Biomedical subjects
Publications and source records attributed to C Labrid.
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The effects of bepridil, nifedipine, verapamil, lignocaïne and amiodarone on the atrial effective refractory period were investigated in the guinea-pig. The observed results permitted elucidation of a remarkable activity by both nifedipine and verapamil, and by bepridil and lignocaïne. In contrast, in the experimental conditions, no activity was detected with amiodarone up to concentrations of 10(-4) M. The efficacity rating of the test compounds is not reflected by their anti-arrhythmic efficacity as demonstrated in vivo in the animal, nor by their therapeutic anti-arrhythmic efficacity as reported in the clinical literature. However, this efficacity rating may be related to the interaction of the compounds with the transmembrane sodium or calcium movements.
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Preparation of the N-(2-diethylaminoethyl) derivatives of lactam (II) and of the N-(3-dimethylaminopropyl) derivative of lactam (XI) is described. Synthesis of the N-[4-(2-hydroxyethyl)piperazinylacetyl]- and 1-carbothiamide derivatives of azepine (I) and of the n-(chloroformyl)- and N-(carbamoyl) derivatives of azepine (XII) are also described. Some pharmacological results indicate a partial tranquilizing activity.
The action of bepridil (5 mg/kg), perhexilene (5 mg/kg) propranolol (0.5 mg/kg), dipyridamole (0.5 mg/kg), amiodarone (10 mg/kg), pentaerythritol tetranitrate (40 microgram/kg) and nitroglycerine (40 microgram/kg) on cardiovascular manifestations of auditory-inducted emotional stress has been investigated in the conscious dog. Bepridil, perhexilene and propranolol considerably reduce tachycardia provoked by the anxiogenic stimulus, with nitroglycerin exerting an attenuated effect and the others with no significant effect on this parameter. Beppridil, nitroglycerin, perhexilene, propranolol and pentaerythritol all significantly reduce the elevation of the Robinson index, the first four with the same intensity. Only amiodarone and dipyridamole are without effect on this parameter of cardiac workload. Finally, none of the products under investigation significantly reduces systolic hypertension, associated with the induction of conditioned anxiety.
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The types of interaction of mepyramine (M), diphenhydramin: (D) and eprozinol (E), with histamine H1-receptors of guinea pig ileal and tracheal smooth muscle, were comparatively studied in vitro. According to the concentrations used, all three substances showed an apparent dualist mechanism of action on both preparations when histamine (dihydrochloride) was used as the agonist. The competitive component of this mechanism (at low concentrations) was characterized by the following pA2 values: 9.01 (M), 7.80 (D) and 5.64 (E) with the ileum; 8.06 (M), 7.00 (D) and 6.02 (E) with the trachea. The so called non specific component (at high concentrations) was of comparable intensity in the two organs. The pD'2 values were 5.54-5.66 (M), 4.65-4.38 (D) and 3.82-3.55 (E) with ileal and tracheal muscle, respectively. At low concentrations the equi-active dose-ratio for N/D/E (1/16/2300 on the ileum) became 1/12/110 when the trachea was used as the effector. This is surprising since histaminergic receptors of the two preparations are of the same H1-type. It is suggested that only diphenhydramine and eprozinol are really dualistic, and that the non-specific mechanism of activity differs for each drug with that of eprozinol being effective on tracheal muscle.
The interaction of papaverine and tiemonium alone or combined, with BaCL2 and histamine on guinea pig ileum and with acetylcholine on rat jejunum have been studied with the help of molecular pharmacology techniques. The competitive antagonist effects of tiemonium and the non competitive antagonist effects of papaverine are evidenced and shown to be strictly additive when the two drugs are combined. This reflects a sequential blockage of the effects of acetylcholine, histamine and barium ions at the smooth muscle level. No such antagonism has been previously described in the case of the interaction with barium chloride with any other combination of two spasmolytic drugs.
Rats with permanent intra-jugular cannula are submitted to an alimentary operant reinforcement schedule with fixed ratio type FR 1, FR5, then FR 20. As a result, the animals are self administering (together with the alimentary inducer) a slow (about 5 sec) intravenous infusion of morphine (0.05 mg/kg). 20 per cent only of the experimental population exhibit a psychogenic dependance afterward. On the other hand, the animals for which morphine self-administration has been substituted to the alimentary reinforcement without respecting a transitory period combining both types of reinforcement have never shown any tendancy toward morphine self-administration. The lack of positive results could be related to the marked duration of the self-injection.
