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e85037de90f9d9227fd3c680bd0ce306

Rats were subchronically primed with nicotine , clozapine or saline .

Nicotine and clozapine cross-prime the locus coeruleus noradrenergic system to induce long-lasting potentiation in the rat hippocampus. A priming-challenge schedule of nicotine treatment causes long-lasting potentiation (LLP), a form of synaptic plasticity closely associated with the norepinephrine (NE) neurotransmitter system, at the medial perforant path (MPP)-dentate gyrus (DG) synapse in the rat hippocampus. Previous reports revealed that nicotine activates the locus coeruleus (LC) noradrenergic (NAergic) system and this mechanism may underlie its beta-adrenoceptor sensitive LLP effects. clozapine, an atypical antipsychotic, is also known to activate the LC. Interactions between nicotine and clozapine are of interest because of the prevalence of smoking in patients with schizophrenia and increasing interest in the use of nicotinic receptor ligands as cognitive enhancers. Rats were subchronically primed with nicotine , clozapine or saline . Twenty-one to twenty-eight days later, the effects of the nicotine, clozapine or saline challenge on the evoked field excitatory postsynaptic potentials (fEPSP) at the MPP-DG monosynaptic pathway were recorded as a measure of LLP. We confirmed the hypothesis that a challenge dose of either nicotine or clozapine induces LLP exclusively in nicotine- and clozapine-primed rats, and not in saline-primed rats, thus indicating a cross-priming effect. Moreover, unilateral suppression of LC using lidocaine abolished the LLP induced by nicotine in clozapine-primed rats. Furthermore, systemic treatment with clonidine (an α2 adrenoceptor agonist that reduces NAergic activity via autoreceptors) prior to the challenge doses blocked the nicotine/clozapine-induced LLP in nicotine- and clozapine-primed rats. These findings may add to understanding of the cognitive enhancing effects of nicotine.

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The chimeric anti- EGFR monoclonal antibody cetuximab has been approved for EGFR-expressing colorectal tumors in patients who progress after irinotecan-based chemotherapy in combination with irinotecan and in squamous cell head and neck carcinomas for patients with locally advanced disease in combination with radiation therapy or after failure of platinum-based chemotherapy in recurrent or metastatic disease ( FDA ) .

The future of anti-EGFR therapy. We report here on the state of our knowledge of the target--namely, the epidermal growth factor (EGF) and its receptor--and the challenges related to the methods of determination of the epidermal growth factor receptor (EGFR) and associated molecular pathways. A critical review of the anti-EGFR therapeutic strategies is also outlined. The chimeric anti- EGFR monoclonal antibody cetuximab has been approved for EGFR-expressing colorectal tumors in patients who progress after irinotecan-based chemotherapy in combination with irinotecan and in squamous cell head and neck carcinomas for patients with locally advanced disease in combination with radiation therapy or after failure of platinum-based chemotherapy in recurrent or metastatic disease ( FDA ) . cetuximab has the potential to provide an improvement of clinical outcome also in other indications and tumor types, particularly when used as first-line therapy combined with standard chemotherapy for metastatic disease or in the adjuvant setting. Possible strategies to improve the effectiveness of anti-EGFR agents are suggested and include (i) the use of predictive tools capable of making a more rational selection of patients; (ii) the development of standardized predictive biomarkers as surrogates for early monitoring of drug efficacy; and (iii) adequate study design, statistical analysis and proper end points of efficacy to be applied in future prospective trials.

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New agents , such as taxane , irinotecan and oxaliplatin , combined with old agents , such as cisplatin and 5-FU , are currently under evaluation to further improve treatment outcomes .

Chemotherapy for advanced gastric cancer: slow but further progress. Gastric cancer remains a significant problem in terms of global health, and is the most common cancer in Korea. Surgery is the only potentially curative treatment for localized gastric cancer, but most cases present at an advanced stage. Randomized trials have demonstrated that chemotherapy for advanced gastric cancer improves the quality of life and extends survival, by 4 approximately 6 months, compared with best supportive care alone. Single agents with a proven activity in a first-line setting include 5-fluorouracil (5-FU), doxorubicin, mitomycin C, cisplatin, taxanes (docetaxel and paclitaxel) and oral fluoropyrimidines (capecitabine and TS-1). Based on the results from several large scale randomized trials, FP (5-FU/cisplatin) and ECF (epirubicin/cisplatin/5-FU) combinations are the most widely used regimen against advanced gastric cancer. Phase II studies of the FP and ECF combination reported a 40~51% response rate in previously untreated patients, and this regimen also produced a significantly higher response rate than the FAM (5-FU/doxorubicin/mitomycin) and FAMTX (5-FU/doxorubicin/methotrexate) regimens, respectively. However, significant treatment related-toxicities and discomfort were reported from ECF, which prevents this combination from becoming the standard treatment regimen. While no one combination chemotherapy regimen is accepted as the standard for advanced gastric cancer, FP is currently considered a suitable reference regimen worldwide. New agents , such as taxane , irinotecan and oxaliplatin , combined with old agents , such as cisplatin and 5-FU , are currently under evaluation to further improve treatment outcomes . Also, oral 5-FU prodrugs are replacing the cumbersome 5-FU long-term infusion due to its convenience and superior toxicity profile. However, the low complete response rate and short response duration are still the main obstacles in the chemotherapy for gastric cancer. Only large scale comparative clinical trials will give clues to improve the results of gastric cancer treatments.

1007329826934be65ae5d787ac699734

Taxinol , Gemcitabine ( GEM ) , Navelbine ( NVB ) , Edatrexate ( ETX ) , CPT-11 and high dose Epirubicin ( EPI HD ) are recommended as new effective drugs .

Non-surgical therapy for patients with advanced non-small cell lung cancer. Advanced non-small cell lung cancer (NSCLC) denotes those of TNM stage III and IV. NSCLC has its specific characteristics in respect of oncological behaviour, molecular biology, sensitivity to chemotherapy (CT) and radiotherapy (RT), and requires different therapeutic strategies in comparison with small cell lung cancer. The therapies include: (1) surgery in combination with new effective drugs is resulted in improved RR from 15% a decade ago to 40-60% today. Cisplatin (C-DDP) is the most attractive drug in the treatment of NSCLC, in lengthening the life-span of Stage IV NSCLC patients and as an indispensable sensitizer in RT. Taxinol , Gemcitabine ( GEM ) , Navelbine ( NVB ) , Edatrexate ( ETX ) , CPT-11 and high dose Epirubicin ( EPI HD ) are recommended as new effective drugs . Response rates recently reported for the combination CT with the drugs mentioned above for NSCLC are from 30-65%, and with 8-42 weeks of MST. Induction or neoadjuvant therapies for advanced NSCLC, with 40-69% of RR, 25-29% of complete resection rate, 8-34% of CR and 17-45% of one year SR are reviewed. Eight random studies comparing MST between CT with C-DDP and best supportive care for NSCLC are statistically significant. (2) RT for Stage III NSCLC with 2 year and 5 year survivals of 20 and 5% respectively. Although such outcome is hardly acceptable, RT sensitizer, modified RT techniques and chemoradiotherapy (CRT) are imperative to improve the effect of RT in advanced NSCLC. Clinical literature suggest that CRT is better than RT, though without marked difference. Further studies and sufficient follow-up are necessary to judge the efficacy in terms of long-term survival and toxic reaction. (3) Biological therapy: gene therapy of NSCLC is still in the experimental and developmental stage. Of biological response modifier (BRM), alpha IFN in 11 cases of NSCLC with RR of 9% and MST of 14 months, IL-2 and LAK cell treatment in 11 cases with RR of 9% and MST of 18 months are reported. Instillation of BRM such as IL-2 or alpha-IFN into the pleura after drainage of cancerous effusion has been reported as the most effective for those whose RR is of 80-90% and the clinical response time is fairly long. Hematological cytokine as a protective adjuvant therapy against CT/RT toxicity makes high dose of CT possible and raises the response and patient tolerance. In multimodality therapy, it plays an important role to reduce post CT infection and septicemia.

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One group was given enalapril ( EN ) 50 mg/l dissolved in the drinking water ; the second received lovastatin ( L ) 15 mg/kg given daily by gavage ; the third received both agents ; the fourth was left untreated , and the final group received no puromycin and served as the control group .

The combination of lovastatin and enalapril in a model of progressive renal disease. puromycin-induced nephrotic syndrome is an animal model of progressive renal disease. Both angiotensin converting enzyme inhibitors and lipid-lowering agents have been used to preserve renal structure and function in this model, although neither completely prevents progression. We tested the hypothesis that the combination of the two agents would be more protective than either alone. Rats were divided into five groups; all were uninephrectomized. Four groups were given puromycin at a dose of 10 mg/100 g body weight (BW) with additional doses of 4 mg/100 g BW given intraperitoneally at 4, 5, and 6 weeks thereafter. One group was given enalapril ( EN ) 50 mg/l dissolved in the drinking water ; the second received lovastatin ( L ) 15 mg/kg given daily by gavage ; the third received both agents ; the fourth was left untreated , and the final group received no puromycin and served as the control group . Eight weeks after the initial dose of puromycin, glomerular filtration rate (GFR), as inulin clearance, and protein excretion were determined and blood was collected for cholesterol and triglycerides. Blood pressure was not different between any of the groups. At the end of the study period, serum cholesterol [mean +/- SD, 252 +/- 185 mg/dl (L), 135 +/- 101 mg/dl (L + EN)] and triglycerides (239 +/- 200, 148 +/- 158 mg/dl) were significantly lower (P < 0.001) in the lovastatin-treated groups than in the untreated puromycin group (535 +/- 255 mg/dl and 579 +/- 561 mg/dl, cholesterol and triglyceride, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

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Using the Killing-curve method , we tested the in vitro bactericidal activity of fosfomycin alone or in combination with vancomycin or teicoplanin at a concentration of 8 microg/mL , that is easily achievable in serum at standard dosing regimens , against seven methicillin-resistant Staphylococcus aureus strains , isolated from patients with well documented device-associated infections unresponsive to or relapsing after glycopeptide therapy .

In vitro activity of fosfomycin in combination with vancomycin or teicoplanin against Staphylococcus aureus isolated from device-associated infections unresponsive to glycopeptide therapy. fosfomycin is a molecule that inhibits the early stage of peptidoglycan synthesis and shows a broad-spectrum bactericidal activity against Gram-positive and Gram-negative bacteria. Using the Killing-curve method , we tested the in vitro bactericidal activity of fosfomycin alone or in combination with vancomycin or teicoplanin at a concentration of 8 microg/mL , that is easily achievable in serum at standard dosing regimens , against seven methicillin-resistant Staphylococcus aureus strains , isolated from patients with well documented device-associated infections unresponsive to or relapsing after glycopeptide therapy . MICs of vancomycin ranged from 1 to 4 microg/mL, MICs of teicoplanin from 2 to 8 microg/mL; MICs of fosfomycin were 8 microg/mL for two strains and >128 microg/mL for the remaining strains. The seven strains proved tolerant when tested for vancomycin and teicoplanin used alone at 2x MIC concentration. fosfomycin was bactericidal (reduction of 2 log of the inoculum) only against the two susceptible strains. In all cases both vancomycin and teicoplanin in combination with fosfomycin developed bactericidal synergism already at a concentration of 1x MIC. If these results are confirmed by in vivo experiments, the combination of fosfomycin with glycopeptides might be useful for treating device-associated infections, and in preventing the phenomenon of increasing MICs for glycopeptides.

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Combination therapy with mitomycin , tamoxifen , and UFT proved to be an effective postoperative chemoendocrine therapy for stage II , ER-positive breast cancer .

UFT and mitomycin plus tamoxifen for stage II, ER-positive breast cancer. Hokkaido ACETBC Study Group. A trial was designed to examine the combination of UFT and mitomycin (Mutamycin) plus tamoxifen (Nolvadex) as postoperative adjuvant therapy in the treatment of patients with stage II, estrogen receptor (ER)-positive primary breast cancer. mitomycin was administered intravenously at 13 mg/m2 on the day of surgery. Patients judged to be ER-positive were randomly allocated to either group A, which received oral tamoxifen 20 mg/day 14 days after surgery for 2 years, or group B, receiving oral UFT 400 mg/day plus tamoxifen 20 mg/day. A total of 219 patients were enrolled in group A, of which 213 (97.3%) were determined to be eligible; 225 patients enrolled in group B and 223 (99.1%) were eligible. The 5-year survival rates were 93.0% for group A and 95.4% for group B, with no significant difference between groups. The 5-year relapse-free survival rates were 83.1% for group A and 90.7% for group B, a significant advantage (P = .020) for the UFT plus tamoxifen group. Combination therapy with mitomycin , tamoxifen , and UFT proved to be an effective postoperative chemoendocrine therapy for stage II , ER-positive breast cancer .

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The remaining 76 patients did not receive anti-thymocyte globulin but were given cyclosporine A and methotrexate or mycophenolate mofetil ( group 3 ) .

The impact of graft-versus-host disease prophylaxis in reduced-intensity conditioning allogeneic stem cell transplant in acute myeloid leukemia: a study from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation. The impact of the intensity of graft-versus-host-disease immunoprophylaxis on transplantation outcomes in patients undergoing transplantation following reduced-intensity conditioning is unclear. This study addresses this issue in 228 adult patients above 50 years of age with acute myeloid leukemia in first complete remission given peripheral blood stem cells from HLA-identical siblings after fludarabine and 2 days of intravenous busulfan reduced-intensity conditioning. A total of 152 patients received anti-thymocyte globulin, either in combination with cyclosporine A in 86 patients (group 1), or with cyclosporine A and mycophenolate mofetil or short course methotrexate in 66 patients (group 2). The remaining 76 patients did not receive anti-thymocyte globulin but were given cyclosporine A and methotrexate or mycophenolate mofetil ( group 3 ) . Incidences of grade II-IV acute graft-versus-host-disease were comparable in the three groups (16.5%, 29.5% and 19.5% in groups 1, 2 and 3, respectively, P=0.15). In multivariate analysis, the absence of anti-thymocyte globulin was the only factor associated with a higher risk of chronic graft-versus-host-disease (P=0.005), while the use of triple immunosuppression (group 3) was associated with an increased risk of relapse (P=0.003). In comparison to anti-thymocyte globulin and cyclosporine A alone, the other two strategies of graft-versus-host-disease prophylaxis were associated with reduced leukemia-free survival and overall survival (P=0.001 for each parameter), independently of the dose of anti-thymocyte globulin. These data suggest that fine tuning of the intensity of this prophylaxis can affect the outcome of transplantation and that anti-thymocyte globulin and cyclosporine A alone should be the preferred combination with the fludarabine-busulfan reduced-intensity conditioning regimen and sibling donors.

b83939edbb4e56478efb8e3be32e53e1

Propranolol significantly decreased the maximum plasma concentration ( Cmax ) and area under the plasma concentration-time curve ( AUC ) of lacidipine ( by 38 % and 42 % , respectively ) whereas lacidipine significantly increased the Cmax and AUC of propranolol ( by 35 % and 26 % , respectively ) ; neither the time to maximum plasma concentration ( tmax ) nor the terminal half-life ( t 1/2 ) were affected .

The pharmacokinetic and pharmacodynamic interaction between lacidipine and propranolol in healthy volunteers. The pharmacokinetic and pharmacodynamic profiles of lacidipine, a 1,4-dihydropyridine calcium antagonist, and the beta-adrenoceptor blocker propranolol were determined alone and in combination in 24 healthy male volunteers. One group (I) of 12 subjects received a single oral dose of 4 mg lacidipine on two separate occasions, which was taken together with a single oral dose of either 160 mg propranolol or placebo; a second group (II) of 12 subjects received propranolol on two occasions, taken with either lacidipine or placebo. Propranolol significantly decreased the maximum plasma concentration ( Cmax ) and area under the plasma concentration-time curve ( AUC ) of lacidipine ( by 38 % and 42 % , respectively ) whereas lacidipine significantly increased the Cmax and AUC of propranolol ( by 35 % and 26 % , respectively ) ; neither the time to maximum plasma concentration ( tmax ) nor the terminal half-life ( t 1/2 ) were affected . With regard to the pharmacodynamics, in Group I, there was a greater reduction in supine systolic blood pressure (6 mm Hg) and diastolic blood pressure (4 mm Hg) compared to the reduction produced by lacidipine alone, and pulse rate was approximately 5 beats/min less. In Group II, a significantly greater reduction (6 mm Hg) in supine systolic blood pressure compared to the reduction produced by propranolol alone occurred, but there was no marked difference in supine diastolic blood pressure and pulse rate. In conclusion, a modest pharmacokinetic and pharmacodynamic interaction is evident and should be evaluated further in patients with hypertension.

f471cf9397ea607071e678ff48f72b27

The patient received chemotherapy comprising vincristine , actinomycin D , doxorubicin , cisplatin , and cyclophosphamide .

Autologous peripheral blood stem cell transplantation in a patient with relapsed pleuropulmonary blastoma. Pleuropulmonary blastoma (PPB) is a rare and aggressive primary intrathoracic neoplasma of children. The prognosis is extremely poor with frequent metastasis to the brain and bone. We present a 4-year-old girl with a tumor mass in the right hemithorax initially diagnosed as pneumoniae. Tumor resection was performed and the histologic report indicated the diagnosis of PPB. The patient received chemotherapy comprising vincristine , actinomycin D , doxorubicin , cisplatin , and cyclophosphamide . Irradiation was performed with total 45 Gy at the right lower pulmonary lobe. She relapsed 29 months later at the pleura between the right middle and lower pulmonary lobe. Tumor resection and total 45 Gy of irradiation were performed again. High-dose chemotherapy comprising cisplatin, adriamycin, and cyclophosphamide was performed followed by autologous peripheral blood stem cell transplantation (PBSCT). The patient achieved complete hematologic recovery. Thirty-one months after PBSCT, no signs of relapse have been observed. Although it might be that the patient could have been cured with second surgery alone or by the surgery and subsequent chemotherapy, high-dose chemotherapy and PBSCT should be considered for the treatment of relapsed PPB.

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It was found that the increase in acoustic startle responses observed with ethanol or nicotine was attenuated by haloperidol .

Nicotine and ethanol enhancements of acoustic startle reflex are mediated in part by dopamine in C57BL/6J mice. nicotine has been shown to have additive as well as antagonistic effects on behavior stimulated by ethanol. Here, we examine the effects of nicotine, ethanol, and the coadministration of each drug on acoustic startle responding in C57BL/6J mice. Mice were tested at a range of decibel levels (80-115 dB, 5 dB increments), with administration of 0.031, 0.062, 0.125, and 0.25 mg/kg nicotine or 0.5, 1.0, 1.5, and 2.0 g/kg ethanol. nicotine and ethanol each caused an increase in the acoustic startle response at the highest and lowest doses tested, respectively. mecamylamine, a nicotinic receptor antagonist, administered in combination with nicotine or ethanol attenuated these increases in acoustic startle responding. nicotine and ethanol, administered together, did not produce greater enhancement of startle than when administered alone. haloperidol (1 mg/kg) was administered in combination with nicotine or ethanol to investigate if dopamine modulated nicotine or ethanol enhancement of acoustic startle. It was found that the increase in acoustic startle responses observed with ethanol or nicotine was attenuated by haloperidol . Thus, ethanol or nicotine may enhance the acoustic startle reflex through a common dopaminergic mechanism.

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The use of tacrolimus ( 88 % vs 77 % , P=.02 ) and cytolytic therapy ( 81 % vs 46 % , P < .0001 ) was likewise greater among patients who received ganciclovir prophylaxis .

Ganciclovir prophylaxis delays but does not prevent cytomegalovirus infection in renal transplant recipients. Cytomegalovirus (CMV) infection is associated with reduced graft and patient survival among renal transplant recipients. The purpose of this study was to examine the effect of routine prophylaxis with 12 weeks of oral ganciclovir on the incidence of CMV infection in a center that predominantly uses antibody induction together with tacrolimus/mycophenolate mofetil-based maintenance immunosuppressive therapy. The control group consisted of a historical patient cohort transplanted immediately prior to the use of oral ganciclovir prophylaxis. The use of tacrolimus ( 88 % vs 77 % , P=.02 ) and cytolytic therapy ( 81 % vs 46 % , P < .0001 ) was likewise greater among patients who received ganciclovir prophylaxis . CMV infection occurred in 20 (9%) patients in the ganciclovir era and 4 (3%) patients in the preganciclovir era (P=.003). The mean time to CMV infection was longer in patients who received ganciclovir prophylaxis than in patients in the preganciclovir era (23.4 +/- 10.9 weeks vs 9.8 +/- 5.6 weeks, P=.03). We conclude that 12 weeks of ganciclovir prophylaxis delays but does not prevent CMV infection from occurring in renal transplant recipients. These results suggest that with the use of 12 weeks of ganciclovir prophylaxis, vigilance for CMV infection is needed well beyond 24 weeks posttransplant.

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Because gemcitabine has been considered a standard treatment for advanced pancreatic cancer for the past decade , several randomized trials have tested the combination of gemcitabine plus a second agent , including platinum based agents , topoisomerase inhibitors , taxanes , bevacizumab and cetuximab , as biologically " targeted " agents .

First-line treatment for advanced pancreatic cancer. Highlights from the "2011 ASCO Gastrointestinal Cancers Symposium". San Francisco, CA, USA. January 20-22, 2011. Pancreatic adenocarcinoma remains a treatment-refractory cancer. Although pancreatic adenocarcinoma is only the 10th most common cause of new cancer in the United States, it is the fourth most common cause of cancer-related death. Most cases are not suitable for resection and a majority is metastatic at presentation. gemcitabine, with or without erlotinib, has been the standard chemotherapy in this setting but the benefit is only modest. Because gemcitabine has been considered a standard treatment for advanced pancreatic cancer for the past decade , several randomized trials have tested the combination of gemcitabine plus a second agent , including platinum based agents , topoisomerase inhibitors , taxanes , bevacizumab and cetuximab , as biologically " targeted " agents . At large this approach has not been successful and novel strategies are clearly needed. In this article, the authors summarizes the data from the 2011 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium, including: Abstract #175 (review of survival data in a large cohort); Abstract #286 (rapid change in prescriber patterns after the suggestion of benefit of a new regimen, FOLFIRINOX); Abstracts #238, #277, #304, and #315 (phase II trials looking at combinations that utilized EGFR blockade); Abstracts #221, #266, and #284 (phase I/II trials including VEGF blockade, anticoagulation, and traditional Chinese medicines).

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Gemcitabine and recently FOLFIRINOX ( 5-flourouracil , leucovorin , oxaliplatin and irinotecan ) have provided some limited survival advantage in advanced pancreatic cancer .

Immunotherapy updates in pancreatic cancer: are we there yet? Pancreatic cancer is a lethal disease and remains one of the most resistant cancers to traditional therapies. Historically, chemotherapy or radiotherapy did not provide meaningful survival benefit in advanced pancreatic cancer. Gemcitabine and recently FOLFIRINOX ( 5-flourouracil , leucovorin , oxaliplatin and irinotecan ) have provided some limited survival advantage in advanced pancreatic cancer . Targeted agents in combination with gemcitabine had not shown significant improvement in the survival. Current therapies for pancreatic cancer have their limitations; thus, we are in dire need of newer treatment options. Immunotherapy in pancreatic cancer works by recruiting and activating T cells that recognize tumor-specific antigens which is a different mechanism compared with chemotherapy and radiotherapy. Preclinical models have shown that immunotherapy and targeted therapies like vascular endothelial growth factor and epidermal growth factor inhibitors work synergistically. Hence, new immunotherapy and targeted therapies represent a viable option for pancreatic cancer. In this article, we review the vaccine therapy for pancreatic cancer.

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No synergism was found against Pneumococci and Meningococci but also no antagonism of the lower MIC and MBC values seen with ampicillin and penicillin G. The combination of chloramphenicol with either penicillin or ampicillin constitutes a clinically successful therapeutic regimen which is now also proven by in vitro investigations .

[Bactericidal action of chloramphenicol and synergism with beta-lactam antibiotics]. Excellent clinical results were observed with the combination therapy of chloramphenicol with beta-lactam-antibiotics in the treatment of purulent meningitis. This came as a surprise as bacteriostatic antibiotics like chloramphenicol are commonly thought to antagonize the bactericidal action of penicillin or ampicillin. We reevaluated the mode of action of chloramphenicol against the three most common meningeal pathogens after the newborn period. chloramphenicol was found to be bactericidal against H. influenzae, Streptococcus pneumoniae and Neisseria meningitidis at clinically achievable levels in the CSF. In addition chloramphenicol showed synergistic action with ampicillin against H. influenzae which can possess clinical relevance particularly with the high inoculum of 10(7) organisms/ml which is frequently seen in bacterial meningitis. No synergism was found against Pneumococci and Meningococci but also no antagonism of the lower MIC and MBC values seen with ampicillin and penicillin G. The combination of chloramphenicol with either penicillin or ampicillin constitutes a clinically successful therapeutic regimen which is now also proven by in vitro investigations .

