1 In¯ammation may in¯uence response to pharmacotherapy. 2 We investigated the eect of in¯ammation on response to sotalol, a b-adrenergic receptor and potassium channel antagonist. Racemic sotalol (40 mg kg 71) was administered to healthy, acutely (interferona 2a-induced) and chronically (Mycobacterium butyricum-induced adjuvant arthritis) in¯amed male Sprague-Dawley rats (n=4 ± 6/group). Another group of interferon-treated rats received 3 mg kg 71 of anti-TNF antibody in¯iximab. Electrocardiogram (ECG) recorded and plasma sotalol concentration monitored for 6 h. The study was repeated in acutely in¯amed rats following administration of stereochemically pure individual sotalol enantiomers [40 mg kg 71 S (potassium channel blocker) or 20 mg kg 71 R (b-adrenergic/potassium channel blocker)]. 3 Chronic arthritis was readily evident. Acute arthritis was associated with elevated segmented neutrophils and increased plasma nitrite and tumour necrosis factor (TNF) concentrations. Sotalol aected ECG in all rats. In both in¯amed groups, however, response to sotalol in prolongation of QT interval (potassium channel sensitivity) was reduced. The eect of PR interval (b-adrenergic activity) was also reduced following administration of the racemate and R-enantiomer. No signi®cant dierences in pharmacokinetics were observed between control and in¯amed rats. 4 In¯iximab reduced nitrite and TNF concentrations and reversed the eect of acute in¯ammation on both PR and QT intervals. 5 The reduced electrocardiographic responses to sotalol is likely due to the in¯uence of in¯ammation on the action of the drug on both b-adrenergic and potassium channel receptors secondary to over-expression of pro-in¯ammatory cytokines and/or nitric oxide. 6 Our observation may have therapeutic consequences in all conditions where in¯ammatory mediators are increased.

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1 Rheumatoid arthritis reduces verapamil oral clearance thereby increases plasma concentration of the drug. This coincides with reduced drug effects through an unknown mechanism. 2 The effect of interferon-induced acute inflammation on the pharmacokinetics and electrocardiogram of verapamil (20 mg kg À1 , p.o.) and nifedipine (0.1 mg kg À1 , i.v.) was studied in SpragueDawley rats. 3 The effect of both acute and chronic inflammation on radioligand binding to cardiac L-type calcium channels was also investigated. 4 Acute inflammation resulted in increased plasma concentration of verapamil but had no effect on that of nifedipine. Verapamil binding to plasma proteins was unaffected. 5 As has been reported for humans, the increased verapamil concentration coincided with a reduction in the degree to which PR interval is prolonged by the drug. The effect of nifedipine on PR interval was also reduced by inflammation. 6 Maximum binding of 3 H-nitrendipine to cardiac cell membrane was significantly reduced from 63.272.5 fmol mg À1 protein in controls to 46.472.0 in acute inflammation and from 66.872.2 fmol mg À1 protein in controls to 42.272.0 in chronic inflammation. 7 Incubation of the normal cardiac cell membranes with 100 and 1000 pg ml À1 of rat tissue necrosis factor-a did not influence the binding indices to the calcium channels. 8 Our data suggest that the reduced calcium channel responsiveness is because of altered binding to channels.

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PEO-b-PHSA micelles with a high level of stearic acid side chain substitution can effectively solubilize AmB, reduce its hemolytic activity yet retain its potent antifungal effects.

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 12.5μg/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.

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)