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F Jamali

Publications and source records attributed to F Jamali.

At least 145 records · Page 8Linked to original sources
PubMedDate not supplied

Stereochemical aspects of pharmacotherapy.

Over the past 15 years stereoselectivity has become a well-recognized consideration in clinical pharmacology. Drugs that have an asymmetric center or plane of symmetry within their molecular structure are said to be chiral. They are available as pairs of nonsuperimposable mirror images, called enantiomers, that share essentially the same physicochemical properties. These three-dimensional structural differences, however, can translate into enantiospecific pharmacologic or pharmacokinetic properties, which may be important in understanding the clinical pharmacology of chiral drugs. Most chiral drugs are available as the racemate, in which equal proportions of the two enantiomers are administered concurrently. The pharmacologic and disposition properties of many chiral drugs are documented to be stereospecific, and this has influenced the regulatory requirements for the approval of new drug candidates. Due to this influence on new drug development, the possible issues surrounding racemic drugs will undoubtedly affect the types of pharmaceuticals that are used clinically in the next century. Accordingly, considerable advances have been made in producing optically pure drug. It should be emphasized, however, that stereochemically pure drugs are not necessarily superior to the respective racemates.

Biotransformation↗
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Pharmacokinetics of dipyrone in man; role of the administration route.

Pharmacokinetics of dipyrone, an aminopyrine derivative and potent analgesic, were studied in human following cross-over oral (p.o.) and intravenous (i.v.) administration of single one g doses to 6 subjects. High-performance liquid chromatographic (HPLC) methods were used to follow the drug and its active metabolite, 4-monomethylaminoantipyrine (MAA) in plasma and urine of subjects. Following p.o. doses, no unchanged dipyrone was detectable in plasma and urine. MAA appeared in plasma no later than 0.5 h after oral doses and reached its maximum concentration (7.52-22.69 micrograms/ml) in 1-2 h. Pharmacokinetic characteristics of MAA indicated a two and a one-compartment open model after i.v. and p.o. administration, respectively. Elimination half-life of MAA was found to be independent of the route of administration and ranged from 1.60 to 3.67 h. Although no significant difference was noticed between the area under plasma MAA concentration-time curves, 2.2-7.5 folds higher MAA was found unchanged in urine following i.v. administration (34.41-158.38 mg) as compared to the oral route (9.56-43.92 mg). It is suggested that after oral administration, dipyrone is rapidly and to a great extent converted to MAA during the first pass through the gut and/or liver before reaching the systemic circulations. Following i.v. administration, on the other hand, a relatively slower process of dipyrone conversion may allow a significant renal excretion of dipyrone which, in turn, is converted to MAA in the kidney and/or urine thereby giving rise to a significantly higher MAA in urine.

Administration, Oral↗
PubMedDate not supplied

Involvement of the rat gut epithelial and muscular layer, and microflora in chiral inversion and acyl-glucuronidation of R-fenoprofen.

In the presence of excised human and rat gut, the pharmacologically inactive R enantiomers of both ibuprofen and fenoprofen (FN) are bioinverted to their anti-inflammatory antipodes. In an attempt to further localize the site of inversion, we incubated R-FN, in oxygenated (O2:CO2, 95:5, v/v) Krebs-Henseleit solution (37 degrees C, pH 7.4) for 3 h in the presence of the intestinal contents, epithelium and muscular layer of upper jejunum and everted jejunum sack of antibiotic treated (500 mg/kg neomycin and erythromycin b.i.d. for 3 days) and control adult female Sprague-Dawley rats. The formation of S-FN and acylglucuronidated FN was examined in the incubation medium using a stereospecific HPLC assay. The metabolic activities are reported per g of wet tissue. The extent of inversion by the everted rat gut was substantial (30.7 +/- 5.1%) but no significant differences between the control and germ-eradicated rats was observed. The epithelial cells were found to be the major site of inversion in the intestinal wall (37.5 +/- 4.7%) with the muscular layer (7.8 +/- 2.1%) and intestinal contents (5.7 +/- 2.2%) contributing only to a small extent to the process. Both enantiomers were substantially acyl-glucuconjugated in the epithelial and muscular layers, and the intestinal content.

