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At least 19 recordsLinked to original sources
PubMed2001

Aminopyridines for symptomatic treatment in multiple sclerosis.

BACKGROUND: Because of their ability to increase nerve conduction in demyelinated nerve fibers, potassium channel blockers 4-aminopyridine (AP) and 3,4-diaminopyridine (DAP) have been proposed as a symptomatic therapy for people with multiple sclerosis (MS). OBJECTIVES: To determine the efficacy and safety of aminopyridines in improving neurological deficits in people with MS. SEARCH STRATEGY: Computerised general (MEDLINE, EMBASE) and specialised databases (Cochrane MS Group's trials register, CCTR). Hand search of bibliographic references from retrieved studies and recent MS symposia reports. Contact with principal investigators of known studies. SELECTION CRITERIA: Trials were included if they fulfilled all following criteria: randomised controlled trials (RCTs); adults with MS, out of exacerbation; AP or DAP treatment versus placebo; clinical endpoints. DATA COLLECTION AND ANALYSIS: We identified 26 potentially pertinent studies. Three reviewers independently extracted data and assessed trial quality from the 16 studies available as full papers. MAIN RESULTS: Five studies (six publications) and 144 participants were considered in this review. Two more abstracts are awaiting assessment. All five studies were single-centre, double-blind, crossover trials. Four studies assessed the efficacy of AP versus placebo, one compared DAP with active placebo. The duration of treatment ranged from hours to three months. The median quality score of the studies was 3 (range 2-5). The heterogeneity of outcome assessment and the absence of information on individual study periods, allowed quantitative pooling of results for few categorical variables. Of the 144 treated patients, there were six major side effects: one acute encephalopathy, three episodes of confusion, and two seizures. Manual muscle testing was assessed in three studies (54 patients), with 29 patients (54%) improving in at least one muscular district during study treatment versus four patients (7%) during placebo (odds ratio [OR] 14.5, 95% confidence interval [CI] 4.7-43.7). Ambulation was assessed in three studies (54 patients): 9 patients (17%) improved during study treatment versus none during placebo (p<0.001). An improvement in EDSS score was found in 13 of the 144 participants during study treatment (9%) versus none during placebo (p<0.001). No improvement in neuropsychological tests was found in the two trials that evaluated cognitive function. Finally, 47 of 136 people with MS (35%) felt improved when receiving the study drug, against 7(5%) on placebo (OR 9.7, 95% CI 4.3-22.0). REVIEWER'S CONCLUSIONS: Based on currently available information, no unbiased statement can be made about the safety or efficacy of aminopyridines for treating MS symptoms. Furthermore, we could not obtain any data on three unpublished RCTs involving more than 300 participants. We conclude that publication bias remains a pervasive problem in this area, and that until the results of these unpublished studies are available to the scientific community, no confident estimate of effectiveness of aminopyridines in the management of MS symptoms is possible.

4-Aminopyridine↗
PubMed1994

4-Aminopyridine is superior to 3,4-diaminopyridine in the treatment of patients with multiple sclerosis.

OBJECTIVE: To compare the efficacy and toxicity of 4-aminopyridine and 3,4-diaminopyridine in patients with multiple sclerosis. DESIGN: Intervention study with a before-after design and a randomized, double-blind, crossover design. SETTING: University referral center. PATIENTS: Twenty-four patients with definite multiple sclerosis who had been treated in a previous clinical trial with 4-aminopyridine. INTERVENTIONS: Nonresponders to treatment with 4-aminopyridine (14 patients) were treated with 3,4-diaminopyridine in a 4-week, open-label trial with doses up to 1.0 mg/kg of body weight (before-after design). Responders to treatment with 4-aminopyridine (10 patients) participated in a comparative study of 6 weeks' duration with 4-aminopyridine and 3,4-diaminopyridine according to a randomized, double-blind, double-crossover design. MAIN OUTCOME MEASURES: Neurophysiologic variables for nonresponders, neurologic functions and symptoms on a visual analogue scale for responders, and side effects for both groups. RESULTS: Toxicity profiles of 4-aminopyridine and 3,4-diaminopyridine were different, and systemic tolerability was reduced for 3,4-diaminopyridine. 4-Aminopyridine was more effective than 3,4-diaminopyridine, especially for ambulation, fatigue, and overall daily functioning. CONCLUSION: Our data suggest that, concerning both efficacy and side effects, 4-aminopyridine is superior to 3,4-diaminopyridine in the treatment of patients with multiple sclerosis.

