• The Neurologists at South Shore Neurologic Associates have been utilizing 4ap therapy for treatment of fatigue and motor performance for those with multiple sclerosis for more than 10 years with variable clinical effectiveness and excellent safety profile.

Dr. Wise Young, M.D., Ph.D.- (SpineWire):

• 4AP is a chemical that blocks the fast voltage sensitive potassium channel. In addition to 1,4-diaminopyridine (1,4-DAP), it is one of a handful of drugs that block this particular channel, which is responsible to shortening the action potential generated by sodium currents in neurons. The drug has been used by neurophysiologists for decades. It has not yet been approved by the FDA for clinical use although it has been on the compounded formulary of many pharmacies and can be prescribed by physicians. It has been estimated that over 10,000 people in the U.S. with multiple sclerosis or spinal cord injury are taking the drug.
• Clinically, the drug increases the duration of action potentials in demyelinated axons and also the presynaptic terminals of axons. Thus, the drug increases the safety factor of conduction in the spinal cord and increases the amount of neurotransmitter released per action potential. In the mid-1980s, the drug was used to treat multiple sclerosis; at least five small clinical trials have been carried out reporting that 4AP can increase sensory and motor function in people with multiple sclerosis. Demyelination also occurs in spinal cord injury and several clinical trials have been reported to improve motor and sensory function in about one third of people with chronic spinal cord injury, particularly in people with "incomplete" spinal cord injury. It also may reduce spasticity and pain.
• The version of the drug that is available from pharmacies is an oral and immediate release formulation which has a plasma half-life of about 3-4 hours. The recommended treatment dose is 40 mg per day, in four divided doses. In overdoses, the drug has a risk of causing seizures in patients with multiple sclerosis; however, seizures have not been reported in any spinal-injured patient who has gotten the drug in doses of 40 mg per day or less. Other side effects include restlessness, parasthesias, and increased frequency of bowel movements. Most of these side effects can be avoided by ramping up the dose over a period of several weeks.
• Acorda Therapeutics is developing a time-release formulation of the drug that can be given b.i.d. and at higher doses (due to reduced peak levels). This formulation is currently in phase 2 clinical trials and phase 3 trials are being planned. Because the compounded immediate release formula varies significantly from pharmacy to pharmacy, the FDA recently requested that Acorda Therapeutic provide its time-release formulation in a open-label clinical trial to all people who are taking compounded 4AP. The company is in the process of complying with this request. However, neither the timing nor the implementation of this open label trial is clear at the moment.

Acorda: Fampridine. ("4-aminopyridine", "4-AP"), a nerve conduction-enhancing compound which is the first ever shown to restore some neurological function to people with SCI. Fampridine has been shown to increase nerve conduction in impaired axons and to result in improved neurological function in numerous in vitro and animal studies. Several initial human trials of fampridine have also been conducted to date, involving a total of over 400 human subjects with chronic SCI or multiple sclerosis (MS). Patients in these trials have shown improvements in a variety of impaired functions, including increased motor, sensory, bladder, bowel and/or sexual functions, as well as reductions in muscle spasticity and/or chronic pain.

Acorda has exclusive, worldwide licenses to patents covering formulations and SCI uses of fampridine. In January 1997, Acorda entered into a collaboration with Elan Corporation of Athlone, Ireland, concerning Elan’s patented, sustained-release oral tablet formulation of fampridine. Acorda obtained an exclusive, worldwide license to Elan’s fampridine patents for SCI markets, and is responsible for all clinical development and marketing. Elan will manufacture and supply the product to Acorda. In April 1998, Acorda established a joint venture with Elan, 80% owned by Acorda, to develop fampridine for worldwide MS markets as well. Fampridine has "orphan product" designations from the U.S. Food and Drug Administration (FDA) for use in both SCI and MS.

Fampridine Background and Mechanism: Researchers have shown that, contrary to popular belief, the majority of patients with SCI do not have severed cords. Most SCI victims have blunt damage to the cord and the majority has some axons that survive the injury. However, the surviving axons often are damaged and lose part of their myelin, the insulating sheath that permits electrical impulses to be conducted down the axon. Nerve impulses "short circuit" in demyelinated axons much like electricity in a wire whose insulation is stripped. Thus, even though a demyelinated axon is alive, it cannot transmit motor or sensory impulses and the patient effectively loses the use of it. In MS the myelin sheath is damaged by the body’s own immune system, rather than by physical trauma as in SCI.Fampridine’s major action is to block specialized potassium channels on axons. These potassium channels normally "reset" the axon after a nerve impulse passes through it to enable the axon to transmit another impulse. When an axon is demyelinated after injury, large numbers of these potassium channels are exposed and "leak" potassium ions, causing the axon to "short circuit." By closing the exposed potassium channels, fampridine permits the axon to transmit impulses again, even in a demyelinated state.

