RESUMEN

1. Six young male volunteers received five single doses of bornaprolol, i.v. (20 mg) and orally (120, 240, 480, 960 mg) administered at 2-week intervals. Plasma concentrations of bornaprolol and its conjugated metabolite were determined by gas chromatography. 2. After i.v. administration, plasma bornaprolol levels were detectable over 8 h, and mean values were 60 l/h for total clearance (C1), 207 l for volume of distribution (V beta), 2.6 h for elimination half-life (t1/2 beta). After oral administration, plasma bornaprolol levels were detectable over 24-48 h, and mean values of pharmacokinetics parameters were 60 l/h for C1, 1500 l for V beta, 20 h for t1/2 beta. Maximum plasma concentrations and area under the plasma concentration-time curve increased in a non-dose-dependent manner. 3. The glucuronide conjugate appeared in the blood within 5-10 min and its plasma level greatly exceeded bornaprolol concentrations. The mean value of the ratio of the metabolite AUC/parent product AUC was 14 after i.v. administration and 13-21 following oral administration, depending on dose. The AUC for the metabolite did not increase proportionally with oral doses. 4. Bornaprolol is principally eliminated after metabolism. This process did not increase with increasing oral doses and bioavailability seemed to decrease inversely with oral dose.

Asunto(s)

RESUMEN

PK 11195 (or 52028 RP; 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline carboxamide), an antagonist of the peripheral-type benzodiazepine receptors which are coupled to calcium channels, was administered to 10 healthy volunteers in order to study the pharmacokinetics and cardiovascular effects of the drug. PK 11195 was randomly administered intravenously (10 mg) and orally in three single dosages (100, 200 and 400 mg). Placebo was only given orally. Heart rate and blood pressure were recorded at rest and during exercise tests which were performed at 0, 1, 3, 6 and 24 h after dosing on each study day. The results showed that after IV administration, PK 11195 was rapidly distributed in two or three open compartments. Its elimination T 1/2 was short (3.7 +/- 3.0 h) with high interindividual variability. After oral ingestion the pharmacokinetics of PK 11195 were linear over the range of 100-400 mg single oral doses with a stable absolute bioavailability (33%). T 1/2 elimination was prolonged (7-12 h) and the presence of secondary increases in plasma concentration at 8-10 h and 22-24 h after drug absorption may have been related to enterohepatic cycling. No unchanged PK 11195 could be detected in urine. PK 11195 did not significantly modify heart rate and blood pressure at rest or during exercise and was well tolerated by the subjects. These data suggest a high inter-individual variability in PK 11195 disposition with extensive metabolism in normal exercising volunteers.

Asunto(s)

RESUMEN

Cardiac electrophysiologic effects of PK 10139 (PK), a new quinoleic antiarrhythmic agent, were compared with those of quinidine sulphate (Q) after three cumulative intravenous doses of 0.75, 1.5, and 3 mg/kg of PK and 5, 10, and 20 mg/kg of Q in anesthetized dogs. A control group of animals received saline solution only. Both PK and Q provoked an increase, correlated with plasma concentrations, in atrionodal (St-H), His-Purkinje system (HV), and auriculoventricular (QS) conduction times, and auricular effective and functional refractory periods (AERP, AFRP). The effects of PK on conduction times were more marked than those of Q. Slopes of the plasma concentration-effect curves were similar for the two drugs for HV and QS but different for St-H. PK was 42.5 times more potent than Q in increasing HV and 46 times more potent than Q in increasing QS. Effects of PK on AFRP and nodal FRP did not differ from those observed in control animals. These findings demonstrate more marked effects of PK, when compared with Q, at doses 6.7 times lower and at plasma concentrations 15 to 42 times less, without chronotropic effects or significant alterations in blood pressure, and without adverse reactions on the central nervous system.

Asunto(s)

RESUMEN

Quinidine induced an increase in digoxin plasma concentrations in rats and dogs. PK 10139, an antiarrhythmic agent 10 times more potent than quinidine, did not change digoxin plasma concentrations in these species. The results indicate that PK 10139 could be associated with digoxin without risk of side-effects.

Asunto(s)

RESUMEN

A subacute treatment, 500 mg/kg I.P. twice daily during 5 days, by L-methionine provoked an increase in the Bmax of [3H]-spiperone binding in the striatum of the rat. This increase was associated to a decrease in membrane microviscosity. However in these conditions no changes were found in the [3H]-DHA, [3H]QNB bindings or in the brain dopamine sensitive adenylate cyclase activity. L-methionine treatment reduced the accumulation of Dopa after NSD 1015 and antagonized the decrease in striatal acetylcholine provoked by haloperidol. Thus L-methionine might be a new potential drug for Parkinson's disease treatment.

Asunto(s)

RESUMEN

LM 24056, a phenothiazine derivative with no central effects, can be classified as a non anti H2 antisecretory agent with a long duration of action. Its activity was demonstrated orally at low dose in pentagastrin stimulated Shay rat and in Heidenhain pouch in dog against gastrin, pentagastrin, carbachol and test meal. LM 24056 possesses very weak affinity to muscarinic receptors in vitro and in vivo. It has negligible anticholinergic properties in rats and mice at the peripheral level but no effect at the central level. The long lasting antisecretory action of LM 24056 may be supported by the persistent presence in plasma of a desmethyl metabolite at higher concentrations than that of LM 24056 at any time. Contrary to LM 24056 sulfoxide and LM 24056 sulfone, desmethyl LM 24056 is a more potent antisecretory drug than LM 24056. Desmethyl LM 24056 possesses more marked affinity to peripheral muscarinic receptor than LM 24056. As the administration of therapeutic doses of LM 24056 was not followed by anticholinergic side-effects, it may be suggested that LM 24056 activity is related to a "prodrug like effect". Finally the activity of LM 24056 may be related to LM 24056 itself and/or a desmethyl metabolite.

Asunto(s)

Asunto(s)

Asunto(s)