Hasan Mm

A RAPID HIGH‐PERFORMANCE LIQUID CHROMATOGRAPHY ASSAY OF GLIBENCLAMIDE IN SERUM

A rapid high‐performance liquid chromatography (HPLC) determination of glibenclamide in human serum is described. Serum samples to which flufenamic acid had been added as internal standard were treated with aceto‐nitrile as a protein precipitant. After centrifugation, separation and recon‐stitution, the redissolved residue was eluted from 5 μ Spherisorb C‐8 reversed phase column at ambient temperature using a mobile phase consisting of acetonitrile‐water (45: 55 v/v) at pH 3·7‐3·8 and pumped at a flow rate 2 ml/min. The effluent was monitored at 230 nm. The analysis time was no longer than 12min. A linear relationship between the peak height ratio (glibenclamide/flufenamic acid) and concentration was obtained in the range 20–400 ng/ml. A typical calibration curve has a regression equation y= 0·0035x + 0·015 (r = 0·9999). The detection limit of glibenclamide in serum was 20 ng/ml. The mean recovery of drug from serum samples spiked with known amounts of glibenclamide was 96·77%. Within‐day and between‐day coefficients of variation were 1·6‐4·0% and 1·4‐3·5%, respectively. Stability testing indicated that glibenclamide was stable for at least 10 days in serum — 20°C. The method developed was applied to determine some pharmacokinetic parameters after the oral administration of 5 mg glibenclamide tablets to a human volunteer.

IN VITRO AND IN VIVO EVALUATION OF SUSTAINED-RELEASE AND ENTERIC-COATED MICROCAPSULES OF DICLOFENAC SODIUM

AbstractThis work examines the release of diclofenac sodium from ethylcellulose (EC) microcapsules made up of different drug to polymer ratios. The release process was found to follow the Higuchi square root equation and not the zero-order or first order equations. However, for drug to polymer ratio of 1:1, a critical time (θ) was reached beyond which the release rate was lower than that predicted on the basis of the Higuchi square root equation. Dissolution experiments in 0.1N HCL revealed that less than 1.5% of the encapsulated drug was released in 6 h. This finding indicates the suitability of the EC microcapsules for enteric-coated preparations. The in vitro release of diclofenac sodium from microcapsules of different drug to polymer ratios was compared with that from a commercial sustained-release product. A distinct similarity between the release profile of the commercial product with that obtained for the 1:2 drug to polymer microcapsules was noted. The in vivo work included determination of the se...

The comparative effects of propofol, thiopental, and diazepam, administered intravenously, on pentylenetetrazol seizure threshold in the rabbit

The anticonvulsant effects of propofol, thiopental, and diazepam, administered intravenously, on pentylenetetrazol (PTZ) seizure threshold were studied and compared in the rabbit. The PTZ seizure threshold determined in various rabbit groups during the control phase of conducted experiments, was found to be in the range of 10.1 +/- 2.0 to 13.5 +/- 3.7 mg/kg. Intravenous administration of comparable doses of propofol, thiopental, and diazepam resulted in marked and significant increases in PTZ seizure threshold. At all administered doses (1.25-10.0 mg/kg), propofol was found to be more effective than thiopental in increasing the PTZ threshold dose. However, the anticonvulsant effects of diazepam were more marked than those of propofol, except at a dose of 10 mg/kg where both agents exhibited equipotent activities. These data demonstrate that propofol enjoys a considerable degree of anticonvulsant activity in the rabbit. This anticonvulsant action is greater than that of thiopental at doses ranging from 2.5 to 10 mg/kg and equipotent with diazepam at the 10 mg/kg dose.

A comparison of the anticonvulsant effects of propofol and thiopentone against pentylenetetrazol-induced convulsions in the rat

1. The anticonvulsant effects of subanaesthetic doses of propofol and thiopentone against PTZ‐induced seizures and mortality were examined in the rat.

The effect of oral activated charcoal on the systemic clearance of gentamicin in rabbits with acute renal failure.

Abstract— The effect of oral administration of activated charcoal on total body clearance of gentamicin administered intravenously (2 mg kg−1) has been studied in normal rabbits and rabbits with induced renal failure. Gastric intubation of a single dose (10 g) of activated charcoal to normal rabbits produced a significant reduction in gentamicin serum concentrations compared to control. Significant differences between treated and control groups, compatible with enhancement of gentamicin elimination, were observed in the calculated pharmacokinetic parameters (Kel, t 1/2, CL and AUC). To examine whether renal failure could augment the effect of activated charcoal in enhancing the systemic clearance of gentamicin, uranyl nitrate was used (0.75 mg kg−1, i.v.) to induce acute renal failure in rabbits. The derived pharmacokinetic parameters of gentamicin during the control phase in these animals were consistent with severe renal failure. The administration of activated charcoal, 2.5 h following gentamicin injection, produced a steeper decline in gentamicin concentration‐time profiles and significant changes in Kel, t 1/2 and CL. The Kel and CL values increased to about 200%, while the t 1/2 value decreased to about 50%. The apparent changes in the pharmacokinetic parameters induced by charcoal administration were more marked in rabbits with renal failure than in normal rabbits; however, induction of renal failure did not augment the charcoal‐induced clearance of gentamicin quantitatively.