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Similarly , nifedipine , nitroglycerin and hydralazine should not to be considered first-line therapies in the management of hypertensive crises because these agents are associated with significant toxicities and/or adverse effects .

Treatment of acute severe hypertension: current and newer agents. Approximately 72 million people in the US experience hypertension. Worldwide, hypertension may affect as many as 1 billion people and be responsible for approximately 7.1 million deaths per year. It is estimated that approximately 1% of patients with hypertension will, at some point, develop a hypertensive crisis. Hypertensive crises are further defined as either hypertensive emergencies or urgencies, depending on the degree of blood pressure elevation and presence of end-organ damage. Immediate reduction in blood pressure is required only in patients with acute end-organ damage (i.e. hypertensive emergency) and requires treatment with a titratable, short-acting, intravenous antihypertensive agent, while severe hypertension without acute end-organ damage (i.e. hypertensive urgency) is usually treated with oral antihypertensive agents. The primary goal of intervention in a hypertensive crisis is to safely reduce blood pressure. The appropriate therapeutic approach of each patient will depend on their clinical presentation. Patients with hypertensive emergencies are best treated in an intensive care unit with titratable, intravenous, hypotensive agents. Rapid-acting intravenous antihypertensive agents are available, including labetalol, esmolol, fenoldopam, nicardipine and sodium nitroprusside. Newer agents, such as clevidipine and fenoldopam, may hold considerable advantages to other available agents in the management of hypertensive crises. Sodium nitroprusside is an extremely toxic drug and its use in the treatment of hypertensive emergencies should be avoided. Similarly , nifedipine , nitroglycerin and hydralazine should not to be considered first-line therapies in the management of hypertensive crises because these agents are associated with significant toxicities and/or adverse effects .

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Bendamustine is effective both with rituximab and as a monotherapy in rituximab-refractory patients .

Bendamustine in chronic lymphocytic leukemia and refractory lymphoma. bendamustine is a water-soluble, bifunctional chemotherapeutic agent with characteristics of both an alkylator and a purine analog. bendamustine combined with rituximab in vitro shows synergistic effects against various leukemia and lymphoma cell lines. Clinical trials supporting these results show that bendamustine plus rituximab is highly effective in relapsed and refractory patients with indolent lymphoma. The results have been found in rituximab-naive, rituximab-pretreated, and rituximab-refractory patients with excellent response rates and toxicity profiles. Bendamustine is effective both with rituximab and as a monotherapy in rituximab-refractory patients . Interim results from a phase III, randomized trial comparing bendamustine and rituximab to a standard CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) and rituximab regimen suggest that combination bendamustine and rituximab may provide a viable alternative for treatment of many indolent lymphomas.

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Ten micromoles of gefitinib reversed topotecan , SN-38 , and mitoxantrone resistance , and increased the intracellular topotecan accumulation in the resistant cells but not in the parental cells .

Gefitinib ("Iressa", ZD1839), an epidermal growth factor receptor tyrosine kinase inhibitor, reverses breast cancer resistance protein/ABCG2-mediated drug resistance. gefitinib ("Iressa", ZD1839) is an orally active, selective epidermal growth factor receptor tyrosine kinase inhibitor, and the single agent is clinically effective in non-small cell lung cancer. Although gefitinib combined with various cytotoxic agents has been reported to enhance cytotoxicity in vitro and in mouse models, the mechanism remains undetermined. Here, to explore the mechanism with topoisomerase I inhibitors, we focused on the efflux pump of the breast cancer resistance protein (BCRP/ABCG2), and then examined whether gefitinib restored drug sensitivity in multidrug-resistant cancer cells overexpressing BCRP. We used PC-6 human small cell lung cancer cells and multidrug-resistant PC-6/SN2-5H cells selected with SN-38 of the active metabolite of irinotecan, and BCRP-overexpressing MCF-7/MX cells selected with mitoxantrone and BCRP cDNA transfectant MCF-7/clone 8 cells. Drug sensitivity against anticancer drugs was determined by tetrazolium dye assay, and intracellular topotecan accumulation by FACScan. The topotecan transport study was done using the plasma membrane vesicles of PC-6/SN2-5H cells. The resistant PC-6/SN2-5H cells overexpressed BCRP but not epidermal growth factor receptor mRNA. Ten micromoles of gefitinib reversed topotecan , SN-38 , and mitoxantrone resistance , and increased the intracellular topotecan accumulation in the resistant cells but not in the parental cells . Furthermore, gefitinib inhibited the topotecan transport into the vesicles, and the K(i) value was 1.01 +/- 0.09 micromol/L in the Dixon plot analysis, indicating direct inhibition of BCRP by gefitinib. However, gefitinib was not transported into the vesicles with the high-performance liquid chromatography method. These results indicate that gefitinib reverses BCRP-mediated drug resistance by direct inhibition other than competitive inhibition as a BCRP substrate. Combination of gefitinib and topoisomerase I inhibitors could be clinically effective in cancers expressing BCRP.

https://pubmed.ncbi.nlm.nih.gov/15735043/

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The effects of multiple combination chemotherapy with vincristine , cyclophosphamide ( Endoxan ) , methotrexate , 5-fluorouracil , adriamycin and prednisolone ( VEMFAH ) for advanced breast cancer .

The effects of multiple combination chemotherapy with vincristine , cyclophosphamide ( Endoxan ) , methotrexate , 5-fluorouracil , adriamycin and prednisolone ( VEMFAH ) for advanced breast cancer . Thirty-eight patients with advanced breast cancer were treated with the 'VEMFAH' multiple-drug combination chemotherapy, consisting of vincristine (V), cyclophosphamide (Endoxan; E), methotrexate (M), 5-fluorouracil (F), adriamycin (A), and prednisolone (H). Disease response was evaluated by the UICC criteria. Among the 35 evaluable cases, 4 complete responses (CR), 23 partial responses (PR), 2 cases of no change (NC), and 6 of progressive disease (PD) were observed. The response rate (CR + PR) was 77.1%. The median duration of response was 52 weeks (8-192 weeks) or 12 months. In 32 patients who received more than two courses of therapy the 50% survival time of responders was 27.0 months, which was significantly longer than the 10.3 months of nonresponders (P less than 0.05). Except for 2 patients who developed myocardial damage, the therapy was never terminated because of side effects. Cumulative cardiotoxicity was not apparent in this study. This multiple-drug combination chemotherapy with 'VEMFAH' is concluded to be an effective treatment for advanced and disseminated breast cancer.

https://pubmed.ncbi.nlm.nih.gov/3902267/

1e789327329484c793977a63b0ab0cfa

Association of rash with outcomes in a randomized phase II trial evaluating cetuximab in combination with mitoxantrone plus prednisone after docetaxel for metastatic castration-resistant prostate cancer .

Association of rash with outcomes in a randomized phase II trial evaluating cetuximab in combination with mitoxantrone plus prednisone after docetaxel for metastatic castration-resistant prostate cancer . cetuximab (C), a chimeric monoclonal antibody that binds epidermal growth factor receptor (EGFR), is active against androgen-independent prostate cancer cell lines and might enhance the activity of chemotherapy. The efficacy of combining cetuximab with mitoxantrone (M) plus prednisone (MP) was evaluated in progressive metastatic castrate-resistant prostate cancer (CRPC) after receiving docetaxel. ### Materials And Methods Patients with progression after receiving docetaxel were eligible and randomized 2:1 to CMP or MP. Therapy was mitoxantrone 12 mg/m(2) intravenously (I.V.) on day 1, oral prednisone 10 mg daily in both arms, and cetuximab 250 mg/m(2) I.V. (400 mg/m(2) day 1, cycle 1) on days 1, 8, and 15 in the CMP arm. Cycles were repeated every 21 days. Radiologic assessments of disease and PSA (prostate-specific antigen) occurred every 4 cycles. The primary endpoint was time to progression (TTP). ### results A total of 115 patients were enrolled, 75 in the CMP and 40 in the MP arm: the median TTP was 4.9 and 6.6 months, respectively; the measurable disease response rate was 2% and 4%, the PSA response rate 7.7% and 17.6%, and median survival 11.9 and 15.7 months, respectively. Key grade 3-4 toxicities were neutropenia 44% and 25.6%, anemia 6.7% and 7.7%, thrombocytopenia 6.7% and 2.6%, and fatigue 8% in both arms. In an unplanned exploratory analysis, median TTP with (n = 24) and without rash (n = 51) in the CMP arm was 10.3 months vs. 2.8 months (P = .004). On multivariable analysis,rash was significantly associated with TTP (hazard ratio [HR] = 0.43; P = .01). ### conclusions The treatment with CMP is not recommended in unselected men with docetaxel-treated CRPC, although rash might help develop tailored therapy.

https://pubmed.ncbi.nlm.nih.gov/22340631/

0a4f78997b6f89533c19850c90d7954f

CDM mice show decreased Homer1a and Homer1b/c mRNA expression in cortex and blood samples , while chronic treatment with imipramine and fluoxetine or acute ketamine application increases their level only in the cortex .

Antidepressant treatment is associated with epigenetic alterations of Homer1 promoter in a mouse model of chronic depression. Understanding the neurobiology of depression and the mechanism of action of therapeutic measures is currently a research priority. We have shown that the expression of the synaptic protein Homer1a correlates with depression-like behavior and its induction is a common mechanism of action of different antidepressant treatments. However, the mechanism of Homer1a regulation is still unknown. ### methods We combined the chronic despair mouse model (CDM) of chronic depression with different antidepressant treatments. Depression-like behavior was characterized by forced swim and tail suspension tests, and via automatic measurement of sucrose preference in IntelliCage. The Homer1 mRNA expression and promoter DNA methylation were analyzed in cortex and peripheral blood by qRT-PCR and pyrosequencing. ### results CDM mice show decreased Homer1a and Homer1b/c mRNA expression in cortex and blood samples , while chronic treatment with imipramine and fluoxetine or acute ketamine application increases their level only in the cortex . The quantitative analyses of the methylation of 7 CpG sites, located on the Homer1 promoter region containing several CRE binding sites, show a significant increase in DNA methylation in the cortex of CDM mice. In contrast, antidepressant treatments reduce the methylation level. ### limitations Homer1 expression and promotor methylation were not analyzed in different blood cell types. Other CpG sites of Homer1 promoter should be investigated in future studies. Our experimental approach does not distinguish between methylation and hydroxymethylation. ### conclusions We demonstrate that stress-induced depression-like behavior and antidepressant treatments are associated with epigenetic alterations of Homer1 promoter, providing new insights into the mechanism of antidepressant treatment.

https://pubmed.ncbi.nlm.nih.gov/33128940/

e1a456796512f6ad85c23e8577c8be04

A retrospective analysis was conducted on the clinical data of 122 advanced NSCLC patients with pleural effusion , and among them , 61 received thoracic hyperthermic perfusion with recombinant human endostatin ( ES ) plus nedaplatin ( Endostatin group ) , while the other 61 underwent thoracic hyperthermic perfusion with cisplatin alone ( Cisplatin group ) .

Effect of thoracic hyperthermic perfusion with recombinant human endostatin plus nedaplatin in treating pleural effusion in patients with advanced non-small cell lung cancer. To explore the efficacy and safety of thoracic hyperthermia perfusion with recombinant human endostatin plus nedaplatin in the treatment of pleural effusion in patients with advanced non-small cell lung cancer (NSCLC). ### methods A retrospective analysis was conducted on the clinical data of 122 advanced NSCLC patients with pleural effusion , and among them , 61 received thoracic hyperthermic perfusion with recombinant human endostatin ( ES ) plus nedaplatin ( Endostatin group ) , while the other 61 underwent thoracic hyperthermic perfusion with cisplatin alone ( Cisplatin group ) . The short-term efficacy, changes in the pleural effusion and serum immunological indicators before and after treatment, quality of life, and incidence of adverse reactions were compared between the two groups of patients. Finally, the progression of pleural effusion in patients were followed up and recorded. ### results After treatment, the overall response rate of patients in endostatin group was considerably higher than that in Cisplatin group (p=0.030). At 2 weeks after treatment, the level of alanine transferase (ALT) rose notably, while that of carcinoembryonic antigen (CEA) declined dramatically in both groups of patients, and the patients in endostatin group had markedly lower levels of ALT and CEA than those in Cisplatin group (p=0.007, p=0.003). After treatment, the Karnofsky Performance status (KPS) score of patients was prominently raised in the two groups, and endostatin group exhibited considerably higher KPS scores than Cisplatin group (p=0.045). The incidence rates of nausea and vomiting as well as diarrhea in endostatin group were prominently lower than those in Cisplatin group (p=0.039, p=0.048). According to the follow-up results, the median time to the progression of pleural effusion in endostatin group was markedly longer than that in Cisplatin group (p=0.008). ### conclusions Compared with the thoracic hyperthermic perfusion with cisplatin alone, the thoracic hyperthermic perfusion with recombinant human endostatin plus nedaplatin showed dramatically potential efficacy, decrease of the incidence rate of adverse reactions in the digestive system, improvement of quality of life of patients, and prolongation of progression of pleural effusion.

https://pubmed.ncbi.nlm.nih.gov/33455108/

0bae4bf9eca270aebdabe9ab47f382f2

In addition , stimulation of erythropoiesis with recombinant human erythropoietin , supplemental iron therapy , and improving haemostasis by aprotinin may further reduce homologous blood requirements .

[Reduction in the use of donated blood in surgical medicine]. After rapid changes in transfusion practice over the past few years, blood conservation techniques have become standard in modern perioperative management. As a result, the amount of homologous blood products transfused has been markedly reduced in some types of surgical procedures. Provided that skillful surgical technique is applied and the use of blood products is restricted, autologous transfusion techniques (predonation of autologous blood, preoperative plasmapheresis, acute normovolaemic haemodilution, and intra- and postoperative blood salvage) can be performed with an acceptable risk for patients. In addition , stimulation of erythropoiesis with recombinant human erythropoietin , supplemental iron therapy , and improving haemostasis by aprotinin may further reduce homologous blood requirements . All patients undergoing elective surgery have to be informed about the side effects of transfusion of homologous blood products and the possibility of blood-saving methods. An individual blood conservation plan, based on the patient's status and surgery, the equipment available, and personal experience should be worked out by the responsible anaesthesiologist, whereby a combination of different methods may be most effective. If storage is necessary, autologous blood products should be preparated like homologous products. The feasibility of predonation and retransfusion of autologous blood in patients with infectious diseases like hepatitis or acquired immune deficiency syndrome and the amount of labaratomy testing are still under discussion. Although blood conservation programs are time-consuming and more expensive, they reduce the various risks of using homologous blood products.

https://pubmed.ncbi.nlm.nih.gov/7762780/

661e745b70596299921deeab58a3d21e

In the presence of heparin and cortisone and of cortisone alone there was a 4.5- and 2.3-fold reduction , respectively , in the growth of the 9L glioma .

Growth inhibition of the 9L glioma using polymers to release heparin and cortisone acetate. Malignant gliomas are difficult to treat systemically because of exclusion of many chemotherapeutic agents by the blood brain barrier. Furthermore, as opposed to other neoplasms, malignant gliomas recur locally, at the site of original presentation. These tumors are remarkably vascular and hence may be more dependent on angiogenesis for continued growth than other tumors. The inhibition of tumor angiogenesis can control tumor growth by preventing the exponential vascular growth phase. We report the inhibition of the growth of the 9L glioma by the localized, controlled release of known angiogenesis inhibitors administered in a biodegradable polyanhydride polymer matrix. In the presence of heparin and cortisone and of cortisone alone there was a 4.5- and 2.3-fold reduction , respectively , in the growth of the 9L glioma . We compared these results to the inhibition of tumor neovascularization in the rabbit cornea by the localized delivery of the same agents. In the rabbit cornea model, the local release of heparin and cortisone and of cortisone alone resulted in a 2.5- and 2.0-fold reduction, respectively, in the angiogenesis response evoked by the VX2 carcinoma. This study introduces two new potential therapeutic modalities for the treatment of malignant gliomas: the use of the combination of heparin and cortisone as antineoplastic agents and the use of polymeric carriers for the local delivery of such agents in the central nervous system.

https://pubmed.ncbi.nlm.nih.gov/1702149/

7dffebdf49843e64c3a7aa9b3812bcc1

Dibutyryl cAMP , forskolin and theophylline stimulated secretion of pancreastatin and somatostatin .

Interaction between phosphoinositide turnover system and cyclic AMP pathway for the secretion of pancreastatin and somatostatin from QGP-1N cells. It is found that secretion of pancreastatin and somatostatin from QGP-1N cells is regulated through muscarinic receptor-mediated activation of phosphatidylinositide hydrolysis system. In this report, whether the cAMP pathway interacts with the phosphoinositide turnover system for the secretion of pancreastatin and somatostatin from QGP-1N cells through muscarinic receptors was studied. Stimulation of QGP-1N cells with carbachol increased intracellular cAMP levels. The carbachol-induced increase in cAMP levels was inhibited by atropine. Calcium ionophore (A23187) and phorbol 12-myristate 13-acetate increased cAMP synthesis. Dibutyryl cAMP , forskolin and theophylline stimulated secretion of pancreastatin and somatostatin . When either dibutyryl cAMP, forskolin or theophylline was added in culture medium with A23187, phorbol ester or carbachol, a synergistic effect was found on pancreastatin and somatostatin secretion. These results suggest that interaction between the phosphoinositide turnover system and the cAMP pathway occurs in QGP-1N cells through muscarinic receptor stimulation for the secretion of pancreastatin and somatostatin.

https://pubmed.ncbi.nlm.nih.gov/1352680/

b8c0eb9ae6e7ea066e515e69ee2799b5

It was the aim of this study to evaluate maintenance therapy with bevacizumab + capecitabine following induction with bevacizumab + capecitabine + oxaliplatin ( XELOX ) versus bevacizumab + XELOX until progression as first-line therapy in metastatic colorectal cancer ( mCRC ) .

Bevacizumab + capecitabine as maintenance therapy after initial bevacizumab + XELOX treatment in previously untreated patients with metastatic colorectal cancer: phase III 'Stop and Go' study results--a Turkish Oncology Group Trial. It was the aim of this study to evaluate maintenance therapy with bevacizumab + capecitabine following induction with bevacizumab + capecitabine + oxaliplatin ( XELOX ) versus bevacizumab + XELOX until progression as first-line therapy in metastatic colorectal cancer ( mCRC ) . ### methods Patients received either bevacizumab (7.5 mg/kg) + XELOX (capecitabine 1,000 mg/m(2) twice daily on days 1-14 + oxaliplatin 130 mg/m(2) on day 1 every 3 weeks) until disease progression (arm A) or the same doses of bevacizumab + XELOX for 6 cycles followed by bevacizumab + capecitabine until disease progression (arm B). The primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS), objective response rate (ORR) and safety. ### results One hundred and twenty-three patients were randomized. Treatment compliance was similar in both groups. Median PFS was significantly longer for arm B than for arm A (11.0 vs. 8.3 months; p = 0.002). There was no significant difference between the two arms for ORR (66.7 vs. 59.0%; p = 0.861) or median OS (23.8 vs. 20.2 months; p = 0.100). Tolerability was acceptable in both treatment arms; the most frequent grade 3/4 treatment-related adverse events (arm B vs. arm A) were fatigue (6.6 vs. 16.1%), diarrhoea (3.3 vs. 11.3%), anorexia (3.3 vs. 11.3%), and neuropathy (1.6 vs. 8.1%). ### conclusions Maintenance therapy with bevacizumab + capecitabine can be considered an appropriate option following induction bevacizumab + XELOX in patients with mCRC instead of continuation of bevacizumab + XELOX.

https://pubmed.ncbi.nlm.nih.gov/24247559/

6f09f4aa6c650b00d751ef90c70bf1df

We chose to assess the chemopreventive effect of three different drugs : pioglitazone , lanreotide and S-trans-trans-farnesylthiosalicylic acid ( FTS ) .

Chemoprevention of hepatocellular carcinoma. Proof of concept in animal models. In the present work, we have evaluated the possibility of preventing liver carcinogenesis in rats at two stages of development. In the first series of experiments, we induced foci of altered hepatocytes, (FAH) which represent the first events in rodent liver carcinogenesis, using the chemical mutagens diethylnitrosamine (DEN) and acetylaminofluorene (AAF). In the second part of the work, we used repeated weekly injections of DEN only that gave rise to significant fibrosis at 11 weeks and the development of malignant tumours at 16 weeks. We chose to assess the chemopreventive effect of three different drugs : pioglitazone , lanreotide and S-trans-trans-farnesylthiosalicylic acid ( FTS ) . pioglitazone (PGZ) is an agonist of peroxisome proliferator-activated receptor gamma (PPARg), itself a member of the nuclear receptor superfamily, responsible for the modulation of a number of metabolic pathways, including cell differentiation, metabolism of lipids and inflammation. lanreotide (LAN) is a somatostatin analogue that has an inhibitory effect on the release of several hormones, such as growth hormone and serotonine. FTS is a specific antagonist of the protoocogene Ras, tested here based on the rationale that Ras is activated in many hepatocellular carcinomas (HCC). We showed that both PGZ and LAN were efficient in the first, pre-neoplastic model, by reducing the size of FAH, decreasing proliferation specifically in FAH by interacting with proteins of the cell cycle. We could also demonstrate that LAN increased apoptosis. In the second model, LAN was able to diminish the number of established HCC by decreasing proliferation, in parallel with an anti-fibrotic action. Furthermore, enhanced apoptosis and antiangiogenic effects were observed when LAN was given from the start of the carcinogenic induction by DEN. The cellular mechanisms leading to its effects warrant further investigations. FTS also strongly inhibited the appearance of FAH and HCC in the second model, through a complete inhibition of Ras activation and the induction of pro-apoptotic pathways. On the contrary, PGZ did not prevent the appearance of neoplastic lesions. For these reasons, we did not analyse further its mechanism of action in the second model. Altogether, the results we obtained demonstrate an activity of both LAN and FTS, at the early onset of liver carcinogenesis, and later on when advanced fibrosis, cirrhosis and HCC are induced. These anti-tumoural effects could be complementary and will be tested in combination in the future.

https://pubmed.ncbi.nlm.nih.gov/21563652/

70606f6869fb0cb024b34ef2853f9163

Etoposide ( 25 mg , twice daily ) and prednisone ( 5 mg , twice daily ) were administered orally .

Oral etoposide and oral prednisone for the treatment of castration resistant prostate cancer. Treatment options for patients with castration-resistant prostate cancer (CRPC) are limited. The purpose of our study was to investigate the safety and efficacy in terms of prostate-specific antigen (PSA) response of a low-dose oral combination of etoposide and prednisone in patients with CRPC. Thirty-nine patients with prostate cancer (median age, 77.9 years) with progressive disease after standard hormonal therapy were enrolled. Etoposide ( 25 mg , twice daily ) and prednisone ( 5 mg , twice daily ) were administered orally . Each cycle comprised 21 consecutive days of treatment followed by a 7-day drug holiday. All patients previously treated with an antiandrogen were required to undergo antiandrogen withdrawal prior to entry into the study. A total of 226 cycles were administered with a median of 6.7 cycles per patient (range, 1-18 cycles). Sixteen of 39 patients (41%) with elevated PSA levels at baseline achieved at least a 50% reduction in PSA levels. Median progression-free survival for all patients was 5.9 months (range, 1-17 months). No Grade 4 toxicities were observed. The predominant toxicities were mucositis, nausea, fatigue, and anemia in twelve, nine, eight, and seven patients, respectively. Hematologic toxicity was infrequent, with no episodes of febrile neutropenia. The combination of low-dose etoposide and prednisone is an efficacious and reasonably well-tolerated oral regimen in the treatment of elderly patients with CRPC. This regimen can be easily administered in an outpatient setting and does not require frequent patient visits.

https://pubmed.ncbi.nlm.nih.gov/24444537/

1a4eea0fb32e8a01c262faf7fad66861

Rosuvastatin + ezetimibe , simvastatin + ezetimibe , and atorvastatin + ezetimibe were the most cost-effective combination therapies for reducing LDL-C levels .

