Adequate Tolerability Research Articles

A systematic review of the safety and efficacy of artemether-lumefantrine against uncomplicated Plasmodium falciparum malaria during pregnancy

Malaria during pregnancy, particularly Plasmodium falciparum malaria, has been linked to increased morbidity and mortality, which must be reduced by both preventive measures and effective case management. The World Health Organization (WHO) recommends artemisinin-based combination therapy (ACT) to treat uncomplicated falciparum malaria during the second and third trimesters of pregnancy, and quinine plus clindamycin during the first trimester. However, the national policies of many African countries currently recommend quinine throughout pregnancy. Therefore, the aim of this article is to provide a summary of the available data on the safety and efficacy of artemether-lumefantrine (AL) in pregnancy. An English-language search identified 16 publications from 1989 to October 2011 with reports of artemether or AL exposure in pregnancy, including randomized clinical trials, observational studies and systematic reviews. Overall, there were 1,103 reports of AL use in pregnant women: 890 second/third trimester exposures; 212 first trimester exposures; and one case where the trimester of exposure was not reported. In the second and third trimesters, AL was not associated with increased adverse pregnancy outcomes as compared with quinine or sulphadoxine-pyrimethamine, showed improved tolerability relative to quinine, and its efficacy was non-inferior to quinine. There is evidence to suggest that the pharmacokinetics of anti-malarial drugs may change in pregnancy, although the impact on efficacy and safety needs to be studied further, especially since the majority of studies report high cure rates and adequate tolerability. As there are fewer reports of AL safety in the first trimester, additional data are required to assess the potential to use AL in the first trimester. Though the available safety and efficacy data support the use of AL in the second and third trimesters, there is still a need for further information. These findings reinforce the WHO recommendation to treat uncomplicated falciparum malaria with quinine plus clindamycin in early pregnancy and ACT in later pregnancy.

A Double-Blind, Placebo-Controlled, and Multiple Dose Escalation Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Ono-7746 in Healthy Subjects

Abstract 4828 Background:ONO-7746 is a potent orally administered thrombopoietin receptor (c-Mpl) agonist and can elevate platelet counts after a single dose in healthy subjects. Therefore, it could be potentially used for the treatment of thrombocytopenia associated with a variety of etiologies. Objectives:This study evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of ONO-7746 after multiple dose administration in healthy subjects. Methods:A total of 60 subjects were randomly assigned to 5 groups of 12 subjects each to receive active ONO-7746 (9 subjects) or placebo (3 subjects) once daily for 14 days at doses of 1, 2, 4, 6, and 10 mg per day. Dose selection was adjusted based on data from earlier cohorts according to the dose-escalation procedures, i.e. Dose escalation was only permitted if adequate safety and tolerability were demonstrated and the results did not meet the stopping rule criteria at the previous dose level as described in the single-dose study. Subjects returned on Day 42 for follow-up assessments. ONO-7746 was administered once daily under fasted conditions at the dose of 1 mg to 10 mg for 14 days. Subjects were admitted to the clinical study site on Day –1 and remained at the site until discharge on Day 32. Intensive safety, tolerability, PK, and PD assessments were made throughout the study. Safety assessments included 12-lead ECGs, vital signs, serum chemistry, hematology, urinalysis and adverse event (AE) reporting. Plasma samples for ONO-7746 concentration-time analysis were collected at several time points. PD parameters included platelet count, platelet activation, and aggregation. Results:Maximum platelet count and change from Baseline values increased with ascending ONO-7746 dose level. The mean platelet counts in the ONO-7746 cohorts increased from Baseline beginning on Days 3 or 4, peaked between Days 12 and 17, decreased from Days 22 to 32, and returned to baseline levels by Day 42. The largest mean percent change from Baseline in average platelet count (145.9%) was observed in the 10-mg cohort, compared with 17.4% in the placebo cohort. Platelet function as measured by the exploratory platelet aggregation and activation tests was not affected by administration of ONO-7746. In general, endogenous TPO values and CD34+ cell counts seemed not to be affected by the administration of ONO-7746. The PK profiles of ONO-7746 showed that Cmax and AUC24h increased with dose and T1/2 after the last dose was similar to that after a single dose. The plasma trough concentration of ONO-7746 reached steady state by Day 10. The PK of ONO-7746 was not affected by multiple-dose administration. Six subjects in the 10-mg cohort had an adverse event of special interest (AESI) of increased platelet count > 500 × 109/L. No treatment- or dose-related trends were observed in AEs, clinical laboratory results, influence on other blood cell counts, physical examination findings, vital sign measurements, 12-lead ECG and telemetry results, or slit lamp examination results. There were no deaths, serious AEs, severe AEs, or AEs that led to study discontinuation. Conclusion:ONO-7746 is safe and well-tolerated at all tested dose levels. The PK, PD, and safety profile demonstrated in this study supports further clinical studies in thrombocytopenic patients.Observed Platelet Count by Study Day [Display omitted] Disclosures:Hunt:ONO Pharma USA: Research Funding. Lu:ONO Pharma USA: Employment. Kawasaki:Ono Pharmaceutical Co., Ltd.: Employment. Hall:ONO Pharma USA: Employment. Komaba:Ono Pharmaceutical Co., Ltd.: Employment. Takeuchi:Ono Pharmaceutical Co., Ltd.: Employment. Imamura:ONO Pharma USA: Employment. Kuter:ONO Pharma USA: Consultancy.

