Sustained improvements in neurological function in spinal cord injured patients treated with oral 4-aminopyridine: three cases

Abstract

Preclinical trials of intravenously administered 4-Aminopyridine (4-AP) have demonstrated transient improvements in neurological function in patients with longstanding spinal cord injury (SCI). The present report describes three patients with SCI who responded favourably in preclinical trials and who were subsequently administered oral (capsule) 4-AP (10 mg b.i.d. or t.i.d.) over a 4 month interval. The three patients (two male: 1 female) all had incomplete tetraplegia (ASIA levels C and D) with the neurological level of the lesion between C5-C7. Following the administration of 4-AP the patients demonstrated marked and sustained reductions in upper (n=1) or lower extremity (n=2) spasticity. Other clinical bene®ts of 4-AP were reduced pain (n=1), restored muscle strength (n=3), improved sensation (n=2), voluntary control of bowel function (n=1), and sustained penile tumescence (n=2). The patients exhibited improved hand function (n=1), enhanced mobility in transfers and gait (n=2), with improved energy and endurance. Only trivial side eects (transient lightheadedness) were observed. In one case, the enhanced neurological function allowed the patient to stand with support for the ®rst time post injury (16 years). The time course of therapeutic response to the initial dose matched the pharmacokinetic elimination pro®le derived from serum and urine analysis. There was no evidence of renal or hepatic toxicity with prolonged use. These results indicate a therapeutic bene®t of oral 4-Aminopyridine in the management of various neurological de®cits in a select group of SCI patients.

Effect of 4-aminopyridine on gait in ambulatory spinal cord injuries: a double-blind, placebo-controlled, crossover trial

“…The lack of quantitative gait improvement contradicts studies that reported gait improvement of subjects. 8,12 This discrepancy between perceived changes in function and a lack of quantitative changes was also seen in the present trial and may be due to several issues. Positive comments from subjects may be attributed to a Hawthorne effect, high expectations 12 or differences in the definition of improvement.…”

“…Past preclinical trials on 4-AP with chronic SCI subjects reported increased muscle strength based on clinically feasible manual muscle grading using the 0-5 ordinal scale. [8][9][10] Appendix 2 outlines the extent of the published preclinical and clinical trials of 4-AP in SCI. There has not been an attempt, in the 4-AP literature, to quantify isometric muscle force using a more sensitive and accurate dynamometer.…”

“…3 Preliminary, preclinical case studies have provided information on safety, dosage and outcome changes. 8,9 Hayes et al 10 reported enhanced volitional electromyographic (EMG) signals in three incomplete SCI patients following a one time, ongoing intravenous 4-AP dose of 24 mg over 4 h. There was no similar change in the three SCI subjects with complete lesions.…”

Neuropathology: the foundation for new treatments in spinal cord injury

“…Nevertheless, their universal application makes therapeutic trials of other drugs difficult to evaluate, for example, the value of GMI gangliosides or the testing of other agents. [23][24][25] The search for a cure…”

Intrathecal administration of 4-aminopyridine in chronic spinal injured patients

“…Further studies of prolonged oral administration of 4-AP have reported maintained clinical bene®t in some patients. 6,7 Most recently, a double-blind placebo-controlled study of a sustainedrelease 4-AP formulation in chronic incomplete SCI patients has demonstrated signi®cant e cacy on a number of neurological measures. 8 Changes in conduction in motor pathways have also been documented electrophysiologically in man using transcranial magnetic stimulation.…”