Paracetamol potentiates isaxonine toxicity in vitro.

The toxicity of isaxonine alone and in combination with the known glutathione depletor, paracetamol, was evaluated using rat hepatocyte primary cultures in vitro by measuring morphometric parameters and the leakage of intracellular lactate dehydrogenase into the culture medium. No cytotoxicity was observed with isaxonine at concentrations up to 10(-3) M, whereas paracetamol was cytotoxic at concentrations above 0.6 x 10(-3) M in the culture medium. Paracetamol cytotoxicity (0.6-3.3 x 10(-3) M) was enhanced in the presence of a non-cytotoxic concentration of isaxonine (10(-7) M). Furthermore cytotoxicity was observed when cells were exposed to a combination of non-cytotoxic concentrations of the paracetamol (0.3 x 10(-3) M) and isaxonine (10(-7) M). These findings demonstrate that isaxonine has no direct cytotoxic effect even at high concentrations. However co-administration of isaxonine with paracetamol greatly potentiates cytotoxicity. We suggest that this effect may be related to glutathione depletion within the cell but additional studies are required to verify this hypothesis.

Haematological and plasma biochemical values for healthy Yucatan micropigs.

Blood samples (n = 135) were collected from 36 male and 35 female 20 +/- 4-week-old Yucatan micropigs and were analysed for 19 haematological and 18 plasma biochemical parameters at weeks 20, 24, 33, 46, 59, 71 and 80. For each parameter, the total number of analyses per sex, mean values, standard deviation, lowest and highest values, and 95% confidence intervals are presented as reference values for this breed. Age- and sex-related differences in these parameters are also discussed.

[Influence of moderate normoxic hypercapnia on the autoregulation of the cerebral circulation in the unanesthetized rabbit]. / Influence d'une hypercapnie normoxique modérée sur l'autorégulation de la circulation cérébrale chez le lapin non anesthésié

In the unanesthetized rabbit autoregulation of cerebral blood flow was evaluated by continuous recording of local cerebral blood flow during progressive hypotension induced by exsanguination. Under hypercapnia induced by CO2, 8 per cent in air, autoregulation was not suppressed but an increase of the threshold under which autoregulation disappears was noted.

Cardiovascular pharmacology of bepridil (1[3 isobutoxy 2 (benzylphenyl) amino] propyl pyrrolidine hydrochloride) a new potential anti-anginal compound.

In dogs intravenous bepridil (2.5 mg/kg) increased coronary sinus blood flow and PVO2. Arterial pressure was briefly lowered, and heart rate was slowed in animals with intact or denervated hearts, or after propranolol administration. Ventricular inotropism was reduced at higher doses. Bepridil (5 mg/kg i.v.) showed a partial antagonist activity on isoprenaline cardiovascular effects (or cardiac sympathetic stimulation effects) i.e. tachycardia, increase in left dP/dt max. and diastolic hypotension. The antitachycardia activity was particularly pronounced. It was found to be non-competitive. It was also found to be non-specific since glucagon, theophylline- and papaverine-induced tachycardia were also reduced. The continuous infusion of high doses of bepridil did not cause any disturbance in atrio-ventricular or intraventricular conduction. In rats, after 50 mg/kg/day p.o., bepridil did not alter myocardial noradrenaline levels.

Pharmacological properties of 2-(2-chloro-p-toluidino)-2-imidazoline-nitrate (tolonidine), a new antihypertensive agent. II. Action on cardiac contraction, circulatory parameters, autonomic receptors and diuresis.

Tolonidine, 2(2-chloro-p-toluidino)-2-imidazoline-nitrate, is a substance chemically related to clonidine. In the anesthetized dog, tolonidine administered i.v. decreased the amplitude of ventricular contractions, reduced aortic blood flow and increased peripheral vascular resistances. In the bivagotomized pithed rat, tolonidine induced a long-lasting increase in blood pressure with no secondary hypotension, thus suggesting peripheral sympathomimetic properties, however, contractions of seminal vesicles in vitro were not obtained. The product proved to have no peripheral sympatholytic or parasympatholytic properties. In the dog and the rat, diuresis was hardly changed. These properties are closely related to those of clonidine, which was studied comparatively. A general discussion is proposed at the end of a third article.

General pharmacological properties of a new non-opiate antitussive: zipeprol (3024 CERM). II. Actions on the cardiovascular system, intestinal transit and central nervous system.

The effects of 1-(2-methoxy-2-phenyl)-ethyl-4-(2-hydroxy-3-methoxy-3-phenyl)-propyl-piperazine-dihydrochloride (zipeprol, 3024 CERM, Respilene), a new nonopiate antitussive agent, have been studied on the cardiovascular system, intestinal function and the central nervous system. Most of these studies were performed comparatively with reference antitussives, particularly codeine, whose activites in these fields are the basis of its undesirable side effects. In the dog, zipeprol showed no hypotensive or cardiac-depressant activity. It did not alter pulmonary arterial pressure. An important antiarrhythmic action was apparent in studies on rhythm disturbances induced by ouabain and coronary ligation. Intestinal function, measured by the recording of peristaltic movements in the dog and the speed of intestinal transit in the rat, was not modified by the product. Zipeprol showed no characteristic action on the central nervous system. Analgesic activity was seen only at doses just below toxic levels. Finally in the rat and the mouse, no evidence of physical dependence was seen after prolonged treatment. This together with the absence of chemical similarity to the morphinics, leads to exclude the possibility of zipeprol treatment leading to addiction. The results of these studies allow zipeprol to be clearly distinguished from the opiate antitussives.