Identification of N-(5-tert-Butyl-isoxazol-3-yl)-N′-{4-[7-(2-morpholin-4-yl-ethoxy)imidazo[2,1-b][1,3]benzothiazol-2-yl]phenyl}urea Dihydrochloride (AC220), a Uniquely Potent, Selective, and Efficacious FMS-Like Tyrosine Kinase-3 (FLT3) Inhibitor

Treatment of AML patients with small molecule inhibitors of FLT3 kinase has been explored as a viable therapy. However, these agents are found to be less than optimal for the treatment of AML because of lack of sufficient potency or suboptimal oral pharmacokinetics (PK) or lack of adequate tolerability at efficacious doses. We have developed a series of extremely potent and highly selective FLT3 inhibitors with good oral PK properties. The first series of compounds represented by 1 (AB530) was found to be a potent and selective FLT3 kinase inhibitor with good PK properties. The aqueous solubility and oral PK properties at higher doses in rodents were found to be less than optimal for clinical development. A novel series of compounds were designed lacking the carboxamide group of 1 with an added water solubilizing group. Compound 7 (AC220) was identified from this series to be the most potent and selective FLT3 inhibitor with good pharmaceutical properties, excellent PK profile, and superior efficacy and tolerability in tumor xenograft models. Compound 7 has demonstrated a desirable safety and PK profile in humans and is currently in phase II clinical trials.

Transitional polytherapy: tricks of the trade for monotherapy to monotherapy AED conversions.

The goal of epilepsy therapy is to help patients achieve seizure freedom without adverse effects. While monotherapy is preferable in epilepsy treatment, many patients fail a first drug due to lack of efficacy or failure to tolerate an initial medication, necessitating an alteration in therapy. Sudden changes between monotherapies are rarely feasible and sometimes deleterious given potential hazards of acute seizure exacerbation or intolerable adverse effects. The preferred method for converting between monotherapies is transitional polytherapy, a process involving initiation of a new antiepileptic drug (AED) and adjusting it toward a target dose while maintaining or reducing the dose of the baseline medication. A fixed-dose titration strategy of maintaining the baseline drug dose while titrating the new medication is preferable when breakthrough seizures are occurring and no adverse effects are present. However, a flexible titration strategy involving reduction of the baseline drug dose to ensure adequate tolerability of the new adjunctive medication is preferred when patients are already experiencing adverse effects. This article reviews pharmacokinetic considerations pertinent for ensuring successful transitional polytherapy with the standard and newer antiepileptic drugs. Practical consensus recommendations “from an expect panel (SPECTRA, Study by a Panel of Experts Considerations for Therapy Replacement and Antiepileptics) for a successful monotherapy” AED conversions are then summarized. Transitional polytherapy is most successful when clinicians appropriately manage the titration strategy and consider pharmacokinetic factors germane to the baseline and new adjunctive medication.

