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Thread: Efficacy and Safety of 4-Aminopyridine in Patients With Long-Term Spinal Cord Injury: A Randomized, Double-Blind, Placebo-Controlled Trial

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    Efficacy and Safety of 4-Aminopyridine in Patients With Long-Term Spinal Cord Injury: A Randomized, Double-Blind, Placebo-Controlled Trial

    This may have been already posted, but I've been super busy lately and haven't kept up with spinewire.
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    I'll post the first page, but it's 5 webpages long. If you want to read the whole thing, click the link.
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    Israel Grijalva, M.D., Ph.D., Gabriel Gu√ɬ*zar-Sahag√ɬļn, M.D., Ph.D., Gilberto Casta√ɬĪeda-Hern√ɬ°ndez, Ph.D., Dolores Mino, M.D., M.S., H√ɬ©ctor Maldonado-Juli√ɬ°n, M.D., Guadalupe Vidal-Cant√ɬļ, M.S., Antonio Ibarra, Ph.D., Omar Serra, M.D., Hermelinda Salgado-Ceballos, Ph.D., and Rita Arenas-Hern√ɬ°ndez, M.S.



    Abstract and Introduction
    Abstract
    Objectives: To study the efficacy and safety of 4-aminopyridine (4-AP), and to document sensorimotor changes after discontinuation of the drug in patients with long-term spinal cord injury.
    Design: Randomized, double-blind, placebo-controlled trial.
    Setting: Clinical research unit.
    Patients: Twenty-seven patients with long-term spinal cord injury.
    Intervention: Patients were randomized to receive either oral 4-AP 5 mg/day, which was increased by 5 mg/week to a maximum dosage of 30 mg/day, or placebo for 12 weeks. They switched to the opposite treatment for the next 12 weeks.
    Measurements and Main Results: Twenty-five patients finished the study. The results from the first 12 weeks were used to test efficacy. Positive gains in motor function, sensation, and independence occurred more frequently in patients receiving 4-AP (69%) than those receiving placebo (46%). Significant functional improvement was also noted in those treated with 4-AP (2, p=0.042). When each evaluation scale was considered separately, significant improvement was seen only in motor function (4-AP 92% vs placebo 46%, Fisher exact test, p=0.03). Persistent effects of the drug were assessed at week 24 in the group that initially received 4-AP. A persistent, significant 4-AP effect was observed in evaluations of sensation and independence (67% and 83% of patients, respectively; Wilcoxon signed rank test, p=0.032 and 0.042, respectively). Fourteen (56%) patients had 26 adverse reactions. One moderate adverse reaction - posterior tibial artery vasospasm - and 25 mild adverse reactions, such as dry mouth, dizziness, nausea, gastritis, oral and peripheral paresthesia, resolved adequately. Six (24%) patients experienced transitory alterations of enzyme levels (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and creatine kinase) and thrombocytopenia.
    Conclusion: Patients who received 4-AP showed significant improvement in motor function, and a persistent effect on sensation and independent function occurred. The drug is safe; however, after starting 4-AP therapy, patients must be carefully monitored for the possible occurrence of peripheral vasospasm.

    Introduction
    Spinal cord injury (SCI) in humans leads to motor, sensory, and autonomic dysfunction. No therapeutic strategy has been unquestionably accepted that significantly improves neurologic alterations in the acute[1, 2] or chronic stage.[3, 4] After SCI, many of the axons that survive in the epicenter of the injured zone are demyelinated.[5-7] Since demyelination may be an important contributing factor to long-term sensory and motor impairment,[8, 9] restoration of conduction in demyelinated fibers has been identified as an important strategy for promoting functional recovery.[9-15] Postmortem examination of humans with SCI indicates that almost two thirds have partially spared spinal cord. In about half of the patients with functionally complete injury, nerve fibers traversed the lesion site.[16] The loss of functionality can be partially due to demyelination of the preserved axons, as SCI animal models have shown.[9-15, 17]