4-Aminopyridine↗
PubMed1997

Stimulated single-fiber electromyography in Lambert-Eaton myasthenic syndrome before and after 3,4-diaminopyridine.

A patient with LEMS unrelated to cancer was studied by stimulated single-fiber electromyography (SFEMG) before and 3 months after the onset of therapy with 3,4-diaminopyridine. All end-plates showed a progressive reduction in blockings and jitter with the increase in stimulation rate. Treatment significantly corrected this feature, but the overall pattern of frequency-improved jitter remained. Such widespread finding is rare but diagnostic for Lambert-Eaton myasthenic syndrome. Stimulated SFEMG can be used to monitor therapy in such patients.

4-Aminopyridine↗
PubMed1998

Effect of 3,4-diaminopyridine on the time course of decay of compound muscle action potential augmentation in the Lambert-Eaton myasthenic syndrome.

3,4-Diaminopyridine (3,4-DAP) is known to be beneficial in the symptomatic treatment of the Lambert-Eaton myasthenic syndrome (LEMS). The effects of 3,4-DAP on the decay of postexercise augmentation were observed in 6 patients with LEMS. After 10 s maximal voluntary contraction, the amplitude of the compound muscle action potential (CMAP) recorded from abductor digiti minimi decayed exponentially after an initial rise. The rate of decay in CMAP amplitude was increased after treatment with 3,4-DAP, suggesting that this drug has an effect on the efflux of calcium ions from the presynaptic nerve terminal.

4-Aminopyridine↗
PubMed2003

Treatment for Lambert-Eaton myasthenic syndrome.

BACKGROUND: Lambert-Eaton myasthenic syndrome is an autoimmune presynaptic disorder of neuromuscular transmission. Treatments have attempted to overcome the harmful autoimmune process, or to improve residual neuromuscular transmission, in order to reverse the principal neurological symptom of muscle weakness. OBJECTIVES: The objective was to examine the efficacy of all forms of treatment in Lambert-Eaton myasthenic syndrome. SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group specialised trials register (September 2002), MEDLINE (January 1966 to November 2002) and EMBASE (January 1980 to November 2002). We checked the bibliographies in reports of the randomised trials and contacted authors to identify additional published or unpublished data. SELECTION CRITERIA: Types of studies: all randomised or quasi-randomised trials. TYPES OF PARTICIPANTS: all adults and children with a diagnosis of Lambert-Eaton myasthenic syndrome, with or without small-cell lung cancer. Types of interventions: any form of medical (pharmacological or physical) treatment. Types of outcome measures: Primary: change in the muscle strength scale score (Quantitative Myasthenia Gravis score), or limb muscle strength measured by myometry. Secondary: improvement in the mean amplitude of the resting compound muscle action potentials. The mean amplitude used was the mean of all muscles tested. DATA COLLECTION AND ANALYSIS: We identified three randomised controlled trials. Individual patient data were only available for one trial. MAIN RESULTS: The three eligible trials included two controlled trials of the effects of 3,4-diaminopyridine compared with placebo in a total of 38 patients with Lambert-Eaton myasthenic syndrome, one of which was of crossover design. A third crossover trial compared intravenous immunoglobulin treatment to placebo in nine patients with Lambert-Eaton myasthenic syndrome. A meta-analysis of the primary endpoint results of these trials was not possible because of differences in comparisons and endpoints and, in two trials, lack of individual patient data. EFFECTS OF 3,4-DIAMINOPYRIDINE: Two trials of 3,4-diaminopyridine reported a significant improvement in the primary endpoint of muscle strength score, or myometric limb measurement following treatment. Both trials also reported a significant improvement in the secondary endpoint of resting compound muscle action potential amplitude following 3,4-diaminopyridine, compared with placebo. A meta-analysis of the primary endpoint results was not possible because of marked differences in these two trials regarding primary outcome measures. However, a meta-analysis of the secondary endpoint (improvement in the amplitude of the mean resting compound muscle action potential) was possible. It was necessary to assume a known correlation (similarity) of the paired responses for each individual in the two treatment periods in order to properly allow for the crossover design of one of the two trials (the correlation coefficient was assumed to be 0.5 in calculations). Using this approach, meta-analysis revealed a significant overall benefit in compound muscle action potential amplitude after 3,4-diaminopyridine treatment. The overall weighted mean difference was 1.80 mV (95% confidence interval 0.82 to 2.78), favouring treatment. These results were not sensitive to the assumption made because the overall benefit estimated was still significant when the correlation was assumed to be less than 0.1. EFFECTS OF INTRAVENOUS IMMUNOGLOBULIN: A crossover trial reported a significant improvement in the primary outcome measure of myometric limb strength when patients received intravenous immunoglobulin compared to placebo infusions. This trial also demonstrated an improvement in the secondary outcome measure of change in the mean resting compound muscle action potential amplitude following intravenous immunoglobulin, but this improvement did not reach significance. Clinical improvement lasted for up to eight weeks. REVIEWER'S CONCLUSIONS: Limited evidence from randomised controlled trials showed that either 3,4-diaminopyridine or intravenous immunoglobulin improved muscle strength scores and compound muscle action potential amplitudes in patients with Lambert-Eaton myasthenic syndrome. There are insufficient data at present to quantify this treatment effect. Other possible treatments, such as plasma exchange, steroids and immunosuppressive agents have not been tested in randomised controlled trials.

