Channel Blockers to Restore Injured SCI Functions

Dr. Shi is elaborating in details why Potassium Channel Blockers as 4-AP (Amino-Pyridine), Ampyra / Fampyra and some new kind mixed in his Lab works to restore Injured SCI Conduction.


Dr. Arvanian findings of NG-2 antibody that may improve conduction of nerves with Incomplete SCI
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3 thoughts on “Channel Blockers to Restore Injured SCI Functions

  1. Sustained improvements in neurological function in spinal cord injured patients treated with oral 4-aminopyridine: three cases. Potter PJ1, Hayes KC, Hsieh JT, Delaney GA, Segal JL.

    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 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.

    PMID:
    9554012
    [PubMed – indexed for MEDLINE]

    Link

    http://www.ncbi.nlm.nih.gov/pubmed/9554012?ordinalpos=42&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

  2. 4-Aminopyridine (4AP or Fampridine-SR): 4AP is a small molecule that restores some function in some individuals with SCI. Basically, it works by improving the conduction of intact but demyelinated neurons that often still transverse the SCI injury site in not only incomplete but clinically classified complete injuries. It has been estimated that a third of those with SCI can accrue some benefit from 4AP.

    Because demyelinated neurons have lost their insulating sheath, they no longer can transmit a signal. Without the insulating myelin, potassium channels (called fast voltage-sensitive potassium channels) are exposed on the axonal surface, letting potassium ions leak out of the axon, in turn, short-circuiting neuronal transmission. By blocking these channels, 4AP increases action potential duration, allowing signal conduction through the demyelinated sections and, as a result, increasing neurotransmitter release from the axon.

    Because its mechanism of action involves demyelinated neurons, 4AP was first tested in individuals with multiple sclerosis (MS). Both SCI and MS are disorders characterized by the loss of insulating myelin around neurons; in SCI, the loss is from injury, and with MS, it is from autoimmune-mediated causes.

    Because 4AP does not stimulate regeneration or improve any post-injury physiology or biology, it not a cure but a transient enhancer of existing function, i.e., a temporary fix.

    Once the body eliminates 4AP, benefits are lost. The sustained-release formulation of 4AP (Fampridine-SR) peaks in the blood about 2-3 hours after administration and has a half life of roughly 6-7 hours. In studies measuring the elimination of orally administered 4AP tagged with a radioactive tracer, virtually all of the drug had been eliminated 24 hours after administration. To maintain a benefit-sustaining plasma level, 4AP must be taken several times daily on an ongoing basis. In other words, any restored function will dissipate after stopping the drug.

    Surveys taken on SCI-focused websites suggest that 15% of those with SCI have taken 4AP, which is available through compounding pharmacies (i.e., pharmacies that make medicines from agents that doctors prescribe). The recommended daily dose of the immediate-release formulation made by the compounding pharmacies is 40 mg/day, administered in periodic 10-mg doses. In contrast, Acorda Therapeutics has developed a sustained-released formulation (Fampridine-SR) with a longer half life. With this formulation, a 40-mg dose can be given twice a day.

    Originally used as a bird repellent (trade name Avitrol), 4AP is not innocuous and can have significant side effects. Finding a dose that maximizes benefits while minimizing side effects has been challenging. In some, the most effective dose is close to one that causes side effects. Because 4AP stimulates the nervous system, side effects include insomnia, nervousness, tingling, increased blood pressure, heart rate, and seizures.

    In a case report, 4AP’s potential toxicity was documented in a 42-year-old man with a C3 injury, who had been taking 4AP prepared by a compounding pharmacy (ref). His 4AP pills contained 10-times the dose indicated on the label, a dose which routinely causes toxicity. As a result, he had to be taken to the hospital emergency room. According to the report, “He recovered with permanent short-term memory loss after a prolonged and complicated hospital course.”

    There seems to be some dichotomy between patients and scientists on 4AP’s risks relative to benefits. Specifically, many professional articles seem to minimize the risks while much of the anecdotal discussion posted on SCI websites suggests benefits are subtle relative to side effects.

    Acorda Therapeutics, a biotechnology company focused on spinal cord dysfunction, has been the leading force behind the development of 4AP as a function-restoring agent for SCI. In fact, many of the published papers have been authored by scientists who have close associations with Acorda.

