COMPARATIVE EVALUATION OF FIRST ORDER, ABSORBANCE RATIO AND BIVARIATE SPECTROPHOTOMETRIC METHODS FOR DETERMINATION OF ATOVAQUONE AND PROGUANIL IN PHARMACEUTICAL FORMULATION MALARONE®

Objective: Three simple, rapid, accurate and precise spectrophotometric methods have been developed for the simultaneous estimation of atovaquone and proguanil hydrochloride in pharmaceutical preparations.Methods: The determination of drugs was carried out using the first order derivative, absorbance-ratio and bivariate spectrophotometric methods. The methods were validated for their linearity, accuracy and precision, recovery and ruggedness according to the ICH guidelines.Results: The linearity was established in the concentration range of 1.0-10 µg/ml for atovaquone and 0.5-8.0 µg/ml for proguanil hydrochloride by all three methods. The limit of detection (LOD) and the limit of quantitation (LOQ) of the methods varied from 0.252 to 0.270 µg/ml and 0.764 to 0.825 µg/ml for atovaquone and 0.119 to 0.156 µg/ml and 0.361 to 472 µg/ml for proguanil hydrochloride respectively. The intra-and inter-batch accuracy (% recovery) and precision (% RSD) ranged from 99.16 to 101.05 % and 0.603 to 1.048 for atovaquone and 99.74 to 101.12 % and 0.593 to 1.001 for proguanil respectively.Conclusion: The proposed methods were applied to a pharmaceutical formulation with acceptable accuracy and precision without any interference from commonly used excipients and additives. The results show that all three methods are comparable, cost effective and rapid and thus can be readily used in quality control labs for routine analysis of these drugs.Â

Simultaneous analysis of aliskiren and hydrochlorothiazide in pharmaceutical preparations and spiked human plasma by HPTLC

AbstractA simple, selective and precise method based on HPTLC has been developed for the simultaneous determination of aliskiren and hydrochlorothiazide in a fixed-dose tablet formulation and human plasma. The chromatography was performed on silica gel 60 GF254 plates, with a mobile phase consisting of methanol–chloroform (6:4, v/v). Densitometric analysis of the analytes was carried out at 225nm. Under optimized conditions, the Rf values were 0.26±0.02 and 0.71±0.02, and the resulting regression plots were linear (r2≥0.9997) in the concentration ranges of 1.00–10.0 and 0.10–1.00μgband−1 for aliskiren and hydrochlorothiazide. The limit of detection and limit of quantitation of the validated method were 0.206 and 0.624μgband−1 for aliskiren and 0.015 and 0.046μgband−1 for hydrochlorothiazide, respectively. The % expected content of aliskiren and hydrochlorothiazide in the commercial tablet formulation was 99.2% and 101.3%, respectively. For spiked plasma sample preparation, the analytes and nebivolol internal standard were extracted from 500μL of plasma sample by solid-phase extraction on LiChrosep® DVB-HL cartridges. The mean extraction recovery of aliskiren and hydrochlorothiazide from human plasma was 87.2% and 76.5%, respectively. In addition, the stability of the analytes in plasma was established under different storage conditions

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Determination of cilostazol and its active metabolite 3,4-dehydro cilostazol from small plasma volume by UPLCâMS/MS

A simple, rapid and sensitive ultra performance liquid chromatography-tandem mass spectrometry (UPLCâMS/MS) method has been developed for the simultaneous determination of cilostazol and its pharmacologically active metabolite 3,4-dehydro cilostazol in human plasma using deuterated analogs as internal standards (ISs). Plasma samples were prepared using solid phase extraction and chromatographic separation was performed on UPLC BEH C18 (50 mmÃ2.1 mm, 1.7 µm) column. The method was established over a concentration range of 0.5â1000 ng/mL for cilostazol and 0.5â500 ng/mL for 3,4-dehydro cilostazol. Intra- and inter-batch precision (% CV) and accuracy for the analytes were found within 0.93â1.88 and 98.8â101.7% for cilostazol and 0.91â2.79 and 98.0â102.7% for the metabolite respectively. The assay recovery was within 95â97% for both the analytes and internal standards. The method was successfully applied to support a bioequivalence study of 100 mg cilostazol in 30 healthy subjects. Keywords: Cilostazol, 3,4-dehydro cilostazol, UPLCâMS/MS, Sensitive, High throughpu

Antiinflammatory therapy with canakinumab for atherosclerotic disease

BACKGROUND: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. METHODS: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P=0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P=0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P=0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P=0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P=0.31). CONCLUSIONS: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. Copyright © 2017 Massachusetts Medical Society