4-Aminopyridine↗
PubMed1996

Toosendanin facilitates [3H]noradrenaline release from rat hippocampal slices.

Slices of hippocampus of the rat, preincubated with [3H]noradrenaline ([3H]NA), were used to investigate the effects of toosendanin on the release of [3H]NA. Toosendanin potently enhanced spontaneous 3H outflow. Seventy-four percent of the enhancement was inhibited by reserpine pretreatment. The toosendanin-induced 3H overflow was in a concentration-dependent manner (5-60 microM) both in the presence and absence of extracellular calcium. Under Ca(2+)-free conditions, the effect of toosendanin on 3H outflow was unchanged by TTX, but inhibited by Ca(2+)-chelator BAPTA-AM; dantrolene sodium failed to affect the toosendanin-induced 3H outflow, while 3,4-diaminopyridine showed an additive effect on the outflow with this substance. The findings suggest that in the absence of extracellular Ca2+, toosendanin enhances [3H]NA release through the liberation of intracellular Ca2+ stores.

4-Aminopyridine↗
PubMed1990

Preliminary trial of 3,4-diaminopyridine in patients with multiple sclerosis.

Ten patients with multiple sclerosis (MS) were enrolled in a preliminary trial of the potassium channel blocker, 3,4-diaminopyridine, to evaluate drug toxicity and pharmacokinetics. The patients were treated with oral 3,4-diaminopyridine, first with increasing single doses up to 100 mg and then with divided dosage for up to 3 weeks. Paresthesias were reported by all patients and abdominal pain was dose limiting in 6 patients. 3,4-Diaminopyridine levels and half-life varied widely from patient to patient. Cerebrospinal fluid levels of 3,4-diaminopyridine were about 10% of those in serum. Neither seizures nor epileptiform changes on electroencephalographic examination occurred. Small reversible improvements in specific neurological deficits were seen on examination in all patients and reversible improvement in visual evoked response latencies were found in 2 patients. These results suggest that further study of 3,4-diaminopyridine in patients with MS is warranted.

4-Aminopyridine↗
PubMed1993

Failure of 3,4-diaminopyridine to reverse conduction block in inflammatory demyelinating neuropathies.

3,4-Diaminopyridine was administered to 6 patients with inflammatory demyelinating neuropathies in whom partial conduction block was demonstrable. Four had Guillain-Barré syndrome and 2 had chronic inflammatory demyelinating neuropathy. Nerve conduction studies were performed before the administration of a single oral dose of 3,4-diaminopyridine, and at regular intervals thereafter. Neither resolution of conduction block nor clinical benefit were seen.

4-Aminopyridine↗
PubMed1994

The current status of studies of aminopyridines in patients with multiple sclerosis.

