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PubMed1983

Absorption, distribution and excretion of 3-(sulfamoyl[14C]methyl)-1,2-benziosoxazole (AD-810) in Rats, Dogs and Monkeys and of AD-810 in Men.

Disposition of 3 - (sulfamoyl[14C]methyl) - 1,2-benzisoxazole ( [14C]AD-810) in rats, dogs and monkeys after oral administration in 20 mg/kg was studied. In preliminary human studies, healthy subjects ingested 200 mg of AD-810. [14C]AD-810 was found to be completely absorbed from digestive tracts in animals, since urinary and biliary excretion accounted for virtually total recovery of dosed radioactivity. Plasma levels reached maxima at several hours after administration in all species examined and decreased exponentially. In rats, tissue levels were virtually similar to plasma levels indicating rather even distribution in the body, and tissue radioactivity disappeared with the similar rate to plasma. Autoradiographic findings on the distribution were consistent with radiometric results. Radioactivity was evenly distributed in fetus in the pregnant rat with the similar level to maternal tissue levels. Like other sulfonamide derivatives, AD-810 was markedly taken up by erythrocytes in all species. [14C]AD-810 radioactivity was mostly excreted within 48 to 72 h after administration and its major route was urine in animals. In men, excretion of unchanged AD-810 and its metabolite in urine was found to be rather slow. No significant differences were found in absorption, distribution and excretion of radioactivity after 7 consecutive daily oral dosings of [14C]AD-810 in rats.

Animals↗
PubMed1982

Therapeutic concentration of antiepileptic drugs and the severity of epileptogenesis.

In sodium valproate monotherapy for generalized seizures and carbamazepine for partial seizures, it was found in a within-patient follow-up study that the effect-developing concentrations which were sufficient to suppress the clinical seizures were significantly higher than the effect-sustaining concentrations by which longstanding suppression was maintained. There was a delayed onset of therapeutic effect which worked to suppress the clinical and electrographic seizure manifestations, and the length of the delay depended on the nature of the epilepsy. In animal experiments, the possibility that the severity of epilepsy may become milder as a consequence of successful pharmacotherapy was reconfirmed in amygdaloid-kindled cats on chronic medication in place of kindling animals on acute prophylactic medication. Only when the established generalized seizures were completely suppressed, was the generalized seizure triggering threshold evidently elevated. Since epilepsy is a long-standing condition lasting for years to decades, short-spanned cross-sectional observations are often misleading. Whatever relationship might exist between the blood levels of antiepileptic drugs and the paroxysmal discharges in the EEG, the severity of epileptogenesis as well as the longitudinal time course must always be taken into consideration in the drug treatment of epilepsy.

Anticonvulsants↗
PubMed1982

Pharmacokinetic studies of AD-810, a new antiepileptic compound. Phase I trials.

Pharmacokinetics of 3-sulfamoylmethyl-1,2-benzisoxazole (AD-810), a new possible antiepileptic compound, were evaluated in Phase I trials in nine healthy male volunteers. The subjects, divided into three groups, were given single oral dose of 200 mg (Group A), and oral doses of 200 mg/d (B) and 400 mg/d (C) for two d, respectively. AD-810 was well tolerated by all subjects. No neurologic side effects were observed. Evaluation of the laboratory screening profiles (hematological and biochemical examination) showed no clinically significant abnormalities. Mean peak plasma concentrations of AD-810 at 5.3-6.0 h after intake were 2.9, 5.1 and 13.0 micrograms/ml in Group A, B and C, respectively, and mean elimination half-life was about 60 h. Mean concentrations of AD-810 in erythrocytes were higher than those in plasma. The unchanged AD-810 and a major metabolite, the glucuronide of the N-O cleft compound, were excreted at 48.7% and 12.4% of the given dose in the urine for 2 weeks in Group C, respectively. The results suggest that AD-810 would induce no severe adverse effects in man at plasma concentrations over 10 micrograms/ml, the therapeutic concentrations predicted from animal experiments.

Adult↗
PubMed1980

3-Sulfamoylmethyl-1,2-benzisoxazole, a new type of anticonvulsant drug. Electroencephalographic profile.

