Factory (PF). Remote monitoring allows scientists to participate in the experiment by watching from their laboratories, without having to come to the beamline. Diffraction image evaluation makes experiments easier, especially when using the sample exchange robot. To implement these two functions, two independent clients have been developed that work specifically for remote monitoring and diffraction image evaluation. In the macromolecular crystallography beamlines at PF, beamline control is performed using STARS (simple transmission and retrieval system). The system adopts a client-server style in which client programs communicate with each other through a server process using the STARS protocol. This is an advantage of the extension of the system; implementation of these new functions required few modifications of the existing system." ], "offsets": [ [ 0, 1481 ] ] } ]

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[ { "id": "passage-95", "type": "abstract", "text": [ " Direct Comparison between ICSI-Mediated DNA Transfer and Pronuclear DNA Microinjection for Producing Transgenic Rats. Production efficiency of transgenic rats was compared directly between the routine pronuclear microinjection of exogenous DNA solution (PNMI-Tg method) and the ooplasmic injection of sperm cells exposed to exogenous DNA solution (ICSI-Tg method) using six DNA constructs. The overall production efficiency per treated oocyte in the ICSI-Tg method (mean 1.1%, range 0.2 to 3.1%) was similar to that in the PNMI-Tg method (mean 1.1%, range 0 to 2.4%). An advantage of the ICSI-Tg method in the production of transgenic rats is noted in cases in which a low yield of pronuclear zygotes is an inevitable fate of the rat strain." ], "offsets": [ [ 0, 752 ] ] } ]

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[ { "id": "passage-96", "type": "abstract", "text": [ " EEG observations in a case with thalamic syndrome. A case of thalamic syndrome of the Déjerine-Roussy type is presented. EEG studies reveal that although bilaterally symmetrical rhythmic activity may be present when the patient is awake, during drowsiness and deeper sleep a marked asymmetry often appears with early disappearance of alpha activity and reduction or abolition of spindles on the side involved. Thalamic integration in the sleep mechanism is briefly discussed." ], "offsets": [ [ 0, 487 ] ] } ]

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[ { "id": "passage-97", "type": "abstract", "text": [ " Distinct cognitive profiles and rates of decline on the Mattis Dementia Rating Scale in autopsy-confirmed frontotemporal dementia and Alzheimer's disease. Neuropsychological studies have shown that patients with Frontotemporal dementia (FTD) perform worse than patients with Alzheimer's disease (AD) on tests of conceptualization and verbal fluency, but better on tests of memory and visuospatial functions. However, it is not known if these distinct cognitive profiles are robust enough to be detected using a relatively brief dementia screening instrument such as the Mattis Dementia Rating Scale (MDRS). To address this issue, the MDRS subscale profiles of patients with autopsy-confirmed FTD (n = 17) or AD (n = 34) were compared. Results showed distinct cognitive profiles in which FTD patients performed worse than AD patients on the Initiation/Perseveration and Conceptualization subscales while performing better on the Memory and Construction subscales. The distinct subscale profiles correctly classified 85% of AD patients and 76% of FTD patients. Profiles were maintained in a subset of mildly-to-moderately demented patients (MDRS > or = ) and correctly classified 89% of these patients. In addition, FTD patients (mean = points/year) declined faster than AD patients (mean = 14.8 points/year) on MDRS total and specific subscale scores. These results suggest that the MDRS may be a useful adjunct to other clinical measures for distinguishing FTD from AD and tracking the progression of the disorder." ], "offsets": [ [ 0, 1533 ] ] } ]

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[ { "id": "passage-98", "type": "abstract", "text": [ " Households' perceived personal risk and responses in a multihazard environment. This study proposed and tested a multistage model of household response to three hazards-flood, hurricane, and toxic chemical release-in Harris County Texas. The model, which extends Lindell and Perry's (1992, ) Protective Action Decision Model, proposed a basic causal chain from hazard proximity through hazard experience and perceived personal risk to expectations of continued residence in the home and adoption of household hazard adjustments. Data from 321 households generally supported the model, but the mediating effects of hazard experience and perceived personal risk were partial rather than complete. In addition, the data suggested that four demographic variables-gender, age, income, and ethnicity-affect the basic causal chain at different points." ], "offsets": [ [ 0, 859 ] ] } ]

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[ { "id": "passage-99", "type": "abstract", "text": [ " An exploratory evaluation of the contribution of personality and childhood sexual victimization to the development of sexually abusive behavior. Scores on the Millon Adolescent Clinical Inventory (MACI) and the Childhood Trauma Questionnaire (CTQ) were collected from two samples of incarcerated delinquent males: 74 adjudicated sexual abusers and 53 nonsexual abusers. In comparison to non-sexually abusive youths, a larger percentage of the sexually abusive youths indicated a history of childhood sexual victimization. The scores were then entered into a logistic regression to assess the contribution of personality characteristics to a social learning \"victim-to-victimizer\" etiological model. After controlling for time in treatment, the model correctly classified 76.6% of the youths. The variables that contributed significantly to the social learning model were the CTQ Sexual Abuse and Physical Neglect scales and the Submissive and Forceful scales on the MACI. Research and treatment implications of these findings are discussed." ], "offsets": [ [ 0, 1051 ] ] } ]

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