Because the symptomatic treatments for multiple sclerosis (MS) are limited, new approaches have been sought. Anatomical studies of MS lesions show a relative preservation of axons, and clinical studies suggest that some of the neurological impairment in patients with MS is physiological. Electrophysiological studies suggest that demyelination exposes axonal potassium channels that decrease action-potential duration and amplitude, hindering action-potential propagation. Potassium channel blockers, including aminopyridines, have been shown to improve nerve conduction in experimentally demyelinated nerves. Two potassium channel blockers, 4-aminopyridine (AP) and 3,4 diaminopyridine (DAP) have been tested in patients with MS. Preliminary studies of AP demonstrated benefit in many temperature-sensitive patients with MS, and improvement of function was found in a large randomized double-blind, placebo-controlled crossover trial of 3 months of oral treatment in 68 patients with MS. An open-label trial of DAP showed improvement in some deficits, and a double-blind placebo-controlled trial showed significant improvements in prospectively defined neurological deficits. A crossover comparison of the two agents suggested that AP produces more central nervous system side effects (dizziness and confusion), whereas DAP produces more peripheral side effects (paresthesias and abdominal pain). Both agents have rarely caused seizures. These studies suggest that aminopyridines may provide a new approach to the symptomatic treatment of MS.

4-Aminopyridine↗
PubMed2002

Improvement of dy/dy dystrophic diaphragm by 3,4-diaminopyridine.

Concerns have been raised that inotropic agents may worsen function of dystrophic muscle due to structural fragility. Studies tested the hypothesis that force increments elicited by potassium (K(+)) channel blockade can be maintained during the course of repetitive stimulation. In vitro twitch force of dy/dy dystrophic mouse diaphragm was significantly lower than normal (796 versus 1271 g/cm(2)). 3,4-Diaminopyridine (DAP) increased twitch force of dystrophic diaphragm by 111 +/- 12% (P <.0001) and increased force at stimulation frequencies of 5-50 Hz by 41-77%. During fatigue-inducing stimulation, force augmentation by DAP was well maintained in dystrophic muscle throughout 25 Hz (P =.0047) and 50 Hz (P =.0059) stimulation. These findings indicate that the K(+) channel blocker DAP augments the force of dystrophic muscle to values close to that of normal muscle over a range of stimulation frequencies. Furthermore, these functional increments can be achieved without causing force to eventually deteriorate below that of untreated dystrophic muscle during fatiguing stimulation. It is possible that DAP may be useful for the clinical management of a variety of disorders causing muscle weakness.

4-Aminopyridine↗
PubMed2007

Myasthenia gravis and Lambert-Eaton myasthenic syndrome in the same patient.

An 18-year-old-woman developed symptoms of generalized myasthenia gravis (MG). Antibodies to the acetylcholine receptor were found in her serum, but electrodiagnostic testing showed abnormalities typical of the Lambert-Eaton myasthenic syndrome (LEMS). Following thymectomy, the thymus gland showed thymic hyperplasia typical of MG, and the patient responded to treatment with 3,4-diaminopyridine and pyridostigmine. There have been few reports in the literature of MG and LEMS coexisting in the same patient. In this case, electrodiagnostic tests, antibody studies, thymus pathology, and response to treatment suggest that both disorders contributed to the patient's symptoms. Thymic hyperplasia, so far only known to be associated with MG, provides strong evidence that both diseases were symptomatic.

4-Aminopyridine↗
PubMed1987

Potassium channel blockers and impulse propagation in murine motor endplate disease.

An electrophysiologic study has been performed on motor nerves of mice affected with hereditary "motor endplate disease" (MED). Bath application of potassium channel blockers, such as tetraethylammonium and 3,4-diaminopyridine, which are almost without effect on the monophasic compound action potential of normal nerves, considerably enhanced the action potential duration in nerves from mutant mice. Furthermore, external current recordings from motor endings revealed an absence of the K-dependent waveform component in MED mice, which indicates a similar K current intensity in the terminal part of the endings and in the heminode. These observations suggest that in the mutant, unlike in normal mice, K channels play a role in action potential electrogenesis. Possible relationships with paranodal dysmyelination are discussed.

4-Aminopyridine↗
PubMed1987

Aminoglycosides and 3,4-diaminopyridine on neuromuscular block caused by botulinum type A toxin.

