Journal de pharmacologie最新文献

We have studied the effect of GABA-linoleamide (GL) (100 mg/kg i.p.) and glycine-linoleamide (LG) (70 mg/kg i.p.), on the pentamethylenetetrazole (PTZ) (82 mg/kg i.p.) convulsions and lethality of rats. LG antagonize more efficiently than GL the PTZ convulsions and lethality. In another experiment, rats have received haloperidol (2 mg/kg i.p.) for 12 days. Four days after the last administration of haloperidol, rats received as previously GL (100 mg/kg i.p.) or LG (70 mg/kg i.p.) and PTZ (82 mg/kg i.p.). GL only antagonized the PTZ convulsions and lethality. The above results seem to demonstrate the importance of GABA-ergic and glycinergic receptors in the control of PTZ convulsions and they are supported by the recent data on the role of the inhibiting neuromediators, GABA and glycine, in the substantia nigra.

The vascular effects induced by histamine and their inhibition by cyproheptadine have been studied on rabbit aortic strips. On arteries pre-contracted with phenylephrine, histamine provokes a dose-dependent relaxation only when mepyramine is present in the bath. This effect is independent of the integrity of endothelium. Cyproheptadine (10(-9) M) required the presence of cimetidine to give a parallel antagonism of the histamine curve (Kb: 0.32 nM). At higher concentrations of cyproheptadine (3 X 10(-9) and 10(-8) M) the effect was non-competitive. Cyproheptadine displaced to the right in a parallel manner the dose response curve of noradrenaline (pA2 = 6.6) and of serotonin (pA2 = 8.9) and reduced the contracting effects of KCl (IC50 = 7.3 10(-7) M) and of angiotensin II (IC50 = 4 X 10(5) M).

Conduction disorders may be logically expected from the digoxin-verapamil association, since each of these drugs is known to increase conduction time (CT) and effective refractory period (ERP) in the atrioventricular (AV) node. When AV conduction is considerably depressed by verapamil (1.27 mg/kg over 90 min) in the absence of vagal tone, digoxin, infused at 1 microgram/kg/min rate over 40 min, elicits a progressive but incomplete regression of the verapamil effects, as does hypercalcaemia up to 5.5 mmol/l. Infused at the 2.5 microgram/kg/min rate over 20 min, its antagonistic effects, like those of hypercalcaemia exceeding 5.5 mmol/l, are less and less marked and even replaced by a certain synergism. When AV conduction is considerably depressed by digoxin (i.v. injection of 40 micrograms/kg) under high vagal tone, verapamil (twice 0.2 mg/kg) does not aggravate this depression and even attenuates it, this attenuation being however more significant on ERP than CT in the AV node. Consequently, as a rule, the interaction does not lead to block, since the maximum action of one drug is associated with the reduction in the action of the other or even the conversion of synergism into antagonism.

Dipetalonema dessetae in Proechimys oris, the natural final host is a rodent filariasis model used as an in vivo antifilarial screening test. The laboratory vector is Aedes aegypti. Infective larvae L3 isolated from the intermediate host develop and remain healthy for up to 30 days in a biphasic culture medium composed of a cell feeder layer (L 929) and RPMI 1640 supplemented with foetal calf serum. This culture technique has enabled us to screen antifilarial compounds on a new in vitro test. This model has been tested to several pharmacological classes of anthelmintics and effective concentrations 90% are given: diethylcarbamazine 430 mg/l, suramin 490 mg/l, Mel W 3.5 mg/l, mebendazole 78 mg/l, flubendazole 45 mg/l, levamisole 0.55 mg/l, morantel 0.62 mg/l, ivermectin 1.2 mg/l, amoscanate 2.3 mg/l. In vitro test response is remarkable for neurotoxic anthelmintics and nitro-compounds. Furthermore, all compounds considered as reference filaricides are active. For each compound, the in vitro and in vivo results have been compared to appreciate usefulness as well as limits of this in vitro test.

The actions of morphine (1.25 to 20 mg/kg i.p.) were compared in several models of experimental polyuria: alcohol--or water--loaded rats and Brattleboro rats (i.e. animals with congenital lack of vasopressin). In normal rats (without load), morphine induced no change except at low dose. In water-loaded rats, the opiate exhibited its dose-related antidiuretic effect and increased Na+, urea and osmolality excretion. After inhibition of vasopressin secretion by alcohol load as well as in Brattleboro rats, morphine induced antidiuretic response for the higher doses and diuretic effects for the lower doses. The morphine --induced changes in urine flow were suppressed by naloxone in normal, water--and alcohol--loaded rats. These results indicate that morphine is able to induce diuretic or antidiuretic action according to the state of hydratation in conscious rats after peripheral administration. This property is due to an interference with opiate receptors without involvement of vasopressin secretion.

