Effects of atorvastatin on talinolol absorption: A potential drug-drug interaction.

In this study, we aimed to determine the drug-drug interaction potential between atorvastatin (ATOR), and talinolol (TAL). Concentration-dependent effects of ATOR on the intestinal permeability of TAL were investigated by an in situ intestinal perfusion method. Dose-dependent effects of ATOR on TAL exposure were evaluated by measuring plasma concentrations after oral administration in rats. ATOR slightly changed the intestinal secretion of TAL in jejunum but not in colon. Plasma AUC levels of TAL were elevated by co-administration of ATOR at low and high doses whereas medium doses of ATOR resulted in a decrease in TAL bioavailability. However, these changes were not statistically significant. In our study, the pharmacokinetics of TAL were not affected by the concurrent use of ATOR in rats. In conclusion, it should be considered that complex interplay between the efflux and uptake transporters in the tissues and inhibition of these transporters by modulating agents may overshadow individual effects of each other.

Triazolam concentration-effect relationships in healthy subjects.

Triazolam was used to study the plasma concentration-effect relationship of a benzodiazepine because it has a very short plasma t1/2. A standard hypnotic dose of 0.25 mg was given by mouth to six healthy subjects, and blood samples were drawn when the subjects had to perform a battery of psychologic tests. Only the digit-symbol substitution test, the card-sorting test according to numbers, and the visual analog scale (energetic-lethargic) gave significant results. Analysis of the concentration-effect relationship in individuals indicated a wide scatter of the data. Mean values revealed a trend for a learning effect in the card-sorting test. The results are consistent with the hypothesis that triazolam is well suited for a study of concentration-effect relationships, but better psychologic tests would be desirable.

P-glycoprotein transporters and the gastrointestinal tract: evaluation of the potential in vivo relevance of in vitro data employing talinolol as model compound.

Among the different application routes peroral administration remains the one most widely used. Hence, mechanisms affecting p.o. bioavailability are of particular interest, also in drug development. In recent years, intestinal drug secretion mediated by the multi-drug resistance gene product P-glycoprotein (Pgp) has been discovered as a possible mechanism of low and erratic bioavailability. Due to the saturability of this process, a dose-dependent apparent oral clearance may be observed which decreases upon increasing dose. However, in vivo intestinal secretion might be revealed only in the lower or subtherapeutic dose range. In permeability studies with Caco-2 cell monolayers, the MDR-reversing agent verapamil inhibits secretion of P-glycoprotein substrates and, hence, increases apical-to-basolateral permeability. The aim of the rat studies with talinolol presented here was to test the relevance of the intestinal secretion process as well as the extent of inhibition by verapamil in ex vivo, in situ, and in vivo talinolol/verapamil drug-drug interaction studies. Intestinal secretion of talinolol was detected indirectly in ex vivo studies via transport inhibition with verapamil and directly in in situ intestinal perfusions in rats following a talinolol i.v. bolus. Both i.v. and p.o. verapamil appear to affect the concentration-time profiles of talinolol. Relevant observations with respect to drug absorption are the decreased apparent oral clearance upon verapamil coadministration as well as the decreased tmax and mean absorption times at high verapamil doses. Talinolol may be regarded as a potential model compound for mechanistic studies on Pgp interactions, including permeability as well as binding studies and the involvement of transporters other than Pgp.

Efficacy of 7-day treatment with metronidazole+miconazole (Neo-Penotran) - a triple-active pessary for the treatment of single and mixed vaginal infections.