Impulse-evoked transmitter release was greatly reduced at frog neuromuscular junctions 3-20 days after botulinum type A toxin (BoTx) poisoning. The reduction in transmitter release was accompanied by an increased variability in the latency between the presynaptic spike and the release of transmitter. The aminoglycoside antibiotics amikacin, gentamycin, and bekanamycin, when applied at concentrations within their therapeutic levels, markedly enhanced the blockade of transmitter release in BoTx-poisoned junctions. 3,4-diaminopyridine strongly antagonized the effects of BoTx at early stages of poisoning, and the combined presynaptic effects of BoTx and aminoglycoside antibiotics provided that transmitter release was not completely blocked by the toxin. The antagonism was apparent at all frequencies of stimulation. Since the aminoglycoside antibiotics enhanced the neuromuscular block caused by BoTx, these drugs should be avoided in patients suspected of poisoning by this toxin.

4-Aminopyridine↗
PubMed1990

Veratridine and other depolarizing agents counteract the inhibitory effect of Mg2+ ions on N-methyl-D-aspartate (NMDA)-induced noradrenaline release in vitro.

Rat brain cortex slices preincubated with 3H-noradrenaline were superfused with Krebs-Henseleit solution with or without Mg2+. In the absence of Mg2+ ions, NMDA evoked 3H-noradrenaline overflow above basal efflux; this effect was concentration-dependently inhibited by Mg2+ (IC50: 19 mumol/l). Despite the presence of 1.2 mmol/l Mg2+, which is known to block cation influx through the ion channel coupled to the NMDA receptor, NMDA evoked 3H-noradrenaline release if the membrane was permanently kept depolarized by 20 or 25 mmol/l K+, 1 mumol/l veratridine or 200 mumol/1 3,4-diaminopyridine; the stimulant effect of NMDA was counteracted by 2-amino-5-phosphonovaleric acid (2-APV), a competitive antagonist at the NMDA receptor and by (+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohept-5,10-imine hydrogen maleate (MK 801), an antagonist acting at the cation channel associated with the NMDA receptor. In contrast, no stimulatory effect of NMDA in the presence of 1.2 mmol/l Mg2+ was observed when the membrane of the nerve terminals was intermittently depolarized by electrical impulses of 2 ms duration at a frequency of 1-3 Hz. It is concluded that continuous depolarization of the nerve membrane counteracts the blocking effect of Mg2+ on cation influx through the NMDA receptor-associated ion channel. Under this condition, noradrenaline release can be stimulated by NMDA receptor activation even in the presence of physiological Mg2+ concentrations.

2-Amino-5-phosphonovalerate↗
PubMed1988

Differential effects of potassium channel blockers on neurohypophysial release of oxytocin and vasopressin. Evidence for frequency-dependent interaction with the endogenous opioid inhibition of oxytocin release.

Isolated rat neurohypophyses were fixed by their stalks to a platinum wire electrode and superfused with Krebs-HEPES solution. Vasopressin and oxytocin released into the medium were determined by specific radioimmunoassays. Hormone secretion was increased by electrical stimulation of the pituitary stalk at different frequencies. The effects of several potassium channel blockers, tetraethyl-ammonium (TEA) ions, 4-aminopyridine (4-AP) and 3,4-diaminopyridine (3,4-DAP) were tested. The release of vasopressin and oxytocin evoked by electrical stimulation with 900 pulses at 15 Hz (about 900 and 1,000 microU, respectively) was about 10 times higher than that evoked by 900 pulses at 3 Hz. Both 10 and 30 mmol/l TEA enhanced the release of vasopressin evoked by stimulation at 3 and 15 Hz, by 25- and 2-fold, respectively, to attain a maximum release of about 1,800 microU per stimulation. The stimulated release of oxytocin attained a maximum of about 9,000 microU at 15 Hz in the presence of 10 mmol/l TEA or at 3 Hz with 30 mmol/l TEA. Thus, in the presence of maximally effective concentrations of TEA both stimulation frequencies (3 and 15 Hz) were equieffective in evoking release of vasopressin and oxytocin. 4-AP or 3,4-DAP enhanced the release of vasopressin evoked by 15 Hz stimulation maximally to about 1,600 microU. In the presence of 4-AP or 3,4-DAP the release of oxytocin evoked by stimulation at 15 Hz increased maximally to about 8,000 microU and that evoked by stimulation at 3 Hz to about 1,500 microU.(ABSTRACT TRUNCATED AT 250 WORDS)

4-Aminopyridine↗