• Segal JL, Pathak MS, Hernandez JP, Himber PL, Brunnemann SR and Charter RS (1999).
  Safety and efficacy of 4-aminopyridine in humans with spinal cord injury: a long-term, controlled trial. Pharmacotherapy. 19 (6): 713-23.
  Summary: STUDY OBJECTIVE: To determine the effects of the long-term administration of 4-aminopyridine (4-AP) on sensorimotor function in humans with long-standing spinal cord injury (SCI). DESIGN: Randomized, open-label, active-treatment control, dosage-blinded study. SETTING: University-affiliated, tertiary-level care, Department of Veterans Affairs Medical Center. PATIENTS: Twenty-one healthy men and women outpatients suffering from traumatic SCI (14 tetraplegic, 7 paraplegic) for 2 years or more. INTERVENTIONS: Dosages of an immediate-release formulation of 4-AP were titrated. At 3 months, 16 subjects were receiving 4-AP 30 mg/day (high dose); 5 subjects were receiving 4-AP 6 mg/day (low dose) and served as an active-treatment control group. MEASUREMENTS AND MAIN RESULTS: Composite motor and sensory scores had statistically significant increases at 3 months. Maximal expiratory pressure, maximal inspiratory pressure, forced vital capacity, and forced expiratory volume in 1 second showed clinically meaningful and/or statistically significant increases among patients receiving 4- AP 30 mg/day. These subjects also had significant decreases in spasticity (modified Ashworth Scale). Serial biochemical profiles and electroencephalographs were unchanged from baseline, and no clinically significant drug toxicity was encountered. CONCLUSIONS: Long-term oral administration of immediate-release 4-AP was associated with improvement in and recovery of sensory and motor function, enhanced pulmonary function, and diminished spasticity in patients with long- standing SCI. 4-Aminopyridine appears to be safe and relatively free from toxicity when administered orally over 3 months. Each patient who received immediate-release 4-AP 30 mg/day showed a response in one or more of the outcome measures.
• Gruner JA and Yee AK (1999).
  4-Aminopyridine enhances motor evoked potentials following graded spinal cord compression injury in rats. Brain Res. 816 (2): 446-56.
  Summary: Although several experimental and clinical studies have demonstrated the ability of 4-aminopyridine (4-AP) to restore electrophysiological and/or behavioral function following chronic spinal cord injury, the mechanism by which this occurs remains unclear. Demonstration of efficacy in rat spinal cord injury has not been reported, evidently because even relatively mild spinal cord contusions that produce only minor permanent locomotor disturbances abolish hind limb myoelectric motor evoked potentials (mMEPs). In this study, mMEPs were recorded acutely 25 days following graded thoracic spinal cord compression in rats. mMEP amplitudes were significantly enhanced by a single, 2 mg/kg i.v. dose of 4-AP. mMEPs were increased in all rats showing some evoked responses initially, and also in some animals which had no responses prior to treatment. 4-AP was further found to increase the maximum following frequency of mMEPs in both normal and injured rats from about 0.1 Hz to between 1 and 10 Hz. These data suggest that 4-AP might act by enhancing synaptic efficacy, as well as enhancing conduction in spinal axons whose myelination has been rendered dysfunctional by trauma. Copyright 1999 Elsevier Science B.V.
• Segal JL and Brunnemann SR (1998).
  4-Aminopyridine alters gait characteristics and enhances locomotion in spinal cord injured humans. J Spinal Cord Med. 21 (3): 200-4.