The cost effectiveness of statin therapies in Spain in 2010, after the introduction of generics and reference prices. HMG-CoA reductase inhibitors (statins) are the first-line drugs for use in the reduction of low-density lipoprotein cholesterol (LDL-C) levels and prevention of coronary heart disease (CHD) in patients with hypercholesterolemia. Generic statins could change the cost effectiveness of statin therapies in Spain, and more population groups could be included in the recommendations for reduction of cholesterol levels based on cost effectiveness. ### objectives The objectives of this study were: (i) to assess the cost effectiveness of available statins for the reduction of LDL-C levels in Spain in 2010, after the introduction of generics and reference prices; (ii) to assess the cost effectiveness of combination therapy using a statin plus cholestyramine or ezetimibe; and (iii) to estimate the mean cost per patient to achieve National Cholesterol Education Program (Adult Treatment Panel-III) therapeutic objectives. ### methods The following treatments were evaluated: rosuvastatin 5-20 mg/day; atorvastatin, simvastatin, and pravastatin 10-40 mg/day; lovastatin and fluvastatin 20-80 mg/day; and combination therapy with a statin plus either cholestyramine 12-24 g/day or ezetimibe 10 mg/day. The cost effectiveness was evaluated in terms of cost per percentage point reduction in LDL-C, comparing the annual treatment costs with the effectiveness in reducing LDL-C. Treatment costs included those for medications (2010 wholesale prices), control measures, and treatment of adverse drug effects. The effectiveness of statins was estimated by developing a meta-analysis of clinical trials published between 1993 and 2005 that met several inclusion criteria. Average and incremental cost-effectiveness ratios were calculated to assess the efficiency of individual statin and combination therapies in reducing LDL-C levels. ### results The effectiveness in terms of percentage reduction in LDL-C ranged from 19% for pravastatin 10 mg/day to 55% for atorvastatin 80 mg/day. Annual treatment costs ranged from Euro 189.7 for simvastatin 10 mg/day to Euro 759.3 for atorvastatin 80 mg/day. The cost-effectiveness ratios, in terms of cost per percentage point reduction in LDL-C, were: Euro 6 for simvastatin, Euro 10-12 for rosuvastatin, Euro 10 for lovastatin, Euro 13-16 for atorvastatin, Euro 13-14 for fluvastatin, and Euro 14-20 for pravastatin. Rosuvastatin + ezetimibe , simvastatin + ezetimibe , and atorvastatin + ezetimibe were the most cost-effective combination therapies for reducing LDL-C levels . rosuvastatin was the most cost-effective statin for achieving the LDL-C therapeutic goal in patients at high risk for CHD, with a mean cost per patient of Euro 516. simvastatin was the most cost-effective statin to achieve the LDL-C goal in patients with moderate or low CHD risk, with a cost per patient of Euro 217 and Euro 190, respectively. ### conclusion rosuvastatin should be the first-choice agent in patients with high CHD risk, while simvastatin should be the first choice in patients with moderate or low risk. The addition of ezetimibe to rosuvastatin, simvastatin, or atorvastatin should be the preferred combination therapies when greater LDL-C reductions are required. The cost effectiveness of all statin therapies has increased in Spain after the introduction of generic statins and reference prices.

https://pubmed.ncbi.nlm.nih.gov/21090830/

5385813964fa22e9fdbad267cad739de

This 40-week open-label extension of the 12-week double-blind Triple Therapy With Olmesartan Medoxomil , Amlodipine , and Hydrochlorothiazide in Hypertensive Patients Study ( TRINITY ) evaluated the efficacy and safety of triple-combination treatments with olmesartan medoxomil , amlodipine besylate , and hydrochlorothiazide ( OM/AML/HCTZ ) in 2112 participants with moderate to severe hypertension .

Long-term efficacy and safety of triple-combination therapy with olmesartan medoxomil and amlodipine besylate and hydrochlorothiazide for hypertension. J Clin Hypertens (Greenwich). 2012;14:149-157. ©2012 Wiley Periodicals, Inc. Most patients with hypertension require combination therapy in order to achieve blood pressure (BP) goals. This 40-week open-label extension of the 12-week double-blind Triple Therapy With Olmesartan Medoxomil , Amlodipine , and Hydrochlorothiazide in Hypertensive Patients Study ( TRINITY ) evaluated the efficacy and safety of triple-combination treatments with olmesartan medoxomil , amlodipine besylate , and hydrochlorothiazide ( OM/AML/HCTZ ) in 2112 participants with moderate to severe hypertension . Following 2 weeks of initial treatment with OM 40/AML 5/HCTZ 12.5 mg, participants not achieving BP goal were titrated to OM 40/AML 5/HCTZ 25 mg or OM 40/AML 10/HCTZ 12.5 mg on a randomized basis. At week 16, participants who did not achieve BP goal were further titrated to OM 40/AML 10/HCTZ 25 mg. At the end of the study, 44.5% to 79.8% of participants reached BP goal and the mean BP decreased from 168.6/100.7 mm Hg (baseline BP at randomization) to 125.0 to 136.8 mm Hg/77.8 to 82.5 mm Hg, depending on treatment. Long-term treatment with OM/AML/HCTZ was well tolerated and effective with no new safety concerns.

https://pubmed.ncbi.nlm.nih.gov/22372774/

13d227c15f3afba751d934f49d59e018

Nithiamide and chlortetracycline + sulfamethazine + penicillin were least effective in preventing SD during the infection + medication and postmedication periods .

A swine dysentery model for evaluation of drug prophylaxis: efficacy of various drugs in the control of swine dysentery. A swine dysentery (SD) model that produces consistent, homogeneous, and severe SD was used in 2 experiments to compare the prophylactic effectiveness of 5 commercially available swine feed additive products. Under the conditions of these studies, carbadox and carbadox + sulfamethazine proved to be the most effective agents in preventing SD during the infection + medication and postmedication periods. Olaquindox was effective in preventing SD in the infection + medication period; however, SD recurrence was high during the postmedication period. Nithiamide and chlortetracycline + sulfamethazine + penicillin were least effective in preventing SD during the infection + medication and postmedication periods .

https://pubmed.ncbi.nlm.nih.gov/7224318/

5c88fa895583c022261c8290cb802c4e

The largest number of strains was resistant to gentamicin , followed by erythromycin .

Sensitivity of antibacterials of Staphylococcus aureus isolated from impetigo patients. We measured the sensitivity to antibacterials of Staphylococcus aureus isolated from impetigo lesions during one year (from July 1994 to July 1995). The largest number of strains was resistant to gentamicin , followed by erythromycin . Few methicillin-resistant S. aureus strains were isolated and few strains were resistant to more than one drug. We conclude that nadifloxacin and tosufloxacin are likely to be most effective against S. aureus, but fusidic acid is more suitable for the treatment of children.

https://pubmed.ncbi.nlm.nih.gov/9283995/

5b3c9e4fed209076e7d197b42242c429

Behavioural impact of intraseptally released vasopressin and oxytocin in rats .

Behavioural impact of intraseptally released vasopressin and oxytocin in rats . The two nonapeptides arginine vasopressin and oxytocin are not only secreted from the neurohypophysis into the general circulation but are also released intracerebrally. Our recent research has focused on the release patterns and effects of oxytocin and vasopressin in brain areas, such as the septum and hypothalamus, that are thought to be involved in the regulation of (1) behavioural responses and (2) responses of the hypothalamo-neurohypophysial system (HNS) to stressor exposure in rats. The results demonstrate that combined physical and emotional stress (induced by exposure to forced swimming) selectively triggers the release of vasopressin within all brain areas under study but not into the general circulation. Under emotional stress conditions (induced by exposure to the 'social defeat' procedure), however, oxytocin rather than vasopressin release increased within the hypothalamus and septum. Experiments aimed at revealing the neuroendocrine and behavioural relevance of the local nonapeptide release provided evidence for an involvement of vasopressin in the regulation of HNS activity (within the hypothalamus) and, moreover, in acute stress-coping strategies, anxiety-related behaviour and learning and memory processes (within the septum). The observed dissociation between central and peripheral nonapeptide release not only supports the hypothesis that plasma vasopressin and oxytocin concentrations do not necessarily reflect central release patterns but also suggests vasopressin and oxytocin neurones are able to independently release their nonapeptide from different parts of their neuronal surface (e.g. from somata/dendrites vs. axon terminals). This remarkable regulatory capacity provides the basis for an differential involvement of vasopressin, and probably also oxytocin, in the co-ordination of neuroendocrine activity, emotionality and cognition at different brain levels to ensure an appropriate behavioural response of the organism to stressful stimuli.

https://pubmed.ncbi.nlm.nih.gov/10795914/

923b1d414c3afb26d65e3beafbdfddf8

Optimized 14 day sequential therapy was non-inferior to , but better tolerated than 10 day bismuth quadruple therapy and both may be used in first-line treatment in populations with low to intermediate clarithromycin resistance .

14 day sequential therapy versus 10 day bismuth quadruple therapy containing high-dose esomeprazole in the first-line and second-line treatment of Helicobacter pylori: a multicentre, non-inferiority, randomized trial. Whether extending the treatment length and the use of high-dose esomeprazole may optimize the efficacy of Helicobacter pylori eradication remains unknown. ### objectives To compare the efficacy and tolerability of optimized 14 day sequential therapy and 10 day bismuth quadruple therapy containing high-dose esomeprazole in first-line therapy. ### methods We recruited 620 adult patients (≥20 years of age) with H. pylori infection naive to treatment in this multicentre, open-label, randomized trial. Patients were randomly assigned to receive 14 day sequential therapy or 10 day bismuth quadruple therapy, both containing esomeprazole 40 mg twice daily. Those who failed after 14 day sequential therapy received rescue therapy with 10 day bismuth quadruple therapy and vice versa. Our primary outcome was the eradication rate in the first-line therapy. Antibiotic susceptibility was determined. ClinicalTrials.gov: NCT03156855. ### results The eradication rates of 14 day sequential therapy and 10 day bismuth quadruple therapy were 91.3% (283 of 310, 95% CI 87.4%-94.1%) and 91.6% (284 of 310, 95% CI 87.8%-94.3%) in the ITT analysis, respectively (difference -0.3%, 95% CI -4.7% to 4.4%, P = 0.886). However, the frequencies of adverse effects were significantly higher in patients treated with 10 day bismuth quadruple therapy than those treated with 14 day sequential therapy (74.4% versus 36.7% P < 0.0001). The eradication rate of 14 day sequential therapy in strains with and without 23S ribosomal RNA mutation was 80% (24 of 30) and 99% (193 of 195), respectively (P < 0.0001). ### conclusions Optimized 14 day sequential therapy was non-inferior to , but better tolerated than 10 day bismuth quadruple therapy and both may be used in first-line treatment in populations with low to intermediate clarithromycin resistance .

https://pubmed.ncbi.nlm.nih.gov/29846605/

5c6c7ff9d0b179779cae4a24b94343f9

Initial treatment with either neoadjuvant chemoradiation ( CRT ) or induction FOLFOX ( 5-Fluorouracil , leucovorin , and oxaliplatin ) chemotherapy followed by CRT is considered standard treatment for locally advanced rectal cancer .

Induction Chemotherapy Reduces Patient-reported Toxicities During Neoadjuvant Chemoradiation with Intensity Modulated Radiotherapy for Rectal Cancer. Initial treatment with either neoadjuvant chemoradiation ( CRT ) or induction FOLFOX ( 5-Fluorouracil , leucovorin , and oxaliplatin ) chemotherapy followed by CRT is considered standard treatment for locally advanced rectal cancer . We compared patient-reported outcomes (PRO) during CRT in patients who had received induction chemotherapy versus those who did not. ### Patients And Methods We reviewed records of patients with locally advanced rectal cancer who were treated with CRT between September 2009 and October 2014, and who had completed ≥ 4 PRO assessments during treatment. Clinician- and patient-reported toxicities were collected each week during treatment. We fit binomial generalized linear models to maximum toxicity scores across all patients' visits. ### results Of 123 patients with ≥ 4 PRO assessments, 87 (71%) patients reported a clinically meaningful PRO score of 3 or higher for diarrhea, and 91 (74%) patients reported a PRO score of ≥ 3 for urgency, during 1 or more weeks of treatment, corresponding to 'very frequent' or worse. Of 116 patients who had also completed ≥ 4 clinician-reported assessments for descriptive analysis, clinically significant diarrhea (Common Terminology Criteria for Adverse Events grade ≥ 2) was reported in 9% of patients, and grade 2 proctitis and cystitis were reported in 20% and 4%, respectively. Eighty-four (68%) patients had undergone induction chemotherapy prior to CRT. Patients who received induction chemotherapy had 68% lower odds of experiencing significant urgency (odds ratio [OR], 0.32; 95% confidence interval [CI], 0.11-0.95; P = .04), 76% lower odds of bleeding (OR, 0.24; 95% CI, 0.1-0.62; P < .01), and 75% lower odds of tenesmus (OR, 0.25; 95% CI, 0.11-0.6; P < .01) versus those treated with upfront CRT. ### conclusion Based on PROs, a high proportion of patients experienced clinically significant symptoms during pelvic CRT, with diarrhea and urgency being most commonly reported. This appears to be under-reported on clinician-reported assessments. Delivery of induction chemotherapy was associated with lower odds of experiencing urgency, bleeding, and tenesmus on PROs during subsequent CRT, with no significant impact on diarrhea and rectal pain.

https://pubmed.ncbi.nlm.nih.gov/31104990/

64dae357e4b90c9b29bcfa07ba6af307

Prior to the procedure , the child was administered a dental cocktail containing chloral hydrate , hydroxyzine , and methadone .

A fatality due to an accidental methadone substitution in a dental cocktail. A 6-year-old male child was scheduled for a dental procedure requiring conscious sedation. Prior to the procedure , the child was administered a dental cocktail containing chloral hydrate , hydroxyzine , and methadone . After returning from the dentist, the child appeared groggy and was allowed to sleep. A few hours later, he was found unresponsive, and following resuscitation attempts at a local medical center, he was pronounced dead. Toxicological analyses of femoral blood indicated the presence of hydroxyzine at less than 0.54 μg/mL, trichloroethanol (TCE) at 8.3 μg/mL, and methadone at 0.51 μg/mL. No meperidine was detected. The cause of death was reported to be due to the toxic effects of methadone. The toxicological analysis was corroborated by the analysis of the contents of the dental cocktail, which revealed the presence of hydroxyzine, chloral hydrate, and methadone. Residue from a control sample obtained from the same pharmacy, but administered to a different subject, was found to contain hydroxyzine, chloral hydrate, and meperidine. This report represents the first known fatality due to accidental substitution of methadone in a dental cocktail.

https://pubmed.ncbi.nlm.nih.gov/21871161/

e447b67e96d1d9d23058ebfd3961dda4

We aimed to compare the effect of four TK inhibitors ( axitinib , sunitinib , vandetanib , and XL184 ) on cell proliferation , RET expression and autophosphorylation , and ERK activation in cell lines expressing a MEN2A ( MTC-TT ) , a MEN2B ( MZ-CRC-1 ) mutation , and a RET/PTC ( TPC-1 ) rearrangement .

The effects of four different tyrosine kinase inhibitors on medullary and papillary thyroid cancer cells. Medullary and papillary thyroid carcinoma (MTC and PTC) are two types of thyroid cancer that can originate from activating mutations or rearrangements in the RET gene. Therapeutic options are limited in recurrent disease, but because RET is a tyrosine kinase (TK) receptor involved in cellular growth and proliferation, treatment with a TK inhibitor might be promising. Several TK inhibitors have been tested in clinical trials, but it is unknown which inhibitor is most effective and whether there is any specificity for particular RET mutations. ### objective We aimed to compare the effect of four TK inhibitors ( axitinib , sunitinib , vandetanib , and XL184 ) on cell proliferation , RET expression and autophosphorylation , and ERK activation in cell lines expressing a MEN2A ( MTC-TT ) , a MEN2B ( MZ-CRC-1 ) mutation , and a RET/PTC ( TPC-1 ) rearrangement . ### design The three cell lines were cultured and treated with the four TK inhibitors. Effects on cell proliferation and RET and ERK expression and activation were determined. ### results XL184 and vandetanib most effectively inhibited cell proliferation, RET autophosphorylation in combination with a reduction of RET expression, and ERK phosphorylation in MTC-TT and MZ-CRC-1, respectively. TPC-1 cells showed a decrease in RET autophosphorylation after treatment with XL184, but no effect was observed on ERK activation. ### conclusion There is indeed specificity for different RET mutations, with XL184 being the most potent inhibitor in MEN2A and PTC and vandetanib the most effective in MEN2B in vitro. No TK inhibitor was superior for all the cell lines tested, indicating that mutation-specific therapies could be beneficial in treating MTC and PTC.

https://pubmed.ncbi.nlm.nih.gov/21470995/

27860521bbec4e5bd55327f4454516d5

Additive beneficial effects of fenofibrate combined with atorvastatin in the treatment of combined hyperlipidemia .

Additive beneficial effects of fenofibrate combined with atorvastatin in the treatment of combined hyperlipidemia . We compared vascular and metabolic responses (and adverse responses) to statin and fibrate therapies alone or in combination in patients with combined hyperlipidemia. ### background The mechanisms of action for statins and fibrates are distinct. ### methods Fifty-six patients were given atorvastatin 10 mg and placebo, atorvastatin 10 mg and fenofibrate 200 mg, or fenofibrate 200 mg and placebo daily during each two-month treatment period of a randomized, double-blind, placebo-controlled crossover trial with two washout periods of two months' each. ### results Lipoproteins were changed to a greater extent with combined therapy when compared with atorvastatin or fenofibrate alone. Flow-mediated dilator response to hyperemia and plasma high-sensitivity C-reactive protein and fibrinogen levels were changed to a greater extent with combined therapy when compared with atorvastatin or fenofibrate alone (p < 0.001, p = 0.182, and p = 0.015 by analysis of variance [ANOVA], respectively). The effects of combined therapy or fenofibrate alone on plasma adiponectin levels and insulin sensitivity (determined by the Quantitative Insulin-Sensitivity Check Index [QUICKI]) were significantly greater than those of atorvastatin alone (p = 0.022 for adiponectin and p = 0.049 for QUICKI by ANOVA). No patients were withdrawn from the study as the result of serious adverse effects. ### conclusions Combination therapy is safe and has beneficial additive effects on endothelial function in patients with combined hyperlipidemia.

https://pubmed.ncbi.nlm.nih.gov/15893182/

88854df818fcc017ecd02baae0d05e44

S. sciuri exhibited pronounced multiresistance , and many isolates were characterised by the carriage of a number of uncommon (multi)resistance genes ( e.g. cfr , apmA , fexA ) and decreased susceptibility towards last resort antibiotics such as linezolid and daptomycin .

Antibiotic resistance profiles of coagulase-negative staphylococci in livestock environments. Livestock-associated methicillin-resistant Staphylococcus aureus (LA-MRSA) have globally emerged in animal husbandry. In addition to methicillin resistance, LA-MRSA may carry a variety of novel and uncommon antimicrobial resistance genes. Occurrence of the same resistance genes in coagulase-negative staphylococci (CoNS) and S. aureus suggests an ongoing genetic exchange between LA-MRSA and other staphylococci whose driving forces in the ecological niche of the farm environment are, however, still poorly understood. To assess the potential of CoNS as putative reservoirs for antibiotic resistance genes, we analysed the antimicrobial susceptibility of CoNS from dust and manure samples obtained in 41 pig farms in Germany, most of them (36 of 41) with a proven LA-MRSA/MSSA history. Among the 344 isolates analysed, 18 different CoNS species were identified and S. sciuri represented the most prevalent species (46%). High resistance rates were detected for tetracycline (71%), penicillin (65%) and oxacillin (64%) as well as fusidic acid (50%), which was mainly due to reduced susceptibility among S. sciuri isolates. S. sciuri exhibited pronounced multiresistance , and many isolates were characterised by the carriage of a number of uncommon (multi)resistance genes ( e.g. cfr , apmA , fexA ) and decreased susceptibility towards last resort antibiotics such as linezolid and daptomycin . The combined data suggest that S. sciuri harbours a significant resistance gene pool that requires further attention. We hypothesise that members of this species, due to their flexible lifestyle, might contribute to the spread of such genes in livestock environments.

https://pubmed.ncbi.nlm.nih.gov/27185355/

6aa114c00b52be0ae72ee4e00cecdb8e

The results showed that chlorhexidine ( 0.5 mM ) was more effective than benzalkonium chloride ( 1 mM ) and piperazine ( 1 mM ) .

The effect of some cationic antiseptics on the acidogenicity of dental plaque in vivo. Two series of experiments were performed in order to compare the ability of different cationic antiseptics to inhibit the acid production in plaque. In addition an attempt was made to evaluate the influence of oral retention on the acid-inhibiting properties of these agents. In one series of experiments acid production, following sucrose applications on plaque, was measured in situ prior to and at given time intervals after rinsing with the individual agents. In a second series the effect of eluting the antiseptics retained in the oral cavity by means of 5 consecutive acetic acid (6 mM) rinses was evaluated. The results showed that chlorhexidine ( 0.5 mM ) was more effective than benzalkonium chloride ( 1 mM ) and piperazine ( 1 mM ) . cetylpyridinium chloride (1 mM) was the least effective. Acidic elution markedly reduced the inhibitory effect of single rinses of chlorhexidine (0.5 mM), benzalkonium chloride (1 mM) and the cetylpyridinium chloride (1 mM). This effect was less pronounced with a higher concentration (2.2 mM) of chlorhexidine. The results gave support to the view that retention of an agent in the mouth and in plaque is of significance for its ability to inhibit acid production of dental plaque.

https://pubmed.ncbi.nlm.nih.gov/6932161/

6ea354435c312ec5e44e62fe484b70f8

Finally , although anidulafungin ( as an echinocandin surrogate susceptibility marker ) and amphotericin B ECVs should identify Candida and Aspergillus isolates with reduced susceptibility to these agents using the Etest , these ECVs will not categorize a fungal isolate as susceptible or resistant , as breakpoints do .

Multicenter Study of Method-Dependent Epidemiological Cutoff Values for Detection of Resistance in Candida spp. and Aspergillus spp. to Amphotericin B and Echinocandins for the Etest Agar Diffusion Method. Method-dependent Etest epidemiological cutoff values (ECVs) are not available for susceptibility testing of either Candida or Aspergillus species with amphotericin B or echinocandins. In addition, reference caspofungin MICs for Candida spp. are unreliable. Candida and Aspergillus species wild-type (WT) Etest MIC distributions (microorganisms in a species-drug combination with no detectable phenotypic resistance) were established for 4,341 Candida albicans, 113 C. dubliniensis, 1,683 C. glabrata species complex (SC), 709 C. krusei, 767 C. parapsilosis SC, 796 C. tropicalis, 1,637 Aspergillus fumigatus SC, 238 A. flavus SC, 321 A. niger SC, and 247 A. terreus SC isolates. Etest MICs from 15 laboratories (in Argentina, Europe, Mexico, South Africa, and the United States) were pooled to establish Etest ECVs. anidulafungin, caspofungin, micafungin, and amphotericin B ECVs (in micrograms per milliliter) encompassing ≥97.5% of the statistically modeled population were 0.016, 0.5, 0.03, and 1 for C. albicans; 0.03, 1, 0.03, and 2 for C. glabrata SC; 0.06, 1, 0.25, and 4 for C. krusei; 8, 4, 2, and 2 for C. parapsilosis SC; and 0.03, 1, 0.12, and 2 for C. tropicalis The amphotericin B ECV was 0.25 μg/ml for C. dubliniensis and 2, 8, 2, and 16 μg/ml for the complexes of A. fumigatus, A. flavus, A. niger, and A. terreus, respectively. While anidulafungin Etest ECVs classified 92% of the Candida fks mutants evaluated as non-WT, the performance was lower for caspofungin (75%) and micafungin (84%) cutoffs. Finally , although anidulafungin ( as an echinocandin surrogate susceptibility marker ) and amphotericin B ECVs should identify Candida and Aspergillus isolates with reduced susceptibility to these agents using the Etest , these ECVs will not categorize a fungal isolate as susceptible or resistant , as breakpoints do .

https://pubmed.ncbi.nlm.nih.gov/27799206/

39b25cd9d4e2b993067672f328365fae

The method decision limits were determined to be 1.27 and 0.59 microg/kg for erythromycin and tylosin , respectively .

