Experience with receptor blockers raised the possibility that prolonged drug exposure might lead to loss of efficacy as a result of the upregulation of potassium channel synthesis. Two studies have addressed the long-term effects of AP in patients with MS. Polman and co-workers (1994a) enrolled 23 patients with MS who had treatment-related improvement during a double-blind, placebo-controlled, crossover trial of AP in an open-label study. Patients were treated for 6 to 32 months, with 20 of the 23 patients reporting sustained benefit. In general, side effects were mild, but two patients had grand mal seizures. One patient developed elevated liver function tests that improved when treatment was stopped. Bever and co-workers (1997) enrolled 22 patients with MS who had participated in studies of the pharmacokinetics of AP in an open-label safety study of the controlled release formulation of AP described previously (see Trials Addressing Formulation Issues). Patients were treated for 6 to 42 months with a total of 52 patient-years of exposure. Sixteen patients reported sustained benefit. One grand mal seizure occurred after 24 months of treatment. These studies provide no support for the idea that upregulation of potassium channel synthesis is occurring. They do show that the risk of seizures persists even after many months of treatment without side effects and that AP may have rare hepatotoxicity. The subjective benefits of AP persist in many patients with long-term treatment.
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