A Phase II Study of the Purine Nucleoside Phosphorylase (PNP) Inhibitor RO5092888 (BCX-4208) in Patients with Moderate to Severe Chronic Plaque Psoriasis: Safety, Tolerability and Lymphocyte Effects

Introduction: PNP is a purine-metabolizing enzyme that catalyzes the phosphorolysis of 2′-deoxyguanosine [dGuo] to guanine and deoxyribose-1-phosphate. In T-cells, PNP inhibition leads to accumulation of deoxyguanosine triphosphate (dGTP), triggering apoptotic cell death. Chronic-plaque type psoriasis (psoriasis) is an autoimmune disorder, in which T-cells contribute, at least in part, to the manifestations and maintenance of the disease. Therefore, targeting T-cells may be a beneficial treatment strategy. Since for chronic inflammatory diseases the safety of potential immunosuppressive drugs is a major consideration, we conducted this study to investigate safety and tolerability of oral RO5092888 (BCX-4208) in patients with moderate to severe chronic plaque psoriasis.Methods: This was a randomized, double-blind, placebo-controlled, dose-ranging study. Sixty-six patients 18 to 70 years old were randomized into one of three groups: placebo, 20mg/d or 120mg/d. The study was conducted from August 2007 to June 2008. Patients received study drug over six weeks and were observed over an additional 4 weeks. Assessments for safety included tracking of adverse events (AEs) including infections; vital signs; ECGs; chemistry panel; LFTs; hematologic parameters including peripheral blood (PB) lymphocyte subsets CD3+, CD4+, CD8+, CD56+, CD20+; and urinalysis.Results: 65 of the 66 enrolled patients were analyzed. One serious AE was observed in the 20mg/d group, a deep vein thrombosis (DVT) in a patient with a history of DVTs, and was considered unrelated to study drug. The percentage of patients experiencing at least one adverse event (AE) of any grade was placebo: 33% (7/21), 20mg: 41% (9/22), and 120mg: 59% (13/22). During treatment, two infections occurred in the placebo group (influenza and sinusitis), one in the 20mg group (nasopharyngitis), and 4 in the 120mg group (2-upper respiratory tract infections, 1 bronchitis, and 1 otitis externa). Reductions in PB lymphocytes and subsets were observed (Table 1). Nine patients showed decreased levels of CD4+ lymphocytes, below 350 cells/μL (20mg/d, 3; 120mg/d, 6).Conclusion: Daily oral administration of 20 mg or 120 mg of RO5092888 for up to 6 weeks demonstrated adequate safety and tolerability. Reductions in PB T cells, T cell subsets and B cells were observed. Further investigation of RO5092888 is warranted in both T-cell and B-cell diseases.Lymphocyte subpopulationMean Nadir (% change from baseline)Placebo (n=21)20 mg (n=22)120 mg (n=22)CD3+24.030.647.5CD4+23.628.944.9CD8+26.131.853.9CD20+37.542.664.2CD56+40.147.772.6Table 1

Safety and efficacy of fondaparinux as an adjunctive treatment to thrombolysis in patients with high and intermediate risk pulmonary embolism