Determination of erythromycin and tylosin residues in honey by LC/MS/MS. Antibiotics are used in apiculture to protect bees against a variety of brood diseases. As a result of the development of resistance to oxytetracycline, erythromycin and tylosin are increasingly used for the prevention and treatment of these diseases. Therefore, Brazilian authorities have added these antibiotics to the National Regulatory Monitoring Program for the control of residues in honey. An analytical method has been developed for the determination of residues of erythromycin and tylosin in honey. The procedure involves solid-phase extraction of diluted honey samples with Bond Elut cartridges, followed by LC/MS with electrospray positive ionization in the multiple reaction monitoring mode. Two characteristic transitions were monitored for both drugs. Average analyte recoveries of erythromycin and tylosin ranged from 99 to 109% from sets of replicate honey samples fortified with drug concentrations of 5, 10, 15, and 20 microg/kg. The method decision limits were determined to be 1.27 and 0.59 microg/kg for erythromycin and tylosin , respectively . The detection capabilities were 5 and 5.2 microg/kg for erythromycin and tylosin, respectively.

https://pubmed.ncbi.nlm.nih.gov/19610392/

92e3dc3dddb96036451c1e9b0f351877

Bevacizumab with or without erlotinib as maintenance therapy in patients with metastatic colorectal cancer ( GERCOR DREAM ; OPTIMOX3 ): a randomised , open-label , phase 3 trial .

Bevacizumab with or without erlotinib as maintenance therapy in patients with metastatic colorectal cancer ( GERCOR DREAM ; OPTIMOX3 ): a randomised , open-label , phase 3 trial . The combination of an anti-VEGF or an anti-EGFR-targeted monoclonal antibody with chemotherapy has shown clinical activity in patients with metastatic colorectal cancer. However, combining both anti-VEGF and anti-EGFR antibodies with chemotherapy in first-line treatment resulted in adverse outcomes. We assessed whether the combination of erlotinib, an EGFR tyrosine kinase inhibitor, with bevacizumab could increase the efficacy of maintenance therapy in patients with unresectable metastatic colorectal cancer. ### methods This randomised, open-label, phase 3 study was undertaken in 49 centres in France, Austria, and Canada. Eligible patients were aged 18-80 years with histologically confirmed, unresectable metastatic colorectal cancer, WHO performance status 0-2, had received no previous therapy for metastatic disease, and had adequate organ function. Patients without disease progression after bevacizumab-based induction therapy were randomly assigned (1:1) by a minimisation technique to bevacizumab (7·5 mg/kg every 3 weeks) or bevacizumab plus erlotinib (150 mg once daily) as maintenance therapy until progression. All patients were stratified by centre, baseline performance status, age, and number of metastatic sites. The primary endpoint was progression-free survival on maintenance therapy analysed by intention to treat. We report the final analysis. This trial is registered with ClinicalTrials.gov, number NCT00265824. ### findings Between Jan 1, 2007, and Oct 13, 2011, 700 eligible patients were enrolled; following induction treatment, patients without disease progression were randomly assigned to bevacizumab (n=228) or bevacizumab plus erlotinib (n=224). At the final analysis, median follow-up was 51·0 months (IQR 36·0-60·0) in the bevacizumab group and 48·3 months (31·5-61·0) in the bevacizumab plus erlotinib group. In the primary analysis (after 231 progression-free survival events), median progression-free survival from randomisation was 5·1 months (95% CI 4·1-5·9) in the bevacizumab plus erlotinib group compared with 6·0 months (4·6-7·9) in the bevacizumab group (stratified hazard ratio [HR] 0·79 [95% CI 0·60-1·06]; p=0·11; unstratified HR 0·76 [0·59-0·99]; p=0·043). In the final analysis, median progression-free survival from randomisation was 5·4 months (95% CI 4·3-6·2) in the bevacizumab plus erlotinib group compared with 4·9 months (4·1-5·7) in the bevacizumab group (stratified HR 0·81 [95% CI 0·66-1·01], p=0·059; unstratified HR 0·78 [0·68-0·96], p=0·019). At the final analysis, median overall survival from maintenance was 24·9 months (95% CI 21·4-28·9) in the bevacizumab plus erlotinib group and 22·1 months (19·6-26·7) in the bevacizumab group (stratified HR 0·79 [95% CI 0·63-0·99], p=0·036; unstratified HR 0·79 [0·64-0·98], p=0·035). The most frequent grade 3-4 adverse events were skin rash (47 [21%] of 220 patients in the bevacizumab plus erlotinib group vs none of 224 patients in the bevacizumab alone group), diarrhoea (21 [10%] vs two [<1%]), and asthenia (12 [5%] vs two [<1%]). ### interpretation Maintenance bevacizumab plus erlotinib might be a new non-chemotherapy-based maintenance option for the first-line treatment of patients with unresectable metastatic colorectal cancer after bevacizumab-based induction therapy. ### funding GERCOR and F Hoffmann-La Roche.

https://pubmed.ncbi.nlm.nih.gov/26474518/

8992547ade8ad225056deedabff483df

Eighteen patients with primary or recurrent ovarian cancer were treated with paclitaxel 150 or 110 mg/m2 , respectively , together with gemcitabine 800 mg/m2 and cisplatin 75 mg/m2 , 3 weekly for 6 cycles .

Peripheral neuropathy due to therapy with paclitaxel, gemcitabine, and cisplatin in patients with advanced ovarian cancer. To evaluate the peripheral neuropathic changes induced by combination chemotherapy including paclitaxel (taxol), gemcitabine and cisplatin (TGC regimen). ### Patients And Methods Eighteen patients with primary or recurrent ovarian cancer were treated with paclitaxel 150 or 110 mg/m2 , respectively , together with gemcitabine 800 mg/m2 and cisplatin 75 mg/m2 , 3 weekly for 6 cycles . Neurologic evaluation and quantitative assessment by vibration perception threshold (VPT) and grip strength took place before therapy, after 3 and 6 cycles of chemotherapy, and thereafter when possible. ### results Both neuropathic symptoms and signs developed in all patients (100%), becoming most prominent 3 months after the last course of chemotherapy. Grade 3 peripheral neuropathy developed in one patient during chemotherapy, and in 3 additional patients after cessation of therapy. No significant differences were observed between chemo-naive patients and pretreated patients. ### conclusion This TGC combination is well tolerated in terms of peripheral neuropathy during therapy, although the off-therapy worsening caused by cisplatin remains a problem.

https://pubmed.ncbi.nlm.nih.gov/12825825/

8e02adf7ef7e1034f79edf03487bc95b

After pretreatment with warfarin ( 0.2 mg/kg/day ) , low-dose rivaroxaban ( 60 mg/kg/day ) , high-dose rivaroxaban ( 120 mg/kg/day ) , or vehicle for 14 days , transient middle cerebral artery occlusion was induced for 90 min , followed by reperfusion with tPA ( 10 mg/kg/10 ml ) .

Reduction of intracerebral hemorrhage by rivaroxaban after tPA thrombolysis is associated with downregulation of PAR-1 and PAR-2. This study aimed to assess the risk of intracerebral hemorrhage (ICH) after tissue-type plasminogen activator (tPA) treatment in rivaroxaban compared with warfarin-pretreated male Wistar rat brain after ischemia in relation to activation profiles of protease-activated receptor-1, -2, -3, and -4 (PAR-1, -2, -3, and -4). After pretreatment with warfarin ( 0.2 mg/kg/day ) , low-dose rivaroxaban ( 60 mg/kg/day ) , high-dose rivaroxaban ( 120 mg/kg/day ) , or vehicle for 14 days , transient middle cerebral artery occlusion was induced for 90 min , followed by reperfusion with tPA ( 10 mg/kg/10 ml ) . Infarct volume, hemorrhagic volume, immunoglobulin G leakage, and blood parameters were examined. Twenty-four hours after reperfusion, immunohistochemistry for PARs was performed in brain sections. ICH volume was increased in the warfarin-pretreated group compared with the rivaroxaban-treated group. PAR-1, -2, -3, and -4 were widely expressed in the normal brain, and their levels were increased in the ischemic brain, especially in the peri-ischemic lesion. warfarin pretreatment enhanced the expression of PAR-1 and PAR-2 in the peri-ischemic lesion, whereas rivaroxaban pretreatment did not. The present study shows a lower risk of brain hemorrhage in rivaroxaban-pretreated compared with warfarin-pretreated rats following tPA administration to the ischemic brain. It is suggested that the relative downregulation of PAR-1 and PAR-2 by rivaroxaban compared with warfarin pretreatment might be partly involved in the mechanism of reduced hemorrhagic complications in patients receiving rivaroxaban in clinical trials. © 2016 Wiley Periodicals, Inc.

https://pubmed.ncbi.nlm.nih.gov/28035779/

20b7ca4fb30c58b4314d757911531693

The cost-minimisation analysis showed that treatment costs for a 12-week course of capecitabine ( Pounds 2132 ) and tegafur with uracil ( Pounds 3385 ) were lower than costs for the intravenous Mayo regimen ( Pounds 3593 ) and infusional regimens on the de Gramont ( Pounds 6255 ) and Modified de Gramont ( Pounds 3485 ) schedules over the same treatment period .

The clinical and economic benefits of capecitabine and tegafur with uracil in metastatic colorectal cancer. Two oral fluoropyrimidine therapies have been introduced for metastatic colorectal cancer. One is a 5-fluorouracil pro-drug, capecitabine; the other is a combination of tegafur and uracil administered together with leucovorin. The purpose of this study was to compare the clinical effectiveness and cost-effectiveness of these oral therapies against standard intravenous 5-fluorouracil regimens. A systematic literature review was conducted to assess the clinical effectiveness of the therapies and costs were calculated from the UK National Health Service perspective for drug acquisition, drug administration, and the treatment of adverse events. A cost-minimisation analysis was used; this assumes that the treatments are of equal efficacy, although direct randomised controlled trial (RCT) comparisons of the oral therapies with infusional 5-fluorouracil schedules were not available. The cost-minimisation analysis showed that treatment costs for a 12-week course of capecitabine ( Pounds 2132 ) and tegafur with uracil ( Pounds 3385 ) were lower than costs for the intravenous Mayo regimen ( Pounds 3593 ) and infusional regimens on the de Gramont ( Pounds 6255 ) and Modified de Gramont ( Pounds 3485 ) schedules over the same treatment period . Oral therapies result in lower costs to the health service than intravenous therapies. Further research is needed to determine the relative clinical effectiveness of oral therapies vs infusional regimens.

https://pubmed.ncbi.nlm.nih.gov/16804526/

07a90e10a5261b7008e02cead48838c6

However , the combination of clindamycin and ciprofloxacin increased mortality associated with B. anthracis Sterne infection , particularly in gamma-irradiated animals .

Clindamycin and quinolone therapy for Bacillus anthracis Sterne infection in 60Co-gamma-photon-irradiated and sham-irradiated mice. Sublethal ionizing doses of radiation increase the susceptibility of mice to Bacillus anthracis Sterne infection. In this study, we investigated the efficacy of clindamycin in 60Co-gamma-photon-irradiated and sham-irradiated mice after intratracheal challenge with B. anthracis Sterne spores. clindamycin has in vitro activity against B. anthracis and inhibits the production of toxin from other species, although no direct evidence exists that production of B. anthracis toxin is inhibited. ### methods Ten-week-old B6D2F1/J female mice were either sham-irradiated or given a sublethal 7 Gy dose of 60Co-gamma-photon radiation 4 days prior to an intratracheal challenge with toxigenic B. anthracis Sterne spores. Mice were treated twice daily with 200 mg/kg clindamycin (subcutaneous or oral), 100 mg/kg moxifloxacin (oral), 50 mg/kg ciprofloxacin (subcutaneous) or a combination therapy (clindamycin + ciprofloxacin). Bacteria were isolated and identified from lung, liver and heart blood at five timed intervals after irradiation. Survival was recorded twice daily following intratracheal challenge. ### results The use of clindamycin increased survival in gamma-irradiated and sham-irradiated animals challenged with B. anthracis Sterne in comparison with control mice (P < 0.001). ciprofloxacin-treated animals had higher survival compared with clindamycin-treated animals in two experiments, and less survival in a third experiment, although differences were not statistically significant. moxifloxacin was just as effective as clindamycin. Combination therapy did not improve survival of sham-irradiated animals and significantly decreased survival among gamma-irradiated animals (P = 0.01) in comparison with clindamycin-treated animals. B. anthracis Sterne was isolated from lung, liver and heart blood, irrespective of the antimicrobial treatment. ### conclusions Treatment with clindamycin, ciprofloxacin or moxifloxacin increased survival in sham-irradiated and gamma-irradiated animals challenged intratracheally with B. anthracis Sterne spores. However , the combination of clindamycin and ciprofloxacin increased mortality associated with B. anthracis Sterne infection , particularly in gamma-irradiated animals .

https://pubmed.ncbi.nlm.nih.gov/16239289/

f5a4e1a3a2fd7c354cb27e3be2de987c

We investigated the maximum tolerated dose , dose-limiting toxicities , and response rate when the selective cyclooxygenase-2 inhibitor celecoxib is added to concurrent irinotecan , cisplatin , and radiation therapy for patients with inoperable stage II-III non-small cell lung cancer ( NSCLC ) .

Phase I study of celecoxib with concurrent irinotecan, Cisplatin, and radiation therapy for patients with unresectable locally advanced non-small cell lung cancer. Preclinical findings suggest that adding targeted therapies to combination radiation-chemotherapy can enhance treatment efficacy; however, this approach may enhance normal tissue toxicity. We investigated the maximum tolerated dose , dose-limiting toxicities , and response rate when the selective cyclooxygenase-2 inhibitor celecoxib is added to concurrent irinotecan , cisplatin , and radiation therapy for patients with inoperable stage II-III non-small cell lung cancer ( NSCLC ) . ### Methods And Materials Eighteen patients were analyzed in a phase I clinical dose-escalation trial. celecoxib was given daily beginning 5 days before radiation followed by maintenance doses for 12 weeks. Toxicity was graded with the Common Terminology Criteria for Adverse Events V3.0 and response with the World Health Organization system. Primary endpoints were maximum tolerated dose of celecoxib and treatment toxicity; secondary endpoints were response and survival rates. ### results The maximum tolerated dose of celecoxib was not reached, in part owing to discontinuation of the drug supply. At doses of 200 or 400 mg/day, no patients experienced any dose-limiting toxicity (acute grade ≥4 esophagitis or pneumonitis, neutropenic fever or thrombocytopenia requiring transfusion, or acute grade ≥3 diarrhea). Grade 3 toxicities were leukopenia (five patients), fatigue (3), pneumonitis (2), dyspnea (1), pain (1), and esophageal stricture (1). Interestingly, pulmonary fibrosis (a late toxicity) was no more severe in the higher-dose (400-mg) group and may have been less common than in the lower-dose group. The clinical response rate was 100% (8 complete, 10 partial). Two-year rates were: overall survival 65%; local-regional control 69%; distant metastasis-free survival 71%; and disease-free survival 64%. ### conclusion Although preliminary, our results suggest that adding celecoxib to concurrent chemoradiation for inoperable NSCLC is safe and can improve outcome without increasing normal tissue toxicity.

https://pubmed.ncbi.nlm.nih.gov/22649768/

a928f7c6c1f1afb1f3997fc61a95654f

The combination of docetaxel and estramustine phosphate ( estramustine ) has been reported to be effective for HRPC .

Docetaxel, low-dose estramustine, and doxifluridine in hormone-refractory metastatic prostate cancer. Advanced prostate cancer, which is one of the most common cancers, usually progresses to hormone-refractory prostate cancer (HRPC). A recent randomized trial of treatment with docetaxel demonstrated improved survival for patients with HRPC. The combination of docetaxel and estramustine phosphate ( estramustine ) has been reported to be effective for HRPC . Low-dose estramustine suppresses the pituitary-gonadal axis. docetaxel plus 5-fluoro-5'-deoxyuridine (5'-dFUrd) had supra-additive cytotoxic effects on HRPC cells consistent with the molecular mechanism. Therefore, we examined the efficacy of adding 5'-dFUrd on the chemotherapy regimen, which consist docetaxel and estramustine. ### methods All of the HRPC patients were treated with estramustine 140 mg orally twice 5'-dFUrd 200 mg orally four times daily on days 1-21, and docetaxel 60 mg/m(2) was administered on day 1. We evaluated serum prostate-specific antigen (PSA) and measurable responses, the progression-free and overall survival, and the impact on adverse effects and the quality of life (QOL). ### results Of 34 patients with a median age of 72.3 years, 73% showed PSA responses and 70% showed measurable responses. The median progression-free survival was 18.0 and 5.8 months for PSA responders and non-responders and the overall survival was 19.4 months, respectively. There were few serious adverse effects. Grade 3/4 neutropenia occurred in 32.4% of the patients, and was easily managed with granulocyte colony-stimulating factor (G-CSF) injection. There was no significant change in the overall QOL scores serially. ### conclusions This study shows that the combined regimen is tolerable and effective in Japanese HRPC patients.

https://pubmed.ncbi.nlm.nih.gov/17375305/

c46f91136c37afe4ed955420e39cc87a

Significant advances have been made in the last decade since the introduction of different tyrosine kinase inhibitors ( TKIs ) such as sunitinib , pazopanib , and sorafenib .

First-line tyrosine kinase inhibitors in metastatic renal cell carcinoma: A regional cancer center experience. Renal cell carcinoma (RCC) is highly resistant to systemic chemotherapy, and historically a poor prognosis for metastatic disease has been reported, with a 5-year survival rate of <10%. Significant advances have been made in the last decade since the introduction of different tyrosine kinase inhibitors ( TKIs ) such as sunitinib , pazopanib , and sorafenib . Unfortunately, even though the TKIs have been used for a long time, there are very few published data regarding the experience of TKI therapy in metastatic RCC (mRCC) from India. ### Materials And Methods This is a single institutional review of mRCC patients treated between January 2012 and July 2017. Patients who received at least 1 month of first-line TKIs were included for analysis of response rates, toxicity, survival outcomes, and prognostic factors. ### results Of the 40 mRCC patients, 31 (77.5%) were males. Median age at diagnosis was 58 years (range: 38-80 years). The most common site of metastasis was lungs (n = 24) followed by bone (n = 19) and liver (n = 7). Three patients had favorable risk disease, whereas 25 had intermediate risk and 12 had poor risk disease according to the MSKCC risk criteria. First-line TKI therapy used was sunitinib in 24, pazopanib in 11, and sorafenib in 5 patients. Toxicities of TKIs were Grade 1 or 2 in 13 patients and Grade 3 or 4 in 9 patients; the most common being fatigue, followed by hand-foot syndrome, skin rash, mucositis, and hypertension. Overall, 29 patients (72.5%) had disease control (complete responses in 1, partial responses in 10, and stable disease in 18 patients), whereas 11 had progression of disease at initial evaluation. At a median follow-up of 16 months (range: 2-38 months), median progression-free survival (PFS) was 10.8 months and median overall survival was 19.1 months. ### conclusions sunitinib and pazopanib are viable first-line options for mRCC and showed a comparable PFS in Indian patients. Careful patient selection, tailoring of TKI doses, and careful toxicity management are essential for optimum therapy.

https://pubmed.ncbi.nlm.nih.gov/30082547/

1d45a41a4087429135570126b747b54e

A fixed-dose combination of artesunate + amodiaquine ( ASAQ ) was recently developed .

Randomized, multicentre assessment of the efficacy and safety of ASAQ--a fixed-dose artesunate-amodiaquine combination therapy in the treatment of uncomplicated Plasmodium falciparum malaria. The use of artemisinin derivative-based combination therapy (ACT) such as artesunate plus amodiaquine is currently recommended for the treatment of uncomplicated Plasmodium falciparum malaria. Fixed-dose combinations are more adapted to patients than regimens involving multiple tablets and improve treatment compliance. A fixed-dose combination of artesunate + amodiaquine ( ASAQ ) was recently developed . To assess the efficacy and safety of this new combination and to define its optimum dosage regimen (once or twice daily) in the treatment of uncomplicated P. falciparum malaria, a multicentre clinical study was conducted. ### methods A multicentre, randomized, controlled, investigator-blinded, parallel-group study was conducted in five African centers in Cameroon, Madagascar, Mali and Senegal from March to December 2006. Efficacy and safety of ASAQ were assessed compared to those of artemether + lumefantrine (AL). The WHO protocol with a 28-day follow-up for assessing the drug therapeutic efficacy was used. Patients suffering from uncomplicated P. falciparum malaria were randomized to receive ASAQ orally once daily (ASAQ1), ASAQ twice daily (ASAQ2) or AL twice daily (AL) for three days. The primary outcome was PCR-corrected parasitological cure rate and clinical response. ### results Of 941 patients initially randomized and stratified into two age groups (<5 years, and >or=5 years), 936 (99.5%) were retained for the intent to treat (ITT) analysis, and 859 (91.3%) patients for the per protocol (PP) analysis. Among ITT population, up to D28, PCR-corrected adequate parasitological and clinical response rates were 95.2% in the ASAQ1 group, 94.9% in the ASAQ2 group and 95.5% in the AL group. Moreover, the cure rate evaluated among PP population was >or=98.5% in both ASAQ therapeutic arms. Therapeutic response rates did not display any significant differences between age groups or between one geographical site and another. Altogether, this demonstrates the non-inferiority of ASAQ1 regimen compared to both ASAQ2 and AL regimens. During follow-up mild and moderate adverse events including gastrointestinal and/or nervous disorders were reported in 29.3% of patients, with no difference between groups in the nature, frequency or intensity of adverse events. ### conclusion The non-inferiority of ASAQ compared with AL was demonstrated. The fixed-dose combination artesunate + amodiaquine (ASAQ) is safe and efficacious even in young children under 5 years of age. Whilst administration on a twice-a-day basis does not improve the efficacy of ASAQ significantly, a once-a-day intake of this new combination clearly appears as an effective and safe therapy in the treatment of uncomplicated P. falciparum malaria both in adults and children. Implications of such findings are of primary importance in terms of public health especially in African countries. As most national policies plan to strengthen malaria control to reach the elimination of this disease, anti-malarial drugs such as the artesunate + amodiaquine fixed-dose ACT will play a pivotal role in this process. ### Trial Registration The protocol was registered with the www.clinicaltrials.gov open clinical trial registry under the identifier number NCT00316329.

https://pubmed.ncbi.nlm.nih.gov/19505304/

0da184f3d08d17f701d7a11270065b3e

All patients have received a median of four and half cycles ( range , 1 - 10 ) of 3-week ( 60 - 75 mg/m2 ) docetaxel regimens and 5 mg prednisone twice per day .

Efficacy and safety of docetaxel and prednisolone chemotherapy in very elderly men with metastatic castration-resistant prostate cancer (mCRPC) in real world: a single institute experience. Prostate cancer is the most common type of malignancy in elderly men. Although elderly patients are commonly encountered in clinical practice, few studies have focused on the value of chemotherapy in elderly patients. In this study, we reviewed the use of docetaxel with prednisolone in elderly men (aged ≥80 years) with metastatic castration-resistant prostate cancer (mCRPC) at Ningbo First Hospital with a focus on efficacy and toxicity. ### methods A retrospective study including a series of men aged ≥80 years with mCRPC and received docetaxel plus prednisone chemotherapy between August 2011 and May 2019. All these cases were selected from the Ningbo First Hospital prostate cancer database located in Zhejiang Province, China. ### results Sixteen patients were identified, with a mean age of 82 years (range, 80 to 87 years). All patients have received a median of four and half cycles ( range , 1 - 10 ) of 3-week ( 60 - 75 mg/m2 ) docetaxel regimens and 5 mg prednisone twice per day . Seven (43.75%) patients completed more than six cycles. Ten (62.50%) patients had a good prostate-specific antigen (PSA) response of ≥50% decline. Eight (50.00%) patients had ostealgia before receiving docetaxel treatment and six of them (75.00%) experienced reduced pain after the treatment. Hematologic toxicity was observed in six (37.50%) patients with neutropenia, one of which was diagnosed with agranulocytosis and had to be admitted for the same reason. Other adverse reactions such as fever, debilitation, and alopecia were also observed. ### conclusions Very elderly patients (aged ≥80 years) with mCRPC are easy to be neglected and infrequently involved in clinical trials. Our study demonstrates that docetaxel chemotherapy plus prednisone is tolerable and effective among Chinese elderly patients (≥80 years) with mCRPC. docetaxel chemotherapy may be given under careful surveillance even in frail elderly patients.

https://pubmed.ncbi.nlm.nih.gov/33081478/

7ad567a67c448d2d87998e69080f20fb

Combination therapy with other agents including anticoagulants , antihypertensive , anti-inflammatory , oral hypoglycemic and antifungal agents as well as beta-blockers , H2 blockers , cyclosporine and digoxin has been also reviewed .

