Journal de pharmacologie最新文献

Aminergic neurotransmitters and their main metabolites concentrations are measured in four areas (posterior cortex, striatum, hippocampus, hypothalamus) of the rat brain, 24 hours after an acute ischemic injury (created by the occlusion of the four cephalic vessels). Simultaneously, spontaneous motility and neurological status are evaluated. The main results are the increase of 5 HIAA in striatum, hippocampus and cortex, associated with an increase of HVA in striatum. Motility as well as neurological scores are significantly decreased in ischemic animals when compared with controls. The conclusion is that this model of cerebral ischemia is may be useful for pharmacological assessment of drugs liable to antagonize cerebrovascular disorders.

Immature female rabbits were tested by the Clauberg-MacPhail technique using progesterone (P), or nomegestrol acetate (NOM), a 19-norprogesterone derivative. The endometrial surface was observed by scanning electron microscopy. Estrogen priming followed by treatment with P induced changes on the endometrial surface which were very close to those observed in menopausal women under sequential estroprogestative therapy. After treatment with NOM the aspect of endometrium surface was very close to those observed after treatment with P. This is in accordance with the pharmacological profile of the product. Scanning electron microscopy confirms the previsional value of Clauberg-MacPhail's test and provides useful complementary information for the pharmacological understanding of a new synthetic progestogen.

Especially because of their physico-chemical properties, and in particular of their lipo-solubility, it was interesting to compare the tissue distribution of two beta 2 sympathomimetics: the clenbuterol and the salbutamol. The study was realised after a direct intravenous administration of clenbuterol chlorhydrate (5 micrograms/kg) and one of salbutamol sulfate (50 micrograms/kg) given to a dog. In a first time, the determination by mass-spectrometry of the two drugs in the plasma allows the pharmacokinetic study in dogs. After a three days wash out, this same experience was repeated. The animals are sacrificed and the assays of the two beta 2 sympathomimetics were effected in lung, bronchial, muscle, heart and brain tissue samples. The tissue distribution was different for clenbuterol and salbutamol and had to be considered as factors of selectivity in the sympathomimetic beta 2 activity. Nervous central diffusion of clenbuterol is higher than salbutamol but cardiac distribution is very important for salbutamol.

A peptide of simple chemical structure has demonstrated its efficiency in preventing the large cellular destruction that locally activated complement produced on the ciliary epithelium of the respiratory tract. Previously (1980), it was demonstrated by the authors that these cellular destructions after sensitization of the epithelium was due to the local activation of the complement (alternate pathway) by immune complexes with secretory IgA. The cellular protection afforded by Naaga was demonstrated by the persistance of a normal ciliary beating when the sensitized mucosa is in contact with the antigen; by electron microscopic studies both in transmission and scanning E.M. contrasting with the complete cellular destructions of the epithelium which appear obvious. The protection appear complete when Naaga (56 mM) is present in the testing solution (or instillated before the test). By in vitro human complement studies; study of the cytolytic sequence inhibition for the classical pathway 1,5.10(-3) M of Naaga produces a 50% inhibition of 1 H50 hemolytic unit. For the alternate pathway, the same inhibition is observed with 1,75.10(-3) M of Naaga; by two-dimensions immuno-electrophoresis: a dilution of 1/2 of C3 in Naaga reduced to 1/10 of its normal value the C3b profile; the "Rockets" technique demonstrated that the same 1/2 dilution of Naaga in complement prevents the clivage of factor B and that this peptide acts by inhibition of the alternate C3 convertase formation (see illustrations). If we consider the subject of this study i.e. the upper respiratory tract mucosa and knowing the physiopathological importance of the muco ciliary complex in preventing dust, microbs and other particulate foreign materiel to penetrate the epithelium, the therapeutic importance of such a simple non toxic and unharmful chemical compound must be stressed.

The effect of L-N6-phenylisopropyladenosine (L-PIA) on the maximum tension developed (Td) and the maximum rate of rise of tension (dT/dt max) of the isolated hemidiaphragm of the rat was investigated during direct electrical stimulation. L-PIA itself (0.07-5.5 mumol l-1) did not produce significant changes in either Td, or dT/dt max. In the presence of a standard concentration of dipyridamole (26.4 mumol l-1), L-PIA produced a significant and concentration-dependent increase in both Td and dT/dt max. In the presence of a standard concentration of aminophylline (640 mumol l-1), L-PIA produced a small and insignificant, but concentration-dependent decrease of both Td and dT/dt max. In the presence of both dipyridamole (26.4 mumol l-1) and of aminophylline (640 mumol l-1), L-PIA (0.07-5.5 mumol l-1) produced a small and insignificant potentiation of the isometric contraction of the isolated hemidiaphragm. It is concluded that antagonistic action between L-PIA and aminophylline probably takes place at A1-receptors. The inhibitory action of L-PIA, observed after blockade of adenosine receptors by aminophylline, is presumably realized through some other mechanism(s) independent of adenosine receptor sites.

