The effects of 4–aminopyridine in multiple sclerosis patients: Results of a randomized, placebo–controlled, double–blind, concentration–controlled, crossover trial

Christopher T. Bever, D. Young, P. A. Anderson, A. Krumholz, K. Conway, J. Leslie, N. Eddington, K. I. Plaisance, H. S. Panitch, S. Dhib-Jalbut, M. J. Fossler, J. Devane, K. P. Johnson

Research output: Contribution to journalArticlepeer-review

161 Scopus citations

Abstract

Because 4-aminopyridine (AP) improves residual deficits in some multiple sclerosis (MS) patients but has a narrow toxic-to-therapeutic margin, we compared the safety andefficacy of two target peak serum concentration ranges (low: 30 to 59 ng/ml and high: 60to 100 ng/ml). We enrolled eight MS patients with temperature-sensitive visual and motordeficits in a randomized, placebo-controlled, double-blind, crossover trial of short-term oral AP treatment. We randomized patients to a sequence of three treatments on three separate days: placebo, low serum concentration, and high serum concentration. We determined dosing to achieve the desired steady-state peak serum concentration ranges from a test dose and population pharmacokinetic parameters using bayesian estimation. Contrast sensitivity, standard neurologic examination, ratings of videotaped neurologic examinations, and quantitative strength assessment all improved with treatment, but flicker fusion frequency, visual evoked response latencies, and Expanded Disability Status Scale scores did not. All patients experienced side effects during the high-serum-concentration arm. A grandmalseizure occurred at a serum AP level of 104 ng/ml, and an acute confusional episode occurred at 114 ng/ml. AP treatment produced improvements in residual deficits in MS patients, but the occurrence of significant toxicity suggests that AP serum levels should be monitored and peak levels above 100 ng/ml should be avoided. Concentration-control methodology may be useful in testing putative treatments for other neurologic diseases.

Original languageEnglish (US)
Pages (from-to)1054-1059
Number of pages6
JournalNeurology
Volume44
Issue number6
DOIs
StatePublished - Jun 1994

All Science Journal Classification (ASJC) codes

  • Clinical Neurology

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