Clinical pharmacology of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. In this article, de novo cholesterol synthesis, its inhibition by HMG-CoA reductase inhibitors (statins) and clinical pharmacology aspects of the statins have been reviewed. Statins are available in both active and pro-drug forms. Their affinity to bind and subsequently to inhibit HMG-CoA reductase activity is approximately 3 orders of magnitude higher than that of natural substrate (HMG-CoA). All members of this group of lipid-lowering agents are, to a varying degree, absorbed from the gut. However, their bioavailability depends on their lipophobicity and their concomitant use with meals. The interaction between HMG-CoA reductase inhibitors and other lipid-lowering agents has been reviewed in more detail. One major side-effect of lipid-lowering combination therapy is myopathy with or without rhabdomyolysis. Combination of statins with gemfibrozil seems to increase risk of this adverse event, particularly in patients with renal impairment, more than combination with other lipid-lowering agents. Combination therapy with other agents including anticoagulants , antihypertensive , anti-inflammatory , oral hypoglycemic and antifungal agents as well as beta-blockers , H2 blockers , cyclosporine and digoxin has been also reviewed . The pleiotropic non-lipid lowering properties of statins and their effects on the quality of lipoprotein particles, the activities of cholesteryl ester transfer protein and lecithin:cholesterol acyltransferase as well as their possible synergistic effects with n-3 fatty acids, phytosterols, vitamin E and aspirin in reducing cardiovascular events warrant further investigation.

https://pubmed.ncbi.nlm.nih.gov/10503952/

dc325ea5ead86b3a17c5f4b4f215509b

Comparative study of tranexamic acid and norethisterone in the treatment of ovulatory menorrhagia .

Comparative study of tranexamic acid and norethisterone in the treatment of ovulatory menorrhagia . To compare the efficacy and safety of tranexamic acid and norethisterone in the treatment of ovulatory menorrhagia. ### design A randomised, double-blind, placebo controlled study. ### setting University Department of Obstetrics and Gynaecology, Addenbrooke's Hospital, Cambridge. ### subjects One hundred and three women complaining of heavy periods with a regular cycle recruited directly from general practitioners within the hospital catchment area and from consultants' gynaecology clinics. ### interventions There were forty-six women on placebo with confirmed ovulatory menorrhagia, defined as menstrual blood loss greater than 80 ml/cycle and mid-luteal serum progesterone concentration greater than 9 nmol/l). Twenty-one received norethisterone (5 mg twice a day on days 19 and 26) and 25 received tranexamic acid (1 g four times daily on days 1 to 4) for two cycles. ### Main Outcome Measures Menstrual blood loss was measured using the alkaline haematin method. Haematological assessments were made both at the beginning and at the end of the study, questionnaires were given to assess subjective endpoints, and patients were asked to report any adverse events during all cycles. ### results tranexamic acid reduced mean menstrual blood loss by 45%, from 175 ml to 97 ml (95% CI for the difference in menstrual blood loss 52 to 108, P < 0.0001), norethisterone increased mean blood loss by 20% from 173 ml to 208 ml (95% CI for the difference in menstrual blood loss -64 to 2, P = 0.26). Fourteen (56%) women who received tranexamic acid achieved a mean menstrual loss of less than 80 ml per cycle during treatment, but only two (9.5%) who received norethisterone achieved this mean menstrual loss. There were no serious adverse events reported for either drug. ### conclusions tranexamic acid is a safe and effective form of medical therapy in women with menorrhagia and is highly likely to normalise blood loss in women losing 80 to 200 ml prior to treatment. norethisterone at this dose is not effective therapy for ovulatory menorrhagia.

https://pubmed.ncbi.nlm.nih.gov/7612535/

97e1c88327c1ea59d0837ea5a5433a97

The results of this work encourage the in vivo examination of the therapeutic potential of the combination of bortezomib and rapamycin in Mantle Cell Lymphoma patients .

The effect of Bortezomib and Rapamycin on Telomerase Activity in Mantle Cell Lymphoma. Mantle cell lymphoma (MCL) is a hematological malignancy with unfavorable prognosis. Novel therapeutic approaches for treating the disease are aimed at the mechanisms regulating growth signals, cellular proliferation, and survival pathways of the malignant clones. bortezomib (Brt), a proteasome inhibitor with pleiotropic activities was shown to be active in MCL and is currently implemented in therapeutic combinations for this disease. Telomerase activity is essential for survival of malignant cells and as such is considered a valid therapeutic target. This study evaluated the effects of bortezomib on telomerase activity and its regulation in MCL cells in vitro and ex vivo. Our study shows that bortezomib exerts a cytotoxic effect in a dose dependent manner in two MCL cell lines, with differential sensitivity. While the IC50 for HBL-2 cells ranged between 2.5 ng/ml to 1.5 ng/ml during 24-72 h respectively, the IC50 for the NCEB cells was twice. bortezomib differentially inhibited telomerase activity (TA): in HBL-2 cells there was a decline of 20%-55% during 24-72 h respectively. However in NCEB cells the decline was much smaller, and did not exceed 25%. Inhibition of telomerase activity is shown to be operated by two separate mechanisms: reduction of the hTERT mRNA expression (controlled by the binding of transcription factors) and reduction in phosphorylation of the catalytic subunit of hTERT by its kinases, AKT and PKCα. A decrease in telomerase activity was demonstrated also in mononuclear cells, isolated from three MCL patients following incubation of the cells in the presence of bortezomib for 24-72 h. In one patient the decrease in TA ranged between 17%-37% respectively, in the second patient between 63%-76% and in the third patient between 70-100% for 24-72 h respectively. The current study indicates that a combination of bortezomib and rapamycin, (an m-Tor pathway inhibitor used in MCL treatment) induced synergistic inhibition of telomerase activity. In HBL-2 cells, the combined treatment of bortezomib and rapamycin decreased TA by 80% compared to the expected value (40%) and for NCEB cells a similar trend was observed. In contrast, there was neither additive nor synergistic effect of this combination on cell proliferation. In the light of the crucial role of telomerase in cancer cells, it was important to characterize the possible relations between telomerase and bortezomib and to distinguish the biochemical mechanisms of its regulation and its interactions with other signal transduction inhibitors such as rapamycin. The results of this work encourage the in vivo examination of the therapeutic potential of the combination of bortezomib and rapamycin in Mantle Cell Lymphoma patients .

https://pubmed.ncbi.nlm.nih.gov/25500084/

3e99a850beac024e20cc6bb5376f01de

Additive effects of combined valsartan and spironolactone on cardiac aldosterone escape in spontaneously hypertensive rats .

Additive effects of combined valsartan and spironolactone on cardiac aldosterone escape in spontaneously hypertensive rats . The additive effects of combined valsartan and spironolactone on plasma and cardiac aldosterone escape were evaluated in spontaneously hypertensive rats (SHRs). Twenty-four SHRs were treated with valsartan (30 mg/kg body weight per day), spironolactone (20 mg/kg body weight per day) and a combination of both for 4 months. Blood was collected and plasma aldosterone (PA) was estimated with radioimmunoassay (RIA). Ex vivo heart perfusion was performed, the ex vivo cardiac aldosterone (EXCA) was assessed by RIA after high-performance liquid chromatography separation. PA and EXCA were significantly decreased after one month but increased after 4 months in valsartan administration group. The combined valsartan and spironolactone therapy normalized cardiac aldosterone levels. This study provides the first evidence that the long-term treatment with Angiotensin II type 1 receptor antagonist (AT1A) induces local aldosterone escape in cardiovascular tissue, whereas the combined AT1A and spironolactone therapy inhibits the escape in hypertensive rats.

https://pubmed.ncbi.nlm.nih.gov/15302230/

206efdfddbfc96d10d86fbfe7dea73ae

54 patients without distant metastases ( T2-T3b , N0-X , M0 ) received 3 cycles of neoadjuvant chemotherapy according to the MVAC protocol ( methotrexate , vinblastine , doxorubicin and cisplatin ) after transurethral resection ( TUR ) followed by cystectomy .

Neoadjuvant chemotherapy (MVAC) in locally invasive bladder cancer. In order to evaluate the efficacy of neoadjuvant chemotherapy in invasive urothelial carcinoma of the bladder a retrospective analysis was performed. 54 patients without distant metastases ( T2-T3b , N0-X , M0 ) received 3 cycles of neoadjuvant chemotherapy according to the MVAC protocol ( methotrexate , vinblastine , doxorubicin and cisplatin ) after transurethral resection ( TUR ) followed by cystectomy . 52 patients had previously undergone cystectomy immediately after TUR. Complete histopathological remission was observed in 9 patients (17.3%) after TUR and in 17 patients (31.5%) after TUR+MVAC. Neoadjuvant MVAC resulted, therefore, in a 14% higher rate of complete remissions. The overall response to TUR was significantly improved by MVAC therapy. Downstaging by neoadjuvant chemotherapy was more readily achieved in initially low-stage tumours (T2: 44.4% and 30.8%, T3a: 47.1% and 19%, T3b: 5.3% and 5.5% in patients receiving TUR+MVAC and TUR alone, respectively). Overall survival did not differ significantly between both groups. Patients who were successfully downstaged to pT0 had a significantly better prognosis, and patients resistant to chemotherapy had the poorest prognosis, showing the shortest survival. In conclusion, histopathological response at cystectomy was improved by neoadjuvant MVAC chemotherapy after TUR and can be expected to be prognostically relevant in those patients who can be downstaged to T0, although overall survival failed to be significantly increased in this relatively small patient sample.

https://pubmed.ncbi.nlm.nih.gov/8869093/

82d01675243026c612a8cdb0a49b6a38

The objective of this study was to compare cycle control , efficacy and tolerance of an oral contraceptive containing 20 microg ethinylestradiol and 150 microg desogestrel with a preparation containing 30 microg ethinylestradiol combined with 75 microg gestodene .

Latin american experience with two low-dose oral contraceptives containing 30 microg ethinylestradiol/75 microg gestodene and 20 microg ethinylestradiol/150 microg desogestrel. The objective of this study was to compare cycle control , efficacy and tolerance of an oral contraceptive containing 20 microg ethinylestradiol and 150 microg desogestrel with a preparation containing 30 microg ethinylestradiol combined with 75 microg gestodene . This study involved 342 women and 4104 cycles use in Argentina, Brazil, Chile, and Mexico. Contraceptive efficacy was good with both formulations. Two pregnancies occurred in the desogestrel group but were not due to method failure. With respect to cycle control, the incidence of intermenstrual bleeding was higher during the first 3 cycles in the desogestrel group; it was significant (p <0.01) during the first 3 days of the cycle for a normal or heavy bleeding only in the Mexican group. Amenorrhea was not reported for any group, but the incidence of dysmenorrhea was significantly higher (p <0.01) in the Brazilian desogestrel group (13.8%) and was significantly lower (p <0.01) in the Mexican gestodene group (8.5%). Adverse events were similar in all the countries with headache, breast tension, and nausea, the most frequently reported symptoms. The range of mean increase in body weight varied from 0.2 kg in the Argentine group to 2.6 kg in the Chilean group (95% confidence limit, +/- 2.51) in the gestodene group, and 0.2 kg in the Argentine group to 2.5 kg in Brazilian group (95% confidence limit, +/- 2.36) in the desogestrel group. Fifteen women discontinued because of headache, but there were no significant differences between the groups regarding discontinuation for this and other medical or non-medical reasons. Both oral contraceptive preparations are reliable and well tolerated, and both have favorable effects on control cycle.

https://pubmed.ncbi.nlm.nih.gov/11124360/

22442dbeede668f6698d00b04a0b5e72

They were assigned to either receiving a COCP containing 20 mcg ethinyl estradiol/150 mg desogestrel for two continuous cycle or NSAID ; mefenamic acid 500 mg TDS for 5 days , 21 days apart for two cycles .

Management of bleeding irregularities among etonogestrel implant users: Is combined oral contraceptives pills or nonsteroidal anti-inflammatory drugs the better option? This study is to evaluate whether unacceptable bleeding among the etonogestrel implant user could be better alleviated using combined oral contraceptive pills (COCP) or nonsteroidal anti-inflammation drugs (NSAID). ### methods This is a prospective randomized study for evaluation of 84 etonogestrel implant (Implanon) users with prolonged or frequent bleeding. They were assigned to either receiving a COCP containing 20 mcg ethinyl estradiol/150 mg desogestrel for two continuous cycle or NSAID ; mefenamic acid 500 mg TDS for 5 days , 21 days apart for two cycles . Bleeding pattern during the treatment was recorded and analyzed. ### results A total of 32 women (76.2%) in COCP group and 15 women (35.7%) in NSAID group stop bleeding within 7 days after the initiation of treatment which was statistically significant (P < 0.05). The mean duration of bleeding and spotting days in women treated with COCP was significantly lesser compared to NSAID group (7.29 ± 3.16 vs 10.57 ± 4.14 days (P < 0.05). ### conclusion We conclude that COCP is more efficient compared to NSAID in managing bleeding irregularities among etonogestrel implant users.

https://pubmed.ncbi.nlm.nih.gov/31958877/

a5c80ba5bf5b384aa07401174cdc1726

Preclinical data suggest that enzastaurin and bevacizumab may have complementary effects in inhibiting angiogenesis .

Randomized, double-blinded, multicenter, phase II study of pemetrexed, carboplatin, and bevacizumab with enzastaurin or placebo in chemonaïve patients with stage IIIB/IV non-small cell lung cancer: Hoosier Oncology Group LUN06-116. : bevacizumab is approved in combination with chemotherapy as first-line treatment for non-small cell lung cancer (NSCLC). Preclinical data suggest that enzastaurin and bevacizumab may have complementary effects in inhibiting angiogenesis . ### methods : ### Eligibility Criteria ≥18 years of age, chemonaïve, stage IIIB/IV nonsquamous NSCLC, and Eastern Cooperative Oncology Group performance status 0 to 1. Patients were randomized to placebo or enzastaurin 500 mg orally daily (after a loading dose), plus pemetrexed 500 mg/m, carboplatin area under the curve 6, and bevacizumab 15 mg/kg, intravenously, every 21 days for four cycles. Patients without progression received maintenance therapy with bevacizumab and placebo or enzastaurin. The primary objective was progression-free survival (PFS). Planned sample size was 90 patients, one-sided alpha of 0.20, with two interim analyses: one for safety and the second for futility, with a PFS hazard ratio of 0.8857. ### results : Forty patients were randomized. No unique safety concerns were noted at the first interim analysis. The early stopping rule for futility was met at the second interim analysis. Median PFS was 3.5 months and 4.3 months (hazard ratio: 1.04, 95% confidence interval: 0.49-2.21), and response rates were 20% and 30% (p = 0.462) for enzastaurin and placebo, respectively. Grade 3 or 4 toxicity was similar between the two arms. Two patients died on study because of respiratory arrest and pulmonary embolism. An additional patient died of sepsis secondary to a gastrointestinal perforation >30 days after study treatment discontinuation. ### conclusions : enzastaurin does not improve efficacy when combined with pemetrexed, carboplatin, and bevacizumab. This combination does not warrant further study in NSCLC.

https://pubmed.ncbi.nlm.nih.gov/20881647/

64476c3ec43afe5a97fb58f0c495f642

The PASI-75 , -90 and -100 were the highest in secukinumab ( 91.3 % , 82.6 % , 41.3 % , respectively ) , followed by ustekinumab ( 79.6 % , 44.9 % , 16.3 % ) , adalimumab ( 64.3 % , 28.6 % , 7.1 % ) and etanercept ( 50.0 % , 30.0 % , 0 % ) .

Real-world efficacy of biological agents in moderate-to-severe plaque psoriasis: An analysis of 75 patients in Taiwan. Real-world clinical data on psoriasis patients receiving different biological agents is needed, especially in Asian populations. ### objectives Our aim is to compare and analyze the efficacy and safety profile of four biological agents (etanercept, adalimumab, ustekinumab and secukinumab) in a real-world setting in Taiwan. ### methods We retrospectively analyzed the clinical data of all patients with moderate-to-severe plaque psoriasis (Psoriasis Area and Severity Index (PASI) ≥ 10) who received etanercept, adalimumab, ustekinumab or secukinumab between January 2011 and December 2018 in a tertiary hospital in Taiwan. ### results A total of 119 treatment episodes in 75 patients were included in this study. ustekinumab was used in 49 treatment episodes, followed by secukinumab in 46 treatment episodes, adalimumab in 14 treatment episodes and etanercept in 10 treatment episodes. The proportion of the biologic-naïve was highest in etanercept (100%) and lowest in secukinumab (23.9%). The PASI-75 , -90 and -100 were the highest in secukinumab ( 91.3 % , 82.6 % , 41.3 % , respectively ) , followed by ustekinumab ( 79.6 % , 44.9 % , 16.3 % ) , adalimumab ( 64.3 % , 28.6 % , 7.1 % ) and etanercept ( 50.0 % , 30.0 % , 0 % ) . The rate of adverse events that required treatment was highest for secukinumab (15.2%), followed by adalimumab (14.3%), ustekinumab (8.2%), and etanercept (0%), including 4 cases of infections, 2 cases of cardiovascular diseases and 4 cases of cancers. ### conclusions This real world data showed differential efficacy and safety of the four biological agents.

https://pubmed.ncbi.nlm.nih.gov/33373425/

502832b2d66be4f7c76573ad6f1b15dc

Trials have demonstrated decreased relapse with perioperative methotrexate , vinblastine , doxorubicin and cisplatin ( M-VAC ) chemotherapy in patients with muscle invasive bladder cancer .

The effect of cystectomy, and perioperative methotrexate, vinblastine, doxorubicin and cisplatin chemotherapy on the risk and pattern of relapse in patients with muscle invasive bladder cancer. Trials have demonstrated decreased relapse with perioperative methotrexate , vinblastine , doxorubicin and cisplatin ( M-VAC ) chemotherapy in patients with muscle invasive bladder cancer . We evaluated whether the benefit of chemotherapy correlates with its effects on distant or pelvic relapse. ### Materials And Methods We retrospectively evaluated the records of all 107 patients who underwent cystectomy for muscle invasive bladder cancer at our institution between 1988 and 1994. Factors predicting relapse were identified and used to group patients at high or low risk. The outcome in each group with and without M-VAC chemotherapy was then analyzed in terms of overall, metastatic and pelvic relapse. Univariate analysis was performed using the Kaplan-Meier method and log rank statistic, and multivariate analysis was done using the Cox proportional hazards model. Median survival was 29 months for patients free of disease. ### results Pathological stage T3 or greater according to the American Joint Committee on Cancer, tumor greater than 3 cm. and creatinine greater than 1.5-fold normal were independent poor prognostic factors in patients treated with cystectomy only. Patients with any of these factors or metastatic involvement of the pelvic lymph nodes were considered at high risk. All 35 low risk patients were treated with cystectomy only and had an excellent outcome with a 3-year relapse-free survival plus or minus standard error of 93% +/- 5%. The 3-year rates in 52 and 20 high risk patients treated without and with chemotherapy, respectively, were 42% +/- 8% versus 57% +/- 13% for relapse-free survival (p = 0.17), 38% +/- 9% versus 8% +/- 8% for pelvic failure (p = 0.02) and 39% +/- 9% versus 38% +/- 13% for distant metastases (not significant). Multivariate analysis of patients who underwent pelvic lymphadenectomy revealed that perioperative chemotherapy improved relapse-free survival and pelvic control but not metastatic control (p = 0.03, 0.02 and 0.31, respectively). ### conclusions Low risk patients have excellent disease control when treated with cystectomy only. Those with high risk features are at substantial risk for pelvic failure (38% at 3 years) after cystectomy only. Perioperative M-VAC chemotherapy has a profound impact on pelvic but not on metastatic failure.

https://pubmed.ncbi.nlm.nih.gov/10751847/

2e405044ef34961a85c429587014c801

m2 on day 1 , oxaliplatin 85 mg/m² day 1 and capecitabine twice-daily dose of 625 mg/ m2 , p.o . for 2 weeks ) every 3

A Modified Epirubicin and Oxaliplatin Plus Capecitabine (EOX) Regimen as a Second- Line Therapy in Patients with Advanced Gastric Cancer Objective: We aimed to evaluate the effectiveness of an mEOX (modified epirubicin, oxaliplatin plus capecitabine) regimen as second line therapy after failure of mDCF (modified docetaxel, cisplatin plus fluorouracil). Methods: Gastic cancer patients for whom first-line therapy was unsuccessful and who subsequently received mEOX (epirubicin 50 mg/ m2 on day 1 , oxaliplatin 85 mg/m² day 1 and capecitabine twice-daily dose of 625 mg/ m2 , p.o . for 2 weeks ) every 3 weeks until disease progression or unacceptable toxicity, were retrospectively analyzed. Results: The study population comprised 129 cases with a median age of 55 years (range= 27-78), the majority being male (76 %). Most (75.2%) had ≥ 2 sites of metastasis. The median number of chemotherapy courses was five (range= 2–9). Forty-nine achieved a partial response and 33 showed stable disease, resulting in a ORR (overall response rate) of 38% and a DCR (disease control rate) of 63.6%. The most frequent features of grade 3-4 hematological and non-hematological toxicity were neutropenia (8.5%) and nausea/vomiting (5.4%). None of the patients suffered death due to toxicity. The median PFS was 4.7 months (95% CI, 4.1–5.3) and the OS was 7.4 months (95% CI, 6.3–8.5). On multivariate analysis, age ≥ 60 years and ECOG performance status (0-1) were independent prognostic factors affecting PFS and OS. Conslusions: In advanced gastric cancer patients, who progress after first line chemotherapy and have an ECOG performance status of 0-1, mEOX is a well tolerated triple regimen associated with a promising OS and PFS.

https://pubmed.ncbi.nlm.nih.gov/29374414/

60e477e5cd5aded203a0a848439207a0

The objective of this analysis was to assess the cost-effectiveness of risedronate compared to generic alendronate in Germany applying the REAL effectiveness data .

The impact of fewer hip fractures with risedronate versus alendronate in the first year of treatment: modeled German cost-effectiveness analysis. The risedronate and alendronate (REAL) cohort study provides unique comparative effectiveness data for real world bisphosphonate treatment of osteoporosis. ### objective The objective of this analysis was to assess the cost-effectiveness of risedronate compared to generic alendronate in Germany applying the REAL effectiveness data . ### Materials And Methods A validated Markov model of osteoporosis was populated with REAL effectiveness data and German epidemiological, cost, and utility data. To estimate the impact of therapy on hip fractures, costs, and quality adjusted life years (QALYs), the analysis included women>or=65 years, treated with risedronate or alendronate and followed for 4 additional years. Country-specific data included population mortality, fracture costs, and annual drug costs, using a German social insurance perspective. Costs and outcomes were discounted at 3%. A differential hip fracture relative risk reduction of 43% was applied to risedronate vs. alendronate. ### results The model predicted that treatment with risedronate would result in fewer hip fractures and more QALYs at a reduced cost (savings of euro278 per treated woman) compared to treatment with generic alendronate. Sensitivity analysis assuming 2 years of treatment and equivalence of effect after 1 year show cost savings as well (euro106 per treated woman). ### discussion Whereas previous economic evaluations involving bisphosphonates have mainly relied on efficacy data from noncomparative clinical trials, this study's strength is in the use of comparative effectiveness data from one data source. The magnitude of the cost savings observed were sensitive to alternative assumptions regarding treatment duration, therapy discontinuation and cost of generic alendronate. ### conclusions Based on "real world" data the analysis supports the first line use of risedronate for the treatment of osteoporotic women in Germany.

https://pubmed.ncbi.nlm.nih.gov/19883401/

5d8e94d769dadafed1e67a36606f7721

However , two phase III trials demonstrated that incorporation of oxaliplatin to capecitabine with RT did not improve early outcomes and , by contrast , increased toxicity .