No data are available on the efficacy and safety of a combination of fondaparinux and thrombolysis in the setting of high to intermediate risk pulmonary embolism (PE). Patients submitted to thrombolysis and fondaparinux, presenting with > or =1 of the following criteria were included: (1) cardiogenic shock, (2) syncope, (3) > or =1 proximal thrombo-embolus at CT scan, (4) positive troponin test, (5) echocardiographic findings indicating right ventricular (RV) dysfunction. In-hospital results included death, recurrent PE, persistent RV dysfunction at 48 h echocardiography, bleeding complications. Twenty seven patients were included; 22 received a 2 h infusion of rt-PA and 5 received a 2 h infusion of streptokinase. Ten patients presented with cardiogenic shock (37%), 8 with syncope (30%), all had RV dysfunction. 82% of patients had an uneventful in-hospital course. One patient died during hospital stay from refractory shock. Thrombolysis failed in 2 patients (7%), requiring successful rescue surgical embolectomy. Bleeding events occurred in 2 patients (7%), of whom 1 required blood transfusion. Despite the small sample size, our data suggest that fondaparinux procures adequate tolerability compared to standard current therapy in combination with thrombolysis in high to intermediate risk PE.

Efficacy of triple therapy with thymalfasin, peginterferon α-2a, and ribavirin for the treatment of hispanic chronic HCV nonresponders: Original Article

Background/Aims: Thymalfasin has shown efficacy in the treatment of chronic HCV infection. The aim of this study was to evaluate the efficacy and tolerability of triple therapy with thymalfasin, peginterferon α-2a (PEG-IFN α-2a), and ribavirin in Hispanic patients with chronic viral hepatitis C who were nonresponders to prior treatment with interferon alfa (IFN-α)/ribavirin. Methods: In this open-label study, 40 subjects received thymalfasin (1.6 mg twice a week), PEG-IFN α-2a (180 μg once a week), and ribavirin (800-1,000 mg/ day) for 48 weeks. All patients had positive HCV RNA by PCR analysis, abnormal levels of ALT, compensated hepatic disease, and liver biopsy with chronic damage. Results: Viral response was observed in 52.5% patients at week 12 and 50% at week 24. Of the per protocol group, 52.6% showed an end-of-treatment response at week 48 and 21.1% achieved an SVR at week 72. Among genotype 1 patients, 23.5% achieved an SVR at week 72. A reduction of the dose of PEG IFN α-2a and ribavirin was required. Thymalfasin was well tolerated without dose reduction. Conclusion: Triple therapy with thymalfasin, PEG IFN α-2a, and ribavirin is an effective treatment option for difficult-to-treat HCV patients who are refractory to prior conventional treatment, with adequate tolerability.

A Prospective Study to Assess the Efficacy and Patient Tolerance of Three Bowel Preparations for Colonoscopy

The adherence to the required clear liquid diet and a high-volume bowel cleansing solution prior to colonoscopy often leads to poor patient compliance and inadequate exams. This study evaluated the efficacy and patient tolerance of three bowel preparation regimens prior to colonoscopy. One hundred fourteen patients were randomized to one of three preparations. Group 1 was assigned a clear liquid diet/magnesium citrate and bisacodyl prep; group 2 was assigned to receive a diet kit/magnesium citrate and bisacodyl prep; and group 3 received a diet kit/polyethylene glycol electrolyte prep. The adequacy of bowel preparation was graded by the endoscopists performing the procedures. The preparations were rated by patients for tolerance, compliance, and side effects. The three methods of preparation did not prove to be significantly different in regards to efficacy of colon cleansing or patient tolerability. There was also no difference in compliance between the three regimens. There were no reported side effects in any of the study groups. This study suggests that a low-residue diet kit, given in conjunction with polyethylene glycol electrolyte or magnesium citrate and bisacodyl, produces adequate colon cleansing and patient tolerability.

