Biomedical subjects

S Sattari

Publications and source records attributed to S Sattari.

10 recordsLinked to original sources

PubMed2003

Synthesis and in vitro antifungal and cytotoxicity evaluation of substituted 4,5-dihydronaphtho[1,2-d][1,2,3]thia(or selena)diazoles.

Unsubstituted 4,5-dihydronaphtho[1,2-d][1,2,3]thia (or selena)diazoles (2a, 2b), prepared from the semicarbazone (1a), were nitrated using fuming nitric acid at 0 degrees C to yield various mono-nitrated dihydronaphthalenes (3a-3e). Related sulfamoyl derivatives (4a, 4b) were prepared using chlorosulfonic acid, followed by the addition of ammonia solution. Synthesis of 6,9-dimethoxy-4,5-dihydronaphtho[1,2-d][1,2,3]thiadiazole derivative (2c) was performed using 5,8-dimethoxy-alpha-tetralone semicarbazone (1b) and thionylchloride at low temperature. At 10 ppm concentration, all compounds showed low toxicity (higher than 80% survival) on brine shrimps, while at 100 ppm concentration compounds 2d, 3d, and 4b exhibited toxicity (less than 60% survival). Compounds 3a, 3e, and especially 4a showed significant antifungal activity against Cryptococcus neoformans. Compound 4a, while being the most active antifungal agent in this series, possessed low toxicity.

Animals↗

PubMed2001

Drug-disease interactions: reduced beta-adrenergic and potassium channel antagonist activities of sotalol in the presence of acute and chronic inflammatory conditions in the rat.

Inflammation may influence response to pharmacotherapy. We investigated the effect of inflammation on response to sotalol, a beta-adrenergic receptor and potassium channel antagonist. Racemic sotalol (40 mg kg(-1)) was administered to healthy, acutely (interferonalpha 2a-induced) and chronically (Mycobacterium butyricum-induced adjuvant arthritis) inflamed male Sprague-Dawley rats (n=4 - 6/group). Another group of interferon-treated rats received 3 mg kg(-1) of anti-TNF antibody infliximab. Electrocardiogram (ECG) recorded and plasma sotalol concentration monitored for 6 h. The study was repeated in acutely inflamed rats following administration of stereochemically pure individual sotalol enantiomers [40 mg kg(-1) S (potassium channel blocker) or 20 mg kg(-1) R (beta-adrenergic/potassium channel blocker)]. Chronic arthritis was readily evident. Acute arthritis was associated with elevated segmented neutrophils and increased plasma nitrite and tumour necrosis factor (TNF) concentrations. Sotalol affected ECG in all rats. In both inflamed groups, however, response to sotalol in prolongation of QT interval (potassium channel sensitivity) was reduced. The effect of PR interval (beta-adrenergic activity) was also reduced following administration of the racemate and R-enantiomer. No significant differences in pharmacokinetics were observed between control and inflamed rats. Infliximab reduced nitrite and TNF concentrations and reversed the effect of acute inflammation on both PR and QT intervals. The reduced electrocardiographic responses to sotalol is likely due to the influence of inflammation on the action of the drug on both beta-adrenergic and potassium channel receptors secondary to over-expression of pro-inflammatory cytokines and/or nitric oxide. Our observation may have therapeutic consequences in all conditions where inflammatory mediators are increased.

Acute Disease↗

PubMed2000

Synthesis and in vitro antifungal and cytotoxicity evaluation of thiazolo-4H-1,2,4-triazoles and 1,2,3-thiadiazolo-4H-1,2,4-triazoles.

The increasing clinical importance of drug-resistant fungal pathogens has lent additional urgency to microbiological and antifungal research. Various thiazolo(or 1,2,3-thiadiazolo)thiosemicarbazides (2a-2e), 3-thiono-1,4-dihydrotriazolothiazoles-(or 1,2,3-thiadiazoles) (3a-3e), their related substituted thio-4H-1,2,4-triazoles (4a-4p) and sulfones (5a-5o) were synthesized. Most of the compounds tested for antifungal activity exhibited significant effects against Cryptococcus neoofrmans and Sacchromyces cerevisiae at MIC ranges of 0.53 to 12.5 micrograms/mL, whereas their activities were moderate against Candida albicans and weak against Aspergillus fumigatus. At 10 ppm concentration, all compounds showed low toxicity on brine shrimps (higher than 80% survival), except compounds 4c and 2c. At 100 ppm concentration most of the compounds showed toxicity except compounds 2b, 2e, 3c, 3d, 3e, and 4e. Compounds 4b, 4c, and 4h showed in vitro cytotoxicity against Kbalb cell lines and compounds 4c and 4g against 143B cell lines at 0.1 mM concentration.

Animals↗

PubMed1994

Evidence of absorption rate dependency of ibuprofen inversion in the rat.