  Summary: Recovery of useful motor function in humans with spinal cord injury (SCI) is a primary and elusive goal. In this preliminary study, we describe efforts to delineate the pharmacological effects of 4- aminopyridine (4-AP) on gait parameters in spinal cord injured humans who have retained some capacity to ambulate bipedally. A sequential entry, open label study was made of the effects of a single oral administration of an immediate-release formulation of 4-AP on the time- course profile of changes in component parameters of bipedal gait in ambulatory volunteers with chronic SCI. Nine healthy, rehabilitated, community-adapted male volunteers (six tetraparetic, three paraparetic), who sustained their injuries more than one year prior to entry into the study, ingested a single 10-mg dose of 4-aminopyridine after an overnight fast. Gait analysis parameters included velocity (meters/min), cadence (steps/min), stride length (meters), gait cycle (seconds), and double limb support (percent of gait cycle). They were measured for 24 hours using a sampling-rich strategy (nine duplicate measurements over 24 hrs). Repeated measures (randomized block) analysis of variance (ANOVA) and paired t-tests were used to test for the significance of differences between means and variances. The apparent pharmacological effect of 4-AP is associated with statistically significant changes in one or more of the component elements used to assess the characteristics and efficiency of bipedal gait. These changes in gait analysis parameters correspond temporally with the improvements in pulmonary function and heart rate variability previously described by us. 4-AP appears to enhance gait in a subset of humans with SCI. In this preliminary study we report, for the first time, an apparent effect of 4-AP on gait in spinal cord injured humans and suggest that the pharmacological effects of 4-AP may have clinically significant application in the restoration of useful motor function.
• Potter PJ, Hayes KC, Hsieh JT, Delaney GA and Segal JL (1998).
  Sustained improvements in neurological function in spinal cord injured patients treated with oral 4-aminopyridine: three cases. Spinal Cord. 36 (3): 147-55.
  Summary: 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 benefits 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 effects (transient light- headedness) were observed. In one case, the enhanced neurological function allowed the patient to stand with support for the first time post injury (16 years). The time course of therapeutic response to the initial dose matched the pharmacokinetic elimination profile derived from serum and urine analysis. There was no evidence of renal or hepatic toxicity with prolonged use. These results indicate a therapeutic benefit of oral 4-Aminopyridine in the management of various neurological deficits in a select group of SCI patients.
• Potter PJ, Hayes KC, Segal JL, Hsieh JT, Brunnemann SR, Delaney GA, Tierney DS and Mason D (1998).
  Randomized double-blind crossover trial of fampridine-SR (sustained release 4-aminopyridine) in patients with incomplete spinal cord injury. J Neurotrauma. 15 (10): 837-49.
  Summary: A randomized double-blind dose-titration crossover trial of the safety and efficacy of oral fampridine-SR (sustained release 4-aminopyridine) was conducted on spinal cord injured (SCI) patients at two centers. Twenty-six patients (n = 26) with incomplete lesions completed the trial. These patients all had chronic (>2 years) and stable neurological deficits. They received fampridine-SR 12.5 and 17.5 mg b.i.d. over a 2-week treatment period, followed by a 1-week washout and 2 weeks of placebo, or vice versa. Patients reported significant benefit of fampridine-SR over placebo on patient satisfaction (McNemar's test, p2 0.05) and quality of life scores (p2 0.01). Sensory scores (p1 0.01), including both pin prick (p1 = 0.059) and light touch (p1 = 0.058), and motor scores (adjusted to reflect only paretic segments) (p1 0.01) all yielded evidence of benefit of fampridine-SR over placebo. The Ashworth scale of spasticity was significantly (p2 0.05) reduced when patients received fampridine-SR. There were no statistically significant benefits of the drug on measures of pain or bowel, bladder and sexual function, or functional independence. Side effects of lightheadedness and nausea were transient and trivial relative to efficacy, and approximately 30 percent of patients reported a wish to continue to use fampridine-SR. The clinical benefits most likely derive from the K+ channel blocking action of the drug. Potassium channel blockade enhances axonal conduction across demyelinated internodes and enhances neuroneuronal and neuromuscular transmission in preserved axons. These results provide the first evidence of therapeutic benefit of fampridine-SR in SCI patients.
• Qiao J, Hayes KC, Hsieh JT, Potter PJ and Delaney GA (1997).
  Effects of 4-aminopyridine on motor evoked potentials in patients with spinal cord injury. J Neurotrauma. 14 (3): 135-49.