Adaptación al castellano y validación del cuestionario Arthritis Treatment Satisfaction Questionnaire

Linguistic adaptation and validation into Spanish of the ARTS questionnaire, a self reported instrument designed to measure four osteoarthritis treatment satisfaction dimensions: treatment advantages, treatment convenience, apprehension about treatment and satisfaction with medical care. Adaptation was performed using conceptual equivalence, supervised by a panel of 6 experts and 4 independent translators, who were in charge of performing translation and back-translation of the items. A sample of patients suffering from knee, hip or column osteoarthritis was used to estimate the psychometric properties of feasibility, reliability, validity and sensitivity to change. Three groups were identified: adequate analgesic effect and tolerability, treatment-switch because of a weak analgesic effect, and treatment- switch due to poor tolerability. The ARTS was administered at baseline, 1 week later for retest, and after 4 weeks of treatment with NSAIDs or Cox II-inhibitors. A sample of 163 patients was formed (67.7 [9.2] years old). No floor or ceiling effects were found, items were well understood and non- response rates were below 1%. Cronbach's alpha for the total scales was 0.85, and the intraclass correlation coefficient was 0.81. Exploratory factor analysis yielded 4 dimensions which were coherent with those proposed by the original authors. Concurrent validity was measured with SF-36, a pain VAS instrument, a treatment compliance VAS, and the Morisky-Green compliance questionnaire. The adapted instrument showed a good discriminatory validity, and it was able to distinguish between patients needing a change in treatment and those who did not need it. It was also sensitive to changes in patients' treatment effectiveness after a 30 days follow up. A psychometrically valid and conceptually equivalent ARTS questionnaire has been produced to explore satisfaction with treatment in patients with osteoarthritis in Spanish speaking countries.

Protective effect of Nimesulide (COX inhibitor), AKBA (5-LOX inhibitor) and their combination in aging associated abnormalities in mice

Several inflammatory processes play a critical role in brain aging and are associated with increased vulnerability to neurodegeneration. Cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX), two enzymes involved in the oxygenation of the arachidonic acid, are upregulated in the central nervous system during aging and are associated with different aging-related brain pathologies. The present experiment was performed to study the effects of 5-LOX inhibitor, acetyl-11-keto-beta-boswellic acid (AKBA), nimesulide (preferential COX-2 inhibitor), and their combination on cognitive performance of young and aged mice, using elevated plus maze test. Chronic administration of AKBA (100 mg/kg, p.o.) and nimesulide (2.42 mg/kg, p.o.) for 15 days significantly reversed the aging-induced retention deficit in mice. Coadministration of AKBA and nimesulide enhanced the cognitive performance in aged mice when compared with that in per se treatment. The aging-related increase in oxidative damage (increased LPO and decreased GSH) was reversed by AKBA, nimesulide, and their combination. Further, per se COX and LOX inhibitors and their combination did not produce any alteration in gastrointestinal parameters; they also reversed the aging-induced motor dysfunction in the aged animals. On the basis of these observations, present findings indicated that the combination of COX and LOX inhibitors (dual inhibitors) may provide a new therapeutic innovation for the treatment of aging-related brain disorders such as Alzheimer's disease and different motor dysfunctions with adequate gastrointestinal tolerability.

Affective disorders in Parkinson's disease

This article reviews the prevalence, phenomenology, main clinical correlates, potential mechanisms, and treatment modalities of depression in Parkinson's disease (PD). In cross-sectional samples of PD patients attending a neurology unit the prevalence of depression is about 40%, but prevalences may be lower in epidemiological samples. Both psychological and autonomic symptoms of depression are specific to the depressive syndrome of PD, except for the symptoms of anergia, motor retardation, and early morning awakening. Depression may start before the onset of motor symptoms, and most patients with PD may eventually develop depression at some point during their longitudinal evolution. Follow-up studies suggest that PD patients with major depression have a significantly faster decline in activities of daily living and cognitive functions, and a faster progression along the stages of the illness as compared to non-depressed PD patients. Finally, there are few controlled studies of antidepressants in PD, but tricyclic compounds demonstrated adequate efficacy and tolerability.