Ibuprofen (IB) is a chiral 2-arylpropionic acid derivative used as a nonsteroidal antiinflammatory drug (NSAID). It undergoes substantial R to S chiral inversion in humans and rats. In addition to systemic inversion, presystemic chiral inversion has been suggested for IB in humans but only after administration of formulations with slow absorption rates. In search for a suitable animal model, the absorption rate dependency of the extent of inversion was examined in male Sprague-Dawley rats given 20 mg/kg of racemic IB in aqueous solution (Tmax, 0.6 h), suspension (Tmax, 1 h) or as sustained release granules (Tmax, 2.3 h). In addition, (R)-IB (5 mg/liter) was incubated in the presence of everted rat gut segments in an organ bath at 37 degrees. After sustained release granules, the S:R AUC ratios (7.3 +/- 1.5) were significantly higher than suspension (3.6 +/- 1.1) and solution (3.5 +/- 0.2). Accordingly, AUCS and AUCR, as percent of the total AUC (S+R), significantly increased and decreased, respectively, after administration of the sustained released granules as compared with the solution and suspension. A significant positive linear correlation was found between the S:R AUC ratios and the corresponding Tmax for (R)-IB (r = 0.82). In vitro, (R)-IB was inverted by everted jejunum (12.2 +/- 1.6%), ileum (14.2 +/- 2.0%), and colon (4.4 +/- 0.6%) segments. IB was also glucuronidated in the presence of the intestinal segments. Therefore, similar to earlier observations made in humans, in the rat, the S:R AUC ratio was positively and significantly correlated with the absorption rate from the dosage form.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗

PubMed1992

Improved high-performance liquid chromatographic assay method for the enantiomers of ibuprofen.

A rapid, inexpensive and sensitive high-performance liquid chromatographic method for the quantitation of ibuprofen enantiomers from a variety of biological fluids is reported. This method uses a commercially available internal standard and has significantly less interference from endogenous co-extracted solutes than do previously reported methods. The method involves the acid extraction of drug and internal standard [(+/-)-fenoprofen] from the biological fluid with isooctane-isopropanol (95:5) followed by evaporation and derivatization with ethylchloroformate and R-(+)-alpha-phenylethylamine. Excellent linearity was observed between the peak-area ratio and enantiomer concentration (r > 0.99) over a concentration range of 0.25-50 micrograms/ml. This method is suitable for the quantitation of ibuprofen from single-dose pharmacokinetic studies involving either rats or humans.

Animals↗

PubMed1992

Human pharmacokinetics of ibuprofen enantiomers following different doses and formulations: intestinal chiral inversion.

The influences of absorption rate and dosage size on the pharmacokinetics of ibuprofen (IB) enantiomers were studied in six healthy subjects. Rapidly absorbed solutions (50, 100, 200, 400, 600, and 1200 mg) and regular 600-mg tablets of racemic IB were given orally, and plasma concentration-time courses of the enantiomers were followed. Solutions were absorbed faster (tmax less than 0.25 h) than the tablet (tmax = 2.17 +/- 1.17 h). While the S:R AUC ratios were unaffected by increasing the dose, they were significantly greater after the tablet (1.35 +/- 0.14) as compared with the solutions (1.15 +/- 0.16 to 1.24 +/- 0.26). This indicates a greater extent of chiral inversion for the tablet, perhaps due to a longer residence time in the gut, thereby allowing more presystemic inversion. To test this hypothesis, R-IB was incubated at 37 degrees C in the presence of excised segments of human ileum and colon obtained from three patients. Chiral inversion was evident in all segments. After 3 h, the extent of inversion ranged from 20.0 to 33.0%. In addition, incubation resulted in the formation of up to 23.3 and 13.0% of acylglucuronides of S- and R-IB, respectively. In all subjects, the AUC-dose relationships were nonlinear, indicating a gradual increase in the clearance of both enantiomers due, perhaps, to a parallel saturation of plasma protein binding sites. In humans, the chiral inversion of IB is not influenced by the dosage size but is enhanced by prolongation of the residence time in the intestine.

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

Application of direct search optimization for pharmacokinetic parameter estimation.

PURPOSE: For simple pharmacokinetic compartmental models, analytical solution to the governing differential equations along with common graphical methods provide a mean to evaluate the associated rate constants. These graphical methods, however, can not be used for the more complex multi-compartment models. Furthermore, parameter estimation using slope and intercept values from the graphical methods is often accompanied with error. In this study a numerical solution is applied for the solution of the governing differential equations and a simple direct search optimization procedure utilizing random numbers is used for pharmacokinetic parameter estimation. METHOD: The methodology is demonstrated with reference to experimental literature data for ciprofloxacin and ofloxacin whose pharmacokinetic behavior has been reported in terms of a two-compartment model. RESULTS: Examination of the predicted drug concentrations from the graphical method and the optimization methodology indicate that both methods have comparable accuracy in predicting the drug concentrations. The graphical method, however, only shows good accuracy in the early stages both after i.v. and oral drug administration whereas the optimization procedure, due to the nature of the objective function formulation, provides good accuracy over the entire range of times after drug administration. CONCLUSIONS: The methodology is simple, provides optimized parameters which accurately predict drug concentrations, and is flexible to include more weight on the early-time data or be extended to multi-compartment models.

Adult↗

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↗