The actions of guanabenz, an alpha 2-adrenoceptor agonist, on submandibulary salivation were examined in the anaesthetized cat. Guanabenz reduces submandibulary salivation evoked by electrical stimulation of the chorda tympani in dose and frequency dependent manner. This effect was antagonized by yohimbine but not by prazosin. Guanabenz increased salivation elicited by intraarterial injection of carbachol. This potentiated effect was suppressed by yohimbine, but not by prazosin. On noradrenaline induced salivation guanabenz has no effect, while prazosin virtually abolished it, indicating involvement of alpha 1-adrenoceptors. It appears that guanabenz reduces peripheral parasympathetically evoked submandibulary salivation influencing the presynaptic control of transmitter release alpha 2-adrenoceptors. Postsynaptic alpha 2-adrenoceptors are not involved in the inhibition of salivation by this agent.

We have prepared and purified an endogenous protein (brain neuropeptide) by extraction with 0.025 N acetic acid and precipitation with a saturated ammonium sulfate solution followed by column chromatography. This protein was isolated and partially purified (approx. 500 times). When added to Triton X-100 treated synaptic membrane preparation obtained from rat CNS, this modulates specific high affinity GABA binding site without affecting low affinity site. This protein was called GABA-modulin (GM). GM like bicuculline (competitive GABA antagonist) modulates the affinity of benzodiazepine receptor ligands. But the effect of bicuculline is more important than that of GM. Bicuculline increases or decreases respectively the binding of 3H-beta-CCM or 3H-flunitrazepam by approximately 60%. In the same conditions, at a concentration of 12 micrograms/ml GM increases or decreases respectively the binding of 3H-beta-CCM or 3H-flunitrazepam by approximately 35% and no more modulation was obtained even the concentration of GM was increased. Bicuculline and GM doesn't modify the specific binding of 3H-Ro 15-1788 to the BZD receptor. It is concluded that GM exhibit a lower ability than bicuculline to modulate the binding of the BZD receptor ligands because GM interacts only with the GABA high affinity binding site without affecting the low affinity binding site. These observations suggest that the two GABA binding sites probably interact with the BZD receptor.

The turnover of catecholamines (CA) in some peripheral tissues and various areas of the rat brain was estimated by measuring the amine depletion after inhibition of their biosynthesis by alpha-methyl-p-tyrosine (alpha-MPT). Acute or chronic treatment with S3341 (3mg/kg i.p.) reduced NA turnover in submaxillary glands, brain stem and rest of the brain but had no effect on NA turnover in the hypothalamus. The dopamine (DA) levels were unaltered following chronic S3341 treatment but the alpha-MPT induced disappearance of DA was significantly retarded in the striatum and rest of the brain. The results of the present study demonstrate that no tolerance to the effect of S3341 on brain CA turnover develops during chronic drug administration. The central biochemical effects of S3341 appear different from those of other agonists of central alpha 2-adrenoceptors such as clonidine.

The simultaneous prescription of a calcium channel blocker and a cardiac glycoside is a frequently used therapeutic combination in cardiology, although its consequences on inotropism have not been really evaluated. This association is studied on isolated rat heart perfused at constant coronary pressure, paced at a constant frequency and working against a left intraventricular balloon. Since the inotropic effects are dependent on the basic level of myocardium contractility, controls were made hypocontractile by lowering external calcium level to 0.25 mM. For the same initial systolic pressure (45 mm Hg) and + dP/dTmax (150 mm Hg X s-1) the inotropic effect of 10(-5) M ouabain was significantly less pronounced in the presence of 10(-6) M verapamil or 10(-7) M nifedipine at 2.5 mM CaCl2 than at the low external calcium concentration of 0.25 mM (increasing the + dP/dtmax by 35% +/- 4, 29% +/- 6 and 110% +/- 18 respectively). Since we know that the inotropic properties of digitalis are probably due to an increase of the slow calcium inward current, we conclude that the observed effect would be due to a blockade of these channels by calcium blockers.

The two-period cross-over design is often used in clinical trials in which subjects serve as their own controls. This procedure may produce a more powerful test, but also may produce bias due to carry-over effects. Three tests have been proposed for the analysis of two-period binary response cross-over trials (McNemar, Gart and Prescott). These tests and a simple test for the carry-over effect are presented in this paper. The contrasts used are similar for the three tests, but McNemar's test does not allow an order effect, contrary to the other methods. The Prescott's test is more powerful, but calculations are heavy and need computer assistance. Therefore, McNemar's test can be used as a first approximation.