  Summary: The potassium (K+) channel-blocking agent 4-aminopyridine (4-AP) is currently being investigated for its potential therapeutic value in patients with spinal cord injury (SCI). The present study was designed to test the hypothesis that 4-AP ameliorates central motor conduction deficits in individuals with SCI. Oral 4-AP (10 mg) was administered to 19 (n = 19) SCI subjects with stable neurological deficits. Their response to the drug was monitored using motor evoked potentials (MEPs) following transcranial magnetic stimulation of motor cortex and various measures of segmental or peripheral reflex activity (F-waves, H-reflex, and M-response) recorded from lower limb muscles. The mean MEP amplitude in the extensor digitorum brevis muscle (left) was significantly (p .05) increased from x = .25 +/- .42 mV to x = .59 +/- 1.04 mV at 2 h after drug administration, and the cortical stimulation threshold was reduced (p ..05) by 5.8 percent. Similar results were obtained in all subjects exhibiting MEPs (n = 13) and in all muscles (n = 6) studied. These changes were maintained at 4 h postdrug. MEP latencies were reduced in all subjects who initially exhibited abnormally prolonged MEP latencies relative to control group (n = 13) values. F- wave, H-reflex, and M-response values (latency and amplitude) were not systematically altered by 4-AP, leading to the conclusion that it was central motor conduction that was enhanced. This interpretation was supported by observed reductions in central motor conduction time (CMCT) in the majority of SCI subjects from whom CMCT measurements were obtained, two of whom anecdotally reported improved motor control after 4-AP, and by increased MEP:M-wave amplitude ratios. The MEP:M-wave ratios indicated that the magnitude of the effect of 4-AP on motoneuron recruitment was not large, in absolute terms (4 percent motoneuron pool), but was appreciable relative to the initial level of motoneuron recruitment. These results provide the first statistically significant, objective evidence of improved functioning of the neuromuscular system in chronically injured SCI subjects receiving 4-AP and suggest that the improvements are mediated through enhanced central conduction. The results further support the emerging view that pharmaceutical management of central conduction deficits may prove to be a useful therapeutic strategy for some patients with long-standing SCI.
• Pinter MJ, Waldeck RF, Cope TC and Cork LC (1997).
  Effects of 4-aminopyridine on muscle and motor unit force in canine motor neuron disease. J Neurosci. 17 (11): 4500-7.
  Summary: Hereditary Canine Spinal Muscular Atrophy (HCSMA) is an autosomal dominant disorder of motor neurons that shares features with human motor neuron disease. In animals exhibiting the accelerated phenotype (homozygotes), we demonstrated previously that many motor units exhibit functional deficits that likely reflect underlying deficits in neurotrans-mission. The drug 4-aminopyridine (4AP) blocks voltage- dependent potassium conductances and is capable of increasing neurotransmission by overcoming axonal conduction block or by increasing transmitter release. In this study, we determined whether and to what extent 4AP could enhance muscle force production in HCSMA. Systemic 4AP (1-2 mg/kg) increased nerve-evoked whole muscle twitch force and electromyograms (EMG) to a greater extent in older homozygous animals than in similarly aged, symptomless HCSMA animals or in one younger homozygous animal. The possibility that this difference was caused by the presence of failing motor units in the muscles from homozygotes was tested directly by administering 4AP while recording force produced by failing motor units. The results showed that the twitch force and EMG of failing motor units could be significantly increased by 4AP, whereas no effect was observed in a nonfailing motor unit from a symptomless, aged-matched HCSMA animal. The ability of 4AP to increase force in failing units may be related to the extent of failure. Although 4AP increased peak forces during unit tetanic activation, tetanic force failure was not eliminated. These results demonstrate that the force outputs of failing motor units in HCSMA homozygotes can be increased by 4AP. Possible sites of 4AP action are considered.
• Segal JL and Brunnemann SR (1997).
  4-Aminopyridine improves pulmonary function in quadriplegic humans with longstanding spinal cord injury. Pharmacotherapy. 17 (3): 415-23.
