Poster Communications

Abstract

It is well known that the anticonvulsant effect of antiepileptic drugs is reduced by repeated administration in both experimental animals and man (Frey and Kampmann, 1965; Masuda et al., 1979; Rawling et al., 1975). The purpose of this investigation was to verify if denzimol, an arylalkylimidazole anticonvulsant agent (Nardi et al., 1981; Graziani et al., 1983) induces tolerance after repeated treatment in mice. Phenobarbitone (PB) and carbamazepine (CB) were used as reference drugs.We have investigated the antielectroshock activity (MES) and the brain levels of denzimol, after acute and repeated treatment, to verify whether the development of denzimol tolerance involves mechanisms of adaptation of the central nervous system or an induction of hepatic microsomial enzymes.Three groups of 20 mice each were treated p.o. for 14 days with denzimol (30 mg/kg), PB (25 mg/kg) or CB (30 mg/kg). Three control groups of mice received the vehicle (0.5% methocel). 24 hours after the end of the prolonged treatment, the respective drugs and vehicle, at the same dose as above, were given to the treated and control groups of animals. The anticonvulsant effect of each drug against MES was examined at 1,2,4,6,8 hrs after the last administration. The protection against the tonic extension of forelimb (TFP) and hindlimb (THP) induced by MES was the criterium used for the assessment of positive response.After MES, animals treated with denzimol were sacrificed and brains were removed for tissue drug levels evaluation (Abbiati et al. 1985).The present study shows that repeated administrations of PB, CB and denzimol resulted in a development of tolerance to their anticonvulsant action. Tolerance induced by denzimol against TFP and THP extension, resulted lower than that of PB and probably of CB. When denzimol was administered in a single dose to denzimol tolerant mice, its brain concentrations was markedly reduced if compared to non-tolerant mice. Moreover the disappearance of brain denzimol concentrations, after a single dose of drug, was alterated by repeated treatment of mice with denzimol. These findings seem to suggest that decreased anticonvulsant activity of denzimol, following repeated administrations, might be due to a development of pharmacokinetic tolerance.Abbiati G.A., Restelli G.V., Graziani G., Testa R. (1985) In previous experim-ents we have shown that prolactin (PRL) secretion in avian species is under a tonic inhibitory control of dopa;-iine (disticb et al.,1979). The present study was carried out in order to assess the role played b, cholinergic mechanisms in the control of PRL secretion in pigeons (Columba livia). In particular, we have assessed the effects of drugs enhancing by different mechanisms cholinergic transmiission, i.e. carbachol, muscarine and physostigmine, on morphology (studied by SEM5 and TEll) of crop-sac mlucosa and pituitary lactoWrophs.Carbachol, microinfused into the III cerebral ventricle (6 nrmiol) for 3 consecutive days, produced intense crop-sac stimulation with rmiilk-like secretion and...