Animals↗
PubMedDate not supplied

Pharmacokinetics of etodolac enantiomers in the rat after administration of phenobarbital or cimetidine.

The influences of phenobarbital and cimetidine on the pharmacokinetics of etodolac enantiomers were studied in male Sprague-Dawley rats. Phenobarbital caused significant reductions in the AUC of both the active S-enantiomer (24%) and the inactive R-enantiomer of etodolac (26%), and an increase in the urinary excretion of glucuronidated S-etodolac. In bile duct-cannulated rats the initial biliary recoveries of the acyl-glucuronidated etodolac enantiomers were not affected by phenobarbital. In vitro, phenobarbital caused no changes in the hepatic microsomal net glucuronidation of etodolac enantiomers after phenobarbital, although it did result in significant increases in the apparent oxidative metabolism of both enantiomers. Therefore, phenobarbital seems to cause an enhanced CL of etodolac by induction of hepatic non-conjugative metabolism. Cimetidine had no discernible effect on the pharmacokinetics of etodolac enantiomers.

Animals↗
PubMedDate not supplied

Effect of nizatidine and ranitidine on 24 hour intragastric pH, pepsin, prostaglandin E2 and serum gastrin concentrations in healthy volunteers.

In order to achieve possible greater therapeutic efficacy, ranitidine 300 mg bid (R2) may be given rather than 300 mg qhs (R1), or nizatidine 300 mg bid (N2) may be given rather than 300 mg qhs (N1). A randomized placebo-controlled crossover study was performed in six healthy volunteers (four males, two females) who ranged in age from 23 to 43 years, comparing R1, R2, N1 and N2 versus placebo (P), measuring 24 h intragastric pH by the aspiration technique, gastric juice pepsin and prostaglandin E2 (PGE2) concentrations, as well as serum gastrin concentrations. In all treatment groups, 24-h intragastric pH was higher than with P; the 24 h and daytime (0800-2200 h) pH was higher with N2 than with N1, but not with R2 versus R1. The percentage pH > or = 3 was greater with N2 than with N1 during the daytime. Night-time (2200-0800 h) and 24 h pepsin concentrations were higher in R2 than in R1, were similar in N1 and N2, and were lower in these treatment groups than in P. The gastric juice PGE2 concentration at night-time, but not at daytime, was increased in the four treatment groups compared with P. Despite the higher pH values at night-time in the treatment groups, the night-time concentrations of serum gastrin were unchanged, and yet during the daytime the higher values of pH were associated with increased gastrin concentrations when R2 or N2 were given, but not with R1 and N1. There was a negative correlation between intragastric juice pH and pepsin concentration during the daytime, and a positive correlation between pH and PGE2 concentration during the night-time. The slopes and y-axis intercepts between pH and pepsin or PGE2 concentrations differed between the placebo and the treatment groups, suggesting that these H2-receptor antagonists may have an effect on lowering pepsin and raising PGE2 concentrations in addition to their effects on pH. As the percentage of time over the 24 h period and night-time periods when the pH was greater than 3 was not different between ranitidine and nizatidine, the two regimens will likely have similar clinical efficacy.

Adult↗
PubMedDate not supplied

Evaluation of gastrointestinal toxicity of ibuprofen using surrogate markers in rats: effect of formulation and route of administration.

OBJECTIVE: To elucidate the mechanism of gastrointestinal (GI) toxicity of ibuprofen and to examine the effect of altered site of drug release using gastroduodenal and intestinal permeability tests in the rat model. METHODS: Adult male Sprague-Dawley rats were administered (n = 6 per group) either: (1) 100 mg/kg immediate or sustained release ibuprofen; (2) 100 mg/kg immediate release and ibuprofen lysinate; or (3) 100 mg/kg or 200 mg/kg ibuprofen po or s.c. Upper and lower GI permeability as a surrogate marker of toxicity were determined at pre-determined times using the urinary excretion of orally administered sucrose and 51Cr-EDTA permeability probes, respectively. RESULTS: Ibuprofen administration resulted in a dose-dependent increase in both upper and lower permeability of the GI tract. Both immediate and sustained release preparations of ibuprofen increased upper and lower GI permeability with no shift of toxicity to the site of drug release. Ibuprofen lysinate also induced significant increased upper and lower GI permeability comparable to immediate release ibuprofen. Oral doses were not more toxic than s.c. doses. CONCLUSION: Ibuprofen-induced increased GI permeable appears to be independent of the type of formulation and route of administration. This indicates that, contrary to some other nonsteroidal anti-inflammatory drugs, ibuprofen's effect on GI permeability is mainly systemic and the direct local effect contributes minimally to its overall GI toxicity. Ibuprofen may be a suitable candidate for sustained release formulations since its effect may be prolonged without the danger of a shift of side effect from the upper to the lower GI tract.

