[Show abstract][Hide abstract] ABSTRACT: Pioglitazone (PIO), an antidiabetic drug and olmesartan medoxomil (OLM), an antihypertensive drug were administered orally alone and in combination to Wistar albino rats for evaluation of pharmacokinetics, pharmacodynamics and repeated dose 28-day oral toxicity of individual drugs and their combination. Pharmacokinetic study was performed by orally administering PIO and OLM at single dose of 3 and 2mg/kg, respectively alone and in combination analyzing the plasma samples using LC-MS/MS. Antidiabetic activity evaluation was done in type-2 diabetes mellitus induced animals at same dose level as in pharmacokinetic study daily for 30 days. PIO and/or OLM were administered orally to animals at daily doses of 50, 100 and 150 mg/kg for 28 days for toxicity study. There was no significant alteration in the pharmacokinetic parameters of either drug indicating absence of any pharmacokinetic interaction when co-administered. Positive pharmacodynamic interaction between PIO and OLM was established in this study. Two drugs in combination showed no evidence of potentiation of 28-day repeated dose toxicity in animals. Again, drugs, alone and in combination, caused only minor changes in clinical-laboratory tests and histopathological change was not found in the experiment performed. In conclusion, PIO and OLM combination can primarily be stated as safe in terms of present toxicity and pharmacokinetics findings.
Regulatory Toxicology and Pharmacology 12/2011; 62(1):7-15. · 2.13 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A simple, high-throughput and specific high-performance liquid chromatography tandem mass spectrometry method has been developed and validated according to the FDA guidelines for simultaneous quantification of olmesartan and pioglitazone in rat plasma. The bioanalytical method consists of liquid-liquid extraction and quantitation by triple quadrupole mass spectrometry using electrospray ionization technique, operating in multiple reaction monitoring and positive ion modes. The compounds were eluted isocratically on a C(18) column with a mobile phase consisting of a mixture of methanol and water (containing 0.5% formic acid) in a ratio of 9:1. The response to olmesartan and pioglitazone was linear over the range 0.01-10 µg/mL. The validation results demonstrated that the method had satisfactory precision and accuracy across the calibration range. Intra- and inter-day precisions ranged from 0.66 to 3.32 and from 0.94 to 2.93% (%CV), respectively. The accuracy determined at three quality control levels was within 91.27-107.28%. There was no evidence of instability of the analytes in rat plasma following the stability studies. The method proved highly reproducible and sensitive and was successfully applied in a pharmacokinetic study after single dose oral administration of olmesartan and pioglitazone to the rat.
[Show abstract][Hide abstract] ABSTRACT: The purpose of this study was to investigate the potential toxicity of gemifloxacin by 28-day repeated oral dose in Wistar albino rats. The test article, was administered daily by gavage to male and female rats at dose levels of 0, 50, 100, 200 mg/kg/day. At the end of treatment period, 12 rats/sex/group was sacrificed, while six extra rats/sex in the vehicle control and highest dose groups sacrificed after 14 days recovery period. During the treatment and recovery periods, clinical signs, mortality, body weights, food and water consumption, ophthalmoscopy, urinalysis, phototoxicity, hematology, serum biochemistry, synovial fluid biochemistry, electrocardiogram (ECG), gross findings, organ weights, microscopic examination of synovial fluid, and histopathology were examined. Hematological and serum biochemical investigations revealed a dose-dependent increase in the total white blood cell (WBC), total bilirubin (T-BIL), glucose (GLU), alanine aminotransferase (ALT) and significant decreases in total protein (TP) were observed in both sexes at the same dose, at the end of treatment period, but the levels returned toward normal during the recovery period. Histopathology of talar joint showed that erosion of the articular surface of that joint in both sexes at the end of treatment period at the dose level of 200 mg/kg/day. Degenerative changes in tendinocytes were observed in Achilles tendon of both sexes at the high dose level at the end of treatment period. In histopathological study shows partial effacement of liver architecture and focal ulceration in gastric mucosa at the high dose level at the end of treatment period. Based on these results, it was concluded that 28 days repeated oral dose of gemifloxacin caused increases in the liver weight, WBC count, T-BIL, glucose level, ALT, decreasing the TP, cause chronic hepatitis and acute gastritis, erosion of the articular surface of joint and histopathologic changes in Achilles tendon in rats at the dose level of 200 mg/kg/day.