OBJECTIVE: To evaluate the efficacy of Neo-Penotran pessaries (metronidazole 500 mg + miconazole nitrate 100 mg) in candidal, bacterial and trichomonal vaginitis and in mixed vaginal infections. METHOD: Ninety-seven patients with clinical diagnosis of vaginitis entered this open, non-comparative study. Each patient inserted one pessary twice daily for 7 days. Gynecological and microbiological assessments were carried out before, and 8-10/21-23 days after the start of treatment. RESULTS: Vaginitis symptoms were resolved in 91% of the 74 patients evaluated, and improved in a further 7%. Microbiological cure rates were 97.3% for trichomonal, 86.6% for bacterial and 81% for candidal vaginitis. Recurrence rates were 2.7, 3.8 and 16.1%, respectively. Overall microbiological cure rate for mixed infections was 86%, with 93% for trichomonal+bacterial, and 73% for bacterial+candidal vaginitis. In two out of three cases with trichomonal+bacterial+candidal infection, the microorganisms were eradicated completely. CONCLUSION: Neo-Penotran provides immediate and effective treatment for vaginitis, irrespective of single or multiple infection, even when the diagnosis may be uncertain.

Synthesis of new 2-arylidene-2H-1,4-benzoxazin-3(4H)-ones.

A number of 2-arylidene-2H-1,4-benzoxazin-3(4H)-ones were synthesized and evaluated for CNS activity. Some of the tested compounds exhibited marked CNS depressant activity in mice.

Gemfibrozil and its oxidative metabolites: quantification of aglycones, acyl glucuronides, and covalent adducts in samples from preclinical and clinical kinetic studies.

A gradient reversed-phase HPLC analysis for the direct measurement of gemfibrozil (GEM) and four oxidative metabolites in plasma and urine of humans and in tissue homogenates of rats was developed. The corresponding acyl glucuronides and the covalently bound protein adducts (in protein precipitates) were determined after liberation from the respective conjugates via alkaline hydrolysis. The limits of detection for the covalent adducts in human plasma are: 10 ng ml(-1) (GEM), 20 ng ml(-1) (M1), 0.5 ng ml(-1) (M2, M4), and 5 ng ml(-1) (M3). The method was validated with respect to selectivity, recovery, linearity, precision, and accuracy. It has been applied to the analysis of preclinical and clinical studies. Pharmacokinetic profiles of gemfibrozil, its metabolites, and covalent adducts in human plasma and rat tissue homogenates are given.

Effect of Aloe vera leaves on blood glucose level in type I and type II diabetic rat models.

Aloe vera (L.) Burm. fil. (= A. barbadensis Miller) (Liliaceae) is native to North Africa and also cultivated in Turkey. Aloes have long been used all over the world for their various medicinal properties. In the past 15 years, there have been controversial reports on the hypoglycaemic activity of Aloe species, probably due to differences in the parts of the plant used or to the model of diabetes chosen. In this study, separate experiments on three main groups of rats, namely, non-diabetic (ND), type I (IDDM) and type II (NIDDM) diabetic rats were carried out. A. vera leaf pulp and gel extracts were ineffective on lowering the blood sugar level of ND rats. A. vera leaf pulp extract showed hypoglycaemic activity on IDDM and NIDDM rats, the effectiveness being enhanced for type II diabetes in comparison with glibenclamide. On the contrary, A. vera leaf gel extract showed hyperglycaemic activity on NIDDM rats. It may therefore be concluded that the pulps of Aloe vera leaves devoid of the gel could be useful in the treatment of non-insulin dependent diabetes mellitus

Excessive motor impairment two hours after triazolam in the elderly.

The pharmacokinetics of triazolam 0.25 mg p.o. and psychomotor coordination were compared in nine healthy, elderly volunteers and nine middle aged controls. Motor coordination, as measured by pursuit rotor performance, was impaired in the elderly even before triazolam administration, and in contrast to the controls it deteriorated to a critical level after the drug. Factors associated with the major decrease in psychomotor performance in the elderly volunteers were poor baseline performance, an additional independent-age factor, and the plasma concentration of free triazolam. Although short acting benzodiazepines may have a less detrimental effect on performance on the morning following their intake, there may be serious motor incoordination and falls may occur if the patients have to rise during the night, particularly when the plasma concentration is high, i.e. about 2 h after dosing.