Animals↗
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Methoxyflurane anesthesia augments the chronotropic and dromotropic effects of verapamil.

INTRODUCTION: Inhalation anesthetics have been shown to have electrical suppressant effects on excitable membranes such as the cardiac conduction system. Therefore, the anesthetized patient or laboratory animal may respond differently to cardiac drugs when compared with their conscious counterparts. The purpose of this study was to assess the effects of anesthesia with methoxyflurane (MF) on the dromotropic and chronotropic effects of verapamil (VER) in the rat. METHODS: A lead I ECG was measured using subcutaneous electrodes placed both axilli and over the xyphoid process in male Sprague-Dawley rats. Dromotropic effect was measured using the PR-interval which indicated the electrical spread across the atria to the AV-node and chronotropic effects were determined using RR-interval. A total of six animals were randomized to receive 10 mg/kg s.c. of verapamil in the presence or absence of general anesthesia containing methoxyflurane. In addition, PR-interval and RR-intervals were determined in the presence of only methoxyflurane and at rest without any drug exposure. The time for the ECG to normalize after exposure to methoxyflurane and/or verapamil was also determined. RESULTS: Exposure to verapamil alone resulted in a 5% prolongation in PR-interval and 6% prolongation in RR-interval. Methoxyflurane alone had a larger effect than verapamil demonstrating a 14.5% prolongation in PR-interval and a 12.3% in RR-interval which was statistically significant. The combination of MF + VER resulted in a synergistic prolongation in PR-interval to 28. 7% while the effect on RR-interval was additive with an increase to 17.6%. The time for the ECG to normalize after exposure to VER, MF and VER + MF was 37.5 15.1 min, 69.8 5.3 min, and 148.5 +/- 6.6 min respectively. CONCLUSION: General anesthesia with MF enhances the dromotropic and chronotropic effect of VER. This should be considered when MF-anesthesia is used in experimental procedure.

Anesthesia, General↗
PubMedDate not supplied

High performance liquid chromatographic determination of cyclooxygenase II inhibitor rofecoxib in rat and human plasma.

Rofecoxib is a relatively new non-steroidal anti-inflammatory drug with high selectivity in cyclooxygenase 2 inhibitory activity. There is only one assay reported for determination of the drug in biological samples. The assay requires a post-column UV reactor for photocyclization before detection with fluorescence detector. In addition, the internal standard (IS) used in the assay in not commercially available. We developed a new assay for determination of rofecoxib. Rat blank plasma (200 microL) or human blank plasma (500 microL) was spiked with rofecoxib to make final concentrations of 10 to 3000 ng/mL, and 100 microl of a 2 microg/mL of ketoprofen as IS, 100 microl of a pH 4.5 acetate buffer, and 6 mL of ethyl acetate were added. The resultant was vortex-mixed for 90 seconds and centrifuged at 2500 g for 3 min. The organic layer was separated and evaporated to dryness under vacuum. The residues were reconstituted in 170 microL of mobile phase and 150 microL was injected into an HPLC consisting of an autoinjector, an isocratic pump, a 10 cm 4.6 i.d. C(18) analytical column packed with 5 microm reversed phase particles, a variable UV spectrophotometer detector set at 272 nm, and an integrator. The mobile phase consisted of water (77%), acetonitrile (23%), acetic acid (0.1%), and triethylamine (0.03%) and was pumped at 1 mL/min at ambient temperature. The drug and IS were eluted at 13 and 24 min, respectively. The peak drug/IS area ratio versus drug concentrations relationship was linear (r>0.99). The extraction efficiency was >87%. The minimum quantifiable concentration was set at 10 ng/mL (correlation coefficient of <10%). This convenient, sensitive, and simple method is suitable to pharmacokinetic studies of rofecoxib in rats and humans.