There is some evidence that blockade of alpha 2-adrenoceptors on adipocytes may lead to an increase in lipolysis, We have therefore carried out a double blind comparative study of the effects of the selective alpha 2-antagonist yohimbine in human obesity. Nineteen obese volunteers participated in the study. Subjects were randomly allocated to the yohimbine group (n = 10, 18 mg yohimbine/day), or to the placebo group (n = 9). All subject were maintained on a hypocaloric diet (1000 kcal/day) during the 8 weeks of the study. There was no difference between the two groups with respect to either body weight, blood pressure supine and erect or heart rate during the different phases of the study. We found no difference in the lipid parameters (triglycerides, cholesterol, glycerol, beta-OH-butyrate, acetoacetate and free fatty acids) between the two groups. These results suggest that at the dose used the yohimbine does not influence the function of the alpha 2-adrenoceptors on the adipocytes; does not increase the lipolysis and does not represent an effective treatment of obesity.

The effects of cimetidine (single or repeated administration) on free unchanged captopril plasma levels, pharmacokinetic parameters and plasma converting enzyme inhibitory effects have been investigated in normal healthy volunteers. Cimetidine affected neither captopril pharmacokinetic parameters nor its biological effects, suggesting that no change in captopril dosing is necessary when cimetidine is co-administered.

Male Wistar rats were treated daily for 7 days with clofibrate (250 mg/kg/d), benfluorex (50 mg/kg/d), tiadenol (200 mg/kg/d), nicoclonate (100 mg/kg/d) or hexanicit (50 mg/kg/d). The cytochrome P 450 level and ethoxycoumarin deethylase activity (ECDE) in liver microsomes were markedly increased by administration of clofibrate and slightly increased by tiadenol. Benfluorex only increased the activity of ECDE and nicoclonate and hexanicit had no effect. Clofibrate, tiadenol and benfluorex increased the activity of microsomal bilirubin UDP-glucuronosyltransferase. On the other hand, the nicotinic derivatives were ineffective. Tiadenol clearly enhanced the inductive effects of phenobarbital.

The effects and interactions of nifedipine and diltiazem with tubocurarine, gallamine and pancuronium and their reversal by edrophonium and neostigmine were studied on isolated skeletal muscle of the chick. The nerve-muscle preparation of the chick biventer cervicis was set up in an organ bath containing Krebs-Henseleit solution and the mechanical responses produced either by motor nerve stimulation or by drug application were recorded isometrically. The results showed that nifedipine (29-1015 microM) and diltiazem (22-572 microM) reduced, in a dose-dependent manner, the amplitude of indirectly-elicited twitch tension, evoked at 0.2 Hz with 5-10 V and 0.2 msec pulse duration, and increased the neuromuscular blockade produced by d-tubocurarine (1-254 microM), gallamine (0.01-2.0 microM) and pancuronium (0.01-7.0 microM). Edrophonium (250 nM) and neostigmine (150 nM) completely reversed the neuromuscular blockade produced by the muscle relaxants, alone and in combination with nifedipine or diltiazem. The mean IC50 values (concentrations to produce 50% of maximum inhibition) of nifedipine and diltiazem-induced depression of twitch response were 324 +/- 16 microM and 143 +/- 11 microM respectively (means +/- S.E., n = 6). Nifedipine, in high concentrations, produced small contractions (0.4 +/- 0.1 g of tension, n = 6), in the chick muscle. In contrast, diltiazem produced no such contractions in the muscle. However, in concentrations which had little effect on twitch response, diltiazem (20 microM) and nifedipine (50 microM) both increased the neuromuscular blockade produced by tubocurarine, gallamine and pancuronium by about 2-fold. Increasing the external calcium concentration, by a 2-fold, did not reverse or antagonize the inhibitory effects of diltiazem or nifedipine. It was concluded that diltiazem and nifedipine inhibit indirectly-elicited twitch tension and intensify neuromuscular blockade produced by muscle relaxants. These effects of nifedipine and diltiazem may be due to blocking influx of calcium and on release of acetylcholine from presynaptic nerve terminals.