Enhancement of Morphine Clearance Following Intravenous Administration by Oral Activated Charcoal in Rabbits

Abstract— A single dose of activated charcoal (10 g) significantly reduced the half‐life of elimination (1.02 ± 0.10 and 0.70 ± 0.04 h for the control and treated groups, respectively) and mean residence time (1.01 ± 0.12 and 0.76 ± 0.05 h for the control and treated groups, respectively) of morphine in rabbits. A 40% increase in the systemic clearance (85.73 ± 7.72 and 122.64 ± 16.32 mL min−1 kg−1 for the control and treated groups, respectively) and a 30% decrease in AUC (204.38 ± 22.20 and 140.03 ± 19.32 μg h L−1 in the control and treated groups, respectively) were also noted. Charcoal administration did not significantly alter the volume of distribution (Varea and VSS) or the apparent distribution half‐life. A two‐compartment model adequately described morphine kinetics in control and treated rabbits; charcoal administration produced a significant increase in the tissue compartment rate constant (K21). This finding indicates that activated charcoal not only enhances the systemic elimination of morphine, but also accelerates the rate of transfer of morphine from the tissue compartment to the central compartment.

The bioavailability of glyburide (glibenclamide) under fasting and feeding conditions: a comparative study

SummaryThis investigation was conducted to study the effect of food on the oral absorption and disposition of glyburide (glibenclamide). The study was carried out under US Food and Drug Administration guidelines on 18 healthy male volunteers, under fasting and feeding conditions using a single oral dose (5 mg tablet) of glyburide. Following drug administration, blood samples were collected over 24 h, and serum harvested from the blood was analysed using a sensitive and specific high-performance liquid chromatographic assay. The results of this investigation indicated that there was a statistically significant difference in the concentration—time profiles of the drug and the obtained pharmacokinetic parameters under fasting and feeding conditions. In fasting conditions, area under the serum concentration—time curve for 24 h and peak serum concentration were significantly higher than feeding conditions. Lag time between administration and appearance of the drug in serum was significantly reduced in fasting conditions compared with feeding situations. There was no significant difference in the time needed to reach peak concentration. These findings clearly indicate that the extent and rate of glyburide absorption is delayed when administered under feeding conditions. The study demonstrates the importance of administration of the drug on empty stomach to achieve a better pharmacokinetic profile.

COMPARATIVE BIOAVAILABILITY OF TWO CEFADROXIL PRODUCTS USING SERUM AND URINE DATA IN HEALTHY HUMAN VOLUNTEERS

1. The aim of the present study was to assess the bioequivalence of two cefadroxil products, namely Ultracef (a reference product) in the form of a 500 mg capsule (produced by Bristol‐Myers Squibb Laboratories, Princeton, NJ, USA) and Roxil (a test product) in the form of a 500 mg capsule (produced by Tabuk Pharmaceutical Manufacturing, Tabuk, Saudi Arabia).

A pharmacokinetic study on two sustained-release formulations of indomethacin in normal subjects following a single dose administration.

A single dose pharmacokinetic study was conducted on two sustained‐release formulations (75 mg) of indomethacin (Indocid capsules ‘A’ and Indogesic tablets ‘B’). The study was carried out on 22 healthy male volunteers, who received a single oral dose (75 mg) of each product according to a randomized crossover design. Blood samples were obtained over a 24 h period, and drug concentrations were determined by an HPLC assay. The two products were not found to be statistically different with respect to the lag time between dosing and first appearance of the drug in the serum (1.0 ± 0.1 and 0.9 ± 0.1 h for A and B, respectively), or in the time needed to attain the peak concentrations (3.3 ± 0.3 and 3.3 ± 0.5 h for A and B, respectively). The two products, however, varied significantly in the peak serum concentrations (2721 ± 220 and 1797 ± 129 ng/ml for A and B, respectively). In terms of the extent of absorption, assessed by estimating the area under the concentration‐time curve over 24 h, the two products were not found to be significantly different (11,575 ± 630 and 10,212 ± 556 ng. h/ml for A and B, respectively). Based on these findings, the two formulations can be considered bioequivalent in the extent but not in the rate of drug absorption.

Synthesis, identification and preliminary evaluation of esters and amide derivatives of diflunisal

Abstract This work examines the suitability of the methyl, ethyl esters and amide derivatives of diflunisal for use as prodrugs to diflunisal. Synthesis, identification and characterization of these forms is described. In vitro hydrolysis studies of these compounds in acidic and alkaline conditions were performed. The compounds were very stable in 0.1 HCl but hydrolyzed to diflunisal at pH 10 following a pseudo-first-order kinetics. The rate of hydrolysis was in the order: methyl ester > amide > ethyl ester, and the rate constants (Kobs) and the half-life of each prodrug was determined. Preliminary in vivo work in rabbits on the methyl ester derivative showed that diflunisal was detected in the blood after 3 h of administration and suggesting that the methyl ester was converted in vivo to the parent drug diflunisal. The very poor water solubility of these derivatives and the very low rate of hydrolysis in 0.1 N HCl may overcome both the bitter taste of the drug and its gastric irritant action, respectively.