Effects of 3-sulfamoylmethyl-1,2-benzisoxazole (AD-180) were examined electroencephalographically (EEG) on seizure activities induced by several means in rats and cats. AD-810 depressed the cortical focal seizure induced by electrical stimulation of the visual cortex at doses ineffective against the thalamic and hippocampal after-discharges in cats. AD-810 suppressed both interictal spikes and secondary generalized seizures (SGS), induced by cortical application of tungstic acid gel, in intact and decerebrated rats. Suppression of the spikes and SGS by AD-810 was also observed in cats with the epileptogenic foci produced by cortical freezing. Neither spontaneous EEG pattern nor EEG arousal response was modified with AD-810. It is suggested that AD-810 supresses the epileptogenic focus activity in the cortex and blocks the seizure propagation from the cortex to the subcortical structures through the effects on the cortex.

Animals↗
PubMed1981

Effects of 3-sulfamoylmethyl-1,2-benzisoxazole (AD-810) and some antiepileptics on the kindled seizures in the neocortex, hippocampus and amygdala in rats.

Effect of 3-sulfamoylmethyl-1,2-benzisoxazole (AD-810) on kindled seizures in the neocortex, hippocampus and amygdala was studied in comparison with that of clinically proved antiepileptics, and the differences in kindled seizure development in the three areas were also studied. The amygdala more rapidly developed a generalized seizure (kindled seizure) than the hippocampus and the neocortex. Although more days of stimulation were needed, the neocortex also developed a kindled seizure similar to limbic kindled seizures. Phenobarbital, carbamazepine, dipropylacetate and diazepam showed a depressant effect on the neocortical kindled seizures. Phenytoin showed a depressant effect only when it was administered intravenously. Phenobarbital and carbamazepine depressed the hippocampal kindled seizures, while phenytoin and diazepam had little effect. Phenobarbital and diazepam caused marked depression on the amygdaloid kindled seizures, but the effect of phenytoin, carbamazepine and dipropylacetate on them was weak or negligible. AD-810 showed a depressant effect on neocortical and hippocampal kindled seizures, but not on amygdaloid ones. The profile of AD-810 is similar to that seen with carbamazepine.

Amygdala↗
PubMed1980

3-Sulfamoylmethyl-1,2-benzisoxazole, a new type of anticonvulsant drug. Pharmacological profile.

The anticonvulsant and neurotoxic properties of 3-sulfamoylmethyl-1,2-benzisoxazole (AD-810) have been demonstrated. AD-810 suppressed electrically and chemically induced maximal seizures but did not prevent minimal seizures in experimental animals. In rats, rabbits and dogs, the anticonvulsant activity of AD-810 against maximal electroshock seizures was more potent than those of diphenylhydantoin and carbamazepine. In rats, AD-810 showed more rapid onset as well as longer duration of anticonvulsant activity than the above two drugs. The anticonvulsant effect of AD-810 was reduced but not abolished by reserpine. No tolerance developed to the anticonvulsant action of AD-810 by consecutive treatment. The compound showed much less neurotoxicity and lethal toxicity than the existing antiepileptic drugs for grand mal, and also showed the least hypnotic effect by itself or by combination with hexobarbital. Thus, AD-810 possesses a profile of anticonvulsant activity most similar to that of diphenylhydantoin or carbamazepine, providing a high protective index as well as other favorable properties.

Animals↗
PubMed1996

[Treatment of the epilepsy: new drugs].

New advances in the knowledge on the physiopathogenesis of epilepsy and their relationship with sodium and calcium channels and with the excitatory and inhibitory neurotransmitters actions have recently been developed. These knowledges have produced the research on new antiepileptic drugs which action places have specially based on the known impaired mechanisms. As the conventional drugs, the new therapeutic tool have produced a great advance in the therapy of epileptic events, specially in the refractory seizures, which represent 25-30% of the whole group of epilepsies. In the present work, we review the new drugs, ones have been registered, in order to their pharmacological properties, their efficacy their safety and their clinical indications as first-election or adjuvant drugs. We also discuss their known side adverse effects.

Acetates↗