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Six barbiturates with diverse time-action characteristics--thiopental, pentobarbital, butabarbital, phenobarbital, diphenylbarbiturate, and barbital--were evaluated for "anticonvulsant" and "neurotoxic" effects. For the former, the MES test, clonic seizures induced by pentylenetetrazol, 90 mg/kg, s.c., and maximal seizures produced by pentylenetetrazol, 200 mg/kg, s.c., were employed. For the latter, we used a rotorod technique. Time to peak activity in the MES test was employed as the time for other tests. Pentobarbital required at least neurotoxic doses to produce substantial "anticonvulsant" activity, its protective index ranging from 0.79 to 0.98 in the three tests. Among the drugs tested, phenobarbital and diphenylbarbiturate exhibited the most favorable protective indices, ranging from 2.71 to 3.41 for phenobarbital and from 3.85 to 5.0 for diphenylbarbiturate. Barbital, another drug with a prolonged duration of action, exhibited a range from 0.84 to 2.81. Although a prolonged duration of action is an important characteristic for antiepileptic activity, this property does not confer per se a favorable protective index.

Because of the association of D-penicillamine (DP) therapy with myasthenia gravis, we have studied long-term DP treatment in five inbred strains of mice with doses comparable to those used in patients with rheumatoid arthritis. No clinical weakness or anti-acetylcholine receptor (AChR) antibody developed with up to 6 months of treatment, but augmented responses did occur to challenge with purified AChR in adjuvant. Anti-AChR antibody titers in C57BL/6 and C3H/He mice were significantly higher after challenge with AChR in DP-treated than in control mice. Augmented anti-AChR titers were not seen in strain A mice, but after 6 months of DP treatment increased susceptibility developed to the induction of experimental autoimmune myasthenia gravis. Nine weeks after challenge with purified AChR, 10 of 11 mice developed clinical weakness, leading to death in 6. Results of edrophonium testing were positive in 5 of 6 mice, and electrophysiological abnormalities were demonstrated in 3 of the surviving mice. Long-term DP treatment is associated with augmented anti-AChR antibody responses in C3H/He and C57BL/6 mice, and increased susceptibility to experimental autoimmune myasthenia gravis in strain A mice.

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