Regulatory Toxicology and Pharmacology 11/2010; 58(2):196-207. · 2.13 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The pharmacokinetics of rabeprazole (CAS 117976-89-3) and diclofenac sodium (CAS 15307-79-6) has been extensively evaluated in adult human volunteers individually after oral administration of tablet formulation. However, no published data is available regarding the combined pharmacokinetics and bioavailability of this particular fixed dose combination. In light of the above, a clinical study was designed to evaluate the bioequivalence of two fixed dose combination (FDC) products (reference and test) of two manufacturers containing rabeprazole 20 mg and diclofenac sodium 100 mg slow release (SR) tablet in healthy Indian male volunteers. Each subject received a test FDC and a reference FDC in a randomized, single dose, fasting state, two period, and crossover study design with a one-week washout period between the doses. Extraction of the drugs from the plasma was carried out by the precipitation method. Analysis of rabeprazole and diclofenac sodium from plasma samples was done by a simple and sensitive HPLC method using a UV detector. An analysis of variance was performed on the pharmacokinetic parameters of Cmax, tmax, AUC(0-t), and AUC(0-infinity), using general linear model (GLM) procedures in which sources of variation were subject, formulation and period. The results of this study indicated that there were no statistically significant differences between the logarithmically transformed AUC(0-infinity) and Cmax values of the two preparations. The 90% confidence interval for the ratio of logarithmically transformed AUC(0-t), AUC(0-infinity) and Cmax were within the bioequivalence limit of 0.80-1.25 and the relative bioavailability of rabeprazole and diclofenac sodium were found to be 98.6% and 98.9% respectively in the test product. Thus, these findings clearly indicated that the two products are bioequivalent in terms of rate and extent of drug absorption.
[Show abstract][Hide abstract] ABSTRACT: A simple, inexpensive and rapid stability indicating liquid chromato-graphic method has been developed for the quantitative determination of oxcarbazepine (OXC) in pharmaceutical formulation in presence of the degradation products. The separation was achieved by using an isocratic mobile phase consisting of the mixture of acetronitrile and water (50:50, v/v), using Hiber C18 (250 mm × 4.6 mm, 5 µm) column at a flow rate of 1.0 mL/min. The detection was carried out at the wave-length of 256 nm. The retention time of oxcarbazepine was about 4.0 min and it shows an excellent linearity over a range of 0.05 to 80 µg/mL (r 2 = 0.999). The drug was exposed to thermal, photolytic, hydrolytic and oxidative stress conditions and the stressed samples were analyzed by the proposed method. The degredation products were well resolved from the main peak. The percentage of the recovery of drug has been ranged from 99.83 to 102.98 % in pharmaceutical dosage form. The developed method was validated with respect to linearity, accuracy, precision, specificity and robustness. Due to its simplicity and accuracy, the method can be used for routine analysis of oxcarbazepine in bulk drug and pharmaceutical formulations.
Asian Journal of Chemistry 01/2010; 22:2051-2057. · 0.25 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A pharmacokinetic-pharmacodynamic (PK-PD) modeling approach was used to investigate the epileptogenic activity of gemifloxacin as a representative antibiotic with concentration-dependent antimicrobial activity. Rats received an intravenous infusion of gemifloxacin at a rate of 4 mg kg of body weight(-1) min(-1) over 50 min. Blood samples were collected for drug assay, and an electroencephalogram (EEG) was recorded during infusion and postinfusion. An important delay was observed between concentrations of gemifloxacin in plasma and the EEG effect; this effect was accompanied by tremors and partial seizures. Indirect effect models failed to describe these data, which were successfully fitted by using an effect compartment model with a spline function to describe the relationship between effect and concentration at the effect site. The robustness of the PK-PD model was then assessed by keeping the dose constant but increasing the duration of infusion to 100 and 200 min. Although this was accompanied by PK modifications, PD parameters did not vary significantly, and the PK-PD model still applied. In conclusion, the successful PK-PD modeling of the gemifloxacin EEG effect in rats should be considered to predict and reduce the epileptogenic risk associated with this antibiotic as a representative fluoroquinolone.
Journal of Pharmaceutical Sciences 09/2009; 99(3):1535-47. · 3.13 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The following article from the Journal of Pharmaceutical Sciences, “Convulsant Activity and Pharmacokinetic–Pharmacodynamic Modeling of the Electroencephalogram Effect of Gemifloxacin in Rats,” by Bikash Roy, Anirbandeep Bose, Uttam Bhaumik, Ayan Das, Nilendra Chatterjee, Animesh Ghosh, Soumendra Darbar, Amlan Kanti Sarkar, Pinaki Sengupta, and T. K. Pal, published online on 7 August 2009 in Wiley InterScience and subsequently on Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the authors; the journal's Editor in Chief, Ronald T. Borchardt; Wiley Periodicals, Inc.; and the American Pharmacists Association. The retraction has been agreed due to the inappropriate use of previously published work.
