PubMed · 8827095
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G Duc, H U Bucher. 1996. Pre-test and post-test error probability.. https://doi.org/10.1111/j.1651-2227.1996.tb14082.x
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The aim of this study was to determine the interaction potential of the new antiepileptic drug felbamate (2-phenyl-1,3-propanediol dicarbamate) with three Ca2+ channel blockers (nicardipine, nifedipine, and flunarizine), one Ca2+ channel activator (Bay K 8644; 1,4-dihydro-2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl)-phenyl]-3-pyridi ne carboxylic acid), and two methylxanthines (caffeine and aminophylline (theophylline2 . ethylenediamine)) which are all known to markedly change protective effects of conventional antiepileptic drugs. To do so, the maximal electroshock seizure test in mice (an experimental model predicting drug efficacy in the treatment of human generalized tonic-clonic seizures) was employed to (1) quantify changes in the protective efficacy and potency of felbamate produced by adjunct drugs and (2) assess the ability of aminophylline and caffeine to affect protective efficacy afforded by a submaximal protective dose of felbamate against maximal electroshock-induced seizures. Doses of adjunct drugs were selected based on their effects on the threshold for electroconvulsions and on appropriate literature. Nicardipine (10-30 mg/kg), nifedipine (5-20 mg/kg), flunarizine (2.5-10 mg/kg), Bay K 8644 (2.5-5 mg/kg), and aminophylline (50-75 mg/kg) did not change the protective efficacy and potency of felbamate against maximal electroshock-induced tonic convulsions. Aminophylline in the dose of 100 mg/kg, however, diminished the protective potency of felbamate as evidenced by a statistically significant increase in the protective ED50 value of felbamate (a dose, in mg/kg, predicted to protect 50% of mice against convulsive stimulus) from 79.6 to 118 mg/kg; P < 0.05). Aminophylline and caffeine only at high doses (100 and 161.7 mg/kg, respectively) significantly diminished the protective efficacy of felbamate (110 mg/kg) from 96% to 27% and 40% (P < 0.05), respectively. In conclusion, felbamate shows low interaction potential with Ca2+ channel modulators and methylxanthines. Such low interaction potential clearly differentiates felbamate from conventional antiepileptic drugs where protective effects are readily altered by the compounds tested in the present study.
Nimodipine, a dihydropyridine derivative central nervous system (CNS) selective calcium channel blocker was studied at four different dosage schedules in five different models of seizures in rats. At a dose of 5 mg/kg, i.p. with pretreatment time of 15 min, nimodipine significantly antagonized aminophylline (175 and 200 mg/kg, i.p.), electroshock (150 mA for 0.2 s), pentylenetetrazole (60 and 75 mg/kg, i.p.), aminophylline (100 mg/kg i.p.) + electroshock (66mA for 0.2 s), and aminophylline (100 mg/kg, i.p.) + pentylenetetrazole (40 mg/kg, i.p.) induced seizures in rats. No hemodynamic alteration was observed with this dose of nimodipine. However, 2 mg/kg, i.p. (pretreatment time of 15 min and 30 min) and 5 mg/kg, i.p. (pretreatment time of 30 min) doses of nimodipine failed to demonstrate any significant anticonvulsant effect. The study highlighted the critical role of calcium ion flux into the neurons for the genesis of seizure activity to aminophylline, electroshock, and pentylenetetrazole in rats. Furthermore, the critical dose requirement for nimodipine could be explained on the basis of its short half-life and shorter duration of protection against seizures. Therefore, nimodipine may be tried clinically as an anticonvulsant in patients who are on aminophylline because of bronchial asthma or chronic obstructive pulmonary disease, when such patients have concomitant epilepsy or other seizure prone neurological deficits or are scheduled to undergo electroshock therapy.
New layered matrix systems designed for zero-order sustained release are presented. The devices consist of a hydrophobic middle layer and press-coated hydrophillic and/or hydrophobic barrier layer(s). The systems overcome the inherent disadvantage of non-linear release associated with diffusion-controlled matrix devices by providing additional releasing surface with time to compensate for the decreasing release rate. The in vitro release of pseudoephedrine hydrochloride as a model compound from the matrices was examined. Modulation of release from a selected matrix containing aminophylline was evaluated in a crossover study using nine beagle dogs. Preliminary in vitro/in vivo correlation was also studied. The systems described in this paper can potentially be scaled up to commercial production.