  Summary: STUDY OBJECTIVE: To test the hypothesis that 4-aminopyridine (4-AP) might cause clinically evident improvement in pulmonary function in humans with chronic spinal cord injury (chronic SCI). DESIGN: Balanced, open-label study with subjects consecutively enrolled. SETTING: Spinal Cord Injury Service, university-affiliated tertiary level care Department of Veterans Affairs Medical Center. PATIENTS: Seventeen healthy men and women suffering from traumatic SCI (11 quadriplegic, 6 paraplegic patients) for more than 1 year. INTERVENTIONS: Each subject was given a single dose of 4-AP 10 mg orally in an immediate-release formulation. MEASUREMENTS AND MAIN RESULTS: Significant increases in mean values of forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), maximal inspiratory pressure (MIP), and maximal expiratory pressure (MEP) that persisted for at least 12 hours were demonstrated in quadriplegic patients beginning 6 hours after 4-AP administration. Tests of pulmonary function that demonstrated statistically significant increases at any time were also numerically, if not statistically, increased at 24 hours compared with pretreatment values obtained in 4-AP-naive subjects. CONCLUSIONS: The administration of a single dose of an immediate-release formulation of 4-AP to humans with longstanding, traumatic quadriplegia is associated with sustained, clinically meaningful, and statistically significant improvements in pulmonary function. We suggest that the administration of 4-AP may have a salutary effect in patients suffering from SCI and appears to be associated with potentially clinically significant reductions in the pathophysiologic pulmonary sequelae of SCI.
• Shi R and Blight AR (1997).
  Differential effects of low and high concentrations of 4-aminopyridine on axonal conduction in normal and injured spinal cord. Neuroscience. 77 (2): 553-62.
  Summary: Blockade of potassium channels with the drug 4-aminopyridine has been shown to effect recovery of action potential conduction in myelinated axons under a variety of pathological conditions, but the mechanism and significance of this phenomenon are not completely understood. This study examined the effects of a range of 4-aminopyridine concentrations on conduction in an experimental model of chronic spinal cord injury in guinea-pigs, using sucrose-gap recording from isolated spinal cord strips. The amplitude of the compound action potential increased in response to bath application of 4-aminopyridine, with a threshold between 0.5 and 1 microM and the peak response between 10 and 100 microns. Conduction was suppressed at concentrations of 1 and 10 mM. Uninjured white matter showed no effect on the compound potential of 4- aminopyridine below 1 mM, but there was a similar suppression at concentrations above 1 mM, accompanied by marked membrane depolarization. Peripheral nerve showed only slight action potential suppression and depolarization in the presence of 10 mM 4- aminopyridine. The sensitivity of injured axons to 1 microM 4- aminopyridine is consistent with the hypothesis that some beneficial effects of the drug seen in patients with spinal cord injury are related to improved conduction in myelinated axons, since cerebrospinal fluid levels of 4-aminopyridine should approach this concentration following clinical systemic doses, although it remains likely that synaptic effects also play a role. The blockade of action potential conduction produced by much higher levels of 4-aminopyridine in vitro is possibly a consequence of interference with the resting potential mechanism of the axon membrane, which appears to differ between central and peripheral nerve fibers.
• Shi R and Blight AR (1996).
  Compression injury of mammalian spinal cord in vitro and the dynamics of action potential conduction failure. J Neurophysiol. 76 (3): 1572-80.
  Summary: 1. White matter strips from the ventral spinal cord of adult guinea pigs were isolated in vitro, and their electrophysiological characteristics and response to controlled focal compression injury were examined. A double sucrose gap technique was used for stimulation and recording at opposite ends of a 12.5 mm-diam central well superfused with oxygenated Krebs solution. 2. The compound action potential recorded with the sucrose gap was similar in form to single fiber potentials recorded with intra-axonal electrodes, including the presence of a prolonged depolarizing afterpotential. 3. Three types of conduction block resulting from compression were identified: an immediate, spontaneously reversible component, which may result from a transient increase in membrane permeability and consequent disturbance of ionic distribution; a second component that was irreversible within 1-2 h of recording, perhaps resulting from complete axolemmal disruption; and a third component, which may have been due to disruption of the myelin sheath, that appeared to be reversible with application of 10-100 microM of the potassium channel blocker 4- aminopyridine. 4. Conduction deficits-decreased amplitude and increased latency of the compound potential-were stable between 5 and 60 min postinjury, and their intensity corellated with the extent of initial compression over a full range of severity. 5. Stimulus-response data indicate that mechanical damage to axons in compression was evenly distributed across the caliber spectrum, suggesting that the susceptibility of large caliber axons seen histopathologically after injury in vivo may be based on delayed, secondary processes. 6. The model provides the ability to monitor changes in the properties of central myelinated axons after compression injury in the absence of pathological variables related to vascular damage. This initial investigation found no evidence of secondary deterioration of axons in the 1st h after injury, although there was evidence of both transient and lasting mechanical damage to axons and their myelin sheaths.
