We evaluated the efficacy and safety of lamotrigine (300 and 500 mg/day) as add-on therapy in a multicenter, randomized, double-blind, parallel-group, placebo-controlled study of 216 patients with refractory partial seizures. During 6 months of treatment, median seizure frequency decreased by 8% with placebo, 20% with 300 mg lamotrigine, and 36% with 500 mg lamotrigine. Seizure frequency decreased by > or = 50% in one-third of the 500-mg group and one-fifth of the 300-mg group. Reductions in seizure frequency and seizure days were statistically significant, compared with placebo, for the 500-mg group but not the 300-mg group. Most adverse events were minor and resolved over time. Nine percent of patients on lamotrigine withdrew because of adverse experiences. Lamotrigine plasma concentrations appeared to be a linear function of dose, and the drug did not affect plasma concentrations of concomitant antiepileptic drugs. Lamotrigine was safe, effective, and well tolerated as add-on therapy for refractory partial seizures.
As a consequence of the interaction between lamotrigine and sodium valproate, a dosage reduction of lamotrigine should be considered in patients taking a combination of valproate and lamotrigine.
Forty derivatives (1-40) of pyrazolo[1,5-a]pyrimidine were synthesized and evaluated for antianxiety properties via gross behavioral observations in rats. Five of these compounds, including 5,7-dimethylpyrazolo[1,5-a]pyrimidine (6) and the 3-fluoro (7), 3-chloro (8), 3-bromo (9), and 3-iodo (10) derivatives, were selected for advanced evaluation. Although 6 and 7 had marginal activity, 8-10 had an anxiolytic effect in animals comparable to the clinically useful benzodiazepines, diazepam, and chlorodiazepoxide. Comparison with chlorpromazine indicated that 6-10 are probably not antipsychotic agents. These compounds also lacked activity in anticonvulsant and analgesic tests. Acute toxicity data (mouse, ip and po) indicated that 8-10 had excellent therapeutic ratios, although 10 was more poorly absorbed than 8 and 9. Further demonstration of anxiolytic efficacy was obtained by comparing the effects of 8 and 9 with the benzodiazepines in modifying provoked aggression in monkeys, rats (muricide), and fighting mice. The most remarkable observation, however, was that 8 and 9 had no effect, at the anxiolytic threshold, in potentiating the CNS depressant effects of ethanol or sodium barbital (po) in treated mice. In contrast, diazepam and chlorodiazepoxide potentiated this drug interaction effect at minimal anxiolytic doses.
The present study was designed to provide evidence that the behavioral effects of physostigmine are related to inhibition of brain acetylcholinesterase (AChE). Adult male Holtzman rats were trained to pole jump to a buzzer as the conditioned stimulus and to electric shock to the grid floor as the unconditioned stimulus. All drugs were given S.C. as base. Physostigmine (0.125-0.25 mg/kg) depressed pole jump behavior in methyl a&opine (2.1 mg/kg) or saline-treated rats. (-) Hyoscyamine (1 mg/kg) blocked the actions of physostigmine, suggesting a central site of action. Total brain acetylcholine (ACh) and AChE were determined in various groups of animals. The increase in brain ACh and the decrease in AChE activity were negatively correlated in physostigmine-treated rats. These changes were highly correlated during the onset and peak of physostigmine behavioral effects but not during the recovery period. Although (-) hyoscyamine antagonized the behavioral effects of physostigmine, it did not alter the increase in brain ACh or decrease in brain AChE. It is concluded that most of the behavioral effects of physostigmine are related to central AChE inhibition.
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