Journal de pharmacologie最新文献

This is a report of a round table organized during the second meeting of Clinical Pharmacology held in Giens (France) in September 1985. At the beginning of the meeting, the clinical aspects of drug-induced nephrotoxicity were reviewed. Thus we tried to precise the real interest of the studies of proteinuria, urinary cytology, enzymuria and fractional clearances of lithium or magnesium. The most interesting part of our discussions was to know the point of view of men working in drugs companies when a renal abnormality is found during a clinical trial of a drug and when previous experimental studies did not find any renal adverse effects of the drug. It was suggested in a such situation to do particular studies. Methods generally used to study renal physiology as autoradiography micropuncture, microinjection had to be performed to localize the action of the drug along the nephron. It was also discussed of the use of isolated perfused kidney as a tool in drug disposition and the use of renal cells culture. A better understanding of the mechanisms of direct renal toxicity of drugs was obtained from the results of experimental models. It is not so easy, at the present time, to know the mechanisms of immunological drug-induced nephrotoxicity. It seems necessary to develop new experimental models. The results obtained in animals with Cl2Hg or D. Penicillamine or gold salts afford to suspect some mechanisms for these types of nephropathies. This aspect of drug induced nephropathy is more complex because there is a large interindividual variation in susceptibility to these drugs.

The effects of metapramine (R.P. 19,560) on dopaminergic and cholinergic activities were mainly studied in the rat striatum. Metapramine, contrarily to apomorphine, is devoid of in vitro affinity for dopamine receptors and does not modify in vivo, the utilisation of dopamine in the striatum. Moreover, metapramine does not modify the increase of dopamine utilisation induced by thioproperazine, a neuroleptic of the phenothiazine family. Consequently metapramine is devoid of direct or indirect effect on nigrostriatal dopaminergic system. Metapramine, like dopaminergic agonists, increases acetylcholine levels in the striatum. Moreover metapramine is inactive in cerebral cortex and hippocampus. Metapramine partly or completely antagonises the decrease of acetylcholine levels induced by two neuroleptics of the phenothiazine family (thioproperazine and prochlorperazine), by reserpine or an association of reserpine and alpha-methyl-p-tyrosine. Metapramine which possesses a clinical antidepressant efficacy could be indicated for correction of extra-pyramidal side effects induced by neuroleptics or observed in parkinsonism.

Glucose is the main stimulator and physiological regulator of insulin secretion. The great sensitivity of the B cell to glucose variations between 1 g/l (5.5 mM) and 3 g/l (16.6 mM) and its rapid response ensure the constant adaptation of its secretion to plasma glucose level. The cellular mechanisms involved in insulin response can be schematically represented in three stages: The first stage is the recognition of the insulinotropic agent. In the case of glucose, this involves its metabolism. The second one is the coupling of the recognition process to activation of the effector system and implies a series of intracellular signals. Coupling factors include metabolites and cofactors, ions, cyclic AMP, polyphosphoinositides. The result of all these cellular events is the increase in cytosolic Ca2+ and the activation of protein-kinases: Ca2+-calmodulin-, cAMP- and Ca2+-phospholipid-dependent protein kinases. The last stage corresponds to a mechanical one, involving granule migration and extrusion. The polymerization of microtubules associated with contraction of microfilaments would cause granule movement. Ca2+-calmodulin-dependent protein kinases would play a major role. While glucose is the main stimulator of insulin secretion, numerous factors can influence it. The regulation of this secretion is essentially under the control of three classes of elements: nutrients, hormones and neurotransmitters. As to stimulation of insulin secretion by nutrients, it seems to be secondary to an increase in intracellular metabolism. However it must be underlined that the insulin secretory effect of most nutrients requires the presence of glucose which is consequently a permissive factor. A number of gastrointestinal and pancreatic hormones stimulate, in presence of glucose, insulin secretion and play an essential role during food intake, which results in a better fitting of insulin secretion to energy supply. The term "incretin" designates a hormonal transmitter between the gastrointestinal tract and the B cell; the "incretin" factors are included in what is termed enteroinsular axis. Of the gastrointestinal hormones, GIP (gastric inhibitory polypeptide) appears to play the most important physiological role in potentiating the insulin secretory effect of glucose. Pancreatic glucagon potentiates the effect of glucose too; it is difficult to distinguish between its endocrine and paracrine role. The pancreatic B cell is under neural regulation. The cholinergic system stimulates insulin secretion and the B cell is fitted with receptors of muscarinic type.(ABSTRACT TRUNCATED AT 400 WORDS)

The important discovery by Pasteur of optical isomerism and the recent developments of stereochemistry showed that a complementarity exist between the geometry of molecules and their pharmacological receptors. The stereochemical bases and the principal configurational nomenclatures are briefly overviewed. The stereospecificity of the biological response and theories leading to an approach to stereochemical structures of main pharmacological receptors are developed. So, the biological activity of steroids is due to junctional modes of cycles and alpha or beta configurations of substituents. Acetylcholine has a skew conformation but it react by an anticlinal/anti-planar conformation with muscarinic receptor. To explain the difference in activity of adrenaline enantiomers, Easson and Stedman proposed a "three points" fixation to the adrenergic receptor. Dopaminergic receptor present a good degree of stereoselectivity: dopamine act by an anti-planar conformation in which the N-O distance is the same as in apomorphine (N-O10). The analgesic activity of morphinans is due to a cis junction of B and C cycles and to the stereoelectronic effect of the unshared lone pair on nitrogen. In the cyclamate sweeteners, some authors proposed for the sweet taste receptor a model with two points fixation (one acceptor and one donor) and two spatial barriers located at precise distances from this two sites. The stereoselectivity of molecules acting as substrates or inhibitors of enzymes is described. For example some oxazolidinone derivatives showed a selective inhibition toward monoamine oxidase A. Finally, the pharmacological activity falls often when molecules are administrated in racemic form. It seems that xenobiotics need to be dissymmetric for chiral recognition by biological systems.

2-N,N-dipropylamino 5,6-dihydroxytetralin (nPr2 ADTN), a potent dopaminergic agonist, induces the same polyphasic effects observed with apomorphine by Protais et al., (1983). The dose related sequence of behaviours in mice can be summed up as followed: to 0.9 to 3.9 micrograms.kg-1, a decrease in motor activity without any other effects; to 7.8 to 15.6 micrograms.kg-1, a return to control level or an increase in motility alone according to experimental conditions; to 31 to 62.5 micrograms.kg-1, a second phase of hypomotility when hypothermia develops; above 125 micrograms.kg-1, a second phase of hypermotility when both stereotypies and climbing behaviour appear. Hypothermia moreover, disappears. The effects of the nPr2 ADTN were compared with those of apomorphine obtained in others studies (Puech et al., 1974; Protais et al., 1983). The tetralin derivative differs from apomorphine in that the first phase of hypermotility it induces is greater, and that hypothermia disappears at high doses.

The nocturnal activity of a primate was used as an evaluation criterium for a stimulating substance: adrafinil (CRL 40028). Ten rhesus monkeys were placed in a controlled environment and their activity was measured, in relative time, using an ultra-sound system. The animals repeatedly received 60, 90 and 120 mg X kg-1 adrafinil per os. Globally, the dose of 60 mg X kg-1 doubled the animals' nocturnal activity whereas 90 and 120 mg X kg-1 increased it fourfold, the activity level becoming practically identical to diurnal activity. The effects of 60 mg X kg-1 were only significant after the second treatment whereas doses of 90 and 120 mg X kg-1 were already significantly efficient after the first administration. A stimulating effect persisted approximately 36 hrs after the second treatment with 90 or 120 mg X kg-1. No sedative effect of recovery was observed during the posttreatment phase.

Thirty seven mature Mangabeys (Cercocebus atys lunulatus), 33 females (5-6 kg) and 4 males (6-7 kg) received large doses of 17-beta-oestradiol by intravenous tracts (continued perfusion and single dose injection) and by subcutaneous implantation in a silastic tube. The CB 154 and TRH tests under oestrogenic treatment were the object of an integrated study. All these experiments began 5 days after menstruation in the case of the females. The experiments were preceded, for each monkey, by a control period that rarely exceeded 5 days. Prolactin and oestradiol were measured by radioimmunoassay. Single intravenous injection and perfusion of 17-beta-oestradiol were followed by an inconstant effect on the immediate secretion of prolactin (+30 to +60 minutes). However, after 4 to 6 hours, serum prolactin rose by about 50% of the basic ratios. This is followed by a more notable elevation of the blood ratios of PRL during the 24 to 72 hours which succeed the end of the oestradiol treatment. The subcutaneous placing of a silastic tube containing oestradiol is followed by a Systematic fall in the Serum PRL for 9 hours (day 0). During the following 3 weeks, the ratios rise but are situated at a normal level (F = 0.2 p greater than 0.5) in spite of a liberation and maintenance of the serum oestrogen at a very high level. Nevertheless, the peak of PRL following a TRH test under oestrogenic treatment is greater (F = 4.7 p less than 0.05) than the peak obtained during the control period with the same dose of TRH.

During the past two decades, essentiality of zinc for man has been established. Deficiency of zinc in man attributable to nutritional factors and several diseased states has been recognized. High phytate content of cereal proteins decreases availability of zinc, thus the prevalence of zinc deficiency is likely to be high in the population subsisting on cereal proteins mainly. Zinc deficiency has been noted to occur in patients with malabsorption syndrome, chronic renal disease, cirrhosis of the liver, sickle cell disease, AE, and other chronically debilitating diseases. Growth retardation, male hypogonadism, skin changes, poor appetite, mental lethargy and delayed wound healing are some of the manifestations of chronically zinc-deficient human subjects. In severely zinc-deficient patients, dermatological manifestations, diarrhea, alopecia, mental disturbances and intercurrent infections predominate. If untreated, the condition becomes fatal. Zinc deficiency affects testicular functions adversely in man and animals. This effect of zinc is at the end-organ level. It appears that zinc is essential for spermatogenesis. Zinc is involved in many biochemical functions. Several zinc metalloenzymes have been recognized in the past decade. Zinc is required for each step of cell cycle in microorganisms and is essential for DNA synthesis. The effect of zinc on protein synthesis may be attributable to its vital role in nucleic acid metabolism. The activities of many zinc-dependent enzymes have been shown to be affected adversely in zinc-deficient tissues. Zinc atoms in some of the enzyme molecules participate in catalysis and also appear to be essential for maintenance of structure of apoenzymes. Zinc also plays a role in stabilization of biomembrane structure and polynucleotide confirmation.(ABSTRACT TRUNCATED AT 250 WORDS)

We have studied the effects of three new GABA-ergics (GABA-linoléamide (GL), GABA-palmitamide (GP) and GABA-steatamide (GS] on rat stereotypies with apomorphine (0,8 mg/kg i.p.). These GABA-ergics have been administered at a high dose (150 mg/kg i.p.) or a low one (10 or 3 mg/kg i.p.) and the following results have been observed: GL and GP at 150 mg/kg i.p. antagonised the locomotor activity and motor stereotypies. All these GABA-ergics (GL, GP and GS) potentiated the oral stereotypies (gnawing) when they are administered at low doses (10 or 3 mg/kg i.p.). GS at 3 mg/kg i.p. also potentiated the locomotor activity and motor stereotypies. These results were discussed in relation with some new data on the role of GABA in the basal ganglia and the nucleus accumbens.

The effects of verapamil and propranolol on the LTD4-induced bronchoconstriction were studied in the isolated, perfused and ventilated guinea pig lungs. Verapamil (4.10(-5) et 1, 2.10(-4)M.1(-1], a calcium antagonist, produces a significative inhibition of LTD4-induced bronchoconstriction. On the other hand, propranolol (10(-7)M and 10(-4)M) does not increase the constrictor effects of LTD4 in guinea-pig isolated lung. These first results obtained in guinea-pig lung, confirmed the protective effect of verapamil, effect previously demonstrated in vivo or in vitro by using lung parenchymal strips. We have also confirmed the difference between the in vivo and in vitro effects of propranolol.