• Hayes KC, Potter PJ, Wolfe DL, Hsieh JT, Delaney GA and Blight AR (1994).
  4-Aminopyridine-sensitive neurologic deficits in patients with spinal cord injury. J Neurotrauma. 11 (4): 433-46.
  Summary: 4-Aminopyridine (4-AP) is a potassium channel blocking agent with the ability to restore conduction in demyelinated internodes of axons of the spinal cord. The present investigation sought to obtain electrophysiologic evidence of the effect of 4-AP in ameliorating central conduction deficits in a group of patients (n = 6) with spinal cord injury (SCI). The group was selected on the basis of having temperature-dependent central conduction deficits. 4-AP (24-25 mg total dose) was delivered intravenously at 6 mgh-1 or 15 mgh-1 while somatosensory evoked potentials (SEPs) and motor evoked potentials (MEPs) were recorded as indices of central conduction. Two patients exhibited marked increases in the amplitude of cortical SEPs, and in one of these, 4-AP brought about a reduced central conduction time from L1 to cortex. Four patients revealed increased amplitude MEPs with concomitant reduction in latency indicative of enhanced conduction in corticospinal or corticobulbospinal pathways. Two of these patients demonstrated increased voluntary motor unit recruitment following 4-AP. Clinical examination revealed reduced spasticity (n = 2), reduced pain (n = 1), increased sensation (n = 1), improved leg movement (n = 3), and restored voluntary control of bowel (n = 1). These results support the hypothesis that 4-AP induces neurologic benefits in some patients with SCI. They are also consistent with the emerging concept that pharmaceutical amelioration of central conduction deficits caused by focal demyelination may contribute to the management of a select group of patients with compressive or contusive SCI.
• Hansebout RR, Blight AR, Fawcett S and Reddy K (1993).
  4-Aminopyridine in chronic spinal cord injury: a controlled, double- blind, crossover study in eight patients [see comments]. J Neurotrauma. 10 (1): 1-18.
  Summary: The potassium channel blocking drug 4-aminopyridine (4-AP) was administered to eight patients with chronic spinal cord injury, in a therapeutic trial based on the ability of the drug to restore conduction of impulses in demyelinated nerve fibers. The study was performed using a randomized, double-blind, crossover design, so that each patient received the drug and a vehicle placebo on different occasions, separated by 2 weeks. Drug and placebo were delivered by infusion over 2 h. An escalating total dose from 18.0 to 33.5 mg was used over the course of the study. Subjects were evaluated neurologically before and after the infusion. Two subjects returned for a second trial after 4 months and were examined daily for 3 to 4 days following drug infusion. Side effects were consistent with previous reports. Administration of the drug was associated with significant temporary neurologic improvement in five of six patients with incomplete spinal cord injury. No effect was detected in two cases of complete paraplegia and one of two severe incomplete cases (Frankel class B). Improvements in neurologic status following drug administration included increased motor control and sensory ability below the injury, and reduction in chronic pain and spasticity. The effects persisted up to 48 h after infusion of the drug, and patients largely returned to preinfusion status by 3 days. Compared with the more rapid elimination of the drug, these prolonged neurologic effects appear to involve a secondary response and are probably not a direct expression of potassium channel blockade.
• Noseworthy JH (1993).
  Clinical trials in multiple sclerosis. Curr Opin Neurol Neurosurg. 6 (2): 209-15.
  Summary: In this past year, there has only been modest progress in the search for an effective treatment for multiple sclerosis and its complications, although a number of carefully designed trials are in progress. No treatment predictably slows the course of active disease. The marginal benefits previously claimed for azathioprine have been strengthened by a meta-analysis of previously published work. Methylprednisolone may have a minor role in the treatment of very severe, acute optic neuritis but prednisone use may predispose patients to recurrent optic neuritis. 4-Aminopyridine and 3,4-diaminopyridine may prove useful for the symptomatic treatment of some multiple sclerosis patients; pemoline may be an alternative to amantadine for the control of fatigue; and acetazolamide may be an alternative to carbamazepine and phenytoin for the treatment of painful tonic spasms.
• van Diemen HA, Polman CH, van Dongen MM, Nauta JJ, Strijers RL, van Loenen AC, Bertelsmann FW and Koetsier JC (1993).
  4-Aminopyridine induces functional improvement in multiple sclerosis patients: a neurophysiological study. J Neurol Sci. 116 (2): 220-6.