    Unfortunately, after a decade of commitment, Acorda 4AP’s research-and-development efforts have fallen short for SCI, and the company is redirecting it efforts toward the substance’s MS benefits.

    Specifically, in 2004, the company completed two phase-3 clinical trials involving their sustained-release formula Fampridine-SR. Perhaps due to a number of confounding issues that lessened study robustness, trial results did not demonstrate sufficient statistical significance for the two endpoints measured, spasticity reduction (using the Ashworth score) and the Subject Global Impression rating. Acorda’s problems underscore the overall difficulty of selecting appropriate test endpoints for potential function-restoring interventions for chronic SCI.

    Considerable animal and human research has been carried out on 4AP over the last several decades. Some of the early animal research leading up to human trials were succinctly reviewed by Dr. Stephen Waxman (New Haven, Conn) (J Neurotrauma 10(1), 1993).

    The following summarizes in chronological order some key human studies:

    1) Hansebout et al. (Hamilton, Ontario) administered 4AP by infusion to eight subjects with chronic SCI using a randomized, crossover design, in which each patient received 4AP or placebo and then switches treatment. Improvements were noted in five of six subjects with incomplete SCI; none were observed in the two patients with complete injuries. Improvements included increased motor control and sensitivity, and reduction in pain and spasticity (J Neurotrauma 10(1), 1993).

    2) Hayes and colleagues (London, Ontario) assessed the effects of intravenous 4AP on electrophysiological conduction in six patients with SCI. Two patients had increases in amplitude of cortical somatosensory evoked potentials (SEPs), and four had increases in amplitude of motor- evoked potentials (MEPs). Clinical improvements included reduced spasticity (2) and pain (1), and increased sensation (1), leg movement (3), and bowel control (1) (J Neurotrauma 11(4), 1994).

    3) Segal et al (Long Beach, California) demonstrated that a single 10-mg dose of 4AP improved pulmonary function in patients with quadriplegia. Specifically improvements were noted in forced vital capacity, maximal inspiratory and expiratory pressure beginning six hours and lasting 12 hours after dosing (Pharmacotherapy 17(3), 1997).

    4) Potter et al. (London, Ontario) described improvements in three patients with incomplete quadriplegia who took 10-mg oral doses of 4AP twice or three times daily over four months. In addition to marked and sustained reduction in spasticity, other benefits included reduced pain (1), restored muscle strength (3), improved sensation (2), voluntary bowel control (1), erectile function (2), improved hand function (1), and enhanced transfers and gait (2). One patient stood with support for the first time since injury 16 years earlier (Spinal Cord 36(3), 1998).

    5) Potter et al (London, Ontario) reported the results of a randomized, double-blind, crossover study designed to assess the safety and efficacy of the Fampridine-SR sustained-release formulation. Twenty-six patients with incomplete SCI received either 4AP or placebo for two weeks followed by a one one-week washout period after which treatments were reversed. Improvements were reported with patient satisfaction, quality of life, sensation, motor function, and spasticity. No statistically significant benefits were documented for pain; bowel, bladder, or sexual function; or functional independence (J Neurotrauma 15(10), 1998).

    6) Segal et al (Long Beach, California) studied 4AP’s effects on ambulatory parameters in nine males (6 quadriplegic and 3 paraplegic) with some walking ability. Parameters included velocity (meters/min), cadence (steps/min), stride length (meters), gait cycle (seconds), and double-limb support (percent of gait cycle). After 4AP dosing, statistically significant changes were noted in various parameters (J Spinal Cord Med 21(3), 1998).

    7) In a randomized, dosage-blinded study, Segal et al (Long Beach, California) compared sensorimotor function in 16 subjects with SCI who had received 30-mg/day 4AP (high-dose) for three months with five subjects who received a 6-mg/day low dose. High-dose patients had decreased spasticity, and improved motor and sensory scores and pulmonary function (Pharmacotherapy 19(6), 1999).

    8) In a randomized, double-blind, crossover study, Van der Bruggen et al (Amsterdam, Netherlands) concluded that 4AP had no statistically significant effects on functional status, walking speed and vibration perception in 20 patients with incomplete SCