Substituent activity relationship studies on new azolo benzoxazepinyl oxazolidinones.

In an effort to discover potent antibacterials based on the entropically favored 'bioactive conformation' approach, a series of novel tricyclic molecules mimicking the conformationally constrained structure of Linezolid is reported. Based on the initial tricyclic molecule 1, the benzazepine derivative 2 was designed where the tricyclic structure had more flexibility around C-N bond compared to 1. While, the molecule 2 was less active, the molecule 3 showed promising antibacterial activity presumably after having obtained rigidity due to pyrrole ring. The syntheses, SAR studies, and evaluation of 3 as a lead compound are reported.

Novel 6,7-diphenyl-2,3,8,8a-tetrahydro-1H-indolizin-5-one analogues as cytotoxic agents.

A series of 6,7-diphenyl-2,3,8,8a-tetrahydro-1H-indolizin-5-one analogues were synthesized and evaluated for cytotoxic activity against eight human cancer cell lines. Compounds 18, 21, 28, 29, 30 and 31 showed cytotoxic activity with GI(50) values in the range of 2.1-8.1 microM concentration. Among these, compounds 21 and 28 exhibited good pharmacokinetic properties. These compounds were further evaluated for their in vivo efficacy in modified hollow fibre assay (HFA).

Lack of effect of sucralfate on the absorption and pharmacokinetics of rosiglitazone.

The aim of the present study was to investigate the effect of sucralfate pretreatment on the pharmacokinetics of rosiglitazone following a single oral dose in healthy male volunteers. After an over night fast, and according to a randomized schedule, each volunteer (n = 9) received a single oral dose of rosiglitazone 8 mg (Avandia tablets, 4 mg x 2) with or without pretreatment of sucralfate 2 g (Recolfate tablets, 1 g x 2) in an open-label crossover study with a 2-week washout period. Plasma samples were collected over a period of 24 hours at regular intervals. Safety assessment included monitoring of the vital signs, blood parameters, and ECG. No statistically significant differences (p > 0.05) were observed for any of the calculated rosiglitazone pharmacokinetic parameters in the two treatment groups. The mean parameters, AUC0-infinity and Cmax, following rosiglitazone administration alone were 3825.02 ng x h/ml and 664.47 ng/ml, respectively, and for rosiglitazone administered after pretreatment with sucralfate were 4848.19 ng x h/ml and 624.88 ng/ml, respectively. The t(max) for rosiglitazone alone and for rosiglitazone after sucralfate treatments was 1.11 and 1.67 hours, respectively. The mean elimination half-life for rosiglitazone and rosiglitazone after sucralfate treatment was 4.35 and 4.51 hours, respectively. Fraction of rosiglitazone absorbed was calculated by the Wagner-Nelson method, and no statistically significant difference (p > 0.05) was observed for the two treatments. Since sucralfate pretreatment did not show any significant difference in the pharmacokinetics of rosiglitazone, no dose adjustment is warranted for rosiglitazone when it is administered with sucralfate.

Novel antidiabetic and hypolipidemic agents. 5. Hydroxyl versus benzyloxy containing chroman derivatives.

Several thiazolidinediones having chroman moieties were synthesized and evaluated for their euglycemic and hypolipidemic activities. Some of the analogues having an aminoalkyl group as a linker between the chroman ring and 4-[5-(2,4-dioxo-1, 3-thiazolidinyl)methyl]phenoxy moiety seem to be better than troglitazone. In vitro transactivation assays of PPARgamma have been carried out with these glitazones to understand their molecular mechanism. For the first time we have found that some of the unsaturated thiazolidinediones are superior to their saturated counterpart in the in vivo assay. A more potent thiazolidinedione analogue than troglitazone is reported. Pharmacokinetic studies have shown that protection of the OH group in the chroman moiety leads to a decrease in metabolism, thereby resulting in a superior pharmacological profile.

High-performance liquid chromatographic determination of the insulin sensitizing agent DRF-2189 in rat plasma.

A high-performance liquid chromatographic method for the determination of DRF-2189, using troglitazone as internal standard, is described. A dichloromethane-ethyl acetate solvent mixture (6:4, v/v) was used as the extraction solvent. A Kromasil C18 column with a mobile phase consisting of 0.05 M phosphate buffer-acetonitrile-methanol (22.5:37.5:40) (pH 5.0) was used at a flow-rate of 1.0 ml/min. The eluate was monitored by using fluorescence detection with excitation and emission wavelengths at 292 nm and 325 nm, respectively. Ratio of peak area of analyte to internal standard was used for quantification of plasma samples. Using this method, the absolute recovery of DRF-2189 from rat plasma was >95% and the limit of quantitation was 50 ng/ml. The intra-day relative standard deviation (R.S.D.) ranged from 1.74 to 7.24% at 1 microg/ml and 1.86 to 3.83% at 10 microg/ml. The inter-day R.S.D.s were 8.34 and 4.91% at 1 and 10 microg/ml, respectively. The method was applied to measure plasma concentrations of DRF-2189 in pharmacokinetic studies in Wistar rats.

Probenecid affects the pharmacokinetics of ofloxacin in healthy volunteers.

OBJECTIVE: The aim of this randomised, double-blind, crossover study was to evaluate the effect of single-dose probenecid on the pharmacokinetics of ofloxacin in eight healthy male volunteers. METHODS: After an overnight fast, and according to a randomised sequence, each volunteer received either single oral ofloxacin 200mg (Hoechst Marion Roussel Ltd., Mumbai, India) or both ofloxacin (1 x 200mg) and probenecid (1 x 500mg) [Geno Pharmaceutical Ltd., Mumbai, India]. Blood samples were collected at regular intervals until 24 hours. Serum concentration versus time profiles for ofloxacin were generated and pharmacokinetic parameters were calculated by noncompartmental model analysis. RESULTS: Elimination half-life, mean residence time and area under the curve were significantly increased (4.86 vs 5.26h; 7.23 vs 7.95h; 10.28 vs 11.9 mg/L . h) [p < 0.01], whereas the total clearance was decreased (19.66 vs 16.95 L/h) [p < 0.01] in the presence of probenecid. Other pharmacokinetic parameters were not significantly affected by coadministration of probenecid. CONCLUSION: Concomitant administration of probenecid with ofloxacin may result in a decreased elimination half-life and consequently increased bioavailability of ofloxacin. Probenecid may be co-prescribed with ofloxacin; patients taking this combination should be closely monitored and dosage reduction should be considered if warranted in high-risk patients.