The role of capecitabine in locally advanced rectal cancer treatment: an update. Preoperative infusional 5-fluorouracil (5-FU) and concurrent radiation therapy (RT) followed by total mesorectal surgery is the current standard of care for locally advanced rectal cancer (LAR). When compared with postoperative 5-FU-based chemoradiation, this strategy is associated with significantly lower rates of local relapse, lower toxicity and better compliance. capecitabine is a rationally designed oral prodrug that is converted into 5-FU by intracellular thymidine phosphorylase. Substitution of infusional 5-FU with capecitabine is an attractive option that provides a more convenient administration schedule and, possibly, increased efficacy. Indeed, incorporation of capecitabine in combined modality neoadjuvant therapy for LAR has been under intense investigation during the last 10 years. Phase I and II clinical trials showed that a regimen consisting of capecitabine 825mg/m(2) twice daily for 7 days/week continuous oral administration in combination with RT is an active and well tolerated regimen, thereby being the preferred concurrent regimen. The definitive demonstration that efficacy of capecitabine/RT is similar to 5-FU/RT has been provided by the NSABP-R-04 and the German Margit trials. One approach to improve outcomes in rectal cancer is to deliver a second RT-sensitizing drug with effective systemic activity. oxaliplatin and irinotecan are therefore good candidates. However , two phase III trials demonstrated that incorporation of oxaliplatin to capecitabine with RT did not improve early outcomes and , by contrast , increased toxicity . capecitabine has also been combined with irinotecan. This regimen showed encouraging results in phase I and II clinical trials, which led to an ongoing phase III clinical trial. New strategies with induction chemotherapy with or without chemoradiation prior to surgery are currently under investigation. Whether or not capecitabine has a role in this setting is being investigated in ongoing trials. Incorporation of agents directed towards new targets, such as anti-epidermal growth factor receptor (EGFR) antibodies or antiangiogenic agents, in combination preoperative regimens, is being hampered by results of early trials in which efficacy outcomes with cetuximab were poor and an excessive rate of surgical complications with bevacizumab was observed. The lack of improvements in efficacy with the addition of cetuximab or bevacizumab in the adjuvant treatment of colon cancer led to concerns about further development of these agents in rectal cancer. The role of capecitabine in the postoperative adjuvant setting is the aim of the ongoing Dutch SCRIPT trial. The prediction of response associated with capecitabine has been based on expression of thymidylate synthase and dihydropyrimidine dehydrogenase, as well as on gene expression arrays. All these procedures require further validation and should be considered as investigational. In conclusion, capecitabine can safely and effectively replace intravenous continuous infusion of 5-FU in the preoperative chemoradiation setting for rectal cancer management. The addition of other new antineoplastic agents to a fluoropyrimidine-based regimen remains investigational.

https://pubmed.ncbi.nlm.nih.gov/22621694/

677fdeeb41810fb495dcbcc5969fcc98

The addition of everolimus to bicalutamide treatment of resistant tumours significantly reduced tumour growth rates and tumour volumes .

Prolonging hormone sensitivity in prostate cancer xenografts through dual inhibition of AR and mTOR. To determine the mechanisms associated with loss of androgen dependency and disease progression in prostate cancer (PCa), we investigated the relationship between the androgen receptor (AR) and mTOR pathways and the impact of inhibiting both pathways in androgen-dependent and castration-resistant PCa models. ### Experimental Design Androgen-dependent (LNCaP) and castration-resistant PCa (HP-LNCaP) cells were grown as tumours in SCID mice. Once tumours reached 500 mm(3), animals were grouped and injected subcutaneous with vehicle, our novel anti-androgen/androgen synthesis inhibitor, VN/124-1, bicalutamide, and everolimus. Tumour volumes were measured biweekly. The PSA and protein analyses were performed after completion of the treatment. ### results The addition of everolimus to bicalutamide treatment of resistant tumours significantly reduced tumour growth rates and tumour volumes . Anti-androgen treatment also increased protein expression of multiple signal transduction pathways earlier than vehicle-treated control xenografts. VN/124-1 plus everolimus acted in concert to reduce tumour growth rates in our castration-resistant xenograft model. ### conclusions This study suggests that dual inhibition of AR and mTOR in castration-resistant xenograft models can restore sensitivity of tumours to anti-androgen therapy. Furthermore, after bicalutamide failure, dual inhibition with VN/124-1 and everolimus was the most effective treatment.

https://pubmed.ncbi.nlm.nih.gov/20842117/

503a43e79ed74f42ff3b6fe92e2e4472

Ropivacaine and bupivacaine were the common drugs used for RA , which were independent of RA utilization .

Regional anesthesia and lipid resuscitation for local anesthetic systemic toxicity in China: results of a survey by the orthopedic anesthesia group of the Chinese Society Of Anesthesiology. Intravenous lipid emulsions have been introduced for the management of patients with Local Anesthetic Systemic Toxicity (LAST). These emulsions have been stated as a first-line treatment in the guidelines of several international anesthesia organizations. Nevertheless, the adoption of lipid rescue therapy by Chinese practitioners remains unknown. We, therefore, evaluated the current approaches to treat LAST and the use of lipid rescue therapy among anesthesiologists in China. ### methods In September 2013, a 23-question survey on regional anesthesia practice and availability of lipid emulsions was sent by e-mail to directors or designated individuals at 41 academic anesthesiology departments listed by the orthopedic anesthesia group of the Chinese Society of Anesthesiology. ### results Responses were received from 36 of the 41 (88 %) anesthesiology departments. To simplify the analysis, responses were divided into two groups according to the annual percentage of patients who received regional anesthesia (RA) for orthopedic anesthesia: 14 departments (39%) with high-utilization (≥ 50%) and 22 departments (61%) low-utilization (<50%) of RA. Ropivacaine and bupivacaine were the common drugs used for RA , which were independent of RA utilization . Interestingly, ultrasound-guided techniques were much more frequently used in low-utilization institutions than in high-utilization institutions (P = 0.025). Lipid emulsion was readily available in 8 of the 36 (22%) responding institutions, with 7 of the other 28 (25%) institutions planning to stock lipid emulsion. No differences in lipid availability and storage plans were observed between high- and low-utilization institutions. Lipid resuscitation was performed in five of the eight departments that had lipid emulsion. Eleven patients were successfully resuscitated and one was not. ### conclusion Lipid emulsion is not widely available in China to treat LAST resulted from RA for orthopedic patients. Efforts are required to promote lipid rescue therapy nationwide. ### Trial Registration Chinese Clinical Trail Registry (Registration number # ChiCTR-EOR-15006960; Date of Retrospective Registration on August 23rd, 2015) http://www.chictr.org.cn/showproj.aspx?proj=11703 .

https://pubmed.ncbi.nlm.nih.gov/26728368/

085af6dcbceb17f4d6d9007c05ca030d

In 13 patients treated with equivalent doses of rotigotine switched from other DAs ( pramipexole , ropinirole , and cabergoline ) , ESS did not increase after treatment ( 10.0 ± 4.6 before and 8.6 ± 4.5 after treatment ) and decreased without worsening of CGI-I in 54 % patients .

Rotigotine Transdermal Patch Does Not Make Parkinson Disease Patients Sleepy During Daytime. To assess quantitatively the influence of rotigotine transdermal patch on daytime sleepiness, the most common adverse event by non-ergot dopamine agonists (DAs), in Parkinson disease (PD) patients. ### methods An open-label study enrolled PD patients with unsatisfactory control of motor symptoms. Treatment with rotigotine transdermal patch was titrated to optimal dose (4-8 mg/24 hours) over 2 to 4 weeks. Primary outcome was Epworth Sleepiness Scale (ESS) for daytime sleepiness. Secondary outcomes included Hoehn&Yahr stage, time spent with dyskinesia, Clinical Global Impression of Improvement (CGI-I) of motor symptoms, adverse events, and compliance. ### results The subjects were 31 PD patients (age 72 ± 8, Hoehn &Yahr stage 2.7 ± 0.9, mean ± SD). The ESS did not increase after rotigotine treatment (7.2 ± 4.9 before treatment, 6.2 ± 4.0 with 4 mg/24 hour, and 8.1 ± 6.4 with 8 mg/24 hour). The CGI-I score improved after treatment; responder rate reached 88.9% with 8 mg/24 hours. No patients showed worsening in other secondary outcomes. In 13 patients treated with equivalent doses of rotigotine switched from other DAs ( pramipexole , ropinirole , and cabergoline ) , ESS did not increase after treatment ( 10.0 ± 4.6 before and 8.6 ± 4.5 after treatment ) and decreased without worsening of CGI-I in 54 % patients . Other secondary outcomes did not worsen after treatment. ### conclusions Twenty four-hour transdermal delivery of rotigotine at doses up to 8 mg/24 hours does not worsen the daytime sleepiness in PD patients and often improves it when switched from other non-ergot DAs. This is achieved together with satisfactory improvement in motor symptoms, demonstrating that this new modality of non-ergot DA is well tolerated and beneficial in PD patients.

https://pubmed.ncbi.nlm.nih.gov/26536020/

2f80aa3ed0868deba396a0cbaf76b31f

To assess plasma steady-state pharmacokinetics ( PK ) of rifampicin , isoniazid , saquinavir and ritonavir in HIV and tuberculosis ( TB ) co-infected patients , and investigate potential interactions between TB drugs and protease inhibitors ( PIs ) .

Pharmacokinetic interaction between rifampicin and the once-daily combination of saquinavir and low-dose ritonavir in HIV-infected patients with tuberculosis. To assess plasma steady-state pharmacokinetics ( PK ) of rifampicin , isoniazid , saquinavir and ritonavir in HIV and tuberculosis ( TB ) co-infected patients , and investigate potential interactions between TB drugs and protease inhibitors ( PIs ) . ### methods Open-label, single-arm, sequential PK study including 22 patients with HIV infection and TB. During the first 2 months, patients received rifampicin, isoniazid and pyrazinamide, with or without ethambutol (first PK study, n = 22). Then patients stopped pyrazinamide and ethambutol and started once-daily antiretroviral therapy (ART) with didanosine, lamivudine, ritonavir (200 mg) and saquinavir (1600 mg) (second PK study, n = 18). Patients stopped all TB drugs after 9 months continuing the same ART (third PK study, n = 15). Differences between TB drug parameters in the first and second PK studies, and between PI parameters in the second and third PK studies were used to assess interactions. ### results Rifampicin and isoniazid pharmacokinetics did not change substantially with saquinavir and ritonavir. A significant 39.5%, 34.9% and 48.7% reduction in median saquinavir AUC(0-24), C(max) and C(trough), respectively, was seen with rifampicin and isoniazid. ritonavir AUC(0-24), C(max) and C(trough) decreased 42.5%, 49.6% and 64.3%, respectively, with rifampicin and isoniazid. ### conclusions There was a significant interaction between saquinavir, ritonavir and rifampicin, with reduction in median plasma concentrations of saquinavir and ritonavir. saquinavir should be given with caution in patients receiving rifampicin. Twice-daily dosing or higher saquinavir doses in once-daily administration should be tested to obtain more appropriate plasma levels.

https://pubmed.ncbi.nlm.nih.gov/17307771/

08a35fc86bac0d38e3375f9b88b26dd4

We randomly assigned 808 patients with HER2-positive metastatic breast cancer to receive placebo plus trastuzumab plus docetaxel ( control group ) or pertuzumab plus trastuzumab plus docetaxel ( pertuzumab group ) as first-line treatment until the time of disease progression or the development of toxic effects that could not be effectively managed .

Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. The anti-human epidermal growth factor receptor 2 (HER2) humanized monoclonal antibody trastuzumab improves the outcome in patients with HER2-positive metastatic breast cancer. However, most cases of advanced disease eventually progress. pertuzumab, an anti-HER2 humanized monoclonal antibody that inhibits receptor dimerization, has a mechanism of action that is complementary to that of trastuzumab, and combination therapy with the two antibodies has shown promising activity and an acceptable safety profile in phase 2 studies involving patients with HER2-positive breast cancer. ### methods We randomly assigned 808 patients with HER2-positive metastatic breast cancer to receive placebo plus trastuzumab plus docetaxel ( control group ) or pertuzumab plus trastuzumab plus docetaxel ( pertuzumab group ) as first-line treatment until the time of disease progression or the development of toxic effects that could not be effectively managed . The primary end point was independently assessed progression-free survival. Secondary end points included overall survival, progression-free survival as assessed by the investigator, the objective response rate, and safety. ### results The median progression-free survival was 12.4 months in the control group, as compared with 18.5 months in the pertuzumab group (hazard ratio for progression or death, 0.62; 95% confidence interval, 0.51 to 0.75; P<0.001). The interim analysis of overall survival showed a strong trend in favor of pertuzumab plus trastuzumab plus docetaxel. The safety profile was generally similar in the two groups, with no increase in left ventricular systolic dysfunction; the rates of febrile neutropenia and diarrhea of grade 3 or above were higher in the pertuzumab group than in the control group. ### conclusions The combination of pertuzumab plus trastuzumab plus docetaxel, as compared with placebo plus trastuzumab plus docetaxel, when used as first-line treatment for HER2-positive metastatic breast cancer, significantly prolonged progression-free survival, with no increase in cardiac toxic effects. (Funded by F. Hoffmann-La Roche/Genentech; ClinicalTrials.gov number, NCT00567190.).

https://pubmed.ncbi.nlm.nih.gov/22149875/

c2679a7e1f713326ad184919894b6e1c

Toxicological studies revealed that the oral LD50 for thiabendazole in mice was 2200 mg/kg , and when combined with 140 mg/kg of aspirin , the LD50 was reduced to 900 mg/kg .

The effect of thiabendazole on pain threshold. thiabendazole significantly increased the reaction time to thermal stimulus. However, in mice treated with morphine, the reaction time was not in any way different from those treated with combined doses of thiabendazole and morphine. thiabendazole was found to have an antinociceptive action. The protective dose for 50% of animal (ED50) against p-benzoquinone-induced writhing reflex was found to be 310 mg/kg. The ED50 for aspirin alone was 140 mg/kg. When the ED50 of aspirin was determined in combination with different dose levels of thiabendazole, it showed a marked reduction in the values reaching 50 mg/kg, when 300 mg of thiabendazole was used in combination. Toxicological studies revealed that the oral LD50 for thiabendazole in mice was 2200 mg/kg , and when combined with 140 mg/kg of aspirin , the LD50 was reduced to 900 mg/kg . These findings indicate that thiabendazole possesses an analgesic activity which is potentiated by aspirin, though aspirin was found to significantly enhance its toxicity.

https://pubmed.ncbi.nlm.nih.gov/4050451/

a9b18b3c6a9e25a33609280998e2412d

Azacitidine and enasidenib are two therapies available for treatment of acute myelogenous leukemia ( AML ) , and the mechanisms of action of these drugs involve alteration of aberrant DNA methylation .

Combination of azacitidine and enasidenib enhances leukemic cell differentiation and cooperatively hypomethylates DNA. Azacitidine and enasidenib are two therapies available for treatment of acute myelogenous leukemia ( AML ) , and the mechanisms of action of these drugs involve alteration of aberrant DNA methylation . We hypothesized that a combination of these agents could have interactive effects on DNA methylation and enhance differentiation in mIDH2 cells. Combination treatment enhanced cellular differentiation in TF-1 cells overexpressing IDJ2R140Q through increased hemoglobinization and increased hemoglobin γ RNA expression compared with the effects of single agents. Furthermore, in primary AML samples (IDH2R140Q or R172K), combination treatment reduced CD34+ cells and increased CD15+ cells to a greater extent than attained with single agents. To explore the mechanism of enhanced differentiation with combination treatment, the TF-1 epigenome was analyzed by profiling 5-hydroxymethylcytosine (5hmC) and 5-methylcytosine (5mC) DNA methylation changes. enasidenib treatment alone increased 5hmC, consistent with reactivation of ten-eleven-translocation (TET) enzyme activity. Compared with treatment with azacitidine alone, combination treatment reduced 5mC levels at greater numbers of sites and these loci were significantly enriched in regions with increased 5hMC (25.8% vs. 7.4%). Results are consistent with a model in which enasidenib-mediated reactivation of ten-eleven-translocation enzymes cooperates with azacitidine-mediated inhibition of DNA methyltransferase enzymes, leading to greater reductions in DNA methylation and enhanced erythroid differentiation.

https://pubmed.ncbi.nlm.nih.gov/33794295/

8c910778beeef8e539f66fd377e27eeb

Good , moderate and mild pain relief were noted in 19 ( 41 % ) , six ( 13 % ) and seven ( 15 % ) patients on lamotrigine and 13 ( 28 % ) , five ( 11 % ) and 15 ( 33 % ) patients on amitriptyline , respectively , by patient 's global assessment of efficacy and safety .

Randomized double-blind study comparing the efficacy and safety of lamotrigine and amitriptyline in painful diabetic neuropathy. To compare the efficacy and safety of lamotrigine and amitriptyline in controlling chronic painful peripheral neuropathy in diabetic patients. ### methods A randomized, double-blind, crossover, active-control, clinical trial with variable dose titration was carried out (n = 53). amitriptyline orally, at doses of 10, 25 and 50 mg at night-time, each dose for 2 weeks, and lamotrigine orally, at doses of 25, 50 and 100 mg twice daily, each dose for 2 weeks, by optional titration were used. There was a placebo washout period for 2 weeks between the two drugs. Assessment for pain relief, overall improvement and adverse events were carried out. ### results Good , moderate and mild pain relief were noted in 19 ( 41 % ) , six ( 13 % ) and seven ( 15 % ) patients on lamotrigine and 13 ( 28 % ) , five ( 11 % ) and 15 ( 33 % ) patients on amitriptyline , respectively , by patient 's global assessment of efficacy and safety . Patient and physicians global assessment, McGill pain questionnaire and Likert pain scale showed no significant difference between the treatments, although improvement with both treatments was seen from 2 weeks. Of the 44 adverse events reported, 33 (75%) were with amitriptyline, sedation being the commonest [in 19 (43%) patients]. lamotrigine caused adverse events in 11 (25%), of which rash in three (7%) and elevations of creatinine in four (9%) were the most common. The preferred lamotrigine dose was 25 mg twice daily. ### conclusions As there are few differences between the two treatments in efficacy, lamotrigine 25 mg twice daily might be the first choice as it is associated with fewer adverse effects in our population.

https://pubmed.ncbi.nlm.nih.gov/17335465/

e3eaa19866764043fe913227f0c1329f

The majority of the evidence comes from studies of bevacizumab and triamcinolone used as primary therapy for DMO .

Anti-vascular endothelial growth factor combined with intravitreal steroids for diabetic macular oedema. The combination of steroid and anti-vascular endothelial growth factor (VEGF) intravitreal therapeutic agents could potentially have synergistic effects for treating diabetic macular oedema (DMO). On the one hand, if combined treatment is more effective than monotherapy, there would be significant implications for improving patient outcomes. Conversely, if there is no added benefit of combination therapy, then people could be potentially exposed to unnecessary local or systemic side effects. ### objectives To assess the effects of intravitreal agents that block vascular endothelial growth factor activity (anti-VEGF agents) plus intravitreal steroids versus monotherapy with macular laser, intravitreal steroids or intravitreal anti-VEGF agents for managing DMO. ### Search Methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2018, Issue 1); Ovid MEDLINE; Ovid Embase; LILACS; the ISRCTN registry; ClinicalTrials.gov and the ICTRP. The date of the search was 21 February 2018. ### Selection Criteria We included randomised controlled trials (RCTs) of intravitreal anti-VEGF combined with intravitreal steroids versus intravitreal anti-VEGF alone, intravitreal steroids alone or macular laser alone for managing DMO. We included people with DMO of all ages and both sexes. We also included trials where both eyes from one participant received different treatments. ### Data Collection And Analysis We used standard methodological procedures recommended by Cochrane.Two authors independently reviewed all the titles and abstracts identified from the electronic and manual searches against the inclusion criteria. Our primary outcome was change in best corrected visual acuity (BCVA) between baseline and one year. Secondary outcomes included change in central macular thickness (CMT), economic data and quality of life. We considered adverse effects including intraocular inflammation, raised intraocular pressure (IOP) and development of cataract. ### Main Results There were eight RCTs (703 participants, 817 eyes) that met our inclusion criteria with only three studies reporting outcomes at one year. The studies took place in Iran (3), USA (2), Brazil (1), Czech Republic (1) and South Korea (1). Seven studies used the unlicensed anti-VEGF agent bevacizumab and one study used licensed ranibizumab. The study that used licensed ranibizumab had a unique design compared with the other studies in that included eyes had persisting DMO after anti-VEGF monotherapy and received three monthly doses of ranibizumab prior to allocation. The anti-VEGF agent was combined with intravitreal triamcinolone in six studies and with an intravitreal dexamethasone implant in two studies. The comparator group was anti-VEGF alone in all studies; two studies had an additional steroid monotherapy arm, another study had an additional macular laser photocoagulation arm. Whilst we judged these studies to be at low risk of bias for most domains, at least one domain was at unclear risk in all studies.When comparing anti-VEGF/steroid with anti-VEGF monotherapy as primary therapy for DMO, we found no meaningful clinical difference in change in BCVA (mean difference (MD) -2.29 visual acuity (VA) letters, 95% confidence interval (CI) -6.03 to 1.45; 3 RCTs; 188 eyes; low-certainty evidence) or change in CMT (MD 0.20 μm, 95% CI -37.14 to 37.53; 3 RCTs; 188 eyes; low-certainty evidence) at one year. There was very low-certainty evidence on intraocular inflammation from 8 studies, with one event in the anti-VEGF/steroid group (313 eyes) and two events in the anti-VEGF group (322 eyes). There was a greater risk of raised IOP (Peto odds ratio (OR) 8.13, 95% CI 4.67 to 14.16; 635 eyes; 8 RCTs; moderate-certainty evidence) and development of cataract (Peto OR 7.49, 95% CI 2.87 to 19.60; 635 eyes; 8 RCTs; moderate-certainty evidence) in eyes receiving anti-VEGF/steroid compared with anti-VEGF monotherapy. There was low-certainty evidence from one study of an increased risk of systemic adverse events in the anti-VEGF/steroid group compared with the anti-VEGF alone group (Peto OR 1.32, 95% CI 0.61 to 2.86; 103 eyes).One study compared anti-VEGF/steroid versus macular laser therapy. At one year investigators did not report a meaningful difference between the groups in change in BCVA (MD 4.00 VA letters 95% CI -2.70 to 10.70; 80 eyes; low-certainty evidence) or change in CMT (MD -16.00 μm, 95% CI -68.93 to 36.93; 80 eyes; low-certainty evidence). There was very low-certainty evidence suggesting an increased risk of cataract in the anti-VEGF/steroid group compared with the macular laser group (Peto OR 4.58, 95% 0.99 to 21.10, 100 eyes) and an increased risk of elevated IOP in the anti-VEGF/steroid group compared with the macular laser group (Peto OR 9.49, 95% CI 2.86 to 31.51; 100 eyes).One study provided very low-certainty evidence comparing anti-VEGF/steroid versus steroid monotherapy at one year. There was no evidence of a meaningful difference in BCVA between treatments at one year (MD 0 VA letters, 95% CI -6.1 to 6.1, low-certainty evidence). Likewise, there was no meaningful difference in the mean CMT at one year (MD - 9 μm, 95% CI -39.87μm to 21.87μm between the anti-VEGF/steroid group and the steroid group. There was very low-certainty evidence on raised IOP at one year comparing the anti-VEGF/steroid versus steroid groups (Peto OR 0.75, 95% CI 0.16 to 3.55).No included study reported impact of treatment on patients' quality of life or economic data. None of the studies reported any cases of endophthalmitis. ### Authors Conclusions Combination of intravitreal anti-VEGF plus intravitreal steroids does not appear to offer additional visual benefit compared with monotherapy for DMO; at present the evidence for this is of low-certainty. There was an increased rate of cataract development and raised intraocular pressure in eyes treated with anti-VEGF plus steroid versus anti-VEGF alone. Patients were exposed to potential side effects of both these agents without reported additional benefit. The majority of the evidence comes from studies of bevacizumab and triamcinolone used as primary therapy for DMO . There is limited evidence from studies using licensed intravitreal anti-VEGF agents plus licensed intravitreal steroid implants with at least one year follow-up. It is not known whether treatment response is different in eyes that are phakic and pseudophakic at baseline.

https://pubmed.ncbi.nlm.nih.gov/29669176/

8d3aa3b09931b7d3aa9d1b62ecf79b24

Doxorubicin and ifosfamide are currently the two main drugs for the treatment of soft tissue sarcomas in adults .