Animals↗
PubMedDate not supplied

Pharmacokinetics of celecoxib in the presence and absence of interferon-induced acute inflammation in the rat: application of a novel HPLC assay.

PURPOSE: Celecoxib (CEL) is a relatively new cyclooxygenase-2 specific inhibitor nonsteroidal anti-inflammatory drug with low incidents of the toxic side effects. We developed and validated an HPLC assay for CEL and delineated pharmacokinetics of the drug in the rat in the presence and absence of inflammation. METHODS: Rat plasma (0.1 mL plasma) was spiked with CEL and ibuprofen as internal standard. The solution was acidified and constituents were extracted with isooctane-isopropanol (95:5). The organic solvent was separated, evaporated and the residue was dissolved in the HPLC mobile phase [acetonitrile-water-acetic acid-triethylamine (47:53:0.1:0.03)]. The HPLC system consisted of an auto-injector, an isocratic pump, a 10 cm C(18) analytical column packed with 5-microm of reversed-phase particles, a UV detector set at 254 nm, and an integrator. Control adult male Sprague-Dawley rats were dosed with CEL [5 mg/kg i.v. (n=8), p.o. (n=6) or i.p. (n=3)]. Acute inflammation was brought about by two (12 and 1 h pre-CEL) s.c. injection of 50,000IU/200 microL interferonalpha2a. Inflamed rats (n=6) received 5 mg oral CEL. Serial blood samples were collected via a inserted catheter at the right jugular vein, and plasma samples were analyzed for CEL. RESULTS: The assay yielded linear response within the examined ranges of 20-1000 ng/mL and 1-100 microg/mL (r(2)>0.99) with an extraction efficiency of >70%, intra- and inter-day variability of <10% and accuracy of >90%. In control rats, CEL had an oral bioavailability of 0.59 due mainly to presystemic hepatic metabolism. A multi-compartmental disposition kinetics with an average terminal t(1/2) of 2.8 +/- 0.7 h, and volume of distribution of 2.3 +/- 0.6 L/kg were found. Acute inflammation had no significant effect on the pharmacokinetics of CEL, although a trend towards increased plasma concentration was noticed. CONCLUSIONS: The validated assay has sufficient accuracy and precision for pharmacokinetic studies of CEL in the rat. The lack of change in CEL pharmacokinetics after acute inflammation maybe due to 1) insensitivity of its metabolic system to the acknowledged inhibitory effect of inflammation, and/or 2) the relatively low pre-systemic metabolism of the drug.

Acute Disease↗
PubMedDate not supplied

The pharmacokinetics of etodolac enantiomers in the rat. Lack of pharmacokinetic interaction between enantiomers.

Pharmacokinetics of the enantiomers of the nonsteroidal anti-inflammatory drug etodolac (ET, (+/- )-1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid), which is marketed as a racemate, were studied in male Sprague-Dawley rats. Following administration of iv racemate, plasma concentrations of inactive R-ET were much greater than those of active S-ET. After iv doses of individual enantiomers, similar results were found, with significantly greater t1/2, CL, and Vdss, and lower AUC, for S- than for R-ET. No evidence of a pharmacokinetic interaction between the enantiomers was observed. Secondary peaks indicative of extensive enterohepatic recirculation were seen in plasma time courses of S-ET. In bile duct-cannulated rats, the AUC of S- but not R-ET, was significantly reduced, and secondary peaks were absent in plasma profiles. The differences between enantiomers were attributed to a greater extent of plasma protein binding of R-ET, and to preferential conjugation and biliary excretion of S-ET. Complete recovery of S-ET was achieved in bile, whereas only 30% of the R-enantiomer was recovered via this route of elimination. Urine was a minor route of elimination of ET. It was concluded that the rat may be a suitable pharmacokinetic model for the study of stereoselective pharmacokinetics of ET because, in some aspects, the results closely paralleled those of ET in man.

Animals↗