  Summary: This study reports on the neurophysiological measurements that were performed in the context of a randomized, double-blind, placebo- controlled, cross-over study with intravenously administered 4- aminopyridine (4-AP) in 70 patients with definite multiple sclerosis (MS). A beneficial effect of 4-AP was found for both visual evoked response and eye movement registration parameters. This study extends the experimental data obtained on animal nerve fibers, showing that 4- AP can improve impulse conduction in demyelinated nerve, to clinical data which indicate that 4-AP induces an objective improvement in the central nervous system function in MS-patients. It thereby also provides a theoretical basis for clinical efficacy of 4-AP in MS.
• Hayes KC, Blight AR, Potter PJ, Allatt RD, Hsieh JT, Wolfe DL, Lam S and Hamilton JT (1993).
  Preclinical trial of 4-aminopyridine in patients with chronic spinal cord injury. Paraplegia. 31 (4): 216-24.
  Summary: 4-Aminopyridine (4-AP) is a K+ channel blocking agent that enhances nerve conduction through areas of demyelination by prolonging the duration of the action potential and increasing the safety factor for conduction. We have investigated the effects of 4-AP (24 mg total dose- intravenous) in 6 patients with spinal cord injury (3 complete, 3 incomplete) with the intent of overcoming central conduction block, or slowing, due to demyelination. Vital signs remained stable and only mild side effects were noted. The 3 patients with incomplete injuries all demonstrated enhanced volitional EMG interference patterns and one patient exhibited restored toe movements. The changes were reversed on drug washout. There were no changes in segmental reflex activities. These results are consistent with those obtained from 4-AP trials with animal models of spinal cord injury, showing modest therapeutic benefit attributable to enhanced central conduction.
• van Diemen HA, Polman CH, van Dongen TM, van Loenen AC, Nauta JJ, Taphoorn MJ, van Walbeek HK and Koetsier JC (1992).
  The effect of 4-aminopyridine on clinical signs in multiple sclerosis: a randomized, placebo-controlled, double-blind, cross-over study. Ann Neurol. 32 (2): 123-30.
  Summary: To find out whether treatment with 4-aminopyridine is beneficial in multiple sclerosis (MS), 70 patients with definite MS entered into a randomized, double-blind, placebo-controlled, cross-over trial in which they were treated with 4-aminopyridine and placebo for 12 weeks each (maximum dose, 0.5 mg/kg of body weight). The estimated effect of the treatment as measured with the Kurtzke expanded disability status scale, which was the main evaluation parameter, was 0.28 point (p = 0.001). A significant decrease in the scale score (1.0 point or more) was encountered in 10 patients (16.4 percent) during oral treatment with 4-aminopyridine whereas it was not seen during placebo treatment (p less than 0.05). A significant subjective improvement (defined as an improvement that significantly affected the activities of normal daily life) was indicated by 18 patients (29.5 percent) during 4-aminopyridine treatment and by 1 patient (1.6 percent) during placebo treatment (p less than 0.05). Significant improvements related to 4-aminopyridine occurred in a number of neurophysiological parameters. No serious side effects were encountered. However, subjective side effects such as paresthesias, dizziness, and light-headedness were frequently reported during 4-aminopyridine treatment. Analysis of subgroups revealed that there was no difference in efficacy between those patients randomized to receive 4-aminopyridine and then placebo and those randomized to receive placebo and then 4-aminopyridine or between patients with and those without subjective side effects. Especially patients with temperature- sensitive symptoms and patients characterized by having a longer duration of the disease and being in a progressive phase of the disease were likely to show clear clinical benefit.
• Stefoski D, Davis FA, Fitzsimmons WE, Luskin SS, Rush J and Parkhurst GW (1991).
  4-Aminopyridine in multiple sclerosis: prolonged administration. Neurology. 41 (9): 1344-8.
  Summary: In an earlier study, we demonstrated efficacy of single oral doses of 4-aminopyridine (4-AP) in improving motor and visual signs in multiple sclerosis (MS) patients for a mean of 4.97 hours. We attempted to determine whether efficacy could safely be prolonged using multiple daily doses over several days by administering 7.5 to 52.5 mg 4-AP to 17 temperature-sensitive MS patients in one to three daily doses at 3- to 4-hour intervals over 1 to 5 days in a double-blind study. Nine of these patients were also tested with identically appearing placebo. Thirteen of the 17 patients (76 percent) given 4-AP showed clinically important motor and visual improvements compared with three of nine in the placebo group. Average peak improvement scores were 0.40 for 4-AP and 0.12 for placebo. Seventy percent of the daily 4-AP improvements lasted 7 to 10 hours. The improvements for two consecutive doses of 4- AP lasted a mean of 7.07 hours (83 percent of the average 8.53-hour treatment- observation period) compared with 2.36 hours for placebo (26 percent of the average 9.06-hour treatment-observation period). No serious side effects occurred. 4-AP is a promising drug for the symptomatic treatment of MS.
• Blight AR, Toombs JP, Bauer MS and Widmer WR (1991).
  The effects of 4-aminopyridine on neurological deficits in chronic cases of traumatic spinal cord injury in dogs: a phase I clinical trial. J Neurotrauma. 8 (2): 103-19.
  Summary: A Phase I trial of 4-aminopyridine (4-AP) was carried out in 39 dogs referred to the veterinary teaching hospital with naturally occurring traumatic paraplegia or paraparesis. The rationale for the study was provided by the observation that 4-AP restores conduction in demyelinated nerve fibers in experimental spinal cord injury. Most injuries (77 percent) resulted from degenerative disk disease, occurring at or near the thoracolumbar junction, and producing chronic, complete paraplegia. Neurological examination of each dog was recorded on videotape before and at intervals after administration of 4-AP. The drug was administered systemically in total doses between 0.5 and 1 mg/kg body weight. Three areas of neurological status changed significantly at 15-45 minutes following administration of 4-AP: (a) striking improvements in hindlimb placing occurred in 18 animals; (b) increased awareness of painful stimuli to the hindlimb in 10 animals; (c) partial recovery of the cutaneus trunci muscle reflex of the back skin in 9 animals. These effects reversed within a few hours of administration. Other animals (36 percent) showed no change in neurological signs except a slight enhancement of hindlimb reflex tone. Significant side effects were seen in 6 dogs receiving higher intravenous doses, with elevation of body temperature and apparent anxiety, leading to mild seizures in 3 of the animals. These seizures were controlled with diazepam. The results indicate that conduction block may contribute significantly to functional deficits in closed-cord injuries and that potassium channel blockade may prove to be a valid, if limited approach to therapeutic intervention in chronic paraplegia and paraparesis.
• Hayes KC, Blight AR, Potter PJ, Brown WF, Wolfe DL, Hsieh JTC and Lam S (1991).
  Effects of intravenous 4-aminopyridine on neurological function in chronic spinal cord injured patients: preliminary observations. Third IBRO World Conf. of Neuroscience.
• Bever CT, Jr., Leslie J, Camenga DL, Panitch HS and Johnson KP (1990).
  Preliminary trial of 3,4-diaminopyridine in patients with multiple sclerosis. Ann Neurol. 27 (4): 421-7.
  Summary: 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 percent 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.
• Davis FA, Stefoski D and Rush J (1990).
  Orally administered 4-aminopyridine improves clinical signs in multiple sclerosis [see comments]. Ann Neurol. 27 (2): 186-92.
  Summary: 4-Aminopyridine (4-AP), a potassium channel blocker, restores conduction in blocked, demyelinated animal nerve. Its administration to multiple sclerosis (MS) patients produces transient neurological improvements. Vision improves after either oral or intravenous administration, whereas motor function improvement has been reported only with the latter. To assess further its potential as a practical symptomatic treatment, we studied the efficacy of single, oral doses of 4-AP on both visual and motor signs in MS. Twenty temperature-sensitive male MS patients were given either 10 to 25 mg of 4-AP or identically appearing lactose placebo capsules. Static quantitative perimetry, critical flicker-fusion, visual acuity, visual evoked potentials, and videotaped neurological examinations were monitored. All of 15 MS patients given 4-AP mildly to markedly improved. Motor functions (power, coordination, gait) improved in 9 of 13 involved, vision in 11 of 13, and oculomotor functions in 1 of 2. Improvements developed gradually at doses as low as 10 mg, usually beginning within 60 minutes after drug administration, and reversed gradually over 4 to 7 hours. No serious adverse effects occurred. No significant changes were observed in 5 MS patients given placebo. We conclude that orally administered 4- AP produces clinically important improvements in multiple, chronic deficits in MS. Further studies are warranted to assess efficacy and safety of prolonged administration.