Perspectives on anthracyclines plus ifosfamide in advanced soft tissue sarcomas. Doxorubicin and ifosfamide are currently the two main drugs for the treatment of soft tissue sarcomas in adults . Given in combination at full doses, with or without dacarbazine, these agents have induced higher response rates than were obtained with single-agent therapy. Because they involve considerable myelotoxicity, however, full-dose regimens should be reserved for patients with good performance status and without potential septic foci. Obviously, higher response rates do not automatically translate into improved survival. In soft tissue sarcomas, full-dose polychemotherapy will most probably provide a survival benefit only in selected patients in whom surgery can be performed in combination with chemotherapy. Prospective trials in such patients, although difficult to carry out, would be highly desirable. The information they would provide might help the clinician tailor treatment in a more rational way and improve chances of cure or long-term survival in at least some patient subgroups.

https://pubmed.ncbi.nlm.nih.gov/8453704/

dff2572ca5c7f865279efd425491fe4b

The skin and oral mucous membrane lesions recurred after effective treatments with methylprednisolone pulse therapy and combination therapy with prednisolone and cyclosporine .

Successful treatment of adolescent pemphigus vulgaris by immunoadsorption method. A 15-year-old girl with pemphigus vulgaris did not respond to oral administration of prednisolone at 45 mg/day. The skin and oral mucous membrane lesions recurred after effective treatments with methylprednisolone pulse therapy and combination therapy with prednisolone and cyclosporine . The finally successful treatment involved eleven cycles of immunoadsorption using a tryptophan column and administration of a moderate dose of prednisolone. Serum gamma-globulin level and anti-intercellular antibody titer decreased from 1.08 g/dl to 0.5 g/dl and 1:320 to 1:20, respectively. She has been well controlled with 21.5 mg/day prednisolone for 8 months after the final adsorption. Considering the physical, mental and social situation of adolescent student patients, immunoadsorption is a highly preferable choice among a variety of treatment modalities for pemphigus vulgaris because it makes the term of hospitalization shorter and avoids undesirable side effects from initial high dose corticosteroids.

https://pubmed.ncbi.nlm.nih.gov/10343469/

b9e3bc7f24bf72f23bc8e89b71cbd677

Incorporation of colistin significantly accelerated the release of ciprofloxacin from the DMPG anionic liposomes .

Co-Delivery of Ciprofloxacin and Colistin in Liposomal Formulations with Enhanced In Vitro Antimicrobial Activities against Multidrug Resistant Pseudomonas aeruginosa. This study aims to develop liposomal formulations containing synergistic antibiotics of colistin and ciprofloxacin for the treatment of infections caused by multidrug-resistant Pseudomonas aeruginosa. ### methods colistin (Col) and ciprofloxacin (Cip) were co-encapsulated in anionic liposomes by ammonium sulfate gradient. Particle size, encapsulation efficiency, in vitro drug release and in vitro antibiotic activities were evaluated. ### results The optimized liposomal formulation has uniform sizes of approximately 100 nm, with encapsulation efficiency of 67.0% (for colistin) and 85.2% (for ciprofloxacin). Incorporation of anionic lipid (DMPG) markedly increased encapsulation efficiency of colistin (from 5.4 to 67.0%); however, the encapsulation efficiency of ciprofloxacin was independent of DMPG ratio. Incorporation of colistin significantly accelerated the release of ciprofloxacin from the DMPG anionic liposomes . In vitro release of ciprofloxacin and colistin in the bovine serum for 2 h were above 70 and 50%. The cytotoxicity study using A549 cells showed the liposomal formulation is as non-toxic as the drug solutions. Liposomal formulations of combinations had enhanced in vitro antimicrobial activities against multidrug resistant P. aeruginosa than the monotherapies. ### conclusions Liposomal formulations of two synergistic antibiotics was promising against multidrug resistant P. aeruginosa infections.

https://pubmed.ncbi.nlm.nih.gov/30094660/

b0b756e4eaeb1d41e01248091673c2d5

MAB using flutamide as second-line hormonal therapy can give a comparatively favourable PSA response with no severe side-effects ; therefore , this therapy may be suitable for patients with HRPC after primary MAB using bicalutamide has failed , particularly in those with no bone metastases or whose disease has progressed for > 1 year after first-line therapy .

Clinical outcome of maximum androgen blockade using flutamide as second-line hormonal therapy for hormone-refractory prostate cancer. To investigate the efficacy of maximum androgen blockade (MAB) using flutamide as second-line hormonal therapy for advanced hormone-refractory prostate cancer (HRPC). ### Patients And Methods The study included 55 patients with HRPC who were treated with MAB using flutamide (375 mg daily) as second-line hormonal therapy. All patients had previously received bicalutamide combined with either surgical or medical castration as first-line hormonal therapy, which failed. The effect of the second-line therapy was evaluated by serum prostate-specific antigen (PSA) level alone, and the response defined as a decrease of >50% from the baseline PSA at the start of second-line therapy. ### results On initiating second-line hormonal therapy there was a reduction in the PSA level in 25 of the 55 patients (45%), among whom 12 (22%) were regarded as responders, while the PSA level continued to increase in the remaining 30 (55%). The median (range) duration of the PSA response was 6 (1-13) months. During the observation period there were no severe side-effects from the second-line MAB therapy. Patients without bone metastases or whose disease progressed >1 year after first-line therapy had a significantly higher incidence of PSA response to second-line therapy, despite no significant effect of other factors examined on the PSA response to second-line therapy. Furthermore, the cause-specific survival in responders to second-line therapy was significantly better than that in nonresponders; however, multivariate analysis showed that no factors, including response to second-line therapy, could be used as independent predictors of cause-specific survival. ### conclusions MAB using flutamide as second-line hormonal therapy can give a comparatively favourable PSA response with no severe side-effects ; therefore , this therapy may be suitable for patients with HRPC after primary MAB using bicalutamide has failed , particularly in those with no bone metastases or whose disease has progressed for > 1 year after first-line therapy .

https://pubmed.ncbi.nlm.nih.gov/16153202/

c5056778116a14b966bbe222b32e1acb

Phase I study of decitabine in combination with vorinostat in patients with advanced solid tumors and non-Hodgkin 's lymphomas .

Phase I study of decitabine in combination with vorinostat in patients with advanced solid tumors and non-Hodgkin 's lymphomas . PURPOSE: This phase I study evaluated the safety, tolerability, pharmacokinetics and preliminary efficacy of the combination of decitabine with vorinostat. PATIENTS AND METHODS: Patients with advanced solid tumors or non-Hodgkin's lymphomas were eligible. Sequential and concurrent schedules were studied. RESULTS: Forty-three patients were studied in 9 different dose levels (6 sequential and 3 concurrent). The maximum tolerated dose (MTD) on the sequential schedule was decitabine 10 mg/m(2)/day on days 1-5 and vorinostat 200 mg three times a day on days 6-12. The MTD on the concurrent schedule was decitabine 10 mg/m(2)/day on days 1-5 with vorinostat 200 mg twice a day on days 3-9. However, the sequential schedule of decitabine 10 mg/m(2)/day on days 1-5 and vorinostat 200 mg twice a day on days 6-12 was more deliverable than both MTDs with fewer delays on repeated dosing and it represents the recommended phase II (RP2D) dose of this combination. Dose-limiting toxicities during the first cycle consisted of myelosuppression, constitutional and gastrointestinal symptoms and occurred in 12/42 (29%) patients evaluable for toxicity. The most common ≥ grade 3 adverse events were neutropenia (49% of patients), thrombocytopenia (16%), fatigue (16%), lymphopenia (14%), and febrile neutropenia (7%). Disease stabilization for ≥ 4 cycles was observed in 11/38 (29%) evaluable patients. CONCLUSION: The combination of decitabine with vorinostat is tolerable on both concurrent schedules in previously treated patients with advanced solid tumors or non-Hodgkin's lymphomas. The sequential schedule was easier to deliver. The combination showed activity with prolonged disease stabilization in different tumor types.

https://pubmed.ncbi.nlm.nih.gov/21152384/

43af8a23a61c911f4823dbc4f666bac8

Epirubicin ( 35 mg/m(2 ) ) and cyclophosphamide ( 400 mg/m(2 ) ) were administered from day 2 to day 4 , every 4 weeks .

Combined 5-fluorouracil infusion with fractionated epirubicin and cyclophosphamide in advanced breast cancer. 5-fluorouracil (5-FU) given by continuous infusion (c.i.) allows higher dose delivery, causes less myelosuppression, and may interfere with repair of DNA damage caused by epirubicin and cyclophosphamide. With this rationale, we conducted a phase II study to test the activity and toxicity of 5-FU c.i., epirubicin, and cyclophosphamide in patients with metastatic breast cancer (MBC). Twenty-eight patients with MBC were entered in the trial. 5-FU (200 mg/m(2)) was administered by c.i. from day 1 to day 20. Epirubicin ( 35 mg/m(2 ) ) and cyclophosphamide ( 400 mg/m(2 ) ) were administered from day 2 to day 4 , every 4 weeks . All patients were evaluable for response and toxicity. A total of 125 courses of chemotherapy were administered, with a median of 4 per patient (range: 2--6). Toxicity, assessed using World Health Organization criteria, was as follows: nausea and vomiting grade III--IV occurred in 36%, alopecia (grade III) in 86%, neutropenia (grade III--IV) in 50%, and cardiac toxicity grade I--II in 11% of patients. Five patients (17.9%) had a complete response to therapy, and 16 (57.1%) had a partial response (response rate 75%, 95% CI 55--89%). Disease stability and progression occurred in 4 (14.3%) and 3 (10.7%) patients, respectively. Median time to progression was 13.1 months (range: 3.4--66.9+), and median survival time was 27.7 months (range: 5.4--67.1+). Outpatient treatment with combined 5-FU c.i., epirubicin, and cyclophosphamide shows high activity in advanced breast cancer and gives prolonged remission with acceptable toxicity.

https://pubmed.ncbi.nlm.nih.gov/11474271/

c4003c230fdd89dca38ff9d23a7fdbb1

Our patient could be weaned from LVAD probably due to the combination management strategy employing mitral valvuloplasty , use of cardiac resynchronization therapy , and taking carvedilol with spironolactone .

Successful bridge to recovery with VAD implantation for anthracycline-induced cardiomyopathy. Anthracyclines are effective antineoplastic drugs, but they are known to be cardiotoxic. Recovery of cardiac function is rare. A few studies on implantation of a ventricular assist device (VAD) have been performed for anthracycline-induced cardiomyopathy. Recovery of left ventricular (LV) function with an LVAD is also rare. Recently, several adjunctive therapies were attempted to restore ventricular function. We report a successful bridge to recovery of ventricular function using VAD implantation for anthracycline-induced cardiomyopathy. The patient was a 57-year-old man who had been diagnosed with diffuse large B-cell lymphoma (DLBCL) at age 52. Combination chemotherapy including hydroxydaunorubicin was started. Complete remission was achieved after chemotherapy. Heart failure symptoms such as fatigue, dyspnea on exertion, and weight gain appeared 5 months later. A cardiac resynchronization device was implanted. His heart function deteriorated. He underwent implantation of a Toyobo LVAD and mitral annuloplasty. After implantation, he was prescribed carvedilol with spironolactone. He was weaned from the LVAD on postoperative day (POD) 239 and discharged on POD 37 after weaning. He remained in New York Heart Association classes within the first- to second-degree range, the LV dimention diastolic/systolic ratio was 56/46 mm, ejection fraction 38%, and mitral regurgitation mild at 3 years after weaning from the LVAD. Our patient could be weaned from LVAD probably due to the combination management strategy employing mitral valvuloplasty , use of cardiac resynchronization therapy , and taking carvedilol with spironolactone . Further studies will be needed to clarify the efficacy of these adjunctive therapies.

https://pubmed.ncbi.nlm.nih.gov/21534011/

8d4b14787de8987d0a9a17e167f7aeec

Serum hydroxyzine and cetirizine concentrations were above the limit of quantitation ( 0.1 ng/ml ) of the assay

Pharmacokinetics of hydroxyzine and cetirizine following oral administration of hydroxyzine to exercised Thoroughbred horses. hydroxyzine is a first-generation antihistamine and cetirizine, a second-generation antihistamine and active metabolite of hydroxyzine. hydroxyzine is commonly used in performance horses and as such its use in closely regulated; however, there are no published studies suitable for establishing appropriate regulatory recommendations. In the current study, 12 exercised Thoroughbred research horses received a single oral administration of 500 mg of hydroxyzine. Blood and urine samples were collected prior to and up to 96 hr postdrug administration and concentrations of hydroxyzine and cetirizine determined using liquid chromatography-tandem mass spectrometry. A joint parent/metabolite population 2-compartment pharmacokinetic model with first-order absorption and elimination was utilized to describe the pharmacokinetics of both compounds. Serum hydroxyzine and cetirizine concentrations were above the limit of quantitation ( 0.1 ng/ml ) of the assay at 96 hr (the last time point sampled). The terminal half-life was 7.41 and 7.13 hr for hydroxyzine and cetirizine, respectively. Findings from this study suggest that a prolonged withdrawal time should be observed if this compound is used in performance administered to performance horses and is classified as prohibited substance by the applicable regulatory body.

https://pubmed.ncbi.nlm.nih.gov/31490561/

9443916aa7d28a5adeec2d2386bee04d

Although well tolerated , the efficacy of everolimus and vinorelbine combination therapy was not superior to vinorelbine monotherapy .

VicTORia: a randomised phase II study to compare vinorelbine in combination with the mTOR inhibitor everolimus versus vinorelbine monotherapy for second-line chemotherapy in advanced HER2-negative breast cancer. Improving the outcome of patients with HER2-negative metastatic breast cancer experiencing tumour progression following first-line chemotherapy remains an urgent medical need. The purpose of the VicTORia trial was to show superiority of everolimus in combination with vinorelbine versus vinorelbine monotherapy as second-line chemotherapy for patients with advanced HER2 negative breast cancer. ### methods In this randomised phase II trial, 133 patients were recruited in 32 centres in Germany. Patients were randomised 1:1 to second-line chemotherapy either with vinorelbine plus everolimus (arm1) or vinorelbine alone (arm2). Primary endpoint was progression-free survival (PFS). Secondary endpoints were PFS rate at 6 months, overall survival (OS), overall response rate (ORR) and safety. Baseline PI3 K mutational status was determined in plasma samples. ### results Median progression-free survival was not different between arms (arm1 vs. arm2: 4.01 months, 95% CI 2.40-6.09 vs. 4.08, 95% CI 2.80-5.33). PFS rate at 6 months (arm1 vs. arm2: 39.4%, 95% CI 27.6-50.9% vs. 36.6%, 95% CI 24.6-48.6%), median OS (arm1 vs. arm2: 16.3 months, 95% CI 11.4-19.0 vs. 13.8 months, 95% CI 10.2-19.1) and ORR were not different between arms. Most frequent grade 3/4 adverse events were neutropenia (50% vs. 40%), gastrointestinal toxicities (19.1% vs. 6.1%), and infections (19.1% vs. 7.7%). PI3 K mutational status was neither associated with PFS nor with OS. ### conclusion Although well tolerated , the efficacy of everolimus and vinorelbine combination therapy was not superior to vinorelbine monotherapy . There was no correlation between PI3 K mutational status and efficacy. EudracCT No 2011-001024-38, ClinicalTrials.gov No NCT01520103.

https://pubmed.ncbi.nlm.nih.gov/31115844/

eb3681c71c2520fe8ab1a0369e10b461

In addition , our results suggested that adalimumab , tocilizumab , rituximab and glucocorticoids may also have beneficial effects in restoring normal transcriptome , but not chloroquine , hydroxychloroquine or interferons .

Transcriptomic signatures and repurposing drugs for COVID-19 patients: findings of bioinformatics analyses. The novel coronavirus SARS-CoV-2 is damaging the world's social and economic fabrics seriously. Effective drugs are urgently needed to decrease the high mortality rate of COVID-19 patients. Unfortunately, effective antiviral drugs or vaccines are currently unavailable. Herein, we systematically evaluated the effect of SARS-CoV-2 on gene expression of both lung tissue and blood from COVID-19 patients using transcriptome profiling. Differential gene expression analysis revealed potential core mechanism of COVID-19-induced pneumonia in which IFN-α, IFN-β, IFN-γ, TNF and IL6 triggered cytokine storm mediated by neutrophil, macrophage, B and DC cells. Weighted gene correlation network analysis identified two gene modules that are highly correlated with clinical traits of COVID-19 patients, and confirmed that over-activation of immune system-mediated cytokine release syndrome is the underlying pathogenic mechanism for acute phase of COVID-19 infection. It suggested that anti-inflammatory therapies may be promising regimens for COVID-19 patients. Furthermore, drug repurposing analysis of thousands of drugs revealed that TNFα inhibitor etanercept and γ-aminobutyric acid-B receptor (GABABR) agonist baclofen showed most significant reversal power to COVID-19 gene signature, so we are highly optimistic about their clinical use for COVID-19 treatment. In addition , our results suggested that adalimumab , tocilizumab , rituximab and glucocorticoids may also have beneficial effects in restoring normal transcriptome , but not chloroquine , hydroxychloroquine or interferons . Controlled clinical trials of these candidate drugs are needed in search of effective COVID-19 treatment in current crisis.

https://pubmed.ncbi.nlm.nih.gov/33312453/

cfb44c26cc0a1b85c41cf38e39dac79a

In addition , biochemical examinations revealed that docetaxel could induce phosphorylation of both bcl-2 and c-raf-1 , but these changes were inhibited when tumor cells were pretreated or simultaneously treated with doxorubicin .

In vitro evaluation of schedule-dependent interactions between docetaxel and doxorubicin against human breast and ovarian cancer cells. docetaxel, a novel member of the taxoid family, has shown greater potency than paclitaxel in the treatment of advanced breast cancer and certain other solid tumors. The promising clinical activity of docetaxel has also promoted considerable interest in combining this drug with other antitumor agents. In this study, we assessed the cytotoxic interaction between docetaxel and doxorubicin administered at various schedules to human breast and ovarian cancer cells. Through a series of in vitro assays including DNA fragmentation analyses, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays, and flow cytometric analyses, we found that the antagonistic interaction occurred when tumor cells were exposed to the two drugs simultaneously or exposed to doxorubicin before docetaxel. However, no antagonism was observed when docetaxel was added before doxorubicin. Further analyses demonstrated that doxorubicin could interfere with the cytotoxic effect of docetaxel on both mitotic arrest and apoptotic cell death. In addition , biochemical examinations revealed that docetaxel could induce phosphorylation of both bcl-2 and c-raf-1 , but these changes were inhibited when tumor cells were pretreated or simultaneously treated with doxorubicin . These results indicate that the interaction between docetaxel and doxorubicin is highly schedule dependent. Exposure of tumor cells to doxorubicin before docetaxel could result in pronounced antagonism. The optimal schedule for this combination might be sequential exposure to docetaxel followed by doxorubicin.

https://pubmed.ncbi.nlm.nih.gov/10999771/

168b963c3be6ac1ded38c2d41bc9b197

Enhancement of radiation-induced downstaging of rectal cancer by fluorouracil and high-dose leucovorin chemotherapy .

Enhancement of radiation-induced downstaging of rectal cancer by fluorouracil and high-dose leucovorin chemotherapy . To determine if fluorouracil (5-FU) plus high-dose leucovorin (LV) enhances local response in patients receiving preoperative radiation therapy (RT) for adenocarcinoma of the rectum, we compared the degree of downstaging in patients receiving preoperative RT with or without chemotherapy. ### Patients And Methods For this comparison, three groups of patients who were treated with identical doses and techniques of preoperative pelvic RT (total dose of 5,040 cGy) were examined. Group 1 included 20 patients with unresectable disease who received combined RT and LV/5-FU. Group 2 included 11 patients with unresectable disease who received preoperative RT. Group 3 included 21 patients with invasive, resectable, primary disease who received preoperative RT. ### results Patients with unresectable disease who received LV/5-FU had a higher rate of pathologic complete response (20% v 0%) and a lower incidence of positive nodes (30% v 64%) compared with those who did not receive chemotherapy. Even when the most favorable group of patients was included (group 3), patients who received LV/5-FU still had a higher complete response rate (20% v 6%) and a lower incidence of positive nodes (30% v 53%) compared with those who received RT without LV/5-FU. Of those patients with initially unresectable disease, the resectability rate was higher in those who received LV/5-FU compared with those who did not receive LV/5-FU (90% v 64%). Patients who received LV/5-FU experienced slightly more grade 1 to 2 fatigue, stomatitis, nausea, and grade 3 diarrhea, tenesmus, and dysuria. ### conclusions Despite the fact that patients who received chemotherapy (group 1) had more advanced disease compared with those with resectable disease (group 3), the addition of LV/5-FU increased the resectability and downstaging rates. The ultimate impact of a complete response as well as a decrease in the incidence of pelvic nodes on local control and survival remains to be determined. However, given the enhancement of down-staging in patients with unresectable rectal cancer, we are encouraged by the combined modality approach.

https://pubmed.ncbi.nlm.nih.gov/1727928/

121a385260e78585b9b54b3081ebe872

Final analysis of a phase II study of nivolumab in combination with ipilimumab for unresectable chemotherapy-naive advanced melanoma .

Final analysis of a phase II study of nivolumab in combination with ipilimumab for unresectable chemotherapy-naive advanced melanoma . nivolumab plus ipilimumab combination is currently one of the preferred regimens for advanced melanoma in recently updated clinical practice guidelines. However, the evidence on the efficacy of the combination for acral or mucosal subtypes remains less robust. This is the final analysis of a multicenter, open-label, uncontrolled phase II study that investigated the long-term efficacy and safety in treatment-naive Japanese patients with advanced melanoma, including acral or mucosal subtypes, and subsequent therapy after discontinuation of the investigational agents. Patients received four doses of nivolumab (1 mg/kg i.v.) in combination with ipilimumab (3 mg/kg i.v.) at 3-week intervals, followed by doses of nivolumab (3 mg/kg i.v.) at 2-week intervals. The median follow-up period was 20.8 months (range, 5.2-35.0). The centrally and locally assessed objective response rates were both 43.3% (13/30; 95% confidence interval [CI], 25.5-62.6). Median progression-free survival was not reached (95% CI, 3.02-not reached), and median overall survival was also not reached (95% CI, 19.52-not reached). The 30-month progression-free survival and overall survival rates were 50.3% and 54.2%, respectively. No new safety concerns were detected. After discontinuation of the investigational agents, 83.3% of patients received some form of subsequent therapy including 43.3% of patients who received nivolumab monotherapy and 26.7% of patients who received radiotherapy. Of the four patients who discontinued the investigational agents because of immune-related adverse events, two received subsequent therapy (nivolumab and ipilimumab, respectively) and the other two showed long-term treatment-free survival (659 and 590 days, respectively). Long-term survival with nivolumab plus ipilimumab was observed in Japanese patients with melanoma including acral and mucosal subtypes, which is consistent with the CheckMate 067 study. Many patients continued to receive some form of treatment safely after stopping treatment with nivolumab plus ipilimumab.

https://pubmed.ncbi.nlm.nih.gov/32812243/

bfc860242fe9e9abc5f6ea5ffa6f1122

In some relatively developed regions in China , infliximab and rituximab may be a favorable cost-effective alternative for moderate to severe RA .

Cost effectiveness of different treatment strategies in the treatment of patients with moderate to severe rheumatoid arthritis in china. To analyse the cost-effectiveness of traditional disease-modifying anti-rheumatic drugs (tDMARDs) compared to biological therapies from the perspective of Chinese society. ### Methodology Principal Findings A mathematical model was developed by incorporating the clinical trial data and Chinese unit costs and treatment sequences from a lifetime perspective. Hypothetical cohorts with moderate to severe RA were simulated. The primary outcome measure-quality-adjusted life years (QALYs)-was derived from disease severity (HAQ scores). Primary analysis included drug costs, monitoring costs, and other costs. Probabilistic and one-way sensitivity analyses were performed. Treatment sequences that included TNF antagonists and rituximab produced a greater number of QALYs than tDMARDs alone or TNF antagonists plus DMARDs. In comparison with tDMARDs, the incremental cost-effectiveness ratios (ICERs) for etanercept, infliximab, and adalimumab without rituximab were $77,357.7, $26,562.4 and $57,838.4 per QALY and $66,422.9, $28,780.6 and $50,937.6 per QALY, for etanercept, infliximab, and adalimumab with rituximab. No biotherapy was cost-effective under the willingness to pay threshold when the threshold was 3 times the per capita GDP of China. When 3 times the per capita GDP of Shanghai used as the threshold, infliximab and rituximab could yield nearly 90% cost-effective simulations in probabilistic sensitivity analysis. ### Conclusions Significance tDMARD was the most cost-effective option in the Chinese healthcare setting. In some relatively developed regions in China , infliximab and rituximab may be a favorable cost-effective alternative for moderate to severe RA .

https://pubmed.ncbi.nlm.nih.gov/23056637/

0b928797b63ebfe5e343e20167824e7c

Topiramate CR treatment produced significant weight loss and meaningful improvements in A1C and blood pressure in obese patients with type 2 diabetes treated with diet and exercise or in combination with metformin .