Mechanisms of anti-bronchoconstrictive effects of eprozinol. II. In vivo studies on the guinea pig.

The possible interactions of the anti-asthmatic compound, eprozinol, with bronchoconstrictors and adrenergic agents were investigated in the anaesthetised guinea pig by means of the following techniques: (1) study of the inhibition of histamine- and serotonin-induced bronchospasm; (2) investigation of potentiation or antagonism between the anti-bronchoconstrictor effects of eprozinol and isoprenaline; (3) investigation of propranolol-induced blockade of the anti-bronchoconstrictor effects of eprozinol and several reference compounds. In the anaesthetised guinea pig, eprozinol (5 mge . kg-1), isoprenaline (2 micrograms . kg-1) and theophylline (15 mg . kg-1) administered intravenously cause a clear inhibition of the bronchospasm induced by intravenous perfusion of histamine or serotonin, with an intensity not significantly different for all three compounds. The anti-bronchoconstrictor activities of eprozinol and isoprenaline with regard to histamine are directly additive and show absolutely no interference with one another. Propranolol is without effect on in vivo anti-bronchoconstrictor activity of eprozinol on tracheal musculature. It is concluded that the mechanisms brought into play by eprozinol to exert anti-bronchoconstrictor and bronchorelaxant activity, are completely independent of the adrenergic system.

Influence of hypercapnia on the cerebrovascular activities of some drugs used in the treatment of cerebral ischemia.

The effects of twelve substances on local cerebral blood flow (LCBF) were studied in the normocapnic and hypercapnic conscious rabbit. In normocapnia, an increase in LCBF was observed after naftidrofuryl (NAF), cinnarizine (CI), viquidil (VI) and heptaminol acefyllinate (HA). The LCBF was only slightly increased or unchanged after hydrogenated ergot alkaloids (HEA), cyclandelate (CY), hexobendine (HE), ifenprodil (IF), piridoxilate (PI), vincamine (VC) and xantinol niacate (XN). It was reduced by theophylline (TH). In hypercapnia, a more pronounced increase in LCBF than in normocapnia was seen with CY, HE, NAF, and VI and a decrease or lesser effect with HA, IF, VC and XN. The decrease in LCBF with TH was enhanced by hypercapnia. The effects of CI, HEA and PI were not modified. The therapeutic implication of these modifications of drug effects by hypercapnia, is discussed.

Pharmacological properties of 2-(2-chloro-p-toluidino)-2-imidazoline-nitrate (Tolonidine), a new antihypertensive agent. I. Action on blood pressure and heart rate.

Tolonidine, 2-(2-chloro-p-toluidino)-2-imidazoline-nitrate, a substance structurally related to clonidine, was studied for its effects on blood pressure and heart rate in anesthetized or conscious, normotensive or hypertensive animals (mainly dogs). In all cases, blood pressure was lowered by tolonidine. Initial short-lasting hypertension was observed after each i.v. administration. Heart rate was markedly lowered irrespective of the experimental process. Comparison with clonidine, guanethidine and mecamylamine in hypertensive anesthetized or unanesthetized animals made it possible to place tolonidine with respect to these reference antihypertensive drugs. A close relationship essentially appears between the effects of both derivatives of imidazoline: tolonidine and clonidine, tolonidine being, however, active at higher doses. The analysis of these results will appear at the end of a series of three articles.

General pharmacological properties of a new non-opiate antitussive: zipeprol (3024 CERM). I. Action on respiratory function and acute toxicity.

1-(2-Methoxy-2-phenyl)-ethyl-4-(2-hydroxy-3-methoxy-3-phenyl)-propyl-iperazine-dihydrochloride (zipeprol, Respilene) is a substance of non-phenanthrenic chemical structure. In the cat, it antagonised cough induced by stimulation of the superior laryngeal nerve or by direct mechanical excitation of the sensitive tracheo-bronchial receptors. The efficacy of zipeprol after enteral administration made it possible both to establish good intestinal absorption and to rank it favourably in relation to several major antitussive reference products; codeine, codethyline, dextromethorphan, diphenhydramine and pentoxyverine. The activity of zipeprol was superior or equal to that of all these substances, excdept codeine. The antitussive properties appeared to be due to a central action. Other properties have been demonstrated which suggest at least a supplementary mechanism in the inhibition of cough, in addition to the central action. These consisted of slight antihistamine and anticholinergic properties, marked local-anesthetic potency and bronchospasmolytic activity. This latter property was demonstrated by the inhibition of histamine and serotonin induced bronchospasm in the guinea-pig. In vitro, using human sputum, zipeprol had a mucolytic action, shown by a decrease in sputum vis viscosity and lysis of DNA and AMPS fibrils. In the dog, at high doses, zipeprol unlike codeine, did not inhibit central stimulation of respiration by hypercapnia, in addition no modification of ventilatory dynamics or blood gases was seen. On the basis of these results, zipeprol can be considered as possessing no respiratory depressant effect even in the upper ranges of its antitussive doses.