[Show abstract][Hide abstract] ABSTRACT: A simple and feasible high-performance liquid chromatographic method with UV detection was developed and validated for the quantification of rimonabant in human plasma. The chromatographic separation was carried out in a Hypersil BDS, C(18) column (250 mm x 4.6mm; 5 microm). The mobile phase was a mixture of 10 mM phosphate buffer and acetonitrile (30:70, v/v) at a flow rate of 1.0 ml/min. The UV detection was set at 220 nm. The extraction recovery of rimonabant in plasma at three quality control (QC) samples was ranged from 84.17% to 92.64%. The calibration curve was linear for the concentration range of 20-400 ng/ml with the correlation coefficient (r(2)) above 0.9921. The method was specific and sensitive with the limit of quantification of 20 ng/ml. The accuracy and precision values obtained from six different sets of QC samples analyzed in separate occasions ranged from 88.13% to 106.48% and 0.13% to 3.61%, respectively. In stability tests, rimonabant in human plasma was stable during storage and assay procedure. The method is very simple, sensitive and economical and the assay was applied to human plasma samples in a clinical (pharmacokinetic) study of rimonabant.
Journal of pharmaceutical and biomedical analysis 03/2009; 49(4):1009-13. · 2.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A simple liquid chromatographic method for the determination of gemifloxacin (CAS number 175463-14-6) in human plasma has
been developed. An aliquot quantity of 1mL plasma sample was taken and 0.1mL internal standard was added and mixed. 1mL
methanol was added to it. The mixture was then sonicated for 10min followed by 20min centrifugation at 5000rpm (g=3600). The supernatant layer was separated and filtered through simple filtration unit (membrane filter, 0.45μm) and injected
into the LC system consisting of Hypersil BDS, C18 (250×4.6mm, 5μm particle size) column, using 1% formic acid : methanol=65:35
(v/v) as mobile phase with ultra violet detection at 328nm. Lower limit of detection was 20ngmL−1 and lower limit of quantitation was 50ngmL−1. Maximum between-run precision was 14.614%. Mean extraction recovery was found to be 87.32 to 89.32%. Stability study showed
that after three freeze-thaw cycles the loss of three quality control samples were less than 10%. Samples were stable at room
temperature for 12h and at −20°C for 3months. Before injecting into LC system, the processed samples were stable for at
least 8h. The method was used to perform bioequivalence study in human volunteers.
[Show abstract][Hide abstract] ABSTRACT: A simple, sensitive and specific liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for quantification of ranolazine in human plasma. The analytical method consists in the precipitation of plasma sample with methanol, followed by the determination of ranolazine by an LC-MS/MS. The analyte was separated on a Peerless Cyano column (33 mm x 4.6 mm, 3 microm) an isocratic mobile phase of methanol-water containing formic acid (1.0%, v/v) (65:35, v/v) at a flow rate of 1.0 ml/min. Protonated ions formed by a turbo ionspray in positive mode were used to detect analyte and internal standard (IS). The MS/MS detection was made by monitoring the fragmentation of m/z 428.20-->279.50 for ranolazine and m/z 448.30-->285.20 for internal standard on a triple quadrupole mass spectrometer. The method was validated over the concentration range of 5-2000 ng/ml for ranolazine in human plasma with correlation coefficient of 0.9937 (S.D.: +/-0.00367, range: 0.9895-0.9963). The accuracy and precision values obtained from six different sets of quality control samples analyzed in separate occasions ranged from 94.53 to 117.86 and 0.14% to 4.56%, respectively. Mean extraction recovery was 82.36-94.25% for three quality control (QC) samples and 88.37% for IS. Plasma samples were stable for three freeze-thaw cycles, or 24h ambient storage, or 1 and 3 months storage at -20 degrees C. Processed samples (ready for injection) were stable up to 72 h at autosampler (4 degrees C). The developed method was successfully applied for analyzing ranolazine in plasma samples for a bioequivalence study with 12 healthy volunteers.
Journal of Pharmaceutical and Biomedical Analysis 10/2008; 48(5):1404-10. · 2.95 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A simple, precise and reproducible liquid chromatography–tandem mass spectrometry method has been developed and validated
according to the Food and Drug Administration guidelines for the simultaneous quantitation of antidiabetic drugs metformin,
glimiperide and pioglitazone in human plasma using glipizide as an internal standard. Quantitation was performed on a triple
quadrupole mass spectrometer employing electrospray ionization technique, operating in multiple reaction monitoring and positive
ion mode. Inter-batch and intra-batch coefficient of variation across four validation runs for the quality control samples
was less than 7%. The accuracy determined at quality control levels was within 92.81–105.13%. The method was applied to a