A randomized, double-blind, placebo-controlled, multicenter study to assess the efficacy and safety of topiramate controlled release in the treatment of obese type 2 diabetic patients. This is a randomized, placebo-controlled study of the weight-loss efficacy and safety of a controlled-release (CR) formulation of topiramate in overweight and obese patients with type 2 diabetes treated with diet and exercise alone or in combination with metformin. ### Research Design And Methods Patients with type 2 diabetes, BMI > or =27 kg/m2, A1C >6.5 and <11.0%, treated with diet and exercise alone or in combination with metformin monotherapy were enrolled. Patients were randomized to placebo or topiramate CR titrated up to 175 mg/day. Treatment consisted of a 7-week titration phase followed by a 9-week maintenance phase. ### results A total of 111 subjects were randomized and analyzed. By the end of week 16, patients in the placebo and topiramate groups lost 2.5 and 6.0 kg, which represented 2.3 and 5.8%, respectively, of their baseline body weight (P < 0.001 vs. placebo). A1C improved from a baseline of 7.4% in the placebo and 7.6% in the topiramate groups to 7.1 and 6.7%, respectively, representing a 0.4 and 0.9% reduction from baseline, respectively (P < 0.001 vs. placebo). topiramate also significantly reduced blood pressure and urinary albumin excretion. Adverse events were predominantly neuropsychiatric or central and peripheral nervous system related. ### conclusions Topiramate CR treatment produced significant weight loss and meaningful improvements in A1C and blood pressure in obese patients with type 2 diabetes treated with diet and exercise or in combination with metformin . However, the central nervous system and psychiatric adverse event profile of topiramate CR makes it unsuitable for the treatment of obesity and diabetes.

https://pubmed.ncbi.nlm.nih.gov/17363756/

b9dfb483cf8d157dbce9404de8005b7c

To compare efficacy and toxicity of bolus application of chemotherapy protocol , oxaliplatin , fluorouracil ( bolus ) , leucovorin ( folfox ) between two groups of patients in the therapy of metastatic colorectal carcinoma ( mCRC ) .

Therapeutic efficacy and toxicity of bolus application of chemotherapy protocol in the treatment of metastatic colorectal cancer. To compare efficacy and toxicity of bolus application of chemotherapy protocol , oxaliplatin , fluorouracil ( bolus ) , leucovorin ( folfox ) between two groups of patients in the therapy of metastatic colorectal carcinoma ( mCRC ) . ### methods A total of 63 patients were treated for mCRC in the period January 2009 - January 2010 at the Department of Oncology of the Cantonal Hospital Zenica, Bosnia and Herzegovina (first group, 30 patients) and at the Department of Oncology of the Clinical Hospital Centre Bežanijska kosa in Belgrade, Serbia, in the period January 2005 - January 2006 (second group, 33 patients). The patients were treated according the same protocol, i.v. bolus infusion, but in different day intervals (D), 1, 8, 15/28 days or D1-D5/28 days, respectively. In all patients the following factors were analyzed: tumor response, overall survival (OS), progression free survival, hematological and non-hematological toxicity . ### results Colon was the primary localization in almost two thirds of patients. There was no statistically significant difference between the groups according to the age, hematological and non-hematological toxicity, as well as in achieved OS. Progression free survival expressed in months was in average 5 months though with a large range between minimal and maximal survival time. ### conclusion Both groups have shown equivalent efficacy to applied chemotherapy protocols. Overall survival in the two groups matched data from the literature. Further research should confirm success of the combination of chemotherapy protocols and their combination with the biological therapy.

https://pubmed.ncbi.nlm.nih.gov/26276661/

9075a075ca48e05ac8a70fe6bf5e903d

Verapamil and quinine were added in patients with tumors failing to respond or progressing on CVAD alone .

Combination chemotherapy with cyclophosphamide, vincristine, adriamycin, and dexamethasone (CVAD) plus oral quinine and verapamil in patients with advanced breast cancer. We evaluated the question of whether the chemosensitizers verapamil and quinine given orally to breast cancer patients failing combination chemotherapy alone would result in additional clinical responses. In vitro studies reported here showed verapamil sensitization of Adriamycin resistance in 18.8% of fresh human breast cancer specimens tested. Patients (27) were first treated with cyclophosphamide, vincristine, Adriamycin and dexamethasone (CVAD) alone. Verapamil and quinine were added in patients with tumors failing to respond or progressing on CVAD alone . Following treatment with CVAD alone there were no complete remissions and 3 patients (11%) developed partial remissions lasting 5.5, 8, 10.5 months. With the addition of verapamil and quinine to the CVAD regimen, one patient (4%) developed a complete remission of 11.8 months duration and 4 additional patients (15%) developed partial remissions lasting 2.8, 17.3, 19 and > 40 months. Thus, the overall rate of CVAD sensitization by verapamil and quinine was 19%. Treatment with CVAD plus verapamil and quinine was generally well tolerated with observed toxicities including: myelosuppression, neuropathy, Cushingoid symptoms and tinnitus and/or dizziness due to quinine. We conclude that addition of the non-cytotoxic chemosensitizers verapamil and quinine to CVAD in patients failing CVAD alone results in additional clinical responses in a small percentage of patients, some with long term durations. The results of this study lend credence to the notion that non-cytotoxic chemosensitizers can enhance the clinical activity of combination chemotherapy and the search for more effective and less toxic chemosensitizers continues.

https://pubmed.ncbi.nlm.nih.gov/9116320/

b01ddd458e6d0f844ef2a2dabc1e9c0d

However , dipyridamole had no effect on both the influx and efflux of epirubicin in doxorubicin-sensitive cells .

[Studies on reversing effect of multidrug resistance by dipyridamole. II. Inhibition of epirubicin efflux from resistant cells by dipyridamole and its pharmacological effect]. We have previously reported that dipyridamole increases the cytotoxicity of epirubicin and alters the cell cycle in doxorubicin-resistant (P388/DOX) cells, increasing the accumulation of G2/M phase by blocking the cell cycle. In cultured cells, dipyridamole increased dose-dependently the intracellular accumulation of epirubicin in the resistant cells. Simultaneous exposure of the resistant cells to epirubicin and 100 microM dipyridamole resulted in a 4.2-fold increase in proportion to the control level of epirubicin after 60 min. dipyridamole inhibited the enhanced efflux of epirubicin in doxorubicin-resistant cells. However , dipyridamole had no effect on both the influx and efflux of epirubicin in doxorubicin-sensitive cells . In mice, lethal and bone marrow toxicity induced by epirubicin were potentiated by administration of high-dose of dipyridamole. In addition, in vivo results also demonstrated that dipyridamole in combination with epirubicin produced a significant reversal of the in vivo antitumor activity of epirubicin in mice bearing P388/DOX cells. These data imply the enhancement effects of dipyridamole on the efficacy and toxicity of epirubicin.

https://pubmed.ncbi.nlm.nih.gov/8721351/

acbfe42000da2810b6325717404141e6

This study aims to evaluate the potential role of combination therapy with docetaxel , flavopiridol , or 5-FU in modulating chemosensitivity and better understand how they might be used clinically .

Efficacy of sequential treatment of HCT116 colon cancer monolayers and xenografts with docetaxel, flavopiridol, and 5-fluorouracil. Clinical treatment of solid tumors with docetaxel, flavopiridol, or 5-fluorouracil (5-FU) often encounters undesirable side effects and drug resistance. This study aims to evaluate the potential role of combination therapy with docetaxel , flavopiridol , or 5-FU in modulating chemosensitivity and better understand how they might be used clinically . ### methods HCT116 colon cancer cells were treated with docetaxel, flavopiridol, and 5-FU in several different administrative schedules in vitro, either sequentially or simultaneously. Cell survival was measured by MTT assay. The activity of caspase-3 was determined by caspase-3 assays and the soft agar colony assay was used to test the colony formation of HCT116 cells in soft agar. We also established xenograft models to extend in vitro observations to an in vivo system. ### results The maximum cytotoxicity was found when human colon cancer HCT116 cells were treated with docetaxel for 1 h followed by flavopiridol for 24 h and 5-FU for another 24 h. This sequential combination therapy not only inhibits tumor cell growth more strongly compared to other combination therapies but also significantly reduces colony formation in soft agar and augments apoptosis of HCT116 cells. Sequencing of docetaxel followed 1 h later by flavopiridol, followed 24 h later by 5-FU in xenograft models, also resulted in delayed tumor growth and higher survival rate. ### conclusion These results highlight the importance of an administrative schedule when combining docetaxel with flavopiridol and 5-FU, providing a rationale explanation for its development in clinical trials.

https://pubmed.ncbi.nlm.nih.gov/17007746/

caa3da2a86157dc41125f56205a1a5d4

Dipyridamole or dipyridamole and acetylsalicyclic acid were used in 22 pregnancies .

The course of pregnancy in patients with artificial heart valves. Twenty-five women with prosthetic heart valves (PHV) became pregnant 28 times. Twenty-six of the pregnancies occurred while the patients were receiving oral anticoagulants and these were continued throughout in 25 pregnancies. Dipyridamole or dipyridamole and acetylsalicyclic acid were used in 22 pregnancies . Eighteen infants were delivered, one with a congenital corneal leukoma; none had hemorrhagic complications; their psychomotor development was normal. Nine women aborted 10 times, including patients with two PHV, pelvic trauma and self-induced abortion. We could not detect excess anticoagulation in eight of the nine who had spontaneous losses; excess anticoagulation occurred five weeks before an abortion. There were no maternal deaths despite numerous complications; in two women, brain embolism was related to short interruptions of anticoagulation. The details of management are mentioned. We lack enough evidence to suggest routine sterilization, routine interruption of coumarin therapy during pregnancy or routine interruption of pregnancy in women with certain types and models of PHV; however, pregnancy under such conditions, plus antithrombotic therapy, carries a high risk for the product and a potential teratogenic effect. Women with one or two PHV can have children if their management is closely supervised and if extreme care is taken with the use of oral anticoagulants.

https://pubmed.ncbi.nlm.nih.gov/973644/

ea455dd922639a395f7675d9beb480a2

Bevacizumab and trastuzumab are efficacious for treatment of advanced or HER2-positive metastatic breast cancer ; however , few data exist for this regimen in inflammatory breast cancer .

Neoadjuvant bevacizumab, trastuzumab, and chemotherapy for primary inflammatory HER2-positive breast cancer (BEVERLY-2): an open-label, single-arm phase 2 study. Bevacizumab and trastuzumab are efficacious for treatment of advanced or HER2-positive metastatic breast cancer ; however , few data exist for this regimen in inflammatory breast cancer . In our phase 2 trial, we aimed to assess efficacy and safety of neoadjuvant bevacizumab combined with trastuzumab and chemotherapy in patients with primary HER2-positive inflammatory breast cancer. ### methods In our phase 2, multicentre, open-label, single-arm, non-comparative trial, we enrolled women (aged ≥ 18 years) with histologically confirmed HER2-positive non-metastatic inflammatory breast cancer at private or public oncology centres in France. Before surgery, patients were treated with fluorouracil, epirubicin, cyclophosphamide, and bevacizumab (cycles 1-4) and docetaxel, bevacizumab, and trastuzumab (cycles 5-8) in 3-week cycles. After surgery, patients received adjuvant radiotherapy, trastuzumab, and bevacizumab. For the primary endpoint, we assessed the proportion of patients who achieved a pathological complete response (defined by central review of surgical specimens according to Sataloff classification, counting missing data as failure) and adverse events in all enrolled patients. This study is registered with ClinicalTrials.gov, number NCT00717405. ### findings Between Oct 23, 2008, and Oct 28, 2009, we enrolled 52 patients at 21 centres. 42 (81%) of 52 patients received all eight cycles of neoadjuvant therapy and 49 (94%) underwent surgery. After neoadjuvant therapy, 33 of 52 patients had a pathological complete response according to central review (63·5%, 95% CI 49·4-77·5). The most common adverse events were asthenia and nausea (both occurred in 36 [69%] of 52 patients). 25 (48%) patients had grade 3-4 neutropenia, which was the most common grade 3-4 adverse event. Only one grade 3 or worse adverse event regarded as related to bevacizumab was reported (hypertension, one patient). Four patients (8%) had cardiac failure. ### interpretation Neoadjuvant treatment with bevacizumab, trastuzumab, and chemotherapy was efficacious and well tolerated in patients with previously untreated primary inflammatory breast cancer. Further confirmation of use of bevacizumab in inflammatory breast cancer is needed. ### funding Roche (France).

https://pubmed.ncbi.nlm.nih.gov/22377126/

17a298de5c61f56d978d1ac05164d0d5

The frequency of their resistance to penicillin and ampicillin was 76.8 % ( 159/207 ) , followed by erythromycin ( 56 % , 116/207 ) , trimethoprim-sulfamethoxazole ( 28.5 % , 59/207 ) , chloramphenicol ( 24.2 % , 50/207 ) , kanamycin ( 19.8 % , 41/207 ) , and doxycycline ( 1.4 % , 3/207 ) .

Antimicrobial susceptibilities of exfoliative toxigenic and non-toxigenic Staphylococcus hyicus strains in Japan. Staphylococcus hyicus isolates (n=207), including 150 exfolitative toxigenic and 57 non-toxigenic strains, were examined for their susceptibility to 13 antimicrobial agents by using the dehydrated 96-well MIC panel system. The frequency of their resistance to penicillin and ampicillin was 76.8 % ( 159/207 ) , followed by erythromycin ( 56 % , 116/207 ) , trimethoprim-sulfamethoxazole ( 28.5 % , 59/207 ) , chloramphenicol ( 24.2 % , 50/207 ) , kanamycin ( 19.8 % , 41/207 ) , and doxycycline ( 1.4 % , 3/207 ) . Resistance to chloramphenicol and trimethoprim-sulfamethoxazole was significantly higher in toxigenic strains than non-toxigenic strains (p<0.01), whereas kanamycin and erythromycin resistance was significantly higher in non-toxigenic strains (p<0.01 and <0.05, respectively). Resistance to two or more antimicrobials was observed in 85.5% (177/207) of total strains, with a significantly higher occurrence in toxigenic strains (89.3%, 134/150 vs. 75.4%, 43/57; p<0.05).

https://pubmed.ncbi.nlm.nih.gov/19498301/

7a43db7cf232e74d3891f1026462d914

Rats were distributed into three groups ( n = 5 ) according to the drug studied namely , 50 % enantiomeric excess bupivacaine mixture ( 5 μg/mL ) ; pancuronium ( 2 μg/mL ) ; 50 % enantiomeric excess bupivacaine mixture + pancuronium .

Effect of 50% enantiomeric excess bupivacaine mixture combined with pancuronium on neuromuscular transmission in rat phrenic nerve-diaphragm preparation; a pilot study. Local anaesthetics are drugs that are widely used in clinical practice. However, the effects of these drugs on the neuromuscular junction and their influence on the blockade produced by non-depolarising neuromuscular blocking drugs are still under investigation. The aim of this study was to evaluate, in vitro, the influence of a 50% enantiomeric excess bupivacaine mixture on neuromuscular transmission and neuromuscular block produced by pancuronium. ### methods Rats were distributed into three groups ( n = 5 ) according to the drug studied namely , 50 % enantiomeric excess bupivacaine mixture ( 5 μg/mL ) ; pancuronium ( 2 μg/mL ) ; 50 % enantiomeric excess bupivacaine mixture + pancuronium . The following parameters were evaluated: (1) Effects of a 50% enantiomeric excess bupivacaine mixture on membrane potential (MP) and miniature endplate potentials (MEPPs); (2) amplitude of diaphragmatic response before and 60 min after the addition of a 50% enantiomeric excess bupivacaine mixture; the degree of neuromuscular block with pancuronium and pancuronium combined with a 50% enantiomeric excess bupivacaine mixture. ### results A 50% enantiomeric excess bupivacaine mixture did not alter the amplitude of muscle response (MP) but decreased the frequency and amplitude of MEPP. The block produced by pancuronium was potentiated by a 50% enantiomeric excess bupivacaine mixture. ### conclusion A 50% enantiomeric excess bupivacaine mixture used alone did not affect neuromuscular transmission, but potentiated the neuromuscular block produced by pancuronium. No action was shown on the muscle fibre, and alterations on MEPPs demonstrated a presynaptic action.

https://pubmed.ncbi.nlm.nih.gov/26755834/

fff07e1e94c80840f59c9458ee5f7de2

Blood was sampled immediately prior to premedication ( temazepam ) , after induction of anaesthesia ( fentanyl and thiopentone ) and at 10-minute intervals until the end of the procedure ( N2O maintenance , vecuronium relaxation ) .

The plasma ACTH, AVP, CRH and catecholamine responses to conventional and laparoscopic cholecystectomy. We compared the responses of the stress hormones, cortisol, ACTH, vasopressin (AVP), corticotrophin releasing hormone (CRH) and catecholamines to elective conventional and laparoscopic cholecystectomy. ### design A right upper quadrant transverse incision was used for conventional cholecystectomy, and four 1-2-cm incisions for the laparoscopic procedure (for insertion of surgical instruments, diathermy, fibreoptic telescope and light source, and carbon dioxide insufflation). Blood was sampled immediately prior to premedication ( temazepam ) , after induction of anaesthesia ( fentanyl and thiopentone ) and at 10-minute intervals until the end of the procedure ( N2O maintenance , vecuronium relaxation ) . A blood sample was taken after reversal, and then at 10-minute intervals for 50 minutes. Plasma sodium and blood pressure were measured at similar intervals. Results are expressed as mean +/- standard error. ### patients Twelve patients were studied (six in each group). ### measurements Peptide hormones were measured by radioimmunoassay, cortisol by ELISA and catecholamines by HPLC. ### results The mean premedication hormone values for the conventional and laparoscopic procedures did not increase significantly after induction of anaesthesia. Within 10 minutes of the first incision, however, there was a marked concordant rise in mean plasma ACTH and AVP levels for both procedures (conventional: ACTH, from a premedication value of 10.2 +/- 1.7 to 80.1 +/- 14.3 pmol/l, AVP from 1.2 +/- 0.4 to 117 +/- 24 pmol/l, P < 0.01 for both hormones; laparoscopic: ACTH from 5.8 +/- 2.6 to 55.1 +/- 26.0 pmol/l, AVP from 1.6 +/- 0.11 to 49.2 +/- 27.09 pmol/l). At the end of both types of operation mean levels of ACTH and AVP were still elevated, although the ACTH: AVP ratio had increased. Greater variability in ACTH and AVP responses was seen in the laparoscopic than in the conventional procedure, three patients showing a relatively small response to surgery. Total secretion of ACTH during both types of surgery was not significantly less both during (P < 0.05), and after (P < 0.01) laparoscopic surgery. For both procedures, the timing of AVP and ACTH peaks was significantly related (P < 0.002). A small but significant rise in CRH was observed 30 minutes after the start of surgery for both procedures P < 0.05). The timing of CRH and ACTH peaks was unrelated. The maximum mean plasma cortisol level for the conventional procedure (1268 +/- 147 nmol/l) was reached 20 minutes after reversal of anaesthesia and remained at this level until the end of sampling. The cortisol response was comparable during the laparoscopic procedure but was beginning to fall at 60 minutes post-operatively. Plasma adrenaline responses to the two types of surgery were not significantly different, but the plasma total noradrenaline response to laparoscopic surgery as indicated by the response area during the first 20 minutes was significantly increased (P < 0.02). Plasma sodium, renin activity and initial systolic blood pressure fall were not significantly different during the two procedures. ### conclusions For both procedures, the peak of ACTH secretion after incision is likely to be AVP dependent, and the timing of peak levels of these two hormones was significantly related. Subsequent ACTH secretion may be the result of an interaction between AVP and CRH. Laparoscopic cholecystectomy results in a smaller AVP rise than does the conventional procedure, and plasma AVP falls more rapidly post-operatively. During the period of observation, ACTH, CRH, cortisol and adrenaline responses were not significantly lessened by the laparoscopic approach, but there was a significant increase in the noradrenaline response. Stress hormone monitoring may assist further improvements in surgical technique.

https://pubmed.ncbi.nlm.nih.gov/8392916/

f953f0ee4e567cff2bf69362b2ed6d37

This study was performed to compare the efficacy of peritonsillar infiltration of bupivacaine , tramadol and combination of bupivacaine-tramadol in post-tonsillectomy pain .

Preemptive peritonsillar infiltration with bupivacaine in combination with tramadol improves pediatric post-tonsillectomy pain better than using bupivacaine or tramadol alone: A randomized, placebo-controlled, double blind clinical trial. Post-tonsillectomy pain is one of the most common problems after anesthesia, therefore use of a good anesthesia technique with minimum side effect is an important aim. This study was performed to compare the efficacy of peritonsillar infiltration of bupivacaine , tramadol and combination of bupivacaine-tramadol in post-tonsillectomy pain . ### Materials And Methods In a double blind trial 120 ASA I and II children condidated for tonsillectomy were randomized into four groups: Peritonsillar infiltration with bupivacaine 1 mg/kg in Group B, tramadol 2 mg/kg in Group T, combination of bupivacaine-tramadol in Group BT and saline in Group C was done. ### results Until 60 minutes in the recovery room, control of pain in the first three groups were better than Group C (P < 0.05) and in the third group it was better than others. Four hours after surgery, control of pain was better in the second and third groups in comparison to Groups B and Group C (P <0.05) and was better in the third group in comparison to the second group. Then, 24 hours after that, only in the group III the control of pain was effective (P < 0.05). ### conclusions In this study we showed that peritonsillar infiltration with combination of bupivacain-tramadol provided less post surgery pain compared with infiltration of bupivacaine and tramadol alone in adenotonsillectomy of children.

https://pubmed.ncbi.nlm.nih.gov/26322280/

4dd39ba2d55cff79d702f364d08a7ac0

The planned concomitant treatment in group B was : bleomycin 5 units twice a week i.m . , total dose 70 units , mitomycin C 15 mg/m2 i.v . after delivery of 10 Gy , and 10 mg/m2 i.v . on the last day of radiotherapy .

Concomitant radiotherapy with mitomycin C and bleomycin compared with radiotherapy alone in inoperable head and neck cancer: final report. To compare the efficacy of concomitant irradiation with mitomycin C and bleomycin in patients with inoperable head and neck carcinoma with radiotherapy alone. ### Methods And Materials Between March 1991 and December 1993, 64 patients with inoperable head and neck carcinoma (41 with oropharyngeal site) were randomized to radiotherapy alone (group A) or radiotherapy combined with simultaneous application of mitomycin C and bleomycin (group B). In both groups patients were irradiated five times weekly with 2 Gy to a total dose of 66-70 Gy. The planned concomitant treatment in group B was : bleomycin 5 units twice a week i.m . , total dose 70 units , mitomycin C 15 mg/m2 i.v . after delivery of 10 Gy , and 10 mg/m2 i.v . on the last day of radiotherapy . To enhance the effect of these two drugs, patients received also nicotinamide, chlorpromazine, and dicoumarol. Because significantly better results were achieved in arm B for patients with inoperable oropharyngeal carcinoma, the study was closed and such patients were after December 1993 routinely treated with the combined therapy (as in arm B). Until October 1996, we treated and followed up 48 such consecutive patients. ### results Median follow-up of our study patients is 42 months. Complete remission (CR) rate in group A was 31% and in group B 59% (p = 0.04); disease-free survival (DFS) in group A was 8% and in group B 37% (P = 0.01); and overall survival (OS) was 7% in group A and 26% in group B (p = 0.08). CR rate for patients with oropharyngeal carcinoma was 29% in group A (N = 21) and 75% in group B (N = 20) (p = 0.007); DFS in group A was 10% and in group B 48% (p = 0.001); and the OS was 10% in group A and 38% in group B (p = 0.019). In patients with inoperable oropharyngeal carcinoma treated after December 1993, complete remission was achieved in 32/48 (67%, 95% CI: 52%-80%). DFS at the median follow-up of 14 months was 60% (95% CI 43-77%) and OS 58% (95% CI 42-74%). ### conclusion From the results of our study it seems that the concomitant treatment significantly improves CR rate, DFS, and OS in patients with inoperable oropharyngeal carcinoma in comparison with radiotherapy alone.

https://pubmed.ncbi.nlm.nih.gov/9719123/