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85888116da06bb6c9a2ad7c9e1ea3c18

The study objectives were to evaluate the safety , tolerability , and preliminary efficacy of multiple doses of dulanermin in combination with modified FOLFOX6 and bevacizumab in previously untreated patients with locally advanced , recurrent , or metastatic colorectal cancer .

A phase 1B study of dulanermin in combination with modified FOLFOX6 plus bevacizumab in patients with metastatic colorectal cancer. The study objectives were to evaluate the safety , tolerability , and preliminary efficacy of multiple doses of dulanermin in combination with modified FOLFOX6 and bevacizumab in previously untreated patients with locally advanced , recurrent , or metastatic colorectal cancer . ### Patients And Methods A total of 23 patients received dulanermin at dosages of 4.5 or 9 mg/kg/d given on days 1 to 3 of each 14-day cycle along with standard dosing of modified FOLFOX6 plus bevacizumab. Dose-limiting toxicities, adverse events (AEs), maximum tolerated dose, and response according to Response Evaluation Criteria in Solid Tumors were assessed. ### results In the first cohort (3 patients given dulanermin at 4.5 mg/kg/d) and second cohort (6 patients given dulanermin at 9 mg/kg/day), no dose-limiting toxicities were observed. The subsequent 14 patients were treated with a dulanermin dosage of 9 mg/kg/d. Patients (N = 23) received 2 to 42 cycles of dulanermin (median 15). The most common grade 3 or 4 AEs were neutropenia (39%), hypertension (17%), peripheral neuropathy (17%), hand-foot syndrome (13%), and pulmonary embolism (13%). Three patients (13%) discontinued the study because of serious AEs. Overall, a best response of partial response was observed in 13 patients (57%) (9 confirmed, 4 unconfirmed), stable disease was observed in 7 patients (30%), and disease progression was observed in 3 patients (13%). The median progression-free survival was 9.9 months (95% confidence interval, 7.0-12.7). ### conclusions Overall, the addition of dulanermin to first-line FOLFOX plus bevacizumab was well tolerated in patients with advanced colorectal cancer, with similar AEs that would be expected from FOLFOX plus bevacizumab. A randomized study is required to assess the clinical efficacy of dulanermin in this patient population.

https://pubmed.ncbi.nlm.nih.gov/24075777/

cdca7eda69e96a52d1fdd56e49cf9261

Inhalatory beta2-mimetics with long-term action ( LABA ) , formoterol and salmeterol , possess a period of action longer than 12 hours .

[A comparison of inhalatory beta2-mimetics with long-term action (formoterol vs. salmeterol)]. Asthma is a serious global health problem. People of all age groups in all countries of the world suffer from this chronic disease of the respiratory tract, which may have a very serious and sometimes fatal course. Most beta2-mimetics with a rapid onset of effect act for 4 to 6 hours. Inhalatory beta2-mimetics with long-term action ( LABA ) , formoterol and salmeterol , possess a period of action longer than 12 hours . formoterol and salmeterol represent great progress in asthma management, particularly in combination with inhalatory corticosteroids (IKS). Their effective bronchodilatory properties and long-term improvement of pulmonary functions are a great clinical contribution for the patients. Both formoterol and salmeterol are strong and effective beta2-agonists, but their different chemical structures produce different pharmacological properties. Due to the fact that the onset of the effect of salmeterol is slower, it should not be used to treat acute symptoms or quickly deteriorating asthma. formoterol exerts a rapid onset of the effect and high internal activity, thanks to which it can be used for relieving treatment. The present paper aims to characterize and compare the properties of long-term acting beta2-mimetics, with detailed focus on their two representatives, formoterol and salmeterol.

https://pubmed.ncbi.nlm.nih.gov/17128593/

82bcf2ff9f17f26be78f8edd00b37e44

This study evaluates the possible protective effects of the calcium channel blocker amlodipine , the angiotensin converting enzyme inhibitor lisinopril , and the xanthine oxidase inhibitor allopurinol against experimental acetaminophen-induced hepatotoxicity , aiming to understand its underlying hepatotoxic mechanisms .

Effect of amlodipine, lisinopril and allopurinol on acetaminophen-induced hepatotoxicity in rats. Exposure to chemotherapeutic agents such as acetaminophen may lead to serious liver injury. Calcium deregulation, angiotensin II production and xanthine oxidase activity are suggested to play mechanistic roles in such injury. ### objective This study evaluates the possible protective effects of the calcium channel blocker amlodipine , the angiotensin converting enzyme inhibitor lisinopril , and the xanthine oxidase inhibitor allopurinol against experimental acetaminophen-induced hepatotoxicity , aiming to understand its underlying hepatotoxic mechanisms . ### Material And Methods Animals were allocated into a normal control group, a acetaminophen hepatotoxicity control group (receiving a single oral dose of acetaminophen; 750 mg/kg/day), and four treatment groups receive N-acetylcysteine (300 mg/kg/day; a reference standard), amlodipine (10 mg/kg/day), lisinopril (20 mg/kg/day) and allopurinol (50 mg/kg/day) orally for 14 consecutive days prior to acetaminophen administration. Evaluation of hepatotoxicity was performed by the assessment of hepatocyte integrity markers (serum transaminases), oxidative stress markers (hepatic malondialdehyde, glutathione and catalase), and inflammatory markers (hepatic myeloperoxidase and nitrate/nitrite), in addition to a histopathological study. ### results Rats pre-treated with amlodipine, lisinopril or allopurinol showed significantly lower serum transaminases, significantly lower hepatic malondialdehyde, myeloperoxidase and nitrate/nitrite, as well as significantly higher hepatic glutathione and catalase levels, compared with acetaminophen control rats. Serum transaminases were normalized in the lisinopril treatment group, while hepatic myeloperoxidase was normalized in the all treatment groups. Histopathological evaluation strongly supported the results of biochemical estimations. ### conclusion amlodipine, lisinopril or allopurinol can protect against acetaminophen-induced hepatotoxicity, showing mechanistic roles of calcium channels, angiotensin converting enzyme and xanthine oxidase enzyme in the pathogenesis of hepatotoxicity induced by acetaminophen.

https://pubmed.ncbi.nlm.nih.gov/27829805/

ae3ea590e974f8fa2cf4dadd985b54a2

The study was conducted in 90 patients operated on for unilateral breast cancer who were then assigned to receive either 12 intravenous cycles of cyclophosphamide , methotrexate and fluorouracil ( CMF ) every three weeks , or no further treatment .

Adjuvant cyclophosphamide, methotrexate and fluorouracil in node-negative and estrogen receptor-negative breast cancer. Updated results. Node-negative breast cancers are considered to comprise a subgroup which is amenable to cure with local-regional therapy alone. However, approximately 30% of affected patients present new disease manifestations within 10 years after surgery. To test the hypothesis that node-negative and estrogen receptor-negative breast cancer patients can benefit from adjuvant chemotherapy, a prospective randomized study was activated at the Istituto Nazionale Tumori of Milan in 1980. ### Patients And Methods The study was conducted in 90 patients operated on for unilateral breast cancer who were then assigned to receive either 12 intravenous cycles of cyclophosphamide , methotrexate and fluorouracil ( CMF ) every three weeks , or no further treatment . Adjuvant chemotherapy was administered in the outpatient clinic of the Division of Medical Oncology. Patient characteristics were fairly well balanced between the two treatment groups except for primary tumor size: 58% of those with a primary tumor measuring > 2 cm in its largest diameter were randomized in the control group compared with 38% in the CMF regimen (P = 0.06). ### results At 12 years after surgery treatment outcome was significantly superior for patients given adjuvant CMF. The relapse-free survival rate was 71% (95% confidence limits (CL): 56-86) versus 43% (95% CL: 28-58), and total survival was 80% (95% CL: 68-92) versus 50% (95% CL: 34-66), respectively. The benefit from the administration of CMF was evident in all patient subsets and was not influenced by menopausal status. ### conclusions The long-term results of this trial of adjuvant combination chemotherapy confirm our previous observations on the efficacy of adjuvant chemotherapy in node-negative breast cancer patients at high risk of early disease relapse.

https://pubmed.ncbi.nlm.nih.gov/8839902/

28dd79429e758bc58daa73abfa6f418a

This study compared the efficacy of topical emedastine 0.05 % ophthalmic solution with that of oral loratadine 10 mg and their combination in the conjunctival allergen challenge model of allergic conjunctivitis .

A randomized, double-blind, placebo-controlled comparison of emedastine 0.05% ophthalmic solution with loratadine 10 mg and their combination in the human conjunctival allergen challenge model. When selecting treatment for allergic conjunctivitis, a primary concern is whether to choose local or systemic therapy. ### objective This study compared the efficacy of topical emedastine 0.05 % ophthalmic solution with that of oral loratadine 10 mg and their combination in the conjunctival allergen challenge model of allergic conjunctivitis . ### methods This was a single-center, randomized, double-masked, placebo-controlled, parallel-group study. At visit 1, eligible subjects underwent conjunctival allergen challenge to identify the dose required to elicit a positive allergic reaction. After 7 days, subjects returned for visit 2, at which the allergen dose was confirmed. At visit 3, which took place 2 weeks later, subjects were randomized to receive either emedastine plus placebo capsules, loratadine plus placebo eyedrops, or both emedastine and loratadine. One hour after receiving study drug, subjects were challenged with allergen in both eyes. Allergic signs and symptoms were graded using standardized 5-point scales. The primary efficacy variables were itching and conjunctival hyperemia. Secondary efficacy variables were ciliary and episcleral hyperemia, chemosis, lid swelling, and tearing. Itching was graded subjectively at 3, 5, and 10 minutes after challenge. All other variables were assessed at 5, 10, and 20 minutes after challenge. ### results Eighty subjects (mean age, 43.68 years) were randomized to receive study treatment. Forty subjects (20 men, 20 women) received emedastine plus placebo capsules, 20 (7 men, 13 women) received loratadine plus placebo eyedrops, and 20 (12 men, 8 women) received both active treatments. In the between-group efficacy comparison at visit 3, the difference in itching and hyperemia scores between emedastine and loratadine was statistically significant at all time points (all, P < 0.05). Efficacy scores for the combination of emedastine and loratadine were significantly better than those for loratadine alone at 2 of 3 time points for itching and all time points for hyperemia (P < 0.05). The combination was significantly better than emedastine alone at I of 3 time points for itching and 6 of 9 time points for hyperemia (P < 0.05). ### conclusion In this study, emedastine was more efficacious than loratadine for reducing the itching and redness associated with allergic conjunctivitis in the human conjunctival allergen challenge model.

https://pubmed.ncbi.nlm.nih.gov/11952027/

0c769f1d92ebcf03959b819c250c55aa

Erythromycin , clindamycin and carbenicillin suppressed the donor flora permanently , as could be seen by the reduced colonization resistance .

Recontamination after gastrointestinal decontamination with non-absorbable antibiotics. In an attempt to restore the colonization resistance we administered anaerobic microflora to prevent an abnormal colonization of the intestine after antibiotic treatment had been discontinued. After the antibiotics had been discontinued and before the donor flora had been administered and had colonized the intestine, microorganisms present were "unopposed" and expanded to a high density. A mouse model was used to investigate which antibiotics negatively influenced the donor flora and reduced the colonization resistance when administered intraperitoneally. Erythromycin , clindamycin and carbenicillin suppressed the donor flora permanently , as could be seen by the reduced colonization resistance . benzylpenicillin, ampicillin, doxycycline and the combination gentamicin-cephalothin affected the colonization resistance as long as these agents were present. gentamicin alone and cephalothin and oxytetracycline had no effect on the colonization resistance.

https://pubmed.ncbi.nlm.nih.gov/6795128/

a44bb4123bef8777f41094293cb87a41

Mycophenolate mofetil resulted in rapid improvement of steroid-refractory immune-related adverse event hepatitis , induced by nivolumab plus ipilimumab .

Successful mycophenolate mofetil treatment of a patient with severe steroid-refractory hepatitis evoked by nivolumab plus ipilimumab treatment for relapsed bladder cancer. Mycophenolate mofetil resulted in rapid improvement of steroid-refractory immune-related adverse event hepatitis , induced by nivolumab plus ipilimumab .

https://pubmed.ncbi.nlm.nih.gov/33598220/

9a000d387e6e636fdacb29a6195a8626

The mannose-linked prodrugs of saquinavir and indinavir display therefore a most promising therapeutic potential provided that bioavailability , penetration into the HIV infected macrophages , and HIV-reservoirs of these PIs are improved .

Synthesis and in vitro biological evaluation of mannose-containing prodrugs derived from clinically used HIV-protease inhibitors with improved transepithelial transport. In an approach to improve the pharmacological properties, safety and pharmacokinetic profiles, and their penetration into HIV reservoirs or sanctuaries, and consequently, the therapeutic potential of the current protease inhibitors (PIs) used in clinics, we investigated the synthesis of various mannose-substituted saquinavir, nelfinavir, and indinavir prodrugs, their in vitro stability with respect to hydrolysis, anti-HIV activity, cytotoxicity, and permeation through a monolayer of Caco-2 cells used as a model of the intestinal barrier. Mannose-derived conjugates were prepared in two steps, in good yields, by condensing an acid derivative of a protected mannose with the PIs, followed by deprotection of the sugar protecting group. With respect to hydrolysis, these PI prodrugs are chemically stable with half-life times in the 50-60 h range that are compatible with an in vivo utilization aimed at improving the absorption/penetration or accumulation of the prodrug in specific cells/tissues and liberation of the active free drug inside HIV-infected cells. These stabilities correlate closely with the low in vitro anti-HIV activity measured for those prodrugs wherein the coupling of mannose to the PIs was performed through the peptidomimetic PI's hydroxyl. Importantly, mannose conjugation to the PIs was further found to improve the absorptive transepithelial transport of saquinavir and indinavir but not of nelfinavir across Caco-2 cell monolayers, by contrast to glucose conjugation which had the opposite effect. The mannose-linked prodrugs of saquinavir and indinavir display therefore a most promising therapeutic potential provided that bioavailability , penetration into the HIV infected macrophages , and HIV-reservoirs of these PIs are improved .

https://pubmed.ncbi.nlm.nih.gov/17105238/

1082f766cc489eaa697664eb74af0378

Resistant isolates emerged quickly and uniformly in all patients administered nevirapine either as monotherapy or in combination with zidovudine ( AZT ) .

Nevirapine resistance mutations of human immunodeficiency virus type 1 selected during therapy. Drug susceptibility and mutations in the reverse transcriptase (RT) gene were analyzed with 167 virus isolates from 38 patients treated with nevirapine, a potent nonnucleoside inhibitor of human immunodeficiency virus type 1 (HIV-1) RT. Resistant isolates emerged quickly and uniformly in all patients administered nevirapine either as monotherapy or in combination with zidovudine ( AZT ) . Resistance developed as early as 1 week, indicating rapid turnover of the virus population. The development of resistance was associated with the loss of antiviral drug activity as measured by CD4 lymphocyte counts and levels of HIV p24 antigen and RNA in serum. In addition to mutations at amino acid residues 103, 106, and 181 that had been identified by selection in cell culture, mutations at residues 108, 188, and 190 were also found in the patient isolates. Sequences from patient clones documented cocirculating mixtures of populations of different mutants. The most common mutation with monotherapy, tyrosine to cysteine at residue 181, was prevented from emerging by coadministration of AZT, which resulted in the selection of alternative mutations. The observations documented that, under selective drug pressure, the circulating virus population can change rapidly, and many alternative mutants can emerge, often in complex mixtures. The addition of a second RT inhibitor, AZT, significantly altered the pattern of mutations in the circulating population of HIV.

https://pubmed.ncbi.nlm.nih.gov/7509000/

250d6ed126d0eaf8fc10454a26a19069

Postoperative combination chemotherapy for six cycles with cisplatin ( 100 mg/m2 per day for 1 day every 3 weeks ) , bleomycin ( 15 units intravenously weekly for 18 weeks ) and etoposide ( 100 mg/m2 per day for 3 days every 3 weeks ) were given and the tumor responded dramatically .

Huge retroperitoneal germinoma presenting with pathological fracture of the spine. Primary retroperitoneal germ cell tumors are extremely rare neoplasms. The most common presenting features are abdominal pain and palpable abdominal masses. Pathological fractures of the spine presenting as bilateral lower leg weakness are exceptionally rare. We describe a 16-year-old girl who developed progressive paraplegia after a minor falling injury. Radiological study demonstrated a huge retroperitoneal tumor with invasion of the T12 vertebral body and spinal canal. A posterior surgical approach was used to perform laminectomy (T12, L1), removal of the intraspinal tumor and internal fixation with transpedical screws (T10, T11 to L2,3), and posterolateral fusion. Postoperative combination chemotherapy for six cycles with cisplatin ( 100 mg/m2 per day for 1 day every 3 weeks ) , bleomycin ( 15 units intravenously weekly for 18 weeks ) and etoposide ( 100 mg/m2 per day for 3 days every 3 weeks ) were given and the tumor responded dramatically . The patient had fully recovered without evidence of sequelae or recurrence at 2 years after operation. To the authors' knowledge, this is the first case in which a huge retroperitoneal germinoma presented as pathological fracture of the spine and spinal cord compression. The effectiveness of the postoperative cisplatin-based chemotherapy against this tumor made major retroperitoneal surgery to remove the main tumor mass unnecessary is also demonstrated.

https://pubmed.ncbi.nlm.nih.gov/12635842/

9238a8d50acf022196b0df5ab094dc79

The other received chemotherapy including prednisone , vincristine , cytarabine and L-asparaginase , combined with intrathecal injections of methotrexate , dexamethasone and Ara-C and supporting treatment .

[Renal tubular acidosis as an initial manifestation in children with malignant lymphoma]. Primary renal lymphoma is one of the malignant lymphomas that initially presents in the extra lymphonode, which is rarely seen in children. This study reported two cases of primary renal lymphoma in children who were definitively diagnosed by renal biopsy. Renal tubular acidosis was the initial manifestation in both cases. They were referred to the hospital with chief complaints of polydipsia, polyuria, debilitation, vomiting and anemia. Imaging and laboratory examinations showed bilateral renomegaly, hypocalcemia, hypophosphatemia, and metabolic acidosis. One of the patients discontinued therapy. The other received chemotherapy including prednisone , vincristine , cytarabine and L-asparaginase , combined with intrathecal injections of methotrexate , dexamethasone and Ara-C and supporting treatment . Twenty-three days after treatment, polydipsia and polyuria were relieved, and acidosis, kaliopenia and anemia were improved in the patient. There were no abnormal findings in the renal B-ultrasound re-examination. It was concluded that when a patient is suspected of renal lymphoma, diagnostic puncture and renal biopsy should be performed early. Early combined therapeutics including chemotherapy, radiation therapy, surgery and supporting treatments may result in a favorable prognosis in patients with this disease.

https://pubmed.ncbi.nlm.nih.gov/18706173/

6ed6398f293569b074c6a6cdf21d3160

Then , neoadjuvant chemotherapy ( NAC ) consisting of a combination of 5-fluorouracil ( 5-FU ) , oxaliplatin , irinotecan , and leucovorin ( FOLFOXIRI ) was planned , followed by primary tumor resection .

A pathological complete response after neoadjuvant triplet chemotherapy for locally advanced transverse colon cancer. Perioperative chemotherapy could improve oncological outcomes for patients with advanced colon cancer. However, the effectiveness of triplet chemotherapy in the neoadjuvant setting is still unknown. ### Presentation Of Case A 61-year-old man was referred to our hospital due to abdominal distention. Abdominal computed tomography showed a huge, 18-cm mass in the right upper abdomen. Biopsy showed well-differentiated adenocarcinoma. Locally advanced transverse colon cancer T4b N2a M0 Stage IIIC was diagnosed. Considering the extensive invasion to surrounding organs and difficulties in achieving margin-negative surgery, an emergency ileostomy was performed first. Then , neoadjuvant chemotherapy ( NAC ) consisting of a combination of 5-fluorouracil ( 5-FU ) , oxaliplatin , irinotecan , and leucovorin ( FOLFOXIRI ) was planned , followed by primary tumor resection . After 6 courses of treatment, the primary tumor shrank remarkably. Finally, laparoscopic radical extended right hemi-colectomy was performed. There were no residual tumor cells in resected specimens, including the primary tumor and surrounding lymph nodes. The pathological diagnosis was complete response. ### conclusion A case of pathological complete response after neoadjuvant treatment followed by radical resection was reported. Further research is needed to confirm the appropriate indications for neoadjuvant FOLFOXIRI therapy for patients with LACC.

https://pubmed.ncbi.nlm.nih.gov/32535526/

893a4fe9446abfbc8679233b84a42857

Interestingly , aspirin not only significantly inhibited the growth of TNBC cells , but also attenuated YAP and β-catenin expression by upregulating the E3 ubiquitin ligase β-TrCP to abolished docetaxel and vinorelbine resistance .

Aspirin attenuates YAP and β-catenin expression by promoting β-TrCP to overcome docetaxel and vinorelbine resistance in triple-negative breast cancer. The use of aspirin has been associated with reduced breast cancer risk, but it is litter known if aspirin overcomes chemoresistance in triple-negative breast cancer (TNBC). Herein, we demonstrated that changes in the expression of Yes-associated protein (YAP) and β-catenin might be a promising predictive biomarker for neoadjuvant chemotherapy sensitivity in TNBC patients. Inhibition of YAP or β-catenin enhanced the cytotoxicity of the anti-microtubule agents docetaxel and vinorelbine against drug-resistant TNBC cells as well as the sensitivity of these cells to the agents in vitro and in vivo. Interestingly , aspirin not only significantly inhibited the growth of TNBC cells , but also attenuated YAP and β-catenin expression by upregulating the E3 ubiquitin ligase β-TrCP to abolished docetaxel and vinorelbine resistance . The combination of aspirin and docetaxel or vinorelbine remarkably inhibited the growth of drug-resistant TNBC cells in vitro and in vivo. Moreover, TNBC patients with high YAP and/or β-catenin expression had a higher risk of relapse or mortality than patients with low YAP and/or β-catenin expression. Collectively, our study discovered a novel role of aspirin based on its anticancer effect, and put forward some possible mechanisms of chemoresistance in TNBC. The combined use of aspirin and anti-microtubule drugs presented several promising therapeutic approaches for TNBC treatment.

https://pubmed.ncbi.nlm.nih.gov/32661222/

933527b89d2e939d859d3827c6181476

No alterations in paclitaxel or doxorubicin pharmacokinetics were observed when the drugs were administered alone versus in combination .

Combination paclitaxel (Taxol) and doxorubicin therapy for metastatic breast cancer. paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) is a very active agent for the treatment of breast cancer, with associated complete response rates of 12% in patients with minimally pretreated metastatic disease. Simultaneous paclitaxel and doxorubicin administration by 72-hour continuous infusion in patients with previously untreated metastatic breast cancer has yielded an overall response rate of 72% with 8% complete responses. No alterations in paclitaxel or doxorubicin pharmacokinetics were observed when the drugs were administered alone versus in combination . Two phase I studies from the M.D. Anderson Cancer Center (Houston, TX) and the University of Indiana (Indianapolis, IN) have shown that administration of a 24-hour paclitaxel infusion prior to doxorubicin results in a significantly higher incidence of mucositis than the reverse sequence. Preliminary pharmacokinetic studies from M.D. Anderson suggest that peak plasma concentration and clearance of doxorubicin are altered by pretreatment with 24-hour paclitaxel. In contrast, in an ongoing phase I study at the Istituto Nazionale Tumori in Milan, Italy, no differences in toxicities have been observed with the combination of intravenous bolus doxorubicin and 3-hour infusional paclitaxel administered by either sequence. Preclinical in vitro and in vivo studies suggest that the combination of paclitaxel and doxorubicin is associated with no or minimal additive antitumor effects. The modest complete response rates that have been observed in patients with metastatic breast cancer to date are in agreement with these observations. A randomized study of paclitaxel versus doxorubicin versus intravenous bolus doxorubicin followed by 24-hour paclitaxel is now being conducted by the Eastern Cooperative Oncology Group.

https://pubmed.ncbi.nlm.nih.gov/7939757/

24dcd3973e994e04cedf76aea5968ffc

Twenty-seven received rituximab mainly in addition to high-dose cytarabine and etoposide ( n = 18 ) and/or ifosfamide , carboplatin , and etoposide ( n = 7 ) .

Outcome of relapse in children and adolescents with B-cell non-Hodgkin lymphoma and mature acute leukemia: A report from the French LMB study. In order to describe relapsed B-cell non-Hodgkin lymphoma and mature acute leukemia in children/adolescents treated with the Lymphomes Malins B (LMB) regimen and their outcome in the rituximab era, relapses in the French LMB2001 study were reviewed. ### methods Between February 2001 and December 2011, 33 patients out of 773 (4.3%) relapsed; 27 had Burkitt lymphoma and six large B-cell histology. Median age at diagnosis was 10.1 years. One patient was initially treated in risk group A, 21 in group B, and 11 in group C. ### results Median time to relapse after diagnosis was 4.5 months (range 2.4-13.6). Thirty-two patients received salvage therapy. Twenty-seven received rituximab mainly in addition to high-dose cytarabine and etoposide ( n = 18 ) and/or ifosfamide , carboplatin , and etoposide ( n = 7 ) . First-line salvage chemotherapy response rate was 66% with 47% being complete remission (CR). Twenty-one patients received high-dose chemotherapy (HDC) followed by autologous (n = 13) or allogeneic (n = 8) transplant. With a median follow-up of 6.8 years, the 5-year survival rate after relapse was 36.4% (95% confidence interval [CI] 22-53%). Twelve patients were still alive; all but one (group A) received consolidation treatment. Achieving CR before consolidation was significantly associated with better survival, with a 5-year survival rate of 75% (95% CI 46.8-91.1%) for patients in CR before HDC, 33% (95% CI 9.7-70%) for patients in partial remission, and 0% for nonresponders (P = .033). ### conclusion Survival of children/adolescents with mature B-cell lymphoma/leukemia remains poor after relapse with no apparent improvement with rituximab. Response rates to salvage chemo-immunotherapies are insufficient and new drugs are urgently needed to improve disease control.

https://pubmed.ncbi.nlm.nih.gov/31207026/

d1b822405fac9b02cb1858fa96693979

A significant reduction in plasma 8-isoprostane and oxLDL levels was observed in all treatment groups [ by 10 % , 8 % and 6 % ( p < 0.05 compared with baseline ) and 41 % , 40 % and 39 % ( p < 0.001 compared with baseline ) in simvastatin , simvastatin/ezetimibe and rosuvastatin groups , respectively ] .

Comparison of the effect of simvastatin versus simvastatin/ezetimibe versus rosuvastatin on markers of inflammation and oxidative stress in subjects with hypercholesterolemia. Statins may exhibit anti-inflammatory and antioxidant effects. Whether different statins at equivalent doses or the combination of low-dose statin with ezetimibe have comparable anti-inflammatory and antioxidant effects is unknown. The aim of this study was to compare the effects of simvastatin, simvastatin/ezetimibe or rosuvastatin at equivalent low-density lipoprotein cholesterol lowering doses on inflammation and oxidative stress indices in subjects with hypercholesterolemia. ### methods This was a pre-specified analysis of a prospective, randomized, open-label, blinded endpoint (PROBE) study. We enrolled one hundred and fifty three (n = 153) hypercholesterolemic subjects who were randomized to receive simvastatin 40 mg or simvastatin/ezetimibe 10/10 mg or rosuvastatin 10 mg daily. Plasma 8-Epi prostaglandin F2 alpha (8-epiPGF2a), oxidized LDL (oxLDL) and lipoprotein-associated phospholipase A2 (Lp-PLA2) activity and mass were measured at baseline and following 12 weeks of treatment. ### results A significant reduction in plasma 8-isoprostane and oxLDL levels was observed in all treatment groups [ by 10 % , 8 % and 6 % ( p < 0.05 compared with baseline ) and 41 % , 40 % and 39 % ( p < 0.001 compared with baseline ) in simvastatin , simvastatin/ezetimibe and rosuvastatin groups , respectively ] . In all treatment groups a significant reduction in total plasma Lp-PLA2 activity and mass was observed (by 36%, 31% and 38% and 36%, 32% and 32% for simvastatin, simvastatin/ezetimibe and rosuvastatin, respectively, p < 0.001 compared with baseline). No intergroup differences were observed. ### conclusions simvastatin 40 mg, simvastatin/ezetimibe 10/10 mg and rosuvastatin 10 mg significantly reduced 8-epiPGF2a, oxLDL and Lp-PLA2 activity and mass to a similar extent.

https://pubmed.ncbi.nlm.nih.gov/24125402/

780f78a0170826430ef2034760acb82d

Both mono and combination therapies achieved the primary efficacy parameters : lowered diastolic blood pressure ( at trough ) more than placebo , p < 01 ( except the 120 mg verapamil SR , NS , 0.5 mg trandolapril , 0.5/180 and 2/120 combinations , p < 05 ) , yielded a trough to peak ratio of > 0.52 and had higher percentages of responders compared to placebo .

Efficacy of combination therapy with trandolapril and verapamil sr in primary hypertension: a 4 x 4 trial design. The Trandolapril Study Group. The Joint National Committee V suggested that combination therapy can provide effective blood pressure control in patients with stage I-IV hypertension. This 4 x 4 factorial trial design assessed the efficacy of monotherapy with trandolapril-an ACE inhibitor, and verapamil SR-a calcium antagonist, each in a range of 3 doses as monotherapy, and in combination therapy in patients with stage I-III diastolic hypertension. After a 4-week, single-blind placebo treatment period, 746 patients in 39 study centers were randomized to 1 of the 16 double-blind treatments for 6 weeks (placebo, verapamil SR monotherapy 120, 180, or 240 mg; trandolapril monotherapy 0.5, 2, or 8 mg; and trandolapril/verapamil SR combinations 0.5/120, 0.5/180, 0.5/240, 2/120, 2/180, 2/240, 8/120, 8/180, or 8/240 mg. Both mono and combination therapies achieved the primary efficacy parameters : lowered diastolic blood pressure ( at trough ) more than placebo , p < 01 ( except the 120 mg verapamil SR , NS , 0.5 mg trandolapril , 0.5/180 and 2/120 combinations , p < 05 ) , yielded a trough to peak ratio of > 0.52 and had higher percentages of responders compared to placebo . Combination therapy was more effective than monotherapy for sitting diastolic blood pressure 2/180, p < 01; 2/240 and 8/240, p < 05. There were no differences between active treatment groups and placebo as a percentage of patients having adverse reactions. trandolapril, 2 and 8 mg, appeared to have a greater incremental effect on the systolic blood pressure reduction of the combination than verapamil SR 180 and 240 mg.

https://pubmed.ncbi.nlm.nih.gov/9107443/

2b6693d5c27ba14a8015f09d746854cd

In metastastic patients , the combination of gemcitabine and cisplatin has become the new standard regimen due to a lower toxicity in comparison to the combination of methotrexate , vinblastine , doxorubicin , and cisplatin ( MVAC ) .

[Neoadjuvant or Adjuvant Chemotherapy for Bladder Cancer?]. Advanced urothelial carcinoma of the bladder is associated with a high metastatic potential. Life expectancy for metastatic patients is poor and rarely exceeds more than one year without further therapy. Neoadjuvant chemotherapy can decrease the tumour burden while reducing the risk of death. Adjuvant chemotherapy has been discussed controversially. Patients with lymph node-positive metastases seem to benefit the most from adjuvant chemotherapy. In selected patients, metastasectomy can prolong survival. In metastastic patients , the combination of gemcitabine and cisplatin has become the new standard regimen due to a lower toxicity in comparison to the combination of methotrexate , vinblastine , doxorubicin , and cisplatin ( MVAC ) . For second-line treatment, vinflunine is the only approved therapeutic agent.

https://pubmed.ncbi.nlm.nih.gov/26077309/

d5d8fcd01d8db1d9d3739da1219f562a

In the last few years , a flurry of new and more potent ALK inhibitors has emerged for the treatment of ALK-positive NSCLC , including ceritinib ( LDK378 ) , alectinib ( RO5424802/CH5424802 ) , AP26113 , ASP3026 , TSR-011 , PF-06463922 , RXDX-101 , X-396 , and CEP-37440 .

ALK inhibitors in non-small cell lung cancer: crizotinib and beyond. The treatment of patients with advanced non-small cell lung cancer (NSCLC) harboring chromosomal rearrangements of anaplastic lymphoma kinase (ALK) has been revolutionized by the development of crizotinib, a small molecule inhibitor of the tyrosine kinases ALK, ROS1, and MET. Resistance to crizotinib invariably develops, however, through a variety of mechanisms. In the last few years , a flurry of new and more potent ALK inhibitors has emerged for the treatment of ALK-positive NSCLC , including ceritinib ( LDK378 ) , alectinib ( RO5424802/CH5424802 ) , AP26113 , ASP3026 , TSR-011 , PF-06463922 , RXDX-101 , X-396 , and CEP-37440 . Cancers harboring ALK rearrangements may also be susceptible to treatment with heat shock protein 90 inhibitors. This review focuses on the pharmacologic and clinical properties of these compounds, either as monotherapies or in combination with other drugs. With so many ALK inhibitors in development, the challenges of how these agents should be studied and ultimately prescribed are also discussed.

https://pubmed.ncbi.nlm.nih.gov/25322323/

b5a06ce3b2c6a8e918a9ac3c2ff81e10

A randomized clinical trial of adjuvant chemotherapy with doxorubicin , ifosfamide , and cisplatin followed by radiotherapy versus radiotherapy alone in patients with localized uterine sarcomas ( SARCGYN study ) .

A randomized clinical trial of adjuvant chemotherapy with doxorubicin , ifosfamide , and cisplatin followed by radiotherapy versus radiotherapy alone in patients with localized uterine sarcomas ( SARCGYN study ) . There is no proven benefit of adjuvant treatment of uterine sarcoma (US). SARCGYN phase III study compared adjuvant polychemotherapy followed by pelvic radiotherapy (RT) (arm A) versus RT alone (arm B) conducted to detect an increase ≥ 20% of 3-year PFS. ### methods Patients with FIGO stage ≤ III US, physiological age ≤ 65 years; chemotherapy: four cycles of doxorubicin 50 mg/m&sup2; d1, ifosfamide 3 g/m&sup2;/day d1-2, cisplatin 75 mg/m&sup2; d3, (API) + G-CSF q 3 weeks. Study was stopped because of lack of recruitment. ### results Eighty-one patients were included: 39 in arm A and 42 in arm B; 52 stage I, 16 stage II, 13 stage III; 53 leiomyosarcomas, 9 undifferenciated sarcomas, 19 carcinosarcomas. Gr 3-4 toxicity during API (/37 patients): thrombopenia (76%), febrile neutropenia (22%) with two toxic deaths; renal gr 3 (1 patient). After a median follow-up of 4.3 years, 41/81 patients recurred, 15 in arm A, 26 in arm B. The 3 years DFS is 55% in arm A, 41% in arm B (P = 0.048). The 3-year overall survival (OS) is 81% in arm A and 69% in arm B (P = 0.41). ### conclusion API adjuvant CT statistically increases the 3 year-DFS of patients with US.

https://pubmed.ncbi.nlm.nih.gov/23139262/

3af3c8177f3067d578e6e60e026f8a52

Combination therapy with irinotecan ( CPT-11 ) , 5-fluorouracil ( 5-FU ) and leucovorin is widely used for the treatment of metastatic colorectal cancer .

Pharmacodynamic study of the Saltz regimen for metastatic colorectal cancer in a hemodialyzed patient. Combination therapy with irinotecan ( CPT-11 ) , 5-fluorouracil ( 5-FU ) and leucovorin is widely used for the treatment of metastatic colorectal cancer . However, little is known about the safety of chemotherapy of malignancies in hemodialysis (HD) patients. We encountered a patient with colorectal carcinoma on HD. We decided to administer combination chemotherapy while monitoring the pharmacodynamics of the patient. ### Case Report A 74-year-old male received regular HD 3 times a week because of type 1 diabetes mellitus. He was diagnosed with stage IV colorectal cancer in November 2004. After sigmoidectomy, the patient received chemotherapy: a weekly schedule of CPT-11 (50 mg/m(2)) was administered followed by l-leucovorin (10 mg/m(2)) and 5-FU (400 mg/m(2)) just after HD. During the course, the plasma concentrations of both SN-38, an active metabolite of CPT-11, and 5-FU were not increased compared with those of patients with normal renal function. Our patient presented with grade III hematological toxicity that was easily recovered by granulocyte colony-stimulating factor. ### conclusion These data suggest that the dose-reduced Saltz regimen can be feasible for colorectal cancer patients receiving dialysis as postoperative adjuvant chemotherapy.

https://pubmed.ncbi.nlm.nih.gov/17952001/

0b47114f991a5b292f543492d5a64fad

Long-term safety and outcome of fludarabine , cyclophosphamide and mitoxantrone ( FCM ) regimen in previously untreated patients with advanced follicular lymphoma : 12 years follow-up of a phase 2 trial .

Long-term safety and outcome of fludarabine , cyclophosphamide and mitoxantrone ( FCM ) regimen in previously untreated patients with advanced follicular lymphoma : 12 years follow-up of a phase 2 trial . fludarabine combinations are very affective in follicular lymphoma (FL) with high rates of complete response and prolonged survival. However, late toxicities could be a concern. The aim of the present study was to analyze the long-term impact on survival, relapse and late toxicities of a trial of treatment with fludarabine, mitoxantrone and cyclophosphamide (FCM regimen) for untreated patients with advanced stage FL. One hundred and twenty patients enrolled in a phase 2 trial of treatment with FCM regimen between 2000 and 2003 were evaluated. After a median follow-up of 12 years, 52 patients eventually relapsed/progressed with 10 year progression-free survival (PFS) of 46 %. Ten patients showed histological transformation to aggressive lymphoma with a risk of transformation of 2 and 9 % at 5 and 10 years, respectively. Three patients developed therapy-related myelodysplastic syndrome/acute myeloid leukaemia (MDS/AML) and seven solid neoplasms with an overall risk of 3 and 8 % at 5 and 10 years, respectively. Twenty-six patients eventually died during the follow-up. Overall survival at 10 years was 83 %. In conclusion, FCM regimen allows excellent long-lasting response in previously untreated patients with FL. The incidence of late events including histological transformation and secondary neoplasia is low but not negligible.

https://pubmed.ncbi.nlm.nih.gov/28101592/

faf925d887ed6a4e48d9695fbf094b0e

After clinical improvement under vemurafenib monotherapy , four cycles of ipilimumab were additionally administered .

18F-FDG PET/CT longitudinal studies in patients with advanced metastatic melanoma for response evaluation of combination treatment with vemurafenib and ipilimumab. Sixteen BRAF-mutation positive, metastatic melanoma patients with highly advanced disease received combination therapy of vemurafenib and ipilimumab as an individual treatment decision. Our aim was to assess the role of fluorine-18-fluorodeoxyglucose (F-FDG) PET/computed tomography (PET/CT) in the evaluation of the clinical benefit (CB) of this combination treatment. After clinical improvement under vemurafenib monotherapy , four cycles of ipilimumab were additionally administered . F-FDG PET/CT was performed before the start, after two cycles and after completion of the combined ipilimumab/vemurafenib treatment. PET-based patient response evaluation to treatment was based on the European Organization for Research and Treatment of Cancer and the PET Response Evaluation Criteria for Immunotherapy criteria. Progression-free survival (PFS) from the end of combination treatment was calculated. According to their best clinical response at the end of combination treatment, eight patients showed CB and eight patients had no-CB. Two patients revealed extraordinary good clinical outcome with PFS of more than 5 years. Overall, 13 out of 16 patients were correctly classified by the European Organization for Research and Treatment of Cancer and 15 out of 16 by the PET Response Evaluation Criteria for Immunotherapy criteria. Median PFS was 8.8 months among PET-responders and 3.6 months among nonresponders. During immunotherapy administration seven patients developed radiologic signs of immune-related adverse events (irAEs), with colitis and arthritis being the most frequent ones; these patients had a significantly longer PFS than those without irAEs (P=0.036). F-FDG PET/CT is a valuable tool for the evaluation of patients receiving a combination of targeted treatment and immunotherapy. The appearance of irAEs on PET/CT might correlate with benefit to immunotherapy.

https://pubmed.ncbi.nlm.nih.gov/30653029/

2280600696c1c1d4dfb49c7feb372ecd

Bevacizumab plus paclitaxel versus bevacizumab plus capecitabine as first-line treatment for HER2-negative metastatic breast cancer ( TURANDOT ): primary endpoint results of a randomised , open-label , non-inferiority , phase 3 trial .

Bevacizumab plus paclitaxel versus bevacizumab plus capecitabine as first-line treatment for HER2-negative metastatic breast cancer ( TURANDOT ): primary endpoint results of a randomised , open-label , non-inferiority , phase 3 trial . The randomised phase 3 TURANDOT trial compared two approved bevacizumab-containing regimens for HER2-negative metastatic breast cancer in terms of efficacy, safety, and quality of life. The interim analysis did not confirm non-inferior overall survival (stratified hazard ratio [HR] 1·04; 97·5% repeated CI [RCI] -∞ to 1·69). Here we report final results of our study aiming to show non-inferior overall survival with first-line bevacizumab plus capecitabine versus bevacizumab plus paclitaxel for locally recurrent or metastatic breast cancer. ### methods In this multinational, open-label, randomised phase 3 TURANDOT trial, patients aged 18 years or older who had an Eastern Cooperative Oncology Group performance status 0-2 and measurable or non-measurable HER2-negative locally recurrent or metastatic breast cancer who had received no previous chemotherapy for locally recurrent or metastatic breast cancer were stratified and randomly assigned (1:1) using permuted blocks of size six to either bevacizumab plus paclitaxel (bevacizumab 10 mg/kg on days 1 and 15 plus paclitaxel 90 mg/m(2) on days 1, 8, and 15 every 4 weeks) or bevacizumab plus capecitabine (bevacizumab 15 mg/kg on day 1 plus capecitabine 1000 mg/m(2) twice daily on days 1-14 every 3 weeks) until disease progression, unacceptable toxicity, or withdrawal of consent. Stratification factors were oestrogen or progesterone receptor status, country, and menopausal status. The primary objective was to show non-inferior overall survival with bevacizumab plus capecitabine versus bevacizumab plus paclitaxel in the per-protocol population by rejecting the null hypothesis of inferiority (HR ≥1·33) using a stratified Cox proportional hazard model. This trial is registered with ClinicalTrials.gov, number NCT00600340. ### findings Between Sept 10, 2008, and Aug 30, 2010, 564 patients were randomised, representing the intent-to-treat population. The per-protocol population comprised 531 patients (266 in the bevacizumab plus paclitaxel group and 265 in the bevacizumab plus capecitabine group). At the final overall survival analysis after 183 deaths (69%) in 266 patients receiving bevacizumab plus paclitaxel and 201 (76%) in 265 receiving bevacizumab plus capecitabine in the per-protocol population, median overall survival was 30·2 months (95% CI 25·6-32·6 months) versus 26·1 months (22·3-29·0), respectively. The stratified HR was 1·02 (97·5% RCI -∞ to 1·26; repeated p=0·0070), indicating non-inferiority. The unstratified Cox model (HR 1·13 [97·5% RCI -∞ to 1·39]; repeated p=0·061) did not support the primary analysis. Intent-to-treat analyses were consistent with the per-protocol results. The most common grade 3 or worse adverse events were neutropenia (54 [19%] of 284 patients in the bevacizumab plus paclitaxel group vs 5 [2%] of 277 patients in the bevacizumab plus capecitabine group), hand-foot syndrome (1 [<1%] vs 43 [16%]), peripheral neuropathy (39 [14%] vs 1 [<1%]), leucopenia (20 [7%] vs 1 [<1%]), and hypertension (12 [4%] vs 16 [6%]). Serious adverse events were reported in 65 (23%) of 284 patients receiving bevacizumab plus paclitaxel and 68 (25%) of 277 receiving bevacizumab plus capecitabine. Deaths in two (1%) of 284 patients in the bevacizumab plus paclitaxel group were deemed by the investigator to be treatment-related. No treatment-related deaths occurred in the bevacizumab plus capecitabine group. ### interpretation bevacizumab plus capecitabine represents a valid first-line treatment option for HER2-negative locally recurrent or metastatic breast cancer, offering good tolerability without compromising overall survival compared with bevacizumab plus paclitaxel. Although progression-free survival with the bevacizumab plus capecitabine combination is inferior to that noted with bevacizumab plus paclitaxel, we suggest that physicians should consider possible predictive risk factors for overall survival, individual's treatment priorities, and the differing safety profiles. ### funding Roche.

https://pubmed.ncbi.nlm.nih.gov/27501767/

bd92e7ffac8bd34d9b66848f322ec216

She underwent rectectomy and adjuvant chemotherapy with fluorouracil , leucovorin plus oxaliplatin for stage IIIB rectal cancer .

Esophageal Metastasis from Rectal Cancer Successfully Treated with Fluorouracil-Based Chemotherapy with Bevacizumab: A Case Report and Review of the Literature. Esophageal metastasis from colorectal carcinoma is uncommon, and diagnosis of esophageal metastasis is difficult. We report a case of a 54-year-old woman with postoperative recurrence of rectal cancer metastasizing to the esophagus. She underwent rectectomy and adjuvant chemotherapy with fluorouracil , leucovorin plus oxaliplatin for stage IIIB rectal cancer . Three years later, she presented with dysphagia and cough. Computed tomography showed thickening of the esophagus wall, enlargement of the lymph nodes in the mediastinum and abdomen, and ground-glass opacities in the right lung. Endoscopy revealed a submucosal tumor of the midthoracic esophagus. Histopathological analysis of the tumor biopsy showed infiltration of adenocarcinoma cells into the stroma of the esophagus; tumor cells were positive for caudal type homeobox 2 and negative for thyroid transcription factor 1. A transbronchial biopsy indicated pulmonary lymphangitic carcinomatosis of rectal adenocarcinoma. Based on those findings, she was diagnosed with recurrent rectal cancer. She received fluorouracil-based chemotherapy plus bevacizumab, which ameliorated her symptoms and induced a durable response without severe adverse events. Diagnosis of esophageal metastasis from rectal cancer can thus be made by repeated biopsy. Furthermore, aggressive systemic treatment with fluorouracil-containing chemotherapy and bevacizumab is a treatment option for colorectal cancer patients with esophageal metastasis.

https://pubmed.ncbi.nlm.nih.gov/28626398/

b3a8d61ce1a9282b5cf5c5a4d0f54a18

We designed this phase II trial to evaluate the safety , tolerability , and efficacy of the combination of carboplatin , paclitaxel , cetuximab , and bevacizumab in chemotherapy-naive patients with advanced , nonsquamous NSCLC .

Phase II trial of carboplatin, paclitaxel, cetuximab, and bevacizumab followed by cetuximab and bevacizumab in advanced nonsquamous non-small-cell lung cancer: SWOG S0536. cetuximab and bevacizumab have each been demonstrated to prolong survival when added to chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC). However, the potential benefit of combining cetuximab and bevacizumab together with a platinum-based doublet had not been explored. We designed this phase II trial to evaluate the safety , tolerability , and efficacy of the combination of carboplatin , paclitaxel , cetuximab , and bevacizumab in chemotherapy-naive patients with advanced , nonsquamous NSCLC . ### methods Patients received with up to six cycles of carboplatin (area under curve 6), paclitaxel (200 mg/m(2)), cetuximab (400 mg/m(2) day 1 then 250 mg/m(2) weekly), and bevacizumab (15 mg/kg) every 21 days. Patients with an objective response or stable disease received maintenance cetuximab (250 mg/m(2) weekly) and bevacizumab (15 mg/kg every 21 days) until disease progression. The primary endpoint was safety as defined by the frequency and severity of hemorrhagic toxicities. Secondary endpoints included response rate, progression-free survival, overall survival, and toxicity. Molecular biomarkers were assessed in an exploratory manner. ### results The primary endpoint of grade 4 or higher hemorrhage of 2% (95% confidence interval: 0%-7%) met prespecified criteria for safety. One hundred ten patients were enrolled. There were four treatment-related deaths including lung hemorrhage (2), infection (1), and unknown (1). Median progression-free survival was 7 months and median overall survival was 15 months. The response rate was 56% with an overall disease control rate of 77%. ### conclusion This regimen was safe, feasible, and effective as a frontline treatment of advanced NSCLC, providing the basis for the ongoing phase III trial S0819.

https://pubmed.ncbi.nlm.nih.gov/24189513/

5f47b0d8abbede477b693d64fb8dd329

All patients underwent mexiletine monotherapy ( M-mono ) , propafenone monotherapy ( P-mono ) , low dose combination therapy ( low M+P ) , and full dose combination therapy ( full M+P ) .

Mexiletine and propafenone: a comparative study of monotherapy, low, and full dose combination therapy. The electrophysiological effects of combination therapy of mexiletine and propafenone were assessed using standard 12-lead electrocardiogram (standard ECG), signal-averaged ECG (SAECG), and ambulatory ECG in 31 patients with ventricular arrhythmias. All patients underwent mexiletine monotherapy ( M-mono ) , propafenone monotherapy ( P-mono ) , low dose combination therapy ( low M+P ) , and full dose combination therapy ( full M+P ) . Full M+P increased the PQ interval and QRS duration to the same extent as P-mono did. Low M+P increased PQ interval and QRS duration to a lesser extent than P-mono and full M+P did. P-mono and full M+P significantly decreased root mean square (RMS) and increased f-QRS in SAECG, while M-mono and low M+P showed only a weak trend. SAECGs with late potentials increased in number with treatments; 9 in predrug control, 11 on M-mono, 15 on P-mono, 10 on low M+P, and 14 on full M+P. The percent suppression of frequent premature ventricular contractions (PVCs) (> 1,000/day) with M-mono, P-mono, low M+P, and full M+P were 46.4 +/- 9.0, 56.6 +/- 10.4, 64.4 +/- 9.2, and 71.4 +/- 7.1, respectively, and those of frequent couplets (> 10/day) were 58.3 +/- 17.7, 62.6 +/- 23.6, 87.5 +/- 6.2, and 92.1 +/- 4.0, respectively. Thus, full dose combination of mexiletine and propafenone exhibited the maximum antiarrhythmic efficacy without enhancement of effects on standard ECG and SAECG. Low dose combination therapy showed better antiarrhythmic efficacy in association with lesser effects on standard ECG and SAECG compared with propafenone monotherapy.

https://pubmed.ncbi.nlm.nih.gov/1279613/

d531c7b35a8bc9c67dad085ae9b7d352

Cephalexin , 500 mg 4 times daily , plus trimethoprim-sulfamethoxazole , 320 mg/1600 mg twice daily , for 7 days ( n = 248 participants ) or cephalexin plus placebo for 7 days ( n = 248 participants ) .

Effect of Cephalexin Plus Trimethoprim-Sulfamethoxazole vs Cephalexin Alone on Clinical Cure of Uncomplicated Cellulitis: A Randomized Clinical Trial. Emergency department visits for skin infections in the United States have increased with the emergence of methicillin-resistant Staphylococcus aureus (MRSA). For cellulitis without purulent drainage, β-hemolytic streptococci are presumed to be the predominant pathogens. It is unknown if antimicrobial regimens possessing in vitro MRSA activity provide improved outcomes compared with treatments lacking MRSA activity. ### objective To determine whether cephalexin plus trimethoprim-sulfamethoxazole yields a higher clinical cure rate of uncomplicated cellulitis than cephalexin alone. ### Design Setting And Participants Multicenter, double-blind, randomized superiority trial in 5 US emergency departments among outpatients older than 12 years with cellulitis and no wound, purulent drainage, or abscess enrolled from April 2009 through June 2012. All participants had soft tissue ultrasound performed at the time of enrollment to exclude abscess. Final follow-up was August 2012. ### interventions Cephalexin , 500 mg 4 times daily , plus trimethoprim-sulfamethoxazole , 320 mg/1600 mg twice daily , for 7 days ( n = 248 participants ) or cephalexin plus placebo for 7 days ( n = 248 participants ) . ### Main Outcomes And Measures The primary outcome determined a priori in the per-protocol group was clinical cure, defined as absence of these clinical failure criteria at follow-up visits: fever; increase in erythema (>25%), swelling, or tenderness (days 3-4); no decrease in erythema, swelling, or tenderness (days 8-10); and more than minimal erythema, swelling, or tenderness (days 14-21). A clinically significant difference was defined as greater than 10%. ### results Among 500 randomized participants, 496 (99%) were included in the modified intention-to-treat analysis and 411 (82.2%) in the per-protocol analysis (median age, 40 years [range, 15-78 years]; 58.4% male; 10.9% had diabetes). Median length and width of erythema were 13.0 cm and 10.0 cm. In the per-protocol population, clinical cure occurred in 182 (83.5%) of 218 participants in the cephalexin plus trimethoprim-sulfamethoxazole group vs 165 (85.5%) of 193 in the cephalexin group (difference, -2.0%; 95% CI, -9.7% to 5.7%; P = .50). In the modified intention-to-treat population, clinical cure occurred in 189 (76.2%) of 248 participants in the cephalexin plus trimethoprim-sulfamethoxazole group vs 171 (69.0%) of 248 in the cephalexin group (difference, 7.3%; 95% CI, -1.0% to 15.5%; P = .07). Between-group adverse event rates and secondary outcomes through 7 to 9 weeks, including overnight hospitalization, recurrent skin infections, and similar infection in household contacts, did not differ significantly. ### Conclusions And Relevance Among patients with uncomplicated cellulitis, the use of cephalexin plus trimethoprim-sulfamethoxazole compared to cephalexin alone did not result in higher rates of clinical resolution of cellulitis in the per-protocol analysis. However, because imprecision around the findings in the modified intention-to-treat analysis included a clinically important difference favoring cephalexin plus trimethoprim-sulfamethoxazole, further research may be needed. ### Trial Registration clinicaltrials.gov Identifier: NCT00729937.

https://pubmed.ncbi.nlm.nih.gov/28535235/

77e0b10b4077f694602171ec11b8fbad

In the NALA trial , neratinib plus capecitabine led to increased PFS and time to intervention for central nervous system disease over the standard regimen of lapatinib plus capecitabine .

Neratinib plus capecitabine for the treatment of advanced HER2-positive breast cancer. Several agents are being developed for advanced HER2-positive breast cancer, such as potent tyrosine kinase inhibitors (TKI) targeting ErbB family receptors, novel antibody-drug conjugates, higher affinity anti-HER2 antibodies, among others. neratinib is an irreversible pan-HER (EGFR, ERBB2, and ERBB4) TKI being tested in early and advanced HER2-positive breast cancer. In the NALA trial , neratinib plus capecitabine led to increased PFS and time to intervention for central nervous system disease over the standard regimen of lapatinib plus capecitabine . The main adverse event in the neratinib arm was diarrhea, which mandates for prophylactic treatment with loperamide. ### Areas Covered In this review, we analyze and discuss preclinical and clinical data with neratinib plus capecitabine. We summarize efficacy and safety results from phase I/II and III trials, and discuss this regimen within the landscape of treatment for patients with HER2-positive metastatic breast cancer progressing after two lines of HER2-directed treatment. ### Expert Opinion neratinib plus capecitabine is a valid treatment option for patients with advanced HER2-positive breast cancer, after progression to at least two anti-HER2-based regimens. Given the multiple options that are being developed in this context, efforts should be employed to establish strong predictive biomarkers of efficacy to each drug and combination.

https://pubmed.ncbi.nlm.nih.gov/32862744/

4a18483d052bd05090b82ed366d8e395

Since the patient had anemia , aspirin and cilostazol were discontinued after diagnosis .

[A Case of Ascending Colon Cancer with Essential Thrombocythemia]. Essential thrombocythemia(ET)is a rare myeloproliferative disorder characterized by thrombocytosis and a risk of thrombotic and hemorrhagic events. ET rarely occurs simultaneously with colorectal cancer. Including our case, only 5 cases of c o l orectal cancer with ET have been reported in Japan. Herein, we report a case of colon cancer in an ET patient who underwent laparoscopic right hemicolectomy. Our perioperative management avoided complications such as thrombosis or bleeding. An 81-year-old woman developed bloody stools. She was previously diagnosed with ET 9 years ago. aspirin, cilostazol, and hydroxyurea(HU)were prescribed. Colonoscopy revealed a tumor at the ascending colon. Histopathological examination showed a well-differentiated tubular adenocarcinoma. Since the patient had anemia , aspirin and cilostazol were discontinued after diagnosis . HU was discontinued from the day before surgery to 2 days after surgery. enoxaparin was subcutaneously administered for 1 to 3 days after surgery. aspirin and cilostazol were resumed on the fourth day post-surgery. The patient could be discharged when her condition stabilizes with no thrombosis and bleeding after 8 days.

https://pubmed.ncbi.nlm.nih.gov/33468948/

f53ebc5049fa66cd3aa251a61ce9a16d

This case report describes a patient with O-NHL which was possibly linked to the combination of methotrexate and etanercept for the treatment of her rheumatoid arthritis .

Oral non-Hodgkin's lymphoma in a patient with rheumatoid arthritis treated with etanercept and methotrexate. Oral non-Hodgkin's lymphomas (O-NHLs) are a rare group of diverse lymphoid tissue malignancies and represent less than 5% of the oral cavity malignancies and 2% of all extra-nodal NHLs. Oral-NHLs affect the Waldeyer's-ring, the salivary glands, the bone of the jaws and the oral mucosa, their clinical appearance is very heterogeneous. Among the risk factors for NHLs are immunosuppression (primary or secondary), autoimmunity and inflammation. O-NHLs share the same risk factors. This case report describes a patient with O-NHL which was possibly linked to the combination of methotrexate and etanercept for the treatment of her rheumatoid arthritis . To our knowledge this is probably among the first cases of O-NHL with possible relation to the use of a Tumor Necrosis Factor (TNF) antagonist biological agent (etanercept). This case could contribute to the sensitization of the dentists for the signs and symptoms of this rare malignancy. It also underlines the need for thorough medical history and medication recording for all the dental patients. Key words:Lymphoma (oral) methotrexate, etanercept.

https://pubmed.ncbi.nlm.nih.gov/25810835/

2385bbe94c2fcb3c8d02c68a6e685707

In a prospective , pragmatic , randomised , parallel group study , 170 patients of mean ( SD ) age 37 ( 12 ) years with acute asthma ( peak expiratory flow ( PEF ) 212 ( 80 ) l/min ) presenting to hospital received treatment with either high dose prednisolone and continuous nebulised salbutamol as recommended in the US or lower dose prednisolone and bolus nebulised salbutamol as recommended in the UK by the BTS .

Randomised pragmatic comparison of UK and US treatment of acute asthma presenting to hospital. Systemic corticosteroids and inhaled beta(2) agonists are accepted first line treatments for acute severe asthma, but there is no consensus on their optimum dosage and frequency of administration. American regimens include higher initial dosages of beta(2) agonists and corticosteroids than UK regimens. ### methods In a prospective , pragmatic , randomised , parallel group study , 170 patients of mean ( SD ) age 37 ( 12 ) years with acute asthma ( peak expiratory flow ( PEF ) 212 ( 80 ) l/min ) presenting to hospital received treatment with either high dose prednisolone and continuous nebulised salbutamol as recommended in the US or lower dose prednisolone and bolus nebulised salbutamol as recommended in the UK by the BTS . ### results Outcome measures were: deltaPEF at 1 hour (BTS 89 l/min, US 106 l/min, p=0.2, CI -8 to 41) and at 2 hours (BTS 49 l/min, US 101 l/min, p<0.0001, CI 28 to 77); time to discharge if admitted (BTS 4 days, US 4 days); rates of achieving discharge PEF (>60%) at 2 hours (BTS 64%, US 78%, p=0.04); time to regain control of asthma as measured by PEF >/=80% best with salbutamol leads to a greater immediate improvement in PEF but the degree of recovery at 24 hours and speed of recovery thereafter is achieved as effectively with lower corticosteroid doses as recommended in the British guidelines.

https://pubmed.ncbi.nlm.nih.gov/12454298/

e4e7a7e096b8a824afdb91ec6603eba7

We report a case of a 78-year-old white male ( weight , 90 kg ) presented to the Department of Medical Oncology and Hematology , Istituto Clinico Humanitas , Rozzano , Milan , Italy , with refractory MM immunoglobulin G kappa ( IgGkappa ) , Durie-Salmon Stage IIA , with progressive renal failure after an oral melphalan , prednisone , and thalidomide regimen ( 4 mg/m2.d , 40 mg/m2.d for 7 days every 6 weeks , and 100 mg/d , respectively ) .

Bortezomib-dexamethasone combination in a patient with refractory multiple myeloma and impaired renal function. Multiple myeloma (MM) is a hematologic neoplasia characterized by the monoclonal proliferation of bone marrow plasma cells. Renal failure occurs in 20% to 30% of MM patients at diagnosis and in >50% with an advanced form of the disease. For those with advanced MM, often a high-risk group of patients with poor prognosis, salvage treatment for renal failure needs to avoid nephrotoxic drugs. ### Case Summary We report a case of a 78-year-old white male ( weight , 90 kg ) presented to the Department of Medical Oncology and Hematology , Istituto Clinico Humanitas , Rozzano , Milan , Italy , with refractory MM immunoglobulin G kappa ( IgGkappa ) , Durie-Salmon Stage IIA , with progressive renal failure after an oral melphalan , prednisone , and thalidomide regimen ( 4 mg/m2.d , 40 mg/m2.d for 7 days every 6 weeks , and 100 mg/d , respectively ) . The patient had documented increments of serum monoclonal component (M-protein), anemia, and renal failure with Bence Jones proteinuria (serum creatinine, 2.9 mg/dL; creatinine clearance, 30 mL/min; hemoglobin, 10.9 g/dL; serum IgGkappa M-protein, 3.9 g/dL; proteinuria 3.5 g/d;light-chain level in urine, 1.2 g/L). After 2 cycles with bortezomib at a reduced dose (1.0 mg/m2 twice weekly for 2 weeks followed by a 10-day rest period) to evaluate tolerability and renal toxicity, the patient completed another 3 cycles at the standard dose (1.3 mg/m2) in combination with dexamethasone (20 mg on the day of bortezomib administration and the day after). This led to an improvement of the renal function with a reduction of serum and urinary M-protein (serum creatinine 1.4 mg/dL; serum IgGkappa M-protein, 2.9 g/dL; proteinuria, 2 g/d; kappa light-chain level in urine, 0.7 g/L). The patient developed thrombocytopenia but did not suffer from some of the more severe adverse events associated with bortezomib, such as infection or peripheral neuropathy, even at full dose. ### conclusion We report an elderly patient with refractory MM and progression with renal failure who responded to bortezomib treatment. bortezomib was well tolerated in this patient.

https://pubmed.ncbi.nlm.nih.gov/16860177/

15b396da057bf3eb9a6ad966cb34cf79

Following an intravitreal injection of ranibizumab , off-label administration of intravitreal dexamethasone was considered to reduce the edema .

Effect of intravitreal dexamethasone on macular edema in von Hippel-Lindau disease assessed using swept-source optical coherence tomography: a case report. Von Hippel-Lindau disease is a rare hereditary syndrome caused by germinal mutations in a von Hippel-Lindau tumor-suppressing gene. Retinal hemangioblastoma is the ocular hallmark lesion of von Hippel-Lindau disease. ### Case Presentation A 20-year-old Caucasian woman presented to our institution with painless visual impairment in the right eye. A fundus ophthalmoscopic evaluation and swept-source optical coherence tomographic examination revealed a retinal hemangioblastoma associated with cystoid macular edema. On the basis of the clinical ocular findings and genetic analysis, von Hippel-Lindau disease was diagnosed. Following an intravitreal injection of ranibizumab , off-label administration of intravitreal dexamethasone was considered to reduce the edema . An almost complete resolution of the edema in the macular area was observed 1 week after the injection. Finally, laser photocoagulation and transconjunctival cryotherapy were performed; the patient developed "ablatio fugax" after cryotherapy. ### conclusions In our experience, intravitreal dexamethasone administration has proven to be a useful tool for reducing retinal hemangioblastoma-related macular edema in von Hippel-Lindau disease and may be considered a potentially valuable treatment that can be used in combination with other therapies.

https://pubmed.ncbi.nlm.nih.gov/30185211/

39c5dd43cb040ee8f6350c3f2071e992

Rabeprazole was similar to omeprazole and superior to placebo in both maintenance of healing and prevention of symptoms in patients with healed GERD in 1-year studies .

Rabeprazole: a review of its use in acid-related gastrointestinal disorders. rabeprazole is an inhibitor of the gastric proton pump. It causes dose-dependent inhibition of acid secretion and has a more rapid onset of action than omeprazole. Duodenal ulcers healed faster after treatment with rabeprazole 20 or 40 mg/day than placebo or ranitidine 150 mg 4 times daily and at a generally similar rate to omeprazole 20 mg/day in patients with duodenal ulcers; rabeprazole was similar or superior to these agents in relieving symptoms. rabeprazole 20 and 40 mg/day healed gastric ulcers faster than placebo, and rabeprazole 20 mg/day healed ulcers at a similar healing rate, to omeprazole 20 mg/day in well controlled 6-week studies. Gastric ulcer symptom relief with rabeprazole was similar or superior to that provided by omeprazole or placebo. In 8-week studies in patients with gastro-oesophageal reflux disease (GERD), rabeprazole 10, 20 and 40 mg/day were more effective than placebo, rabeprazole 20 mg/day was more effective than ranitidine 150 mg twice daily, and rabeprazole 20 mg/day was similar in efficacy to omeprazole 20 mg/day. Symptom relief with rabeprazole in 8-week trials in patients with GERD was superior to that provided by placebo, and similar to ranitidine or omeprazole. Rabeprazole was similar to omeprazole and superior to placebo in both maintenance of healing and prevention of symptoms in patients with healed GERD in 1-year studies . One-week triple therapy with rabeprazole 20 mg twice daily plus 2 antibacterial agents achieved > or = 90% Helicobacter pylori eradication, but, as would be expected, a regimen of rabeprazole 20 mg twice daily plus 1 antibacterial agent was less successful. The drug was as effective as omeprazole and lansoprazole as part of triple therapy for H. pylori eradication. rabeprazole successfully reduced acid output to target levels and prevented further pathological changes in 10 patients with Zollinger-Ellison syndrome. Usual dosages of rabeprazole are 20 mg/day for 4 weeks to treat duodenal ulcers, 6 weeks for gastric ulcers and 8 weeks for GERD, although some patients with duodenal ulcer may respond to a 10 mg/day dosage. For long term maintenance of GERD healing, 10 or 20 mg daily doses are adequate. Patients with hypersecretory states may need individualised dosages starting at 60 mg/day. The drug was well tolerated in clinical trials, with headache, rash, infection, diarrhoea and flu syndrome as the most common adverse events. In conclusion, rabeprazole appears to be a well tolerated proton pump inhibitor with a rapid onset of action and a low potential for drug interactions. The drug may be used to achieve healing and the relief of symptoms of duodenal ulcer, gastric ulcer and GERD, maintain GERD healing, and can form part of effective regimens to eradicate H. pylori.

https://pubmed.ncbi.nlm.nih.gov/10551440/

aea6e5bbd17d903de73866d5840bb07f

We performed a prospective , preplanned , pooled analysis of six randomized , phase 3 trials that were conducted concurrently to evaluate the noninferiority of adjuvant therapy with either FOLFOX ( fluorouracil , leucovorin , and oxaliplatin ) or CAPOX ( capecitabine and oxaliplatin ) administered for 3 months , as compared with 6 months .

Duration of Adjuvant Chemotherapy for Stage III Colon Cancer. Since 2004, a regimen of 6 months of treatment with oxaliplatin plus a fluoropyrimidine has been standard adjuvant therapy in patients with stage III colon cancer. However, since oxaliplatin is associated with cumulative neurotoxicity, a shorter duration of therapy could spare toxic effects and health expenditures. ### methods We performed a prospective , preplanned , pooled analysis of six randomized , phase 3 trials that were conducted concurrently to evaluate the noninferiority of adjuvant therapy with either FOLFOX ( fluorouracil , leucovorin , and oxaliplatin ) or CAPOX ( capecitabine and oxaliplatin ) administered for 3 months , as compared with 6 months . The primary end point was the rate of disease-free survival at 3 years. Noninferiority of 3 months versus 6 months of therapy could be claimed if the upper limit of the two-sided 95% confidence interval of the hazard ratio did not exceed 1.12. ### results After 3263 events of disease recurrence or death had been reported in 12,834 patients, the noninferiority of 3 months of treatment versus 6 months was not confirmed in the overall study population (hazard ratio, 1.07; 95% confidence interval [CI], 1.00 to 1.15). Noninferiority of the shorter regimen was seen for CAPOX (hazard ratio, 0.95; 95% CI, 0.85 to 1.06) but not for FOLFOX (hazard ratio, 1.16; 95% CI, 1.06 to 1.26). In an exploratory analysis of the combined regimens, among the patients with T1, T2, or T3 and N1 cancers, 3 months of therapy was noninferior to 6 months, with a 3-year rate of disease-free survival of 83.1% and 83.3%, respectively (hazard ratio, 1.01; 95% CI, 0.90 to 1.12). Among patients with cancers that were classified as T4, N2, or both, the disease-free survival rate for a 6-month duration of therapy was superior to that for a 3-month duration (64.4% vs. 62.7%) for the combined treatments (hazard ratio, 1.12; 95% CI, 1.03 to 1.23; P=0.01 for superiority). ### conclusions Among patients with stage III colon cancer receiving adjuvant therapy with FOLFOX or CAPOX, noninferiority of 3 months of therapy, as compared with 6 months, was not confirmed in the overall population. However, in patients treated with CAPOX, 3 months of therapy was as effective as 6 months, particularly in the lower-risk subgroup. (Funded by the National Cancer Institute and others.).

https://pubmed.ncbi.nlm.nih.gov/29590544/

c2b21e29d41a7690c76cf73efa04e478

Growth inhibition and apoptosis were significantly ( P < 0.05 ) higher in BxPC-3 , HPAC , and PANC-1 cells treated with celecoxib and erlotinib than cells treated with either celecoxib or erlotinib .

Simultaneous targeting of the epidermal growth factor receptor and cyclooxygenase-2 pathways for pancreatic cancer therapy. The aims of this study were to determine the effects of (a) combining the epidermal growth factor receptor (EGFR) blocker (erlotinib) and the cyclooxygenase-2 inhibitor (celecoxib) on cell growth and apoptosis in human pancreatic cancer cell lines, (b) baseline EGFR expression on the potentiation of erlotinib-induced apoptosis by celecoxib, and (c) the effects of the combination on the expression of the COX-2, EGFR, HER-2/neu, and nuclear factor-kappaB (NF-kappaB). Baseline expression of EGFR was determined by Western blot analysis in five human pancreatic cancer cell lines. BxPC-3, PANC-1, and HPAC had high EGFR and MIAPaCa had low EGFR. Cells were grown in culture and treated with erlotinib (1 and 10 micromol/L), celecoxib (1 and 10 micromol/L), and the combination. Growth inhibition was evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and apoptosis was assayed by ELISA. Reverse transcriptase-PCR was used to evaluate COX-2 and EGFR mRNA. EGFR, COX-2, and HER-2/neu expression was determined by Western immunoblotting. Electrophoretic mobility shift assay was used to evaluate NF-kappaB activation. Growth inhibition and apoptosis were significantly ( P < 0.05 ) higher in BxPC-3 , HPAC , and PANC-1 cells treated with celecoxib and erlotinib than cells treated with either celecoxib or erlotinib . However, no potentiation in growth inhibition or apoptosis was observed in the MIAPaCa cell line with low expression of the EGFR. Significant down-regulation of COX-2 and EGFR expression was observed in the BxPC-3 and HPAC cells treated with the combination of erlotinib (1 micromol/L) and celecoxib (10 micromol/L) compared with celecoxib- or erlotinib-treated cells. celecoxib significantly down-regulated HER-2/neu expression in BxPC-3 and HPAC cell lines. Significant inhibition of NF-kappaB activation was observed in BxPC-3 and HPAC cell lines treated with erlotinib and celecoxib. (a) celecoxib can potentiate erlotinib-induced growth inhibition and apoptosis in pancreatic cell lines, (b) high baseline EGFR expression is a predictor of this potentiation, and (c) the down-regulation of EGFR, COX-2, and HER-2/neu expression and NF-kappaB inactivation contributes to the potentiation of erlotinib by celecoxib.

https://pubmed.ncbi.nlm.nih.gov/16373709/

d85f44a5e953a3b8e43b5bf99e30a3b5

Subcutaneous aspirin , 100 mg/kg , which reduced duodenal PGE2 generation to a greater degree than either ulcerogen , given in conjunction with pentagastrin , did not produce visible duodenal ulceration.(ABSTRACT TRUNCATED AT 250 WORDS )

Role of prostanoids in experimental duodenal ulcer in rat. The purposes of this study were to determine whether inhibition of cyclooxygenase is a mechanism by which cysteamine and mepirizole produce duodenal ulcers, identify qualitative or quantitative differences in prostanoid production between gastric mucosa and duodenum, and determine whether differences in cyclooxygenase sensitivity to inhibition by aspirin exist between these two tissues. In fed female rats, gastric mucosal prostaglandin E2 (PGE2) and prostacyclin (PGI2) generation was 235 +/- 25 and 832 +/- 40 ng/g/min, respectively, whereas full-thickness duodenal PGE2 and PGI2 generation was 665 +/- 46 and 662 +/- 49 ng/g/min, respectively. Over an intraperitoneal dose range of 0-25 mg/kg, aspirin-induced cyclooxygenase inhibition was dose-dependent and similar for the two tissues. Duodenal ulceration (16.7 mm2) produced by cysteamine, 425 mg/kg, was associated with a 46% reduction in duodenal PGE2 generation, while having no effect on PGI2 generation; however, cysteamine, 213 mg/kg, produced no visible duodenal mucosa injury yet reduced duodenal PGE2 generation 39% compared to control values. In fed male rats, gastric mucosal PGE2 and PGI2 generation was 179 +/- 18 and 813 +/- 61 ng/g/min, respectively, whereas duodenal PGE2 and PGI2 generation was 321 +/- 27 and 454 +/- 38 ng/g/min, respectively. Duodenal ulceration (7.7 +/- 2.3 mm2) produced by oral mepirizole was associated with a 63% reduction in duodenal PGE2 generation compared to control values, while having no effect on PGI2 generation. Subcutaneous aspirin , 100 mg/kg , which reduced duodenal PGE2 generation to a greater degree than either ulcerogen , given in conjunction with pentagastrin , did not produce visible duodenal ulceration.(ABSTRACT TRUNCATED AT 250 WORDS )

https://pubmed.ncbi.nlm.nih.gov/3131076/

4c286a03b81e5883cc213110576889fa

Prevalence of metronidazole , clarithromycin , and amoxicillin resistance is high in developing world including Africa .

The magnitude of antibiotic resistance to Helicobacter pylori in Africa and identified mutations which confer resistance to antibiotics: systematic review and meta-analysis. Worldwide Helicobacter pylori (H.pylori) treatment is of great challenge due to increased antibiotic resistance. The burden of H. pylori antibiotic resistance in Africa is high with unclear information regarding the real magnitude. This systematic review and meta-analysis was conducted to investigate the magnitude of H.pylori antibiotic resistance in Africa to gain insight of the extent of the problem among H.pylori naïve treatment patients. ### method The search was performed in the academic databases, Embase, PubMed, Web of Science and Africa Wide Information. ProQuest Dissertation and Theses, Scopus, Ethos, Africa Index Medicus (WHO), BioMed Central Proceedings, BASE, British Library, Open grey, Library of Congress and the New York Academy of Grey Literature Report were additionally searched for grey literature. Published articles from Africa on H.pylori antibiotic resistance between 1986 and June 2017 were systematically reviewed to estimate the H. pylori extent of resistance to macrolides, quinolones, amoxicillin, tetracycline and metronidazole. ### results In 26 articles a total of 2085 isolates were tested for metronidazole, 1530 for amoxicillin, 1277 for tetracycline, 1752 for clarithromycin and 823 for quinolones.The overall pooled proportion of H.pylori resistance to quinolones, clarithromycin, tetracycline, metronidazole and amoxicillin were: (17.4%, 95%CI 12.8 - 21.9), (29.2%, 95%CI:26.7-31.8), (48.7%, 95%CI: 44.5-52.9), (75.8%, 95% CI: 74.1-.77.4) and (72.6%, 95% CI: 68.6-76.6), respectively. The commonest mutation detected were A2143G (49/97) for clarithromycin, RdxA (41/56) for metronidazole and D87I (16/40) for quinolones. ### conclusion Prevalence of metronidazole , clarithromycin , and amoxicillin resistance is high in developing world including Africa . This could impair the first line triple therapy of the H.pylori infection. There is a need of conducting surveillance of H.pylori susceptibility pattern in Africa for dual and triple resistance which can be used for the empirical treatment.

https://pubmed.ncbi.nlm.nih.gov/29699490/

c17fc0df1fea762c276a5d2457332e93

These results indicate that low-dose 100 microg levonorgestrel and 20 microg ethinyl estradiol given for 21 days is effective in suppressing ovarian activity and they confirm the contraceptive efficacy observed in clinical trials ( Pearl index of 0.8 ) .

The effects on ovarian activity of a monophasic oral contraceptive with 100 microg levonorgestrel and 20 microg ethinyl estradiol. An open-label, single-center, noncomparative study was conducted to determine the effects of a monophasic oral contraceptive containing 100 microg levonorgestrel and 20 microg ethinyl estradiol on ovarian activity. The subjects were 26 healthy women 20 to 35 years of age who had normal ovulatory cycles and were not at risk for becoming pregnant. For 3 treatment cycles, they took 1 tablet of active drug daily for 21 days followed by placebo tablets for 7 days. Follicle diameters and serum progesterone and 17beta-estradiol levels were measured before, during, and after treatment. In 2 (2.7%) of 73 cycles, luteinized unruptured follicles were present and in another 2 (2.7%) cycles, ovulation was confirmed by the disappearance of the enlarged follicle. Ovarian activity, as reflected by mean serum progesterone levels, was restored after treatment. The results of this study are in agreement with those of other studies that showed suppression of ovarian activity in women treated with a monophasic oral contraceptive containing 100 microg levonorgestrel and 20 microg ethinyl estradiol. These results indicate that low-dose 100 microg levonorgestrel and 20 microg ethinyl estradiol given for 21 days is effective in suppressing ovarian activity and they confirm the contraceptive efficacy observed in clinical trials ( Pearl index of 0.8 ) .

https://pubmed.ncbi.nlm.nih.gov/10561676/

f5280bfb01586dd9949743d020881015

The combination of ixabepilone and capecitabine in the phase II study resulted in an ORR of 23 % in triple-negative patients .

Efficacy of ixabepilone in ER/PR/HER2-negative (triple-negative) breast cancer. Patients with ER/PR/HER2-negative (triple negative) breast cancer are not candidates for hormonal therapy or HER2-targeted agents. Ongoing research is aimed at identifying and understanding the benefit of established and emerging therapies in this disease setting. Triple-negative patients may achieve early responses to anthracyclines and taxanes, but novel strategies are also eagerly sought. The epothilone B analog ixabepilone acts to stabilize microtubules and demonstrates antitumor activity in recent breast cancer studies. Herein, we have analyzed efficacy and safety data of ixabepilone specifically for the treatment of women with triple-negative disease. A retrospective analysis was completed using activity and toxicity data in the triple-negative subsets from 5 phase II studies. In addition, a prospective pooled analysis of triple-negative patients from 2 phase III trials is also reviewed. Of 2,261 patients evaluated in these trials, 556 (24.5%) had triple-negative tumors. In the neoadjuvant setting, ixabepilone produced a pathologic complete response rate in the breast of 26% in triple-negative patients (vs. 15% in the non-triple-negative population). In patients with metastatic breast cancer whose pretreatment status ranged from no prior therapy to progression on several classes of agents, overall response rates (ORR) in the phase II ixabepilone monotherapy trials ranged from 6 to 55%, comparable to rates seen in patients with non-triple-negative tumors. The combination of ixabepilone and capecitabine in the phase II study resulted in an ORR of 23 % in triple-negative patients . A similar ORR (31%) was observed for a preplanned pooled analysis of triple-negative patients in the phase III trials of ixabepilone plus capecitabine. The median progression-free survival (PFS) was significantly longer for triple-negative patients treated with ixabepilone plus capecitabine (4.2 months) compared with treatment with capecitabine alone (1.7 months). No increase in toxicity was noted in the triple-negative subgroup compared with other patients. ixabepilone shows notable antitumor activity in patients with triple-negative breast cancer when used in a variety of settings. The addition of ixabepilone to capecitabine results in an approximately twofold increase in median PFS for triple-negative patients versus capecitabine alone and responses to ixabepilone in triple-negative disease are comparable to those seen in patients with non-triple-negative tumors.

https://pubmed.ncbi.nlm.nih.gov/20229176/

f1876516f12f16458a9741e1e09fd6e9

We report the rare case of a 27-year-old premenopausal woman with locally advanced breast cancer that was marked by rapid tumor necrosis followed by massive hemorrhage shortly after bevacizumab and paclitaxel administration .

Rapid tumor necrosis and massive hemorrhage induced by bevacizumab and paclitaxel combination therapy in a case of advanced breast cancer. bevacizumab when combined with chemotherapy exerts significant activity against many solid tumors through tumor angiogenesis inhibition; however, it can induce severe side effects. We report the rare case of a 27-year-old premenopausal woman with locally advanced breast cancer that was marked by rapid tumor necrosis followed by massive hemorrhage shortly after bevacizumab and paclitaxel administration . On the basis of histopathological examination of a biopsy specimen and computed tomography findings, she was diagnosed with stage IV estrogen and progesterone receptor-negative and human epidermal growth factor receptor type 2-positive breast cancer with multiple organ metastases when she had entered gestational week 24. cyclophosphamide, Adriamycin®, fluorouracil therapy was initiated, but multiple liver metastases continued to progress. A healthy fetus was delivered by induced delivery and trastuzumab-based treatment was initiated. Although the multiple liver metastases were controlled successfully by trastuzumab combined with paclitaxel, the primary tumor continued to expand even after subsequent administration of three other treatment regimens including anti-human epidermal growth factor receptor type 2 agents and cytotoxic drugs. To inhibit primary tumor growth, a combination therapy with paclitaxel and bevacizumab was subsequently initiated. Following therapy initiation, however, the large tumor occupying the patient's entire left breast became necrotic and ulcerated rapidly. Furthermore, massive hemorrhage from the tumor occurred 5 weeks after bevacizumab-based therapy initiation. Although hemostasis was achieved by manual compression, the patient required blood transfusion for the massive blood loss. She eventually succumbed to respiratory failure. This case report demonstrates that primary breast cancer lesions with skin involvement have the potential to cause massive hemorrhage after bevacizumab-based treatment.

https://pubmed.ncbi.nlm.nih.gov/24124381/

5b276187d854e37f1e11f2a96b3f7f34

More recently , paclitaxel plus carboplatin also has been evaluated in previously untreated patients .

Current status of chemotherapy for ovarian cancer. Standard treatment for patients with advanced ovarian cancer has been cytoreductive surgery followed by combination chemotherapy. Until recently, platinum-based chemotherapy was considered optimal and patients were treated with regimens built around either cisplatin or carboplatin. Recently, paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) has been shown to be a highly active agent in refractory ovarian cancer patients. Subsequently, the Gynecologic Oncology Group performed a prospective randomized trial of paclitaxel plus cisplatin compared with cisplatin plus cyclophosphamide in suboptimal stage III and IV ovarian cancer patients. Based on higher response rates, longer time to progression, and marked improvement in median survival (37.5 months compared with 24.4 months), the Gynecologic Oncology Group currently considers paclitaxel plus cisplatin to be the new standard regimen for patients with advanced disease. More recently , paclitaxel plus carboplatin also has been evaluated in previously untreated patients . Using area under the curve dosing for carboplatin, it was demonstrated that this agent could be combined with paclitaxel (175 mg/m2 in a 3-hour infusion) with acceptable toxicity. All current Gynecologic Oncology Group protocols for untreated patients with ovarian cancer use a paclitaxel-based regimen. These clinical trials are evaluating the relative efficacy of carboplatin plus paclitaxel versus cisplatin plus paclitaxel as well as differences in dose and schedule and number of cycles of treatment. Investigational studies are continuing with high-dose chemotherapy that requires hematologic support as well as with intraperitoneal therapy (cisplatin or paclitaxel).

https://pubmed.ncbi.nlm.nih.gov/7481863/

a29a75ad6709d12bac212da17d06c3d6

Mitoxantrone and cyclophosphamide in advanced breast cancer : a pilot study .

Mitoxantrone and cyclophosphamide in advanced breast cancer : a pilot study . A trial of combination chemotherapy using mitoxantrone-cyclophosphamide was started in 1983. Sixteen patients with widely metastatic cancer of the breast, including one man, received mitoxantrone, 10 mg/m2 intravenously (IV) over 30 minutes on day 1, followed by cyclophosphamide, 200 mg/m2 by mouth (PO) daily in divided doses on days 3 to 6. It is too early to evaluate four patients at present. The remaining 12 received three or more courses of treatment, and three of these patients achieved a complete response. Another four patients went into partial remission, amounting to an overall response rate of 58%. The other evaluable patients showed stable disease with improved symptoms. Hematologic toxicity was mainly granulocytopenia, but thrombocytopenia occurred in two patients. Alopecia, nausea, and vomiting were attributed to the cyclophosphamide component of the therapy. mitoxantrone appeared to have no cardiac toxicity. It was concluded that mitoxantrone-cyclophosphamide is an effective chemotherapeutic combination with minimal toxicity and should be further studied in larger controlled trials.

https://pubmed.ncbi.nlm.nih.gov/6385260/

1106afc2c9fb4c7a9ae5de454d4c4e8e

We retrospectively analyzed the data of 37 patients who had postprandial hyperglycemia ( ≥10.0 mmol/L ) with BOT ( long-acting insulin plus glimepiride ) with their insulin titrated enough to keep preprandial glycemia < 7.2 mmol/L , and who had their treatment changed to liraglutide monotherapy , with the subsequent addition of glimepiride , when required .

Efficacy of liraglutide therapy in Japanese type 2 diabetic patients insufficiently controlled with basal-supported oral therapy. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2012.00223.x, 2012) Aims/Introduction:  We assessed the efficacy of liraglutide therapy in Japanese type 2 diabetic patients insufficiently controlled with basal-supported oral therapy (BOT). ### Materials And Methods We retrospectively analyzed the data of 37 patients who had postprandial hyperglycemia ( ≥10.0 mmol/L ) with BOT ( long-acting insulin plus glimepiride ) with their insulin titrated enough to keep preprandial glycemia < 7.2 mmol/L , and who had their treatment changed to liraglutide monotherapy , with the subsequent addition of glimepiride , when required . Those who achieved the glycemic target at all points (preprandial glycemia <7.2 mmol/L and postprandial glycemia <10.0 mmol/L) were regarded as responders and the efficacy of liraglutide therapy was assessed. We also explored the predictive clinical characteristics associated with its efficacy. ### results Daily doses of insulin and glimepiride with BOT were 14 ± 9 units and 1.5 ± 0.9 mg, respectively. After the change to liraglutide therapy, 37% of the patients appeared to be responders to the therapy, whereas 12% had their glycemic control rather deteriorated. Efficacy of liraglutide therapy was significantly associated with baseline insulin dosage and post-breakfast glycemia with BOT. The C-statistic of the model was calculated to be 0.90. ### conclusions There were responders and non-responders to liraglutide therapy in Japanese BOT failures. It is likely that baseline insulin dosage and post-breakfast glycemia with BOT are clinically useful indicators for the efficacy of liraglutide therapy.

https://pubmed.ncbi.nlm.nih.gov/24843616/

be5a1c925d0cb0e6d439ac0b5e827128

It was shown that the H2 receptor antagonist cimetidine when combined with N , N-diethyl-2-[4-(phenylmethyl)phenoxy]-ethanamine-HCl ( DPPE ) , a tamoxifen derivate , inhibits the proliferation of HT168 cells .

Cimetidine and a tamoxifen derivate reduce tumour formation in SCID mice xenotransplanted with a human melanoma cell line. Histamine is produced by many cells expressing histidine decarboxylase (HDC), the enzyme responsible for the synthesis of histamine. Since melanoma cells and tissue contain relatively large amounts of histamine, the functional significance of histamine was examined using specific antihistamines in vitro and in vivo in the human melanoma cell line HT168 and severe combined immunodeficiency (SCID) mice. It was shown that the H2 receptor antagonist cimetidine when combined with N , N-diethyl-2-[4-(phenylmethyl)phenoxy]-ethanamine-HCl ( DPPE ) , a tamoxifen derivate , inhibits the proliferation of HT168 cells . Furthermore, it is suggested that there is a factor(s) that interferes with the exponential growth of HT168 cells xenografted to immunodeficient mice, and cimetidine and DPPE together significantly influence this factor(s). This combination of antihistamines also increases the survival of human melanoma-grafted mice. These changes are accompanied by enhanced infiltration of interferon-gamma- producing mouse macrophages into the tumour tissue. These findings suggest that two different mechanisms are probably acting concordantly: direct inhibition of tumour cell proliferation by the H2 receptor antagonists, and activation of the local immune response characterized by interferon-gamma production. These findings may help to elucidate the possibility of a rationally designed antihistamine strategy in melanoma therapy.

https://pubmed.ncbi.nlm.nih.gov/12140379/

371012fb02d83cd72167038138c75fc9

We report here on a case of successful treatment of a patient suffering with severe liver dysfunction and metastatic gastric cancer ; the patient was treated with a combination of capecitabine and oxaliplatin ( XELOX ) .

Capecitabine and oxaliplatin (XELOX) for the treatment of patients with metastatic gastric cancer and severe liver dysfunction. Gastric cancer patients with severe liver dysfunction secondary to hepatic metastases have limited treatment options. Most cytotoxic drugs have a narrow therapeutic index. Although both capecitabine and oxaliplatin have been well tolerated as single agents for patients with severe hepatic dysfunction, the combination of these drugs has not been investigated. We report here on a case of successful treatment of a patient suffering with severe liver dysfunction and metastatic gastric cancer ; the patient was treated with a combination of capecitabine and oxaliplatin ( XELOX ) . The initial bilirubin level of the patient was 10.9 mg/dL. After two cycles of treatment, his bilirubin level decreased to 2.1 mg/dL. He has experienced an excellent radiological response and he has received six cycles of XELOX chemotherapy. XELOX chemotherapy is feasible and it can be associated with positive outcomes for the patients suffering with metastatic gastric cancer and severe liver dysfunction.

https://pubmed.ncbi.nlm.nih.gov/17249509/

866cea479a93e1b7b5b53f5813e3c8af

From 1987 to 1991 , 194 previously untreated patients received vincristine and ifosfamide plus dactinomycin or etoposide for 1 - 2 years .

Renal toxicity of ifosfamide in pilot regimens of the intergroup rhabdomyosarcoma study for patients with gross residual tumor. The purpose of this review is to characterize the nephrotoxicity noted in newly diagnosed patients under 21 years of age after treatment with ifosfamide-containing chemotherapy regimens and local irradiation for localized gross residual rhabdomyosarcoma or undifferentiated sarcoma. ### Patients And Methods From 1987 to 1991 , 194 previously untreated patients received vincristine and ifosfamide plus dactinomycin or etoposide for 1 - 2 years . ifosfamide was given at 1.8 g/m2/day for 5 days with sodium mercaptoethane sulfonate, or 9 g/m2 of ifosfamide per course. The three-drug regimen was repeated every 3-4 weeks. ### results Twenty-eight patients (14%) developed renal toxicity: 19 had renal tubular dysfunction (RTD) characterized by low serum phosphate (< or = 3 mg/dl) or bicarbonate (< 20 or = mEq/L) levels, five had decreased glomerular function (DGF), and four had both RTD and DGF. When nine or more courses of ifosfamide (> 72 g/m2) were given, children < 3 years of age had a higher incidence of RTD than did children > or = 3 years of age (34% versus 6%; p < 0.001). A similar age difference was observed even when eight or fewer courses (< or = 72 g/m2) were given (p = 0.03). A matched case-control comparison showed that renal abnormalities at diagnosis, chiefly hydronephrosis, also increased the risk of renal tubular injury by ifosfamide by a factor of 13 (p < 0.001). Patients with DGF tended to be older than those with RTD, and all but one received > 72 g/m2 of ifosfamide. ### conclusions Patients who are < 3 years of age who receive more than eight courses (> 72 g/m2) of ifosfamide and who have a preexisting renal abnormality have an increased risk of RTD and DGF. The renal function of patients being considered for ifosfamide treatment must be carefully monitored. ifosfamide should be avoided in patients with renal abnormalities at diagnosis unless the potential benefit clearly exceeds the risk of further renal impairment.

https://pubmed.ncbi.nlm.nih.gov/7978043/

8e992315910c8453b24e152e7b079ea9

This nested substudy of the AVALON trial assessed the effects of coadministered amlodipine and atorvastatin vs. either therapy alone or placebo on arterial compliance , to evaluate the vascular benefits of coadministered therapy .

Coadministered amlodipine and atorvastatin produces early improvements in arterial wall compliance in hypertensive patients with dyslipidemia. Combining statins with antihypertensive therapy has been demonstrated to provide an early reduction in cardiovascular events. This nested substudy of the AVALON trial assessed the effects of coadministered amlodipine and atorvastatin vs. either therapy alone or placebo on arterial compliance , to evaluate the vascular benefits of coadministered therapy . ### methods During an initial 8-week, double-blind phase, patients with concomitant hypertension and dyslipidemia were randomized into four treatment groups (placebo, amlodipine 5 mg, atorvastatin 10 mg, or coadministered amlodipine 5 mg and atorvastatin 10 mg). The sustained effect of combined therapy was evaluated during subsequent 8-week, single-blind, and 12-week, open-label periods. In the single-blind phase, all patients were coadministered amlodipine 5 mg and atorvastatin 10 mg, which were then titrated to optimize blood pressure and low-density lipoprotein cholesterol control during the open-label phase. Arterial compliance was assessed every 4 weeks using the HDI/Pulsewave CR-2000. ### results Overall, 668 patients (61% male, mean age 55 years) were randomized to treatment. A 19% improvement in small artery compliance (C2) was observed with coadministered amlodipine and atorvastatin from baseline to week 8, which was significantly greater than with either treatment alone or with placebo (P = 0.03 to 0.0001). After 28 weeks, C2 was increased from baseline in all groups, but the overall improvement was greatest in the group receiving coadministered drugs for the entire study period (P < 0.05). ### conclusions Early and sustained improvement in small artery compliance was observed following coadministration of amlodipine and atorvastatin, thus demonstrating a vascular benefit with simultaneous treatment of hypertension and dyslipidemia.

https://pubmed.ncbi.nlm.nih.gov/19057518/

e925c82c9d2d2338c659d275057e5ecd

We analysed the serial dermatoscopic photographs of atypical melanocytic lesions taken from patients with advanced metastatic melanoma on four different systemic therapies ( selective BRAF-inhibitor monotherapy , dabrafenib combined with trametinib [ D&T ] , anti-programmed cell death protein 1 [ anti-PD1 ] therapies , and anti-PD1 combined with ipilimumab ) seen from February 2013 to May 2016 .

Melanocytic lesion evolution patterns with targeted therapies and immunotherapies for advanced metastatic melanoma: An observational study. Various cutaneous side-effects have been reported with anti-melanoma systemic therapies. This study investigated the changes in melanocytic lesion pigmentation in patients on four different therapies. ### methods We analysed the serial dermatoscopic photographs of atypical melanocytic lesions taken from patients with advanced metastatic melanoma on four different systemic therapies ( selective BRAF-inhibitor monotherapy , dabrafenib combined with trametinib [ D&T ] , anti-programmed cell death protein 1 [ anti-PD1 ] therapies , and anti-PD1 combined with ipilimumab ) seen from February 2013 to May 2016 . We compared these changes with the melanocytic lesions of 10 control patients. ### results In the control group, 19% of naevi lightened, 64% did not change and 17% darkened. Only the BRAF inhibitor group showed more darkened lesions than controls (37%, P < 0.001). Meanwhile, there were more lightened naevi in the D&T therapy group (86%, P < 0.001) as well as the anti-PD1 and ipilimumab groups (59%, P < 0.001) than controls. Patients on anti-PD1 monotherapy had more lightened (49%) and fewer darkened naevi (9%) than controls, but differences were not significant. ### conclusions Our study showed that different anti-melanoma systemic therapies have different effects on the pigmentation of melanocytic lesions. BRAF inhibitor may have the propensity to cause darkening while D&T therapy and anti-PD1 caused lightening compared with controls. The findings emphasise the importance of regular dermatological monitoring in specialised clinics for patients on anti-melanoma systemic therapy. Clinicians should expect changes in the global pigmentation of melanocytic lesions but be suspicious of lesions with structural changes.

https://pubmed.ncbi.nlm.nih.gov/28707403/

05b1012375dc91d3f46f44b59e1fd1fb

He received six cycles MOPP-induction therapy followed by a chlorambucil maintenance therapy with procarbazine and prednisone reinforcements .

Acute erythroleukemia following chemotherapy for Hodgkin's disease. A case of erythroleukemia developing in a patient 6.5 years after therapy for Hodgkin's disease (HD) is described. The patient had chemotherapy alone for a stage III B lymphocyte-predominant HD. He received six cycles MOPP-induction therapy followed by a chlorambucil maintenance therapy with procarbazine and prednisone reinforcements . To our knowledge this is the first case of erythroleukemia following HD treated with chemotherapy alone.

https://pubmed.ncbi.nlm.nih.gov/6932816/

a361c296e0a5fe7615178d1738c3cc72

The introduction of rituximab , alemtuzumab , and bendamustine has improved the current outlook for patients with CLL .

Standard of care and novel treatments for chronic lymphocytic leukemia. The standard of care and novel treatments for chronic lymphocytic leukemia (CLL) are reviewed. ### summary Recent advances in the treatment of CLL have dramatically changed the therapeutic landscape for both patients and health care professionals. The majority of conventional first-line therapies are noncurative and are only used to treat disease that is symptomatic or progressive and include chlorambucil, monotherapy with purine analogues, and combination chemotherapy. Immunotherapeutic agents such as rituximab and alemtuzumab may be indicated in select patient populations. However, because clinical trials have found that overall survival does not depend on the initial therapy, selection of first-line therapy should be based on patient-specific factors and the patient's goals for therapy with respect to response, survival, and symptom palliation. Progression-free survival time and time to treatment are critical endpoints for CLL treatment. An increasingly important endpoint is minimal residual disease (MRD), as it is considered to be the major cause of relapse in CLL. Finally, comparison of toxicities between different therapies is critical in CLL, as it is in other disease states. Several new agents are currently being evaluated for use in CLL, including alvocidib, oblimersen, and lumiliximab. ### conclusion Chemotherapy remains the mainstay of treatment for the majority of patients with CLL. The introduction of rituximab , alemtuzumab , and bendamustine has improved the current outlook for patients with CLL . As overall survival does not appear to depend on the initial therapy, treatment should be selected based on patient-specific factors and goals. Challenges in CLL include determining when to initiate therapy, eradicating MRD, and managing therapeutic resistance.

https://pubmed.ncbi.nlm.nih.gov/20966144/

4459519c47bc0fd3fbadcc6fff8f621d

Ten patients were treated with pirfenidone ( 2403 mg/die ) and 1 with nintedanib

Possible value of antifibrotic drugs in patients with progressive fibrosing non-IPF interstitial lung diseases. Fibrosing, non-idiopathic pulmonary fibrosis (non-IPF) interstitial lung diseases (fILDs) are a heterogeneous group of diseases characterized by a different amount of inflammation and fibrosis. Therapy is currently based on corticosteroids and/or immunomodulators. However, response to these therapies is highly variable, sometimes without meaningful improvement, especially in more fibrosing forms. pirfenidone and nintedanib have recently demonstrated to reduce functional decline in patients with IPF. However, their antifibrotic mechanism makes these two drugs an interesting approach for treatment of fibrosing ILDs other than IPF. ### objectives We here report our experience with antifibrotic drugs in fibrosing non-IPF ILDs patients having a progressive phenotype during immunosuppressive therapy. ### methods Patients with a multidisciplinary team diagnosis of fibrosing non-IPF ILDs experiencing a progressive phenotype during treatment with corticosteroids and/or immunomodulators between October-2014 and January-2018 at our tertiary referral Center for ILDs were retrospectively analyzed. Antifibrotic therapy was administered after application with the respective health insurance company and after consent by the patient. Pulmonary-function-tests and follow-up visits were performed every 6 ± 1 months. ### results Eleven patients were treated with antifibrotic drugs (8 males, mean age 62 ± 12.8 years, mean FVC% 62.8 ± 22.3, mean DLCO% 35.5 ± 10.7, median follow-up under antifibrotic treatment 11.1 months). Patients had a diagnosis of unclassifiable ILD in 6 cases, pleuroparenchymal fibroelastosis in 2 cases, idiopathic-NSIP in 1 case, asbestos-related ILD in 1 case and Hermansky-Pudlak syndrome in 1 case. Treatment before antifibrotics consisted of corticosteroids in all patients: 5 combined with Azathioprin, 1 with either methotrexate or cyclophosphamide (i.v.). Ten patients were treated with pirfenidone ( 2403 mg/die ) and 1 with nintedanib (300 mg/die). Median FVC was 56, 56, 50%, at time points - 24, - 12, - 6 before initiation, 44% at time of initiation and 46.5% at 6 months after initiation of antifibrotic treatment. Antifibrotic treatment was generally well tolerated with a need of dose reduction in 2 cases (rash and nausea) and early termination in 3 cases. ### conclusions Antifibrotic treatment may be a valuable treatment option in patients with progressive fibrosing non-IPF ILD if currently no other treatment options exist. However, prospective, randomized clinical trials are urgently needed to assess the real impact of antifibrotic therapy in these patients.

https://pubmed.ncbi.nlm.nih.gov/31718637/

aca07ce099defc39959faeabed961a9a

More recently , case-control and cohort studies and well-conceived , phase II/III clinical trials have been done or are under way to evaluate putative chemopreventive agents including established drugs like aspirin and non-steroidal anti-inflammatory drugs ( NSAIDs ) , 5-aminosalicylates and statins ; more controversial drugs like cyclo-oxygenase-2 ( COX-2 ) inhibitors , ursodeoxycholic acid ; various vitamins and micronutrients including calcium , selenium , folic acid , and dietary fibre , fat and protein content .

Chemoprevention of colorectal cancer. Colorectal cancer is a major cause of mortality and treatment costs are considerable. Advocating lifestyle modification, faecal occult blood testing and surveillance colonoscopy in appropriate populations are already in practice. A developing concept is chemoprevention. Several models of carcinogenesis in colorectal cancer have been developed and there is an increasing database on the major molecular mechanisms involved in carcinogenesis mainly from preclinical experiments and phase I trials. There have been several large epidemiological and observational studies to evaluate possible protective effects of >200 agents. More recently , case-control and cohort studies and well-conceived , phase II/III clinical trials have been done or are under way to evaluate putative chemopreventive agents including established drugs like aspirin and non-steroidal anti-inflammatory drugs ( NSAIDs ) , 5-aminosalicylates and statins ; more controversial drugs like cyclo-oxygenase-2 ( COX-2 ) inhibitors , ursodeoxycholic acid ; various vitamins and micronutrients including calcium , selenium , folic acid , and dietary fibre , fat and protein content . Despite promising outcome in preclinical studies, there is currently very limited data from well-controlled and appropriately powered clinical studies. The most promising agents currently are aspirin, traditional NSAIDs and COX-2 inhibitors. The recent reports of cardiovascular risks of the COX-2 inhibitors and some traditional NSAIDs have resulted in stagnation of the field. Pending the expected release of results from several phase III trials in the near future, chemoprevention for colorectal cancer can only be practically considered in the very-high-risk population like those with familial adenomatous polyposis and ulcerative colitis, in conjunction with surveillance colonoscopy. This article reviews the major models of colorectal carcinogenesis, the concept of chemoprevention with special reference to colorectal cancer and the current state of clinical literature and the future direction of colorectal cancer chemoprevention for both researcher and clinician alike.

https://pubmed.ncbi.nlm.nih.gov/17947819/

121cc940e6c7801b8ef91dd420bbcd5a

Frontline bortezomib and rituximab for the treatment of newly diagnosed high tumour burden indolent non-Hodgkin lymphoma : a multicentre phase II study .

Frontline bortezomib and rituximab for the treatment of newly diagnosed high tumour burden indolent non-Hodgkin lymphoma : a multicentre phase II study . There is a lack of published data examining non-cytotoxic options for the frontline treatment of patients with high-tumour burden (HTB) indolent non-Hodgkin lymphoma (iNHL). We completed a multicentre phase II study for patients with untreated HTB iNHL (NCT00369707) consisting of three induction cycles of weekly bortezomib and rituximab followed by an abbreviated consolidation. Forty-two patients were treated and all were evaluable; the most common histology was follicular lymphoma (FL) (n = 33, 79%). Patient characteristics included median age 62 years (40-86); 38% bulky disease; 19% malignant effusions; 91% advanced-stage disease; and median FL International Prognostic Index (FLIPI) score was 3. Therapy was well tolerated with few grade 3/4 toxicities including minimal neurotoxicity. On intent-to-treat, the overall response rate (ORR) at end of therapy was 70% with a complete remission (CR) rate of 40% (FL: ORR 76%, CR 44%). With 50-month median follow-up, 4-year progression-free survival (PFS) was 44% with 4-year overall survival (OS) of 87% (FL: 44% and 97%, respectively). Four-year PFS for FLIPI 0-2 vs. 3-5 was 60% vs. 26% respectively (P = 0·02), with corresponding OS rates of 92% and 81% respectively (P = 0·16). Collectively, bortezomib/rituximab is a non-cytotoxic therapeutic regimen that was well tolerated and resulted in long-term survival rates approximating prior rituximab/cytotoxic chemotherapy series for untreated HTB FL.

https://pubmed.ncbi.nlm.nih.gov/24761968/

2a53d260b295d78e2f2e900107f15b71

The ifosfamide , carboplatin and etoposide ( ICE ) regimen was developed to address these challenges .

Ifosfamide, carboplatin, etoposide (ICE)-based second-line chemotherapy for the management of relapsed and refractory aggressive non-Hodgkin's lymphoma. Despite advances in the management of aggressive non-Hodgkin's lymphoma, the treatment of relapsed and primary refractory disease remains a major challenge. High-dose chemotherapy or radio-chemotherapy followed by autologous or allogeneic stem cell transplantation (SCT) is a potentially curative treatment approach; however, the applicability of this approach is restricted to patients responding to second-line chemotherapy. Thus, second-line therapy must be both efficacious and without stem cell or organ toxicity that would compromise the ability to proceed to SCT. The ifosfamide , carboplatin and etoposide ( ICE ) regimen was developed to address these challenges . In a series of prospective clinical trials, 222 patients were treated with the ICE regimen. with an overall response rate of 72%. The mobilization of stem cells with this regimen was excellent,with 86% of patients mobilizing at least 2.0 x 10(6) CD34+ cells/kg. The incidence of treatment-related toxicity precluding SCT after ICE is very low. Herein, we report the clinical results of this treatment program for 222 patients with 5-year median follow-up for surviving patients. rituximab was subsequently added to the ICE regimen for patients with diffuse large B-cell lymphoma (DLBCL) to improve upon these favorable results. This resulted in an increased complete remission rate. Additional follow-up is necessary to determine if this improvement in the complete remission rate will confer an increase in the overall survival following SCT.

https://pubmed.ncbi.nlm.nih.gov/12736224/

b740d6e2917c26c5d772eb2155529a4f

Tofacitinib combination therapy was also associated with the lower PMPM cost compared with adalimumab combination therapy in the TNF-IR analysis .

An Economic Evaluation of Tofacitinib Treatment in Rheumatoid Arthritis: Modeling the Cost of Treatment Strategies in the United States. tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). tofacitinib is approved in the United States for use in adults with moderately to severely active RA and an inadequate response or intolerance to methotrexate. ### objectives To (a) evaluate, using an economic model, the treatment costs of an RA strategy including tofacitinib, compared with adalimumab, etanercept, certolizumab and tocilizumab biologic RA treatment strategies, which are commonly prescribed in the United States, and (b) assess the economic impact of monotherapy and combination therapy in patients who had an inadequate response to methotrexate therapy (MTX-IR analysis) and to combination therapy in patients who had an inadequate response to a tumor necrosis factor inhibitor (TNF-IR analysis). ### methods A transparent, Excel-based economic model with a decision-tree approach was developed to evaluate costs over a 1- and 2-year time horizon. The model compared tofacitinib 5 mg twice a day (BID) either as monotherapy or in combination with MTX with similarly labeled biologic therapies. Response to treatment was modeled as American College of Rheumatology (ACR) 20/50/70 response. ACR20 represented clinical response and determined whether patients continued therapy. ACR response rates at 6-month intervals were sourced from prescribing information and safety event rates from a published meta-analysis. Following an adverse event or a lack of response to treatment, it was assumed that 75% of patients switched to the next line of treatment (first to abatacept and then to rituximab). The perspective was that of a U.S. payer. Costs were reported in 2015 U.S. dollars and included drug wholesale acquisition costs, monitoring, drug administration, and treatment for minor and serious adverse events. The patient population eligible for treatment was based on the total number of members (i.e., RA and non-RA) in a payer organization; members with RA treated with biologic therapies were estimated using epidemiological data. Sensitivity analyses were conducted to explore the impact of varying key parameters, including treatment-switching probability, product rebate, major rates of adverse drug reaction, and ACR20 rates, on the model outcomes. ### results tofacitinib combination therapy after MTX failure was associated with the lowest cost per member per month (PMPM) over a 2-year time frame at $5.53, compared with $6.49 for adalimumab, $6.43 for etanercept, $5.95 for certolizumab, and $5.89 for tocilizumab. Similar savings were observed when all biologics were administered as monotherapy. Tofacitinib combination therapy was also associated with the lower PMPM cost compared with adalimumab combination therapy in the TNF-IR analysis . tofacitinib was also among the lowest cost per ACR20 responder in each analysis. Sensitivity analyses demonstrated that tofacitinib would potentially be cost saving even in the least optimistic scenarios. ### conclusions This analysis suggests that tofacitinib 5 mg BID following MTX failure is a lower cost per patient treatment option when used either as monotherapy or combination therapy, compared with adalimumab, etanercept, certolizumab and tocilizumab biologic regimens. tofacitinib + MTX in TNF-IR patients was also predicted to be a lower-cost treatment option compared with adalimumab+MTX and was associated with the lowest cost per ACR 20/50/70 responder. ### disclosures This study was funded by Pfizer, which determined the research topic and paid York Health Economics Consortium to develop the analysis and conduct the research. York Health Economics Consortium has received consultancy fees from Pfizer. Gerber, Wallenstein, Mendelsohn, Bourret, Singh, and Moynagh are employees and shareholders of Pfizer. Editorial support was funded by Pfizer and was provided by Claxton, Jenks, and Taylor, who are employees of York Health Economics Consortium. Study concept and design were contributed primarily by Taylor, Jenks, Gerber, and Singh, along with the other authors. Gerber, Moynagh, and Singh collected the data, assisted by Bouret and Mendelsohn; data interpretation was performed by Claxton, Gerber, Bouret, and Mendelsohn. The manuscript was written primarily by Claxton, with assistance from the other authors, and revised by Claxton, Gerber, Bouret, and Mendelsohn, with assistance from the other authors.

https://pubmed.ncbi.nlm.nih.gov/27579831/

aa7244029b3ff67b517ef6f9a89e4e34

Effect of sequential treatments with alendronate , parathyroid hormone ( 1 - 34 ) and raloxifene on cortical bone mass and strength in ovariectomized rats .

Effect of sequential treatments with alendronate , parathyroid hormone ( 1 - 34 ) and raloxifene on cortical bone mass and strength in ovariectomized rats . Anti-resorptive and anabolic agents are often prescribed for the treatment of osteoporosis continuously or sequentially for many years. However their impact on cortical bone quality and bone strength is not clear. ### methods Six-month old female rats were either sham operated or ovariectomized (OVX). OVX rats were left untreated for two months and then were treated with vehicle (Veh), hPTH (1-34) (PTH), alendronate (Aln), or raloxifene (Ral) sequentially for three month intervals, for a total of three periods. Mid-tibial cortical bone architecture, mass, mineralization, and strength were measured on necropsy samples obtained after each period. Bone indentation properties were measured on proximal femur necropsy samples. ### results Eight or more months of estrogen deficiency in rats resulted in decreased cortical bone area and thickness. Treatment with PTH for 3months caused the deposition of endocortical lamellar bone that increased cortical bone area, thickness, and strength. These improvements were lost when PTH was withdrawn without followup treatment, but were maintained for the maximum times tested, six months with Ral and three months with Aln. Pre-treatment with anti-resorptives was also somewhat successful in ultimately preserving the additional endocortical lamellar bone formed under PTH treatment. These treatments did not affect bone indentation properties. ### summary Sequential therapy that involved both PTH and anti-resorptive agents was required to achieve lasting improvements in cortical area, thickness, and strength in OVX rats. Anti-resorptive therapy, either prior to or following PTH, was required to preserve gains attributable to an anabolic agent.

https://pubmed.ncbi.nlm.nih.gov/25016965/

b701ddeb0bd97b91f62fe6b654023d06

Atorvastatin and metformin both have pleiotropic effects .

Atorvastatin Plus Metformin Confer Additive Benefits on Subjects with Dyslipidemia and Overweight/Obese via Reducing ROCK2 Concentration. Atorvastatin and metformin both have pleiotropic effects . Whether atorvastatin combined with metformin could provide additive benefits on subjects with dyslipidemia and overweight/obese is unknown. And the mechanism is also not fully clear yet. ### methods A cross-sectional research was performed and 130 subjects with dyslipidemia and overweight/obese were enrolled and randomly assigned into combined group (20 mg of atorvastatin daily plus 500 mg of metformin twice daily) and control group (20 mg of atorvastatin daily). At baseline and 8 weeks later, parameters of interest were recorded and fasting venous blood was drawn for laboratory examination. ### results The rates of overweight (76.9% vs. 73.8%) and obese (23.1% vs. 26.2%) in both group were comparable. Dyslipidemia in both groups were featured by increased serum levels of triglyceride (TG), total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C). Serum level of high sensitivity C-reactive protein (Hs-CRP) was comparably elevated in both groups at baseline, and leukocyte rho-associated kinase 2 (ROCK2) and serum nitric oxide (NO) concentrations were also comparable. Generally, the baseline characteristics between these 2 groups were no significant differences. 8 weeks later, compared to baseline, body mass index (BMI), the rates of overweight and obese, daily exercise time, smoking status, lipid profiles, Hs-CRP level, leukocyte ROCK2 and serum NO concentrations in both groups were improved. Notably, compared to control group, the rate of obese, Hs-CRP level, leukocyte ROCK2 and serum NO concentrations were improved more profoundly in the combined group (p<0.05). After adjusted for age, gender, BMI, TG, LDL-C, Hs-CRP and exercise time, atorvastatin plus metformin was positively associated with serum NO concentration, with odds ratio (OR) of 1.146 (95% confidence interval (CI) 1.089-1.164, combined group vs. control group, p<0.05), and inversely associated with leukocyte ROCK2 concentration, with OR of 0.853 (95% CI 0.834-0.872, combined group vs. control group, p<0.05). ### conclusion In subjects with dyslipidemia and overweight/obese, atorvastatin plus metformin may confer additive benefits through reducing leukocyte ROCK2 concentration.

https://pubmed.ncbi.nlm.nih.gov/27123784/

3ddf01008a6da5a27b7b3ed32a532cba

Bevacizumab , a monoclonal antibody targeting vascular endothelial growth factor , is the first antiangiogenic drug to show improved efficacy when used in combination with irinotecan and oxaliplatin for first- and second-line treatment of CRC .

Targeted agents for adjuvant therapy of colon cancer. Among patients with colorectal cancer (CRC) diagnosed in the United States, 37.2% are diagnosed with stage III and 27.9% with stage II disease. In locoregionally advanced CRC, surgery is the primary treatment modality and has a curative intent. The survival depends on the pathologic stage and varies from 30%-60% for stage III to 60%-80% for stage II. However, as much as 40%-50% of patients will relapse and require additional treatment of the disease. Clinical failure after resection of CRC is predominantly secondary to the clinical progression of previously undetected distant metastatic disease. Until very recently, the absolute benefit for survival obtained with adjuvant therapy compared with control was about 6%. Introduction of oxaliplatin in the adjuvant setting has shown a reduction of 23% in the risk of relapse when compared with 5-fluorouracil alone (MOSAIC). Recent phase III studies have shown that targeted agents improved survival in patients with advanced-stage CRC. Bevacizumab , a monoclonal antibody targeting vascular endothelial growth factor , is the first antiangiogenic drug to show improved efficacy when used in combination with irinotecan and oxaliplatin for first- and second-line treatment of CRC . cetuximab, another monoclonal antibody targeting epidermal growth factor receptor, has shown efficacy in third-line therapy and promising results in first-line phase II studies. There is great interest in whether the biologic agents bevacizumab and cetuximab can improve survival in the adjuvant-therapy setting. This article reviews the adjuvant therapy for colon cancer and discusses the potential role and current trials involving the targeted agents.

https://pubmed.ncbi.nlm.nih.gov/16796791/

f53a76b0f77943392506a7584cb6fb49

Available data indicate that GLY and aclidinium have similar efficacy to tiotropium in terms of improving lung function , dyspnea , exacerbations , and health status .

Practical considerations when prescribing a long-acting muscarinic antagonist for patients with COPD. COPD is characterized by persistent airflow limitation, progressive breathlessness, cough, and sputum production. Long-acting muscarinic antagonists (LAMAs) are one of the recommended first-choice therapeutic options for patients with COPD, and several new agents have been developed in recent years. A literature search identified 14 published randomized, placebo-controlled studies of the efficacy and safety of LAMAs in patients with COPD, with improvements seen in lung function, exacerbations, breathlessness, and health status. A greater weight of evidence currently exists for glycopyrronium (GLY) and tiotropium than for umeclidinium and aclidinium, especially in terms of exacerbation reductions. To date, there have been few head-to-head clinical studies of the different LAMAs. Available data indicate that GLY and aclidinium have similar efficacy to tiotropium in terms of improving lung function , dyspnea , exacerbations , and health status . Overall, evidence demonstrates that currently available LAMAs provide effective and generally well-tolerated therapy for patients with COPD. Delivery devices for the different LAMAs vary, which may affect individual patient's adherence to and preference for treatment. Subtle differences between individual therapeutic options may be important to individual patients and the final treatment choice should involve physician's and patient's experiences and preferences.

https://pubmed.ncbi.nlm.nih.gov/29670345/

3d0d59d4e485f6a55293b551396a97b1

Between Oct 24 , 2016 , and Jan 24 , 2018 , 861 patients were randomly assigned to receive pembrolizumab plus axitinib ( n=432 ) or sunitinib monotherapy ( n=429 ) .

Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow-up from a randomised, open-label, phase 3 trial. The first interim analysis of the KEYNOTE-426 study showed superior efficacy of pembrolizumab plus axitinib over sunitinib monotherapy in treatment-naive, advanced renal cell carcinoma. The exploratory analysis with extended follow-up reported here aims to assess long-term efficacy and safety of pembrolizumab plus axitinib versus sunitinib monotherapy in patients with advanced renal cell carcinoma. ### methods In the ongoing, randomised, open-label, phase 3 KEYNOTE-426 study, adults (≥18 years old) with treatment-naive, advanced renal cell carcinoma with clear cell histology were enrolled in 129 sites (hospitals and cancer centres) across 16 countries. Patients were randomly assigned (1:1) to receive 200 mg pembrolizumab intravenously every 3 weeks for up to 35 cycles plus 5 mg axitinib orally twice daily or 50 mg sunitinib monotherapy orally once daily for 4 weeks per 6-week cycle. Randomisation was done using an interactive voice response system or integrated web response system, and was stratified by International Metastatic Renal Cell Carcinoma Database Consortium risk status and geographical region. Primary endpoints were overall survival and progression-free survival in the intention-to-treat population. Since the primary endpoints were met at the first interim analysis, updated data are reported with nominal p values. This study is registered with ClinicalTrials.gov, NCT02853331. ### findings Between Oct 24 , 2016 , and Jan 24 , 2018 , 861 patients were randomly assigned to receive pembrolizumab plus axitinib ( n=432 ) or sunitinib monotherapy ( n=429 ) . With a median follow-up of 30·6 months (IQR 27·2-34·2), continued clinical benefit was observed with pembrolizumab plus axitinib over sunitinib in terms of overall survival (median not reached with pembrolizumab and axitinib vs 35·7 months [95% CI 33·3-not reached] with sunitinib); hazard ratio [HR] 0·68 [95% CI 0·55-0·85], p=0·0003) and progression-free survival (median 15·4 months [12·7-18·9] vs 11·1 months [9·1-12·5]; 0·71 [0·60-0·84], p<0·0001). The most frequent (≥10% patients in either group) treatment-related grade 3 or worse adverse events were hypertension (95 [22%] of 429 patients in the pembrolizumab plus axitinib group vs 84 [20%] of 425 patients in the sunitinib group), alanine aminotransferase increase (54 [13%] vs 11 [3%]), and diarrhoea (46 [11%] vs 23 [5%]). No new treatment-related deaths were reported since the first interim analysis. ### interpretation With extended study follow-up, results from KEYNOTE-426 show that pembrolizumab plus axitinib continues to have superior clinical outcomes over sunitinib. These results continue to support the first-line treatment with pembrolizumab plus axitinib as the standard of care of advanced renal cell carcinoma. ### funding Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc.

https://pubmed.ncbi.nlm.nih.gov/33284113/

d762cec75711543c49da82dff94ed22a

Patients received 175 mg/m of paclitaxel over a 3 h infusion , followed by nedaplatin 80 mg/m in a 1 h infusion on day 1 every 3 weeks for up to 6 treatment cycles .

A retrospective study of paclitaxel combining nedaplatin chemotherapy for esophageal cancer. The aim of this study was to evaluate the efficacy and tolerability of the combination of paclitaxel and nedaplatin in patients with advanced esophageal cancer. Patients (n = 310) with recurrent or metastatic esophageal squamous cell carcinoma, who had a maximum of one previous chemotherapy regimen, were enrolled in this study. All patients had bidimensionally measurable disease. Patients received 175 mg/m of paclitaxel over a 3 h infusion , followed by nedaplatin 80 mg/m in a 1 h infusion on day 1 every 3 weeks for up to 6 treatment cycles . The overall response rate was 47.7%, with complete and partial response rates of 6.1 and 41.7%, respectively. The median time to progression for all patients was 6.8 months (95% confidence interval, 6.2-7.4 months) and the 3-year disease-free survival probability was 3 (15.8%). The major toxicity observed was cumulative neutropenia, with 29% patients developing grade 4 toxicity. There was no treatment-related death. The most common nonhematologic toxicity encountered with this regimen was pain and cumulative peripheral neuropathy, with 26% patients experiencing grade 2 or 3 toxicity. The combination of paclitaxel and nedaplatin shows significant antitumor activity and a favorable toxicity profile in patients with metastatic carcinoma of esophageal cancer.

https://pubmed.ncbi.nlm.nih.gov/25222530/

b6c21f8f5634747e728badfc6d8eb528

After a median follow-up of 9.5 years , 10-year OS rates in the bolus/infusional fluorouracil plus leucovorin ( LV5FU2 ) and LV5FU2 plus oxaliplatin ( FOLFOX4 ) arms were 67.1 % versus 71.7 % ( hazard ratio [ HR ] , 0.85 ; P = .043 ) in the whole population , 79.5 % versus 78.4 % for stage II ( HR , 1.00 ; P = .980 ) , and 59.0 % versus 67.1 % for stage III ( HR , 0.80 ; P = .016 ) disease .

Adjuvant Fluorouracil, Leucovorin, and Oxaliplatin in Stage II to III Colon Cancer: Updated 10-Year Survival and Outcomes According to BRAF Mutation and Mismatch Repair Status of the MOSAIC Study. The MOSAIC (Multicenter International Study of oxaliplatin/fluorouracil/leucovorin in the Adjuvant Treatment of Colon Cancer) study has demonstrated 3-year disease-free survival (DFS) and 6-year overall survival (OS) benefit of adjuvant oxaliplatin in stage II to III resected colon cancer. This update presents 10-year OS and OS and DFS by mismatch repair (MMR) status and BRAF mutation. ### methods Survival actualization after 10-year follow-up was performed in 2,246 patients with resected stage II to III colon cancer. We assessed MMR status and BRAF mutation in 1,008 formalin-fixed paraffin-embedded specimens. ### results After a median follow-up of 9.5 years , 10-year OS rates in the bolus/infusional fluorouracil plus leucovorin ( LV5FU2 ) and LV5FU2 plus oxaliplatin ( FOLFOX4 ) arms were 67.1 % versus 71.7 % ( hazard ratio [ HR ] , 0.85 ; P = .043 ) in the whole population , 79.5 % versus 78.4 % for stage II ( HR , 1.00 ; P = .980 ) , and 59.0 % versus 67.1 % for stage III ( HR , 0.80 ; P = .016 ) disease . Ninety-five patients (9.4%) had MMR-deficient (dMMR) tumors, and 94 (10.4%) had BRAF mutation. BRAF mutation was not prognostic for OS (P = .965), but dMMR was an independent prognostic factor (HR, 2.02; 95% CI, 1.15 to 3.55; P = .014). HRs for DFS and OS benefit in the FOLFOX4 arm were 0.48 (95% CI, 0.20 to 1.12) and 0.41 (95% CI, 0.16 to 1.07), respectively, in patients with stage II to III dMMR and 0.50 (95% CI, 0.25 to 1.00) and 0.66 (95% CI, 0.31 to 1.42), respectively, in those with BRAF mutation. ### conclusion The OS benefit of oxaliplatin-based adjuvant chemotherapy, increasing over time and with the disease severity, was confirmed at 10 years in patients with stage II to III colon cancer. These updated results support the use of FOLFOX in patients with stage III disease, including those with dMMR or BRAF mutation.

https://pubmed.ncbi.nlm.nih.gov/26527776/

89852eabc5c5a033839f43602db85e9b

[ Effects of combined use of dofetilide and verapamil on the action potential of papillary muscles in guinea pigs ] .

[ Effects of combined use of dofetilide and verapamil on the action potential of papillary muscles in guinea pigs ] . To test the effects of combined use of dofetilide and verapamil on the action potential of papillary muscles in guinea pigs. ### methods Under the stimulation of different frequencies (0.2, 0.5, 1.0, 1.25 or 2.0 Hz), the action potential of papillary muscles in guinea pigs was recorded with the standard microelectrode techniques. The impacts of different concentrations of amiodarone (1, 5 or 10 micromol/L), dofetilide (10, 50, 100 nmol/L), and a combination of 100 nmol/L dofetilide and 1 micromol/L verapamil on the action potential were tested. ### results amiodarone prolonged the action potential duration (APD) significantly, measured both at 50% (APD50) and 90% (APD90) of repolarization, in a concentration-dependent manner independent from stimulation frequencies. dofetilide prolonged APD in a concentration-dependent manner, which was negatively dependent on stimulation frequencies. The frequency-dependent effect was ameliorated by adding 1 micromol/L verapamil to dofetilide. ### conclusion Both amiodarone and dofetilide prolong APD in a concentration-dependent manner. The class III antiarrhythmic compounds, amiodarone, has less frequency-dependent effect than the pure class III antiarrhythmic drug. A combined use of potassium and calcium antagonists may reduce the frequency-dependence of the pure class III antiarrhythmic drug.

https://pubmed.ncbi.nlm.nih.gov/19950594/

e54f6bdb2e26e38522cbd9d86f9cda86

Patients with pancreatic adenocarcinoma , pre-treated with gemcitabine-based chemotherapy , were treated with capecitabine ( 800 mg/m(2 ) orally , twice a day for 14 days ) and docetaxel ( 75 mg/m(2 ) i.v , on day 1 ) , every 3 weeks .

Second-line chemotherapy with capecitabine (Xeloda) and docetaxel (Taxotere) in previously treated, unresectable adenocarcinoma of pancreas: the final results of a phase II trial. To investigate the efficacy and toxicity of the docetaxel and capecitabine combination in patients with previously treated, unresectable adenocarcinoma of the pancreas. ### Patients And Methods Patients with pancreatic adenocarcinoma , pre-treated with gemcitabine-based chemotherapy , were treated with capecitabine ( 800 mg/m(2 ) orally , twice a day for 14 days ) and docetaxel ( 75 mg/m(2 ) i.v , on day 1 ) , every 3 weeks . The primary end-point was overall response rate (RR). ### results Thirty-one patients were enrolled in the study; 93.6% of them had a performance status (PS) of 0-1 and 96.8% had stage IV disease. Patients received a median of 4 cycles/patient, and the main reason for treatment discontinuation was disease progression. Partial response was observed in three (9.7%) patients, stable disease in seven (22.6%) (disease control rate: 32.3%, 95% CI: 15.80-48.71%) and disease progression in 21 (67.6%). The median progression-free survival (PFS) was 2.4 months (95% CI: 1.6-3.13) and the median overall survival (OS) was 6.3 months (95% CI: 3.38-9.23); the estimated 1-year survival rate was 14.7%. Grade III/IV neutropenia occurred in 10 (32.2%) patients and febrile neutropenia in one patient. Other severe non-hematologic toxicities were mild and manageable. After 2 chemotherapy cycles, pain control occurred in 20% of patients and stabilization of body weight in 40%. ### conclusion The combination of docetaxel/capecitabine may confer good disease control associated with improvement of quality of life as second-line chemotherapy in patients with metastatic pancreatic cancer.

https://pubmed.ncbi.nlm.nih.gov/20428874/

e57340a652b30cdb82156c64b7b39d08

Comparative study of dose escalation versus interval reduction to obtain dose-intensification of epirubicin and cyclophosphamide with granulocyte colony-stimulating factor in advanced breast cancer .

Comparative study of dose escalation versus interval reduction to obtain dose-intensification of epirubicin and cyclophosphamide with granulocyte colony-stimulating factor in advanced breast cancer . A potential application of hematopoietic growth factors is to obtain an increased dose-intensity. This can be achieved by either higher doses of chemotherapy with standard intervals, or by standard doses with shorter intervals. The potential of these approaches has not been investigated systematically. ### Patients And Methods In a randomized, multicenter study, 49 advanced breast cancer patients were treated with granulocyte colony-stimulating factor (G-CSF) and either increasing doses of epirubicin and cyclophosphamide with fixed intervals (arm one) or progressively shorter intervals with fixed doses of epirubicin and cyclophosphamide (arm two). A cohort of at least six patients was studied at each interval/dose. A more intensified interval/dose was given if less than 50% of patients encountered a dose-intensity limiting criterium (DILC) in the first three courses. ### results In arm one, epirubicin 140 mg/m2 and cyclophosphamide 800 mg/m2 every 21 days was too toxic. Subsequently, epirubicin 120 mg/m2 and cyclophosphamide 700 mg/m2 was tested with two of 10 patients encountering a DILC. All initial DILCs consisted of febrile neutropenia. In arm two, epirubicin 75 mg/m2 and cyclophosphamide 500 mg/m2 could be administered safely with 14- and 12-day intervals. In the 10-day interval, eight of 12 patients completed the first three cycles without a DILC. In the 8-day interval, seven of eight patients encountered a DILC. Incomplete neutrophil recovery, and to a lesser extent stomatitis, were dose-limiting. ### conclusion In combination with G-CSF, epirubicin 120 mg/m2 and cyclophosphamide 700 mg/m2 every 21 days was feasible (projected dose-intensity, 40 mg/m2/wk and 233 mg/m2/wk, respectively). epirubicin 75 mg/m2 and cyclophosphamide 500 mg/m2 could be administered safely every 10 days, allowing a projected dose-intensity of 52.5 mg/m2/wk and 350 mg/m2/wk, respectively.

https://pubmed.ncbi.nlm.nih.gov/9193328/

90f9283bb0869bd11721e467f718e869

The hearts were treated during the whole procedure either with vehicle , 0.5 μM flecainide ( sodium channel blocker ) or 100 μM streptomycin ( here used as stretch-activated ion-channel blocker ) .

Arrhythmogenic effects by local left ventricular stretch: effects of flecainide and streptomycin. Mechanical stretch has been shown to provoke arrhythmia. We wanted to analyze ventricular arrhythmia induced by local left ventricular stretch in order to find out, where arrhythmias originate and whether they can be prevented pharmacologically. Isolated rabbit hearts (Langendorff technique) were submitted to increased left ventricular stretch at the left wall by insertion of an additional intraventricular balloon and adjusting the end-diastolic pressure (EDP) to 25 mmHg for 10 min followed by 20 min recovery at normal EDP of 5-8 mmHg. Activation and repolarization processes were investigated by ventricular 256 electrode epicardial mapping. The hearts were treated during the whole procedure either with vehicle , 0.5 μM flecainide ( sodium channel blocker ) or 100 μM streptomycin ( here used as stretch-activated ion-channel blocker ) . In addition, we performed a series of experiments, in which we enhanced EDP to 30 mmHg (global stretch instead of local stretch) by inflating the left ventricular pressure balloon (strain, 0.148 ± 0.034). Each series was performed with n = 6. Stretch resulted in local strain of 25% at the left wall together with a local slowing of the activation process at the left wall, in a change in the activation pattern, and in ventricular arrhythmia. Coronary flow was not affected. Ventricular arrhythmias originated from the border between the stretched area and the non-stretched region. flecainide and streptomycin reduced the prolongation of the activation process at the stretched left wall and mitigated the difference in total activation time between left and front wall but only partially prevented arrhythmia. In the additional global stretch experiments relative coronary flow and the other parameters remained unchanged, in particular TAT. Thus, in contrast to the local stretch series, there was no difference in the change in TAT between left and front wall. Only rare single ventricular extrasystoles (<1/min; originating from LV (front and left wall) i.e. from within the stretched region) were seen during stretch (but not at the beginning) and during recovery. Local left ventricular stretch can elicit ventricular arrhythmias. Local slowing of electrical activation seems involved so that the difference in total activation time of the stretched free left wall and the non-stretched increased.

https://pubmed.ncbi.nlm.nih.gov/24858181/

fd589e56235bfb107bb352c60763500e

In the APHINITY study ( NCT01358877 , BIG 4 - 11/BO25126/TOC4939 G ) , pertuzumab added to trastuzumab and chemotherapy significantly improved invasive disease-free survival as adjuvant treatment for patients with HER2-positive early breast cancer .

Pharmacokinetics of pertuzumab administered concurrently with trastuzumab in Chinese patients with HER2-positive early breast cancer. In the APHINITY study ( NCT01358877 , BIG 4 - 11/BO25126/TOC4939 G ) , pertuzumab added to trastuzumab and chemotherapy significantly improved invasive disease-free survival as adjuvant treatment for patients with HER2-positive early breast cancer . The objective of this analysis was to assess the pharmacokinetics of pertuzumab in combination with trastuzumab in Chinese patients with early breast cancer. Samples for pertuzumab and trastuzumab pharmacokinetic analysis were taken from Chinese patients during cycle 1 of treatment and at steady-state in cycle 10. Noncompartmental analysis was used to estimate minimum and maximum serum concentrations (Cmax and Cmin), area under the concentration-time curve, clearance, and other pharmacokinetic parameters. In 15 patients, mean steady-state Cmax and Cmin pertuzumab serum concentrations (368 ± 177 μg/ml, and 122 ± 47 μg/ml, respectively) were numerically higher than observed previously in a pharmacokinetic analysis of the global population in APHINITY and in patients treated in the metastatic setting. The geometric mean ratio and corresponding 90% confidence interval for trastuzumab Cmax and Cmin in the presence (n = 15) or absence (n = 17) of pertuzumab were 104.6 (91.09-120) and 98.23 (84.58-114), respectively, indicating no apparent impact of pertuzumab on the pharmacokinetics of trastuzumab. Increases in pertuzumab Cmax and Cmin were not associated with an increase in adverse events. The APHINITY Chinese pharmacokinetic substudy analysis supports the dosing regimen for pertuzumab (840 mg loading dose followed by 420 mg maintenance doses every 3 weeks administered by intravenous infusion) in a Chinese HER2-positive early breast cancer patient population.

https://pubmed.ncbi.nlm.nih.gov/31305270/

842c481f52d8e56971342febee357ad0

In two trials , an anti-EGFR antibody ( panitumumab or cetuximab ) reduced median survival when added to bevacizumab in previously untreated patients .

Chemotherapy of metastatic colorectal cancer. Without treatment, patients with inoperable or metastatic colorectal cancer have a median life expectancy of about 8 months. The following article is an update of our 2005 review of chemotherapy regimens used in metastatic colorectal cancer, based on the standard Prescrire methodology. In 2005, the de Gramont protocol, based on fluorouracil (always combined with folinic acid) plus either oxaliplatin (Folfox protocol) or irinotecan (Folfiri protocol), was the standard first-line chemotherapy in this setting. Four trials comparing monotherapy versus combination therapy in previously untreated patients showed that initial fluorouracil (or fluorouracil precursor) monotherapy, followed by the Folfox or Folfiri protocol in case of failure, was not associated with shorter overall survival. Two trials compared first-line treatment with the Folfiri regimen versus the Folfoxiri regimen (fluorouracil + oxaliplatin + irinotecan). One of these studies showed an increase in median survival with the Folfoxiri protocol (24 versus 17 months), but at a cost of greater neurotoxicity. The only tangible advantage of capecitabine and tegafur, two oral fluorouracil precursors, is their convenience of use. pemetrexed was less effective and more toxic than the Folfiri protocol in one trial. bevacizumab and panitumumab have yielded disappointing results in previously untreated patients. Neither of these monoclonal antibodies has yet been shown to improve overall survival. Three trials have assessed the addition of cetuximab to combinations consisting of fluorouracil or capecitabine plus oxaliplatin or irinotecan. In two of these trials, the median survival time of patients whose tumours carried the wild-type KRAS gene was about 3 months longer in the cetuximab arms, although the increase was statistically significant in only one trial. cetuximab had no impact on survival time in the third trial. In two trials , an anti-EGFR antibody ( panitumumab or cetuximab ) reduced median survival when added to bevacizumab in previously untreated patients . When progression occurs after treatment with the Folfiri protocol (or equivalent), a combination of the Folfox protocol and bevacizumab seems to increase median survival time by about 2 months versus Folfox alone, but it is also more toxic. In patients who progress after receiving the fluorouracil + oxaliplatin combination (Folfox) or the fluorouracil+ irinotecan combination (Folfiri), neither panitumumab nor cetuximab has been shown to provide a clinically meaningful increase in overall survival. It remains to be shown whether these drugs are more effective in patients with the wild-type KRAS gene than in patients with KRAS mutations. In early 2010, the standard cytotoxic drugs for treatment of metastatic colorectal cancer are fluorouracil (combined with folinic acid), oxaliplatin and irinotecan. Initial combination therapy may be beneficial when the metastases are borderline operable. When the metastases are inoperable and are unlikely to become operable after chemotherapy, it seems best to begin treatment with single-agent fluorouracil (+ folinic acid) or capecitabine. The use of monoclonal antibodies in first-line treatment of patients with colorectal cancer is not justified. Further trials of these drugs are warranted as second-line treatment for patients with KRAS wild-type tumours.

https://pubmed.ncbi.nlm.nih.gov/21180382/

32d6f9ea24ebefa67b7f337223591178

The results of the APPEARANCE trial indicate that adapalene does not prevent acne-like rash over placebo when added to topical moisturizer and oral minocycline but instead may have a detrimental effect .

Adapalene Gel 0.1% Versus Placebo as Prophylaxis for Anti-Epidermal Growth Factor Receptor-Induced Acne-Like Rash: A Randomized Left-Right Comparative Evaluation (APPEARANCE). The results of the APPEARANCE trial indicate that adapalene does not prevent acne-like rash over placebo when added to topical moisturizer and oral minocycline but instead may have a detrimental effect . Therefore, adapalene is not recommended as prophylaxis against acne-like rash induced by anti-epidermal growth factor receptor therapies.Given that acne-like rash was completely controlled with placebo in approximately half of patients, predictive measures to identify patients needing intensive prophylaxis are required. ### background Anti-epidermal growth factor receptor (EGFR) therapies are frequently associated with acne-like rash. To evaluate the prophylactic efficacy of adapalene, a topical retinoid used as first-line therapy for acne vulgaris, we conducted a randomized, placebo-controlled, evaluator-blinded, left-right comparative trial. ### methods Patients with non-small cell lung, colorectal, or head and neck cancer scheduled to receive anti-EGFR therapies were randomly assigned to once-daily adapalene application on one side of the face, with placebo on the other side. All patients had topical moisturizer coapplied to both sides of the face, and received oral minocycline. The primary endpoint was the difference in total facial lesion count of acne-like rash at 4 weeks. Secondary endpoints included complete control rate (CCR) of acne-like rash (≤5 facial lesions) and global skin assessment (Investigator's Global Assessment [IGA] scale, grade 0-4) at 4 weeks. Two blinded dermatologists independently evaluated the endpoints from photographs. ### results A total of 36 patients were enrolled, of whom 26 were evaluable. adapalene treatment was associated with a greater lesion count than placebo at 4 weeks, although the difference was not statistically significant (mean, 12.6 vs. 9.8, ### conclusion adapalene is not recommended as prophylaxis against acne-like rash induced by anti-EGFR therapies.

https://pubmed.ncbi.nlm.nih.gov/30890624/

fe491984e9df643f36a53c19d1b92689

Both regimens included cyclophosphamide , methotrexate , 5-FU , prednisone , and doxorubicin .

Randomized comparison of two combination chemotherapy regimens containing doxorubicin in patients with metastatic breast cancer: a Western Cancer Study Group trial. Ninety-six patients with metastatic breast cancer were entered in a prospectively randomized trial comparing a five-drug doxorubicin (Adriamycin)-containing regimen given in two different schedules. Both regimens included cyclophosphamide , methotrexate , 5-FU , prednisone , and doxorubicin . On one schedule, referred to as "combination" treatment, doxorubicin was given every 21 days and cyclophosphamide was given daily. On the less intensive "fixed-rotation" schedule, doxorubicin was given on alternative cycles every 42 days and cyclophosphamide was given for 21 days of the 42-day cycle. Response frequency and survival were comparable among patients receiving either regimen. Significantly less (P < 0.05) nausea and leukopenia occurred on the fixed-rotation schedule. Therefore, similar therapeutic benefit along with decreased toxicity was obtained by use of combination chemotherapy involving doxorubicin and cyclophosphamide given in the less intensive schedule.

https://pubmed.ncbi.nlm.nih.gov/7004635/

d8c8bee379a8e9440c10b70d55a1dd89

In 2011 , new drugs were approved by the U.S. Food and Drug Administration , including peginterferon alfa-2b for patients with stage III disease , vemurafenib for patients with metastatic melanoma with the BRAF V600E mutation , and ipilimumab , a monoclonal antibody directed to the CTLA-4 T lymphocyte receptor , to combat metastatic melanoma in patients who do not have the BRAF V600E mutation .

Cutaneous melanoma: new advances in treatment. Cutaneous melanoma is a challenge to treat. Over the last 30 years, no drug or combination of drugs demonstrated significant impact to improve patient survival. From 1995 to 2000, the use of cytokines such as interferon and interleukin become treatment options. In 2011 , new drugs were approved by the U.S. Food and Drug Administration , including peginterferon alfa-2b for patients with stage III disease , vemurafenib for patients with metastatic melanoma with the BRAF V600E mutation , and ipilimumab , a monoclonal antibody directed to the CTLA-4 T lymphocyte receptor , to combat metastatic melanoma in patients who do not have the BRAF V600E mutation . Both ipilimumab and vemurafenib showed results in terms of overall survival. Other trials with inhibitors of other genes, such as the KIT gene and MEK, are underway in the search for new discoveries. The discovery of new treatments for advanced or metastatic disease aims to relieve symptoms and improve patient quality of life.

https://pubmed.ncbi.nlm.nih.gov/24770508/

7710b6d76f366019125879999cf7208f

Individual studies have reported differences between antiandrogens in terms of both tolerability and efficacy-for example , bicalutamide has been shown to be better tolerated than flutamide , and may be associated with improved survival .

Combination hormonal therapy: a reassessment within advanced prostate cancer. Combination hormonal therapy, comprising a luteinising hormone-releasing hormone analogue (LHRHa) with an antiandrogen, is widely used in the treatment of advanced prostate cancer. There is ongoing debate regarding the use of combination hormonal therapy as opposed to LHRHa monotherapy. The pivotal consideration is whether there are adequate benefits with combination hormonal therapy in terms of increased survival and decreased disease progression to outweigh the increased risk of adverse events and additional cost. The most recent meta-analysis by the Prostate Cancer Trialists' Collaborative Group indicates a small but statistically significant survival benefit with combination hormonal therapy using nonsteroidal antiandrogens. It is, however, noteworthy that combined conclusions derived from such meta-analyses may not apply across each of the individual antiandrogens. Individual studies have reported differences between antiandrogens in terms of both tolerability and efficacy-for example , bicalutamide has been shown to be better tolerated than flutamide , and may be associated with improved survival . In addition, it is essential that treatment decisions are taken in consultation with the patient. Owing to an increasing proportion of cases presenting with early-stage disease, combination hormonal therapy is increasingly used in the neoadjuvant or adjuvant setting with radiotherapy and, in cases of prostate-specific antigen recurrence after prior localised therapy. Further data are awaited to optimise the use of combination hormonal therapy in these new settings.

https://pubmed.ncbi.nlm.nih.gov/15365575/

778960b473d357bcf187c40c2b8bd36f

A Randomized , Multicenter , Double-blind , Phase III Study to Evaluate the Efficacy on Allergic Rhinitis and Safety of a Combination Therapy of Montelukast and Levocetirizine in Patients With Asthma and Allergic Rhinitis .

A Randomized , Multicenter , Double-blind , Phase III Study to Evaluate the Efficacy on Allergic Rhinitis and Safety of a Combination Therapy of Montelukast and Levocetirizine in Patients With Asthma and Allergic Rhinitis . The aim of this study was to evaluate the efficacy and safety of a fixed-dose combination of montelukast and levocetirizine in patients with perennial allergic rhinitis with mild to moderate asthma compared with the efficacy and safety of montelukast alone. ### methods This study was a 4-week, randomized, multicenter, double-blind, Phase III trial. After a 1-week placebo run-in period, the subjects were randomized to receive montelukast (10 mg/day, n = 112) or montelukast (10 mg/day)/levocetirizine (5 mg/day) (n = 116) treatment for 4 weeks. The primary efficacy end point was mean daytime nasal symptom score. Other efficacy end points included mean nighttime nasal symptom score, mean composite symptom score, overall assessment of allergic rhinitis by both subjects and physicians, forced expiratory volume in 1 second (FEV ### findings Of 333 patients screened for this study, 228 eligible patients were randomized to treatment. The mean (SD) age of patients was 43.32 (15.02) years, and two thirds of subjects were female (66.67%). The demographic characteristics were similar between the treatment groups. Compared with the montelukast group, the montelukast/levocetirizine group reported significant reductions in mean daytime nasal symptom score (least squares mean [SE] of combination vs montelukast, -0.98 [0.06] vs -0.81 [0.06]; P = 0.045). For all other allergic rhinitis efficacy end points, the montelukast/levocetirizine group showed greater improvement than the montelukast group. Similar results were observed in overall assessment scores and in FEV ### implications The fixed-dose combination of montelukast and levocetirizine was effective and safe in treating perennial allergic rhinitis in patients with asthma compared with montelukast alone. ClinicalTrials.gov identifier: NCT02552667.

https://pubmed.ncbi.nlm.nih.gov/29945738/

dec2ee86c2d3ab1e469f8cc6645bcc97

Intravenous administration of cefoperazone and sulbactam given as individual agents compared with the combination did not show pharmacokinetic differences that are likely to produce clinically relevant effects .

Multiple-dose pharmacokinetics and toleration of intravenously administered cefoperazone and sulbactam when given as single agents or in combination. The multiple-dose pharmacokinetics and toleration of cefoperazone (3 g every 12 h) and sulbactam (1.5 g every 12 h) were studied when these antimicrobial agents were administered continuously over 7 days as a 15-min infusion of individual agents and as a 3/1.5-g cefoperazone-sulbactam combination. Fourteen male volunteers participated in an open, three-way crossover study of Latin Square design with a 1-week washout period between phases. On days 1 and 7 of each phase, serial serum samples and urine were collected for drug assay over a 12-h period. Hematological and clinical chemistry determinations were made within 10 days before the first antibiotic dose and for each treatment phase just before the first dose, on day 4 of treatment, and within 24 h of the last dose. For cefoperazone as a single agent on days 1 and 7, the average maximal concentration in serum (Cmax) was approximately 430 micrograms/ml, the terminal elimination half-life (t1/2) was 1.8 h, and the average percentage of dose excreted unchanged in the urine (%Ur) was 30%. For sulbactam as a single agent, the Cmax was approximately 90 micrograms/ml, the t1/2 was 1 h, and the %Ur was 89% on days 1 and 7. When comparing individual versus simultaneous drug administration, the only pharmacokinetic alteration observed was a statistically significant but minor (about 10%) decrease in sulbactam renal clearance, on both days 1 and 7, resulting in a similar decrease in total body clearance (CL). The area under the curve, apparent volume of distribution by the area method (V), t1/2, and Cmax were not significantly altered. Although cefoperazone pharmacokinetic parameters were not significantly altered when comparing single-agent to combination drug administration, the area under the curve was slightly lower and CL, nonrenal clearance, and V were modestly higher from day 1 to day 7. Because Cmax and t1/2 were unaffected, these minor day effects would not be of clinical significance. Intravenous administration of cefoperazone and sulbactam given as individual agents compared with the combination did not show pharmacokinetic differences that are likely to produce clinically relevant effects . The combination of cefoperazone and sulbactam was well tolerated, and the safety profile of the combination was similar to that either drug given alone under the conditions of this study.

https://pubmed.ncbi.nlm.nih.gov/3348612/

97fe69f307e811dcf18ff2b21cef466f

HDC with cyclophosphamide , carmustine and thiotepa was given from day -7 to -5 .

Interleukin-2 and granulocyte-macrophage-colony-stimulating factor immunomodulation with high-dose chemotherapy and autologous hematopoietic stem cell transplantation for patients with metastatic breast cancer. Immunomodulation with cytokines was used to improve the result of high-dose chemotherapy (HDC)/autologous hematopoietic stem cell transplantation (AHST). We examined the use of IL-2 and growth factors for mobilization, ex vivo activation of peripheral blood stem cell (PBSC) and maintenance therapy after HDC/AHST in metastatic breast cancer. Eligible patients with metastatic breast cancer for HDC/AHST were assigned to 1 of 3 protocols for PBSC mobilization: G-CSF (group 1); IL-2 + G-CSF (group 2); or IL-2 + G-CSF + GM-CSF (group 3). HDC with cyclophosphamide , carmustine and thiotepa was given from day -7 to -5 . PBSCs were treated ex vivo with IL-2 for 24 h and reinfused on day 0. Maintenance therapy included low-dose IL-2, followed by 2 courses of intermediate-dose IL-2. GM-CSF was given from day 1 until neutrophil recovery. Thirty-four patients (10 in group 1, 14 in group 2, and 10 in group 3) were included. Comparable numbers of CD34(+) cells were collected from all 3 groups; incremental increases of CD3(+) cells were collected from groups 1 to 2 and to 3 (p = 0.03). Major adverse effects from IL-2 were fever, hypotension and fatigue; no treatment-related mortality was seen. At a median follow-up of 790.5 days (range 150-2,722 days), median progression-free survival was 434 days and median overall survival was 1,432 days. Estimated 3-year progression-free and overall survival rates were 31 and 57%. Our study suggested that the use of IL-2 and growth factors immunomodulation with HDC/AHST was feasible with comparable survival rates.

https://pubmed.ncbi.nlm.nih.gov/19998065/

44ad2538e2540fa90b878956d4de15df

Melatonin or sulpiride could replace these environmental factors .

Controlling retinal pigment epithelium injury after experimental detachment of the retina. Damage induced by detachment of the neural retina and the retinal pigment epithelium (RPE) can be reduced by dark adaptation. The authors evaluated the influence of the duration of dark adaptation, time of day, and modification of the melatonin-dopamine pathway on acute RPE lesions induced by mechanical detachment. ### methods BALB/c mice were studied at different times of day and different periods of dark adaptation. Some mice were treated with melatonin or sulpiride, a D2 dopamine receptor antagonist. Enucleated eyes and different saline solutions were used in experiments ex vivo. Retinal detachments in vivo were made by subretinal injections of hyaluronic acid. RPE cell damage was quantitatively evaluated with a dye exclusion procedure, and their viability was tested by preservation of tight junctions in culture. Lectin histochemistry was used to examine the interphotoreceptor matrix (IPM). ### results Significant propidium iodide (PI) incorporation in RPE cells was detected after ex vivo separation during daytime, but it was very low when detachment took place at night after 24 to 48 hours of dark adaptation. PI exclusion was achieved during daytime after a single hour of dark adaptation when mice were pretreated with melatonin or sulpiride. Reduction of RPE cell damage was accompanied by decreased lectin binding to cone sheaths. ### conclusions A combination of time of day and length of dark adaptation decreased damage induced by detachment of the retina ex vivo and in vivo. Melatonin or sulpiride could replace these environmental factors . Therefore, melatonin and dopamine pathways might be involved in the control of IPM properties and retina/RPE interactions.

https://pubmed.ncbi.nlm.nih.gov/17325183/

1df7aefd099152b9e422ca4f3480841f

Trastuzumab and Pertuzumab Plant Biosimilars : Modification of Asn297-linked Glycan of the mAbs Produced in a Plant with Fucosyltransferase and Xylosyltransferase Gene Knockouts .

Trastuzumab and Pertuzumab Plant Biosimilars : Modification of Asn297-linked Glycan of the mAbs Produced in a Plant with Fucosyltransferase and Xylosyltransferase Gene Knockouts . Plant biosimilars of anticancer therapeutic antibodies are of interest not only because of the prospects of their practical use, but also as an instrument and object for study of plant protein glycosylation. In this work, we first designed a pertuzumab plant biosimilar (PPB) and investigated the composition of its Asn297-linked glycan in comparison with trastuzumab plant biosimilar (TPB). Both biosimilars were produced in wild-type (WT) Nicotiana benthamiana plant (PPB-WT and TPB-WT) and transgenic ΔXTFT N. benthamiana plant with XT and FT genes knockout (PPB-ΔXTFT and TPB-ΔXTFT). Western blot analysis with anti-α1,3-fucose and anti-xylose antibodies, as well as a test with peptide-N-glycosidase F, confirmed the absence of α1,3-fucose and xylose in the Asn297-linked glycan of PPB-ΔXTFT and TPB-ΔXTFT. Peptide analysis followed by the identification of glycomodified peptides using MALDI-TOF/TOF showed that PPB-WT and TPB-WT Asn297-linked glycans are mainly of complex type GnGnXF. The core of PPB-WT and TPB-WT Asn297-linked GnGn-type glycan contains α1,3-fucose and β1,2-xylose, which, along with the absence of terminal galactose and sialic acid, distinguishes these plant biosimilars from human IgG. Analysis of TPB-ΔXTFT total carbohydrate content indicates the possibility of changing the composition of the carbohydrate profile not only of the Fc, but also of the Fab portion of an antibody produced in transgenic ΔXTFT N. benthamiana plants. Nevertheless, study of the antigen-binding capacity of the biosimilars showed that absence of xylose and fucose residues in the Asn297-linked glycans does not affect the ability of the glycomodified antibodies to interact with HER2/neu positive cancer cells.

https://pubmed.ncbi.nlm.nih.gov/28371609/

ab76770db4af60662537ffbe504aa0c9

A recently reported phase II trial has demonstrated that trastuzumab plus vinorelbine is both effective ( overall response rate 75 % ) and well tolerated , with the major side effects being typical of single-agent vinorelbine .

New combinations with Herceptin in metastatic breast cancer. Preclinical data indicate that trastuzumab (Herceptin) has the potential for synergistic or additive effects in combination with therapies including chemotherapy and hormonal agents, providing the rationale for a number of clinical trials in women with HER2-positive metastatic breast cancer. A recently reported phase II trial has demonstrated that trastuzumab plus vinorelbine is both effective ( overall response rate 75 % ) and well tolerated , with the major side effects being typical of single-agent vinorelbine . Other combinations of trastuzumab with a variety of other chemotherapeutic and hormonal agents are also being assessed. In an effort to overcome the cardiotoxicity observed with trastuzumab plus doxorubicin in the pivotal phase III trial, combination regimens involving potentially less toxic anthracyclines such as epirubicin and liposomal formulations of doxorubicin are ongoing. In addition, trials are investigating whether trastuzumab can reverse the resistance to hormonal therapy that develops in most women with metastatic breast cancer. These and other studies will identify the regimens that produce the best outcomes with the fewest possible side effects in women with HER2-positive breast cancer.

https://pubmed.ncbi.nlm.nih.gov/11694788/

e1c3fcbebfbf9bd3d6eb900c930c8bc1

Men with prostate cancer were randomly assigned to one of four treatment arms : leuprorelin , goserelin , cyproterone acetate ( CPA ) , or close clinical monitoring .

Quality of life compared during pharmacological treatments and clinical monitoring for non-localized prostate cancer: a randomized controlled trial. To investigate the effects of different management strategies for non-localized prostate cancer on men's quality of life and cognitive functioning. ### Patients Subjects And Methods Men with prostate cancer were randomly assigned to one of four treatment arms : leuprorelin , goserelin , cyproterone acetate ( CPA ) , or close clinical monitoring . In a repeated-measures design, men were assessed before treatment (baseline) and after 6 and 12 months of treatment. A community comparison group of men of the same age with no prostate cancer participated for the same length of time. The men were recruited from public and private urology departments from university teaching hospitals. All those with prostate cancer who were eligible for hormonal therapy had no symptoms requiring immediate therapy. In all, 82 patients were randomized and 62 completed the 1-year study, and of the 20 community participants, 15 completed the study. The main outcome measures were obtained from questionnaires on emotional distress, existential satisfaction, physical function and symptoms, social and role function, subjective cognitive function, and sexual function, combined with standard neuropsychological tests of memory, attention, and executive functions. ### results Sexual dysfunction increased for patients on androgen-suppressing therapies, and emotional distress increased in those assigned to CPA or close clinical monitoring. Compared with before treatment there was evidence of an adverse effect of leuprorelin, goserelin, and CPA on cognitive function. ### conclusions In deciding the timing of androgen suppression therapy for prostate cancer, consideration should be given to potential adverse effects on quality of life and cognitive function.

https://pubmed.ncbi.nlm.nih.gov/15142146/

7bd97010e6ca716490f2fe6f366d14b6

There were no significant differences between the two treatment groups , except that amantadine was inferior to mycophenolate mofetil regarding the outcome failure to achieve end-of treatment virological response ( low quality of evidence ) .

Aminoadamantanes versus other antiviral drugs for chronic hepatitis C. Hepatitis C virus infection affects around 3% of the world population or approximately 160 million people. A variable proportion (5% to 40%) of the infected people develop clinical symptoms. Hence, hepatitis C virus is a leading cause of liver-related morbidity and mortality with hepatic fibrosis, end-stage liver cirrhosis, and hepatocellular carcinoma as the dominant clinical sequelae. Combination therapy with pegylated (peg) interferon-alpha and ribavirin achieves sustained virological response (that is, undetectable hepatitis C virus RNA in serum by sensitivity testing six months after the end of treatment) in approximately 40% to 80% of treated patients, depending on viral genotype. Recently, a new class of drugs have emerged for hepatitis C infection, the direct acting antivirals, which in combination with standard therapy or alone can lead to sustained virological response in 80% or more of treated patients. Aminoadamantanes, mostly amantadine, are antiviral drugs used for the treatment of patients with chronic hepatitis C. We have previously systematically reviewed amantadine versus placebo or no intervention and found no significant effects of the amantadine on all-cause mortality or liver-related morbidity and on adverse events in patients with hepatitis C. Overall, we did not observe a significant effect of amantadine on sustained virological response. In this review, we systematically review aminoadamantanes versus other antiviral drugs. ### objectives To assess the beneficial and harmful effects of aminoadamantanes versus other antiviral drugs for patients with chronic hepatitis C virus infection by conducting a systematic review with meta-analyses and trial sequential analyses of randomised clinical trials. ### Search Methods The Cochrane Hepato-Biliary Group Controlled Trials Register (1996 to December 2013), the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 11 of 12, 2013), MEDLINE (1946 to December 2013), EMBASE (1974 to December 2013), Science Citation Index EXPANDED (1900 to December 2013), the WHO International Clinical Trials Registry Platform (www.who.int/ictrp), Google Scholar, and Eudrapharm up to December 2013. Furthermore, full text searches were conducted until December 2013. ### Selection Criteria Randomised clinical trials assessing aminoadamantanes in participants with chronic hepatitis C virus infection. ### Data Collection And Analysis Two authors independently extracted data. RevMan Analysis was used for statistical analysis of dichotomous data using risk ratio (RR) with 95% confidence intervals (CI). Methodological domains were used to assess the risk of systematic errors ('bias'). We used trial sequential analysis to assess risk of random errors ('play of chance'). ### Main Results Six randomised clinical trials with 581 participants with chronic hepatitis C were included. All trials had high risk of bias. The included trials compared amantadine versus other antiviral drugs: ribavirin, mycophenolate mofetil, interferon-alpha, or interferon-gamma. Standard antiviral therapy (interferon-alpha, interferon-alpha plus ribavirin, or peg interferon alpha) was administered equally to the intervention and the control groups in five trials, depending on when the trial was conducted. Four trials compared amantadine versus ribavirin. There were no deaths or liver-related morbidity in the two intervention groups (0/216 (0%) versus 0/211 (0%); 4 trials; very low quality of the evidence). The lower estimated risk for (serious) adverse events leading to treatment discontinuation with amantadine was imprecise (RR 0.56, 95% CI 0.27 to 1.16; based on 10/216 (5%) versus 18/211 (9%) participants in 4 trials; very low quality of the evidence). There were more participants with failure of sustained virological response in the amantadine group than in the ribavirin group (206/216 (96%) versus 176/211 (84%); RR 1.14, 95% CI 1.07 to 1.22, 4 trials; low quality of the evidence). amantadine versus ribavirin more often failed to achieve end-of follow-up biochemical response (41/46 (89%) versus 31/46 (67%); RR 1.31, 95% CI 1.05 to 1.63; 2 trials; very low quality of the evidence). One trial compared amantadine versus mycophenolate mofetil. There were no significant differences between the two treatment groups , except that amantadine was inferior to mycophenolate mofetil regarding the outcome failure to achieve end-of treatment virological response ( low quality of evidence ) . One trial each compared amantadine versus interferon-alpha or interferon-gamma. Both comparisons showed no significant differences in the treatment outcomes (very low quality of the evidence). The observed effects could be due to real effects, systematic errors (bias), or random errors (play of chance). This possible influence on the observed effect by play of chance is due to the fact that trial sequential analyses could not confirm our findings. We were not able to perform meta-analyses on failure of histological improvement and quality of life due to lack of valid data in all trial comparisons. ### Authors Conclusions This systematic review has identified evidence of very low quality for the key outcomes of all-cause mortality or liver-related morbidity and adverse events in people with chronic hepatitis C when treated with amantadine compared with ribavirin, mycophenolate, interferon-alpha, or interferon-gamma. The timeframe for measuring the composite outcome was insufficient in the included trials. There was low quality evidence that amantadine led to more participants who failed to achieve sustained virological response compared with ribavirin. This observation may be real or caused by systematic errors (bias), but it does not seem to be caused by random error (play of chance). Due to the low quality of the evidence, we are unable to determine definitively whether amantadine is less effective than other antivirals in patients with chronic hepatitis C. As it appears less likely that future trials assessing amantadine or potentially other aminoadamantanes for patients with chronic hepatitis C would show strong benefits, it is probably better to focus on the assessments of other direct acting antiviral drugs. We found no evidence assessing other aminoadamantanes in randomised clinical trials in order to recommend or refute their use.

https://pubmed.ncbi.nlm.nih.gov/24937404/

1b70191abaf8f7a0e189322a31ad5a10

Furthermore , more incidences of severe fatigue , thrombocytopenia , and neutropenia were recorded for sunitinib , but pazopanib had more liver toxicity .

Pazopanib has equivalent anti-tumor effectiveness and lower Total costs than Sunitinib for treating metastatic or advanced renal cell carcinoma: a meta-analysis. sunitinib and pazopanib are extensively used as first-line treatment of metastatic renal cell carcinoma (mRCC). We performed this meta-analysis to assess the anti-tumor effectiveness, toxicity, and total costs of the two drugs among patients with mRCC/advanced RCC (aRCC). ### Materials And Methods PubMed, ScienceDirect, Scopus, Web of Science, Ovid MEDLINE, the Cochrane Library, Embase, and Google Scholar were searched to obtain eligible articles. The endpoints included progression-free survival (PFS), overall survival (OS), adverse effects (AEs), and per-patient-per-month (PPPM) costs. ### results We included 14 medium- to high-quality studies. Both drugs were valid for mRCC/aRCC, with equivalent PFS (hazard ratio (HR) =1.06, 95% confidence interval [CI]: 0.98-1.15, P = 0.13), OS (HR = 0.92, 95% CI: 0.79-1.07, P = 0.29), objective response rate (ORR, risk ratio (RR) =1.03, 95% CI: 0.93-1.13, p = 0.58), and disease control rate (DCR, RR = 1.03, 95% CI: 0.94-1.22, P = 0.54). sunitinib had more dosage reductions and higher PPPM (weighted mean difference = - 1.50 thousand US dollars, 95% CI: - 2.27 to - 0.72, P = 0.0002). Furthermore , more incidences of severe fatigue , thrombocytopenia , and neutropenia were recorded for sunitinib , but pazopanib had more liver toxicity . In subgroup analysis, studies from the US reported longer OS (HR = 0.86, 95% CI: 0.77-0.95, P = 0.004) and higher ORR (RR = 1.24, 95% CI: 1.03-1.51, P = 0.03). ### conclusions pazopanib provides equivalent anti-tumor effectiveness and lower PPPM as compared with sunitinib for mRCC/aRCC. Great care should be given to pazopanib-treated patients with abnormal liver function. Nevertheless, more large-scale, high-quality studies are required.

https://pubmed.ncbi.nlm.nih.gov/31122210/

0b7d45d16b3ab6f016d055f1cfd7b822

Streptomycin appears to be the most effective agent followed by gentamicin and the least active was netilmicin .

Activity of aminoglycosides against phagocytosed bacteria. The intracellular activity of streptomycin, gentamicin, and netilmicin on Escherichia coli phagocytosed by murine peritoneal macrophages was studied using a sensitive and standardized method. Intracellular activity of streptomycin and gentamicin at therapeutic concentrations was seen after 1 h of incubation of antibiotics with macrophages containing phagocytosed bacteria, whilst for netilmicin a significant intracellular activity was observed only after 3 h exposure. The activity of these antibiotics against intraphagocytic bacteria was significantly lower than that observed against extracellular bacteria. Sub-inhibitory concentrations of streptomycin were active against intracellular E. coli. streptomycin was also active for a phagocytosed streptomycin-resistant strain of E. coli, but this activity was eliminated when the O2-dependent killing mechanisms of macrophages were inhibited by sodium fluoride. The data demonstrate that aminoglycosides may exert a dose-dependent intraphagocytic activity against E. coli that correlates with the time of incubation of the antibiotics with infected macrophages. Streptomycin appears to be the most effective agent followed by gentamicin and the least active was netilmicin . In the case of streptomycin, the intraphagocytic activity seems to be due, at least in part, to the stimulation of O2-dependent cellular microbactericidal mechanisms.

https://pubmed.ncbi.nlm.nih.gov/1816186/

ef0a5c606391305316e0d00ede66a186

Neither behavioral therapy , clomipramine , methylphenidate , buspirone , nor naltrexone was effective in monotherapeutic trials .

Comprehensive management of trichotillomania in a young autistic girl. The coexistence of trichotillomania and autistic disorder has rarely been reported in psychiatric literature. The current study describes successful treatment of trichotillomania in a young autistic girl, using combined clomipramine and behavioral therapy. Neither behavioral therapy , clomipramine , methylphenidate , buspirone , nor naltrexone was effective in monotherapeutic trials . We postulate a synergistic effect of combined treatment with clomipramine and behavioral therapy, suggesting that both pharmacological and behavioral treatment of hair pulling may be necessary for many patients. This model is consistent with the extant literature and suggests that future clinical trials of clomipramine for trichotillomania, in both developmentally disabled and normal subjects, must evaluate this multimodal approach.

https://pubmed.ncbi.nlm.nih.gov/8005911/

b95a84fc95f0619053e07be8a81b50c8

Pharmacokinetic PET imaging data analysis quantitatively showed the pharmacological effects of teriparatide-induced suppression of upper gastrointestinal motility and its restoration by granisetron and mosapride .

Exploration of Antiemetics for Osteoporosis Therapy-Induced Nausea and Vomiting Using PET Molecular Imaging Analysis to Gastrointestinal Pharmacokinetics. To select appropriate antiemetics relieving teriparatide-induced nausea and vomiting during osteoporosis treatment using PET molecular imaging and pharmacokinetic analysis. ### methods Rats were pretreated with subcutaneous teriparatide, followed by oral administration of antiemetics with different pharmacological effects. The pharmacokinetics of antiemetics were assessed by oral administration of 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG) under free moving conditions in vivo. The effect of teriparatide on the permeability of Caco-2 cell membranes to [(18)F]FDG was assessed in vitro. The effects of antiemetics on teriparatide-induced suppression of gastrointestinal motility in vivo was assayed by positron emission tomography (PET) using orally administered [(18)F]FDG. ### results Teriparatide delayed the time-radioactivity profile of [(18)F]FDG in blood and significantly reduced its absorption rate constant (k a ), determined from non-compartmental analysis, to 60% of control. In contrast, co-administration of granisetron or mosapride restored the time-radioactivity profile and k a of [(18)F]FDG to control levels. Teriparatide had no effect on Caco-2 membrane permeability to [(18)F]FDG. Pharmacokinetic PET imaging data analysis quantitatively showed the pharmacological effects of teriparatide-induced suppression of upper gastrointestinal motility and its restoration by granisetron and mosapride . ### conclusions Teriparatide-induced abdominal discomfort might be attributed to GI motility, and PET imaging analysis is a useful tool to for the selection of appropriate antiemetics.

https://pubmed.ncbi.nlm.nih.gov/26869173/

836714985a9765014b9095f0827ada4d

Differences were observed when palbociclib or ribociclib was used in combination with letrozole or anastrozole or fulvestrant .

First clinical experience with CDK4/6 inhibitors in breast cancer therapy. For hormone receptor-positive, HER2-negative breast cancer patients with metastatic or advanced disease, therapy with CDK4/6 inhibitors in addition to aromatase inhibitors (AIs) or to the estrogen receptor (ER) downregulator fulvestrant has resulted in an additional therapy option and a longer progression-free survival. In the Gynecologic-Oncology Clinic, Diakonie-Klinikum Schwäbisch Hall, we followed and registered our initial clinical experience with CDK4/6 inhibitors, following the side effects and tumor response over two years since they were officially approved for general use in Germany. Differences were observed when palbociclib or ribociclib was used in combination with letrozole or anastrozole or fulvestrant . The dynamic side effects and tumor response under therapy with palbociclib or ribociclib were found to be comparable with the main reported data in the official drug information. The CDK4/6 inhibitors have an important and promising role in the therapy of breast cancer patients. Patient age and therapy duration do not influence the use of palbociclib or ribociclib, although it may be important which AI is used in combination with palbociclib.

https://pubmed.ncbi.nlm.nih.gov/33815595/

df9fa8081eca7b7f4600cb17b04878f1

Resolution of muscle damage followed discontinuation of cyclosporine and lovastatin therapy .

Rhabdomyolysis and renal injury with lovastatin use. Report of two cases in cardiac transplant recipients. Hyperlipidemia, particularly hypercholesterolemia, occurs in cardiac transplant recipients both as a preexisting condition and as a consequence of immunosuppressive therapy. lovastatin (Mevacor) has emerged as an agent that may effectively manage this condition. Few serious side effects of this drug have been observed. We describe two cardiac transplant recipients treated with lovastatin in conjunction with their other medications, including cyclosporine, who developed acute renal failure and rhabdomyolysis. Resolution of muscle damage followed discontinuation of cyclosporine and lovastatin therapy . We postulate that hepatic dysfunction secondary to cyclosporine predisposed these patients to lovastatin-induced muscle damage. Use of this drug in cardiac and other organ transplant recipients should be accompanied by close surveillance of creatine kinase, hepatic transaminases, and cyclosporine levels.

https://pubmed.ncbi.nlm.nih.gov/3290520/

0297c1d33bb07c4fa544ea21c302579a

In order to elucidate the possible interference of the antiparkinson drug 1-aminoadamantane ( D-1 , PK Merz ) and the antispastic compound 1,3-dimethyl-5-aminoadamantane ( DMAA , D-145 , memantine , Memantine ) on neurotransmitter metabolism , the effect of D-1 and its C-alkyl derivatives memantine , 1-amino-3,5,7-trimethyladamantane ( D-191 ) , and 1-amino-3-(n)-butyladamantane ( D-178 ) on MAO activity in brain , liver , and kidney of the rat was investigated .

Effect of 1-aminoadamantanes on the MAO activity in brain, liver, and kidney of the rat. In order to elucidate the possible interference of the antiparkinson drug 1-aminoadamantane ( D-1 , PK Merz ) and the antispastic compound 1,3-dimethyl-5-aminoadamantane ( DMAA , D-145 , memantine , Memantine ) on neurotransmitter metabolism , the effect of D-1 and its C-alkyl derivatives memantine , 1-amino-3,5,7-trimethyladamantane ( D-191 ) , and 1-amino-3-(n)-butyladamantane ( D-178 ) on MAO activity in brain , liver , and kidney of the rat was investigated . A radioisotope method using [14C]5-hydroxytryptamine as substrate was used. The highest MAO activity was found in liver followed by brain and kidney (Vmax: 137, 64, and 26 nmol/mg protein X h, respectively). The Km values did not differ significantly for the three tissues (liver: 107 mumol/l; brain: 96 mumol/l; kidney: 86 mumol/l). The MAO activity in liver, brain and kidney was noncompetitively inhibited by all 1-aminoadamantanes studied, each derivative, respectively, showing in all three tissues about the same percentage inhibition. The inhibitory activity was found to be increased with the degree of C-alkylation: D-1 (Ki approximately 1 mmol/l) less than D-145 (Ki approximately 0.1 mmol/l) less than D-191 (Ki approximately 0.07 mmol/l) less than D 178 (Ki approximately 0.02 mmol/l).

https://pubmed.ncbi.nlm.nih.gov/6891223/

4a0c95a8282db45a6e5e58d864180a45

Primary chemotherapy with gemcitabine , liposomal doxorubicin and docetaxel in patients with locally advanced breast cancer : results of a phase I trial .

Primary chemotherapy with gemcitabine , liposomal doxorubicin and docetaxel in patients with locally advanced breast cancer : results of a phase I trial . The primary objective was to determine the optimal doses for gemcitabine (prolonged infusion), liposomal doxorubicin (Myocet) and docetaxel as primary (neoadjuvant) chemotherapy for locally advanced breast cancer. Secondary objectives included evaluation of the safety and efficacy of the regimen. Patients (n=19) with histologically confirmed stage II or III breast cancer were treated with liposomal doxorubicin (50-60 mg/m2) and docetaxel (60-75 mg/m2) on day 1, and gemcitabine as 4-h infusion (350-400 mg/m2) on day 4. Treatment was repeated every 3 weeks for a maximum of 6 cycles. The maximum tolerated doses were gemcitabine 350 mg/m2, liposomal doxorubicin 60 mg/m2 and docetaxel 75 mg/m2. Dose-limiting toxicities were stomatitis, diarrhea and infection. The predominant hematologic toxicity was mild-to-moderate myelosuppression with grade 3/4 neutropenia in 20% of cycles. Non-hematologic toxicity was generally mild, with no grade 4 toxicities being observed. Predominant non-hematologic toxicity was stomatitis, which occurred in 95% of patients. Grade 3 toxicities were reported for stomatitis, nausea, diarrhea, infection and constipation. No cases of cardiac, renal, pulmonary or neurotoxicity were observed. The clinical response rate was 83% and histologically confirmed, clinically complete remissions occurred in two patients (11%). We conclude that the combination of gemcitabine (prolonged infusion), liposomal doxorubicin and docetaxel is safe and highly effective in patients with locally advanced breast cancer as defined by maximum tolerated doses. The evaluated schedule is suitable for phase II studies.

https://pubmed.ncbi.nlm.nih.gov/15613900/

c7bfe36d9357817f952f9c2af200774e

A single bolus of dexamethasone , given before a single large meal , produces a delayed ( 6-hour ) but long-lasting increase in serum leptin ( over 16 hours ) .

Effect of one morning meal and a bolus of dexamethasone on 24-hour variation of serum leptin levels in humans. We have previously shown that morning administration of dexamethasone in combination with food induces a doubling of serum leptin levels starting at 7 hours after dexamethasone administration, with a maximum effect at 10 hours, the latest time point that we have studied. However, dexamethasone given in the absence of food had no effect on serum leptin at 10 hours. The present experiment was undertaken to determine the duration of the effect of dexamethasone on 24-hour serum leptin under fasted and fed conditions in humans. ### Research Methods And Procedures Six healthy non-obese male volunteers were studied under the following four conditions: 1) dexamethasone (2 mg intravenously, given at 0900 hours) with fasting; 2) dexamethasone with food (1,700 kcal, 55% carbohydrate, 15% protein, and 30% fat, given in one meal 2 hours after dexamethasone administration at 1100 hours); 3) saline with food (same meal); 4) saline with fasting. Serum leptin, glucose, insulin, and cortisol were monitored every 30 minutes for 24 hours. ### results 1) Under the fasting condition, dexamethasone increased leptin nocturnal secretion between 2100 and 2400 hours. 2) A single meal (1,700 kcal) at 1100 hours increased nocturnal leptin secretion when compared with the fasting condition. The peak increase of leptin was 123% over baseline between 2100 and 2400 hours, 10 to 14 hours after the meal. 3) In the fed + dexamethasone condition, leptin levels increased from baseline starting 8 hours after dexamethasone injection, reached a maximum increase of 260% between 2100 and 2400 hours, then decreased thereafter, remaining elevated compared to baseline for 16 hours. There was a correlation between 24-hour leptin secretion and insulin secretion after a single morning meal. ### discussion A single bolus of dexamethasone , given before a single large meal , produces a delayed ( 6-hour ) but long-lasting increase in serum leptin ( over 16 hours ) . Under fasted conditions, dexamethasone does not increase daytime leptin but does increase leptin during the night.

https://pubmed.ncbi.nlm.nih.gov/11068953/

7bcebbcb6a938a791d5b515ab0b481eb

The aim of this single-blind , randomized , controlled trial was to investigate treatment efficacy and safety of aripiprazole as an adjunct to valproic acid ( Ari+Val ) , compared with haloperidol plus valproic acid ( Hal+Val ) , in acute manic patients .

Combination treatment with aripiprazole and valproic acid for acute mania: an 8-week, single-blind, randomized controlled trial. Despite the fact that combination treatment for patients with acute bipolar is prevalent in clinical practice, the outcomes of adjunct treatment with aripiprazole and a mood stabilizer have rarely been reported. The aim of this single-blind , randomized , controlled trial was to investigate treatment efficacy and safety of aripiprazole as an adjunct to valproic acid ( Ari+Val ) , compared with haloperidol plus valproic acid ( Hal+Val ) , in acute manic patients . ### methods Treatment efficacy was prospectively assessed for 8 weeks in 42 patients with acute mania using the Young Mania Rating Scale and the Clinical Global Impression-Severity of illness scale. Emergent adverse events were assessed by the Drug-Induced Extrapyramidal Symptoms Scale and the Liverpool University Neuroleptic Side Effect Rating Scale. ### results Both Ari+Val and Hal+Val produced a high rate of response (85.7% and 92.9%, respectively) and remission (82.1% and 85.7%, respectively) after the 8-week trial. Changes in the Young Mania Rating Scale and the Clinical Global Impression-Severity of illness scale over the study period and time to remission and response were not significantly different between the 2 groups. Patients treated with Ari+Val showed significantly fewer extrapyramidal adverse events than those treated with Hal+Val (t = -2.048, F = 40, P = 0.048). However, significant weight gain was more prevalent in the Ari+Val group than the Hal+Val group (t = 2.055, F = 40, P = 0.046). ### conclusions Our findings suggest that both combination strategies with Ari+Val and Hal+Val are beneficial for acute manic episode. Although patients receiving Ari+Val showed fewer extrapyramidal symptoms than those taking Hal+Val, careful consideration of adverse events such as weight gain and sedation is warranted.

https://pubmed.ncbi.nlm.nih.gov/22592508/

634afdc7ed4ee4894a3426d33dc96600

Because the incidence of nausea and vomiting is significantly reduced when ketorolac is used in place of opioids to attenuate postoperative pain , it would appear to be an appropriate choice of agent to use following propofol anesthesia .

Ketorolac and propofol administration for prevention of nausea and vomiting in patients undergoing minor gynecologic surgery. This clinical review explores the efficacy of the nonsteroidal antiinflammatory agent, ketorolac tromethamine, added to an anesthetic regimen utilizing intravenous propofol. Both agents have been shown to reduce the incidence of nausea and vomiting postoperatively when administered to patients undergoing minor gynecologic surgery. Because the incidence of nausea and vomiting is significantly reduced when ketorolac is used in place of opioids to attenuate postoperative pain , it would appear to be an appropriate choice of agent to use following propofol anesthesia . The use of this combination of drugs may not only reduce the incidence of postoperative nausea and vomiting in patients undergoing minor gynecologic surgery, but could reduce the duration of hospitalization and enhance recovery from anesthesia.

https://pubmed.ncbi.nlm.nih.gov/8499507/

ac00391719a33cac85ce9aa4f853c2d6

The combination of vandetanib and bicalutamide was associated with considerable toxicity and did not have superior efficacy over bicalutamide alone .

A randomized phase II efficacy and safety study of vandetanib (ZD6474) in combination with bicalutamide versus bicalutamide alone in patients with chemotherapy naïve castration-resistant prostate cancer. To investigate the efficacy and safety of combining vandetanib, an orally available multi-targeted tyrosine kinase inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2) and epidermal growth factor receptor (EGFR), with bicalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC). ### methods This was an open-label, randomized phase II multi-center study. Eligible patients had rising PSA on androgen deprivation therapy, minimal symptoms and were chemotherapy-naïve. Protocol therapy was either vandetanib 300 mg oral daily plus bicalutamide 50 mg oral daily (Arm A) or bicalutamide 50 mg oral daily alone (Arm B) with cross-over to vandetanib monotherapy at progression. The primary endpoint was PSA response (≥ 50 % decline from baseline). ### results Thirty-nine patients were recruited, 19 in Arm A and 20 in Arm B. PSA response was comparable in Arm A and Arm B (18 vs. 19 %). Time to PSA progression was 3.16 months (95 % confidence interval (CI): 1.09, not reached (NR)) for Arm A and 3.09 months (95 % CI: 1.22, NR) for Arm B. Treatment discontinuation due to adverse events was more common in Arm A compared to Arm B (42 vs. 5 %; p = 0.019). Treatment with vandetanib was associated with a reduction in soluble VEGFR-2 levels after two cycles but an increase in plasma VEGF levels. ### conclusion The combination of vandetanib and bicalutamide was associated with considerable toxicity and did not have superior efficacy over bicalutamide alone . Further evaluation of this combination is not warranted in mCRPC.

https://pubmed.ncbi.nlm.nih.gov/24671507/

4f1afbea8c1eaa64ea7cb68414fcde1a

Our data indicate that the addition of Aspirin or of Atenolol to Metformin might be beneficial for BC control , and that this activity is likely due to effects on both BC and microenvironment cells .

Aspirin and atenolol enhance metformin activity against breast cancer by targeting both neoplastic and microenvironment cells. metformin can induce breast cancer (BC) cell apoptosis and reduce BC local and metastatic growth in preclinical models. Since metformin is frequently used along with aspirin or beta-blockers, we investigated the effect of metformin, aspirin and the beta-blocker atenolol in several BC models. In vitro, aspirin synergized with metformin in inducing apoptosis of triple negative and endocrine-sensitive BC cells, and in activating AMPK in BC and in white adipose tissue (WAT) progenitors known to cooperate to BC progression. Both aspirin and atenolol added to the inhibitory effect of metformin against complex I of the respiratory chain. In both immune-deficient and immune-competent preclinical models, atenolol increased metformin activity against angiogenesis, local and metastatic growth of HER2+ and triple negative BC. aspirin increased the activity of metformin only in immune-competent HER2+ BC models. Both aspirin and atenolol, when added to metformin, significantly reduced the endothelial cell component of tumor vessels, whereas pericytes were reduced by the addition of atenolol but not by the addition of aspirin. Our data indicate that the addition of Aspirin or of Atenolol to Metformin might be beneficial for BC control , and that this activity is likely due to effects on both BC and microenvironment cells .

https://pubmed.ncbi.nlm.nih.gov/26728433/

b0b46e31b844bb0b6f220eb00e3d2031

Coadministration of vorinostat and oxaliplatin induced G2/M phase arrest , triggered caspase-dependent apoptosis , and decreased tumorigenicity both in vitro and in vivo .

Vorinostat enhances the anticancer effect of oxaliplatin on hepatocellular carcinoma cells. oxaliplatin-based systemic chemotherapy has been proposed to have efficacy in hepatocellular carcinoma (HCC). We investigated the combination of vorinostat and oxaliplatin for possible synergism in HCC cells. SMMC7721, BEL7402, and HepG2 cells were treated with vorinostat and oxaliplatin. Cytotoxicity assay, tumorigenicity assay in vitro, cell cycle analysis, apoptosis analysis, western blot analysis, animal model study, immunohistochemistry, and quantitative PCR were performed. We found that vorinostat and oxaliplatin inhibited the proliferation of SMMC7721, BEL7402, and HepG2 cells. The combination index (CI) values were all <1, and the dose-reduction index values were all greater than 1 in the three cell lines, indicating a synergistic effect of combination of the two agents. Coadministration of vorinostat and oxaliplatin induced G2/M phase arrest , triggered caspase-dependent apoptosis , and decreased tumorigenicity both in vitro and in vivo . vorinostat suppressed the expression of BRCA1 induced by oxaliplatin. In conclusion, cotreatment with vorinostat and oxaliplatin exhibited synergism in HCC cells. The combination inhibited cell proliferation and tumorigenicity both in vitro and in vivo through induction of cell cycle arrest and apoptosis. Our results predict that a combination of vorinostat and oxaliplatin may be useful in the treatment of advanced HCC.

https://pubmed.ncbi.nlm.nih.gov/29239146/

3e9de2eafaad5ecdb3048a0e6206a0e1

Randomized open trial of gentamicin and doxycycline for eradication of Bartonella quintana from blood in patients with chronic bacteremia .

Randomized open trial of gentamicin and doxycycline for eradication of Bartonella quintana from blood in patients with chronic bacteremia . Chronic Bartonella quintana bacteremia is known to occur in homeless people exposed to lice. We present here the results of an open randomized trial performed to evaluate the efficacy of doxycycline in combination with gentamicin in the eradication of B. quintana bacteremia. From 1 January 2001 to 1 April 2002, homeless people with blood cultures positive for B. quintana were randomized to receive either no treatment (untreated controls) or a combination of gentamicin (3 mg/kg of body weight/day intravenously for 14 days) and doxycycline (200 mg/day orally for 28 days). Patients were evaluated from the results of blood cultures performed between day 28 (the end of treatment) and day 90 postinclusion. Intention-to-treat analysis of 20 included patients showed eradication of bacteremia in 7 out of 9 treated patients versus 2 out of 11 untreated controls (P = 0.01). In the per-protocol analysis, eradication was obtained for 7 out of 7 treated patients versus 2 out of 9 untreated controls (P = 0.003). This study demonstrates the efficiency of the combination of doxycycline and gentamicin in eradicating B. quintana bacteremia.

https://pubmed.ncbi.nlm.nih.gov/12821469/

d6a60e2a3810f7b91e415ab7ad060e5d

The role of dual antiplatelet therapy combining aspirin and clopidogrel , is controversial .

[TREATMENT WITH DUAL ANTIPLATELET THERAPY FOR SECONDARY PREVENTION OF STROKE - PROS AND CONS]. The role of dual antiplatelet therapy combining aspirin and clopidogrel , is controversial . There are two settings in which such treatment might be considered: (a) patients presenting with a first ischemic event at high risk for a recurrence; and (b) patients who experience a second ischemic event while being treated with aspirin or clopidogrel monotherapy. In this paper we review the literature dealing with secondary prevention of ischemic stroke, with an emphasis on dual antiplatelet therapy. We examine international guidelines and present a case study which illustrates the application of this information.

https://pubmed.ncbi.nlm.nih.gov/30582310/

ed0f2792fe2d83f42414b3c006dad894

We conducted a dose-escalating study of daunorubicin combined to fixed doses of IM ( imatinib mesylate , 600 mg/d ) and cytarabine ( 200 mg/d for 7 days ) , followed by hematopoietic stem cell transplantation or maintenance therapy with single-agent IM in patients with MBC-CML at onset or after failure of therapy excluding TKIs .

The addition of daunorubicin to imatinib mesylate in combination with cytarabine improves the response rate and the survival of patients with myeloid blast crisis chronic myelogenous leukemia (AFR01 study). The median survival of patients with chronic myelogenous leukemia in myeloid blast crisis (MBC-CML) is poor even for patients treated with tyrosine kinase inhibitors (TKIs). ### Design And Methods We conducted a dose-escalating study of daunorubicin combined to fixed doses of IM ( imatinib mesylate , 600 mg/d ) and cytarabine ( 200 mg/d for 7 days ) , followed by hematopoietic stem cell transplantation or maintenance therapy with single-agent IM in patients with MBC-CML at onset or after failure of therapy excluding TKIs . ### results Thirty-six patients were evaluated. Median follow-up is 6.1 years. daunorubicin was escaladed up to 45 mg/m(2)/d 3 days. Twenty eight patients (77.7%) had hematologic response including 20 patients (55.5%) in complete hematologic response (CHR). Patients who received daunorubicin at 30-45 mg/m(2)/d had higher CHR rates compared to other patients. Median overall survival was 16 months. Overall survival in patients with hematological response was 35.4 months. Better results were observed in patients diagnosed with MBC-CML at onset. ### conclusions The combination of IM with a standard "3+7" regiment was well tolerated and provided a high response rate. More than 55% of the patients achieved CHR and hematopoietic stem cell transplantation (SCT) was feasible in half of the cases. This trial was registered at www.clinicaltrials.gov as # NCT00219765.

https://pubmed.ncbi.nlm.nih.gov/21145590/

2ba04bc0fd1492479197971616f7e32b

[ Combination chemo-endocrine therapy of metastatic and stage IV breast cancer with cyclophosphamide , adriamycin , prednisolone and tamoxifen (CAPT)--with special reference to management of brain and liver metastasis ] .

[ Combination chemo-endocrine therapy of metastatic and stage IV breast cancer with cyclophosphamide , adriamycin , prednisolone and tamoxifen (CAPT)--with special reference to management of brain and liver metastasis ] . Sixty-three evaluable patients with metastatic and stage IV breast cancer who had not previously undergone chemo-endocrine therapy were treated with a combination chemoendocrine therapy regimen consisting of cyclophosphamide 100 mg p.o. every day, adriamycin 10 mg i.v. on day 1 to 5, prednisolone 10 mg or 20 mg (20 mg was given on day 1 to 5) p.o. every day, and tamoxifen 20 mg p.o. every day. Adriamycin on day 1 to 5 was repeated three times every two weeks. After a total dose of 150 mg of adriamycin, the patients were changed to maintenance therapy consisting of cyclophosphamide 100 mg p.o., prednisolone 10 mg p.o. and tamoxifen 20 mg p.o. every day. After 72 months of the treatment there were 61 patients good for evaluation, 13 patients achieved a complete response (21.3%) with a median survival of 30.5 months and 18 patients had a partial response (29.5%) with a median survival of 21.0 months, and 30 patients failed to respond (49.2%) with a median survival of 8.5 months. There was a significant difference in survival time between responders (CR + PR) and non-responders (NC + PD) (p less than 0.001). Responses by site were seen in lung 10/18 (55.6%), liver 3/6 (50.0%), brain 2/4 (50.0%), bone 6/17 (35.3%) and soft tissue 14/24 (56.3%). A Satisfactory response for brain and liver metastasis, which are usually viewed as a sign of grim prognosis, was obtained similar to other sites of metastasis. Retreatment with CAPT, which was attempted in patients with secondary brain metastasis who responded to CAPT for initial brain metastasis, was uniformly effective. High ration of androgen to corticosteroid, positive estrogen receptors, long disease-free survival (over two years), premenopausal, high Broca' index (above 110) resulted from the chemo-endocrine therapy regimen CAPT. Toxicity was minimal and consisted of nausea, vomiting, alopecia and leucopenia.

https://pubmed.ncbi.nlm.nih.gov/2919892/