    4-Aminopyridine (4-AP) blocks voltage-gated, fast potassium channels. The drug may be capable of improving neurologic function by restoring conduction in demyelinated axons,[8-15] enhancing synaptic efficacy,[15] potentiating transmitter release at the neuromuscular junction level,[18] and increasing skeletal muscle twitch tension.[19] Several SCI animal models have shown that 4-AP produces significant improvement in both behavioral and electrophysiologic evaluations.[9-11, 13-15, 20] Experimental studies of 4-AP in humans with SCI have demonstrated improvement in several functions.[3, 21-28]

    Single intravenous or long-term oral 4-AP administration induces a persistent neurologic gain of 24-48 hours[21, 22] to 1-2 weeks[26, 27] in some patients. However, interpretation of most clinical results of 4-AP therapy in patients with SCI is limited by the fact that the data were obtained in open trials. Interpretation is further complicated by the fact that the results of the two blinded, randomized, crossover, behavioral clinical trials reported in the literature yielded contradictory results.[3, 4]

    Concerning safety in patients with SCI, several adverse reactions occurred in those who received oral 4-AP 10-45 mg/day during treatment periods of 2 weeks-4 months. Adverse reactions included lightheadedness, nervousness, dizziness, gastric upset, nausea, and abdominal cramps.[3, 4, 26, 27] Characteristics and time dependency of these adverse reactions, however, have not been described in detail.

    Our objective was to study the efficacy and safety of 4-AP, and to document sensorimotor changes after discontinuation of the drug in patients with long-term SCI.



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    Section 1 of 5


    From the Research Medical Unit for Neurological Diseases, Specialties Hospital (Drs. Grijalva, Gu√ɬ*zar-Sahag√ɬļn, Maldonado-Juli√ɬ°n, Ibarra, Serra, and Salgado-Ceballos), and Health Research Coordination (Dr. Mino), Centro M√ɬ©dico Nacional Siglo XXI, Instituto Mexicano del Seguro Social; the Pharmacology and Toxicology Department (Dr. Casta√ɬĪeda-Hern√ɬ°ndez and Ms. Vidal-Cant√ɬļ) and the Pharmacology External Section (Ms. Arenas-Hern√ɬ°ndez), Centro de Investigaci√ɬ≥n y Estudios Avanzados, Instituto Polit√ɬ©cnico Nacional, M√ɬ©xico City, M√ɬ©xico.

    -Bob

  2. #2
    This is very interesting. Here are some initial impressions:

    1. The trial was completed in June 2000 (3 years ago).

    2. They used gelcaps and microcrystalline cellulose (which I think is the immediate release formulation) but their highest dose is a only 30 mg per day, 25% lower than the 10 mg four times a day (i.e. 40 mg/day) that most people here have gone up to. They may have gotten even better results if they went up to 40 mg/day.

    3. They did a double-blind cross-over trial with no washout period. In other words, the patients were switched from drug to placebo or from placebo to drug with no rest period between the phases to avoid any lingering effect of the drug. They in fact found that the drug effect persisted as long as 12 weeks after the drug was stopped.

    4. According to their Table 1, of 13 patients that received 4-AP in the first phase, 7 were ASIA B or B+ (I am not sure what they mean by the + sign, by the way), 4 patients were C, and one was a D. So, they were all incomplete in that group. The group that received placebo first followed by 4-AP were different. Of 13 patients, 3 were ASIA A or A+, 6 were B or B+, 2 were C, and 2 were D. I find it very interesting that they found that patients with ASIA B designation had the greatest response to the drug.

    5. They had a high placebo response rate. This is very interesting because this is what was seen in the phase 2 trials that Acorda ran.

    6. I am surprised by the relatively high incidence of enzyme alternations. They did not indicate their source of 4-AP.

    7. The discussion is careful and thoughtful. This is a useful study.

    Wise.
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