Anticholinergic potentialities of four standard anti-secretory drugs (N-methyl-scopolammonium methylsulfate, atropine, diphemanil and prifinium) have been investigated with the help of molecular pharmacology techniques. The results gained with two different agonists (acetylcholine and carbachol) on rat and dog intestinal cholinergic receptors-jejunum and duodenum respectively-show : 1) That relative potentialities of the anticholinergic drugs (pA2) as well as those of the cholinomimetic agonists (pD2) are markedly modified according to which effector is used. 2) The N-methyl scopolammonium methylsulfate remains in any event the most potent anticholinergic drug investigated.
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The effects of tiemonium on various membrane events preceding smooth muscle fibre contraction, have been studied in vitro. Classical molecular pharmacological models and methods were used: stimulation of muscarinic, histamine H1 and alpha-adrenergic receptors; induction of contraction by release of membrane phospholipid bound Ca2+ ions, or by intracytoplasmic influx of this cation in depolarized preparations. At each level of investigation, tiemonium was studied comparatively with two reference antispasmodics, atropine and papaverine. Like atropine, tiemonium competitively antagonizes cholinergic stimulation. It also interferes with the contracting effects of BaCl2, as does papaverine. In contrast to papverine, however, tiemonium shows an affinity for histamine H1-receptors, and does not affect alpha-adrenergic receptor stimulation. Tiemonium is therefore a novel antispasmodic which blocks the cholinergic receptor, but being less specific than atropine. This non-specific facet makes it almost as polyvalent as papaverine, in its general inhibition of spasmogenic substances, but its mechanism of action is very different. Whereas papaverine slows intracytoplasmic Ca2+ influx, tiemonium inhibits release, and thus availability, of the same ion. Tiemonium has a totally different mechanism of antispasmodic action from that other substances in the same pharmacological class. The marked competitive interference with acetylcholine and the very weak competitive antagonism of histamine are completed by a membrane stabilizing action. In particular, the latter reinforces the binding of calcium to membrane phospholipids. The absence of any interaction of tiemonium with noradrenaline is compatible with recent theories for noradrenaline's action, which evoke calcium exchanges in an intracytoplasmic compartment. Finally, the results raise the question of the pharmacological suitability of the term "papaverine-like" for describing non-specific antispasmodics.
Overall assessment following the creation of denervated antral and fundic pouches, in 64 mongrel dogs, leads to the recommendation of certain important technical options: surgical intervention carried out in 1 stage; respecting of precise operative timetable; reestablishement of digestive continuity by gastro-jejunostomy with large anastomosis mouth; inutility of scraping the walls of vessels irrigating the pouches.
The "gastric chamber" technique, performed in the anaesthetised rat, enables the study of gastric mucosal fragility induced by doses of phenylbutazone, which do not themselves cause ulceration or exulceration. The perfusion of buffered solution at pH 2-8 into the gastric chamber shows that prior oral administration of phenylbutazone 50 mg/kg increases the fragility of the mucosa. The optimal delay separating this administration from the time of experimentation is 6 hours. The effects seen are essentially vascular disorders.
The pharmacological properties of 2-(2-chloro-p-toluidino)-2-imidazoline-nitrate (tolonidine) a new synthetic derivative of imidazoline are reported in a series of three successive articles. This compound has been shown to possess hypotensive and antihypertensive properties. After i.v. administration, the hypotensive phase was preceded by hypertension related to the potent direct alpha-sympatheticomimetic properties of the product. This pressor response, which was not seen after oral administration, was accompanied by a marked decrease in cardiac output and a significant increase in peripheral vascular resistance. The hypotensive action of the product was due to a drop in cardiac output probably reinforced by a decrease in vasoconstrictor sympathetic tone due to a central action. Whatever the route of administration, tolonidine slowed heart rate independently of blood pressure variations, due essentially to an increase in vagal tone. In studies of diuresis, liquid and salt loss were observed in the cat, not in the dog. At doses which induce a drop in blood pressure tolonidine did not produce a reduction in pilocarpine-induced salivary secretion and only partially inhibited gastric secretion. In the central nervous system, tolonidine produced a sedation which first appeared at doses having an antihypertensive effect but which was only fully apparent with increased doses. A decrease in the release of cerebral amines, serotonin and noradrenaline by tolonidine is proposed. Tolonidine was compared with three other antihypertensive agents: clonidine, which is structurally related, and guanethidine and mecamylamine, which are structurally unrelated and have a different mode of action. A close resemblance of the pharmacological properties of tolonidine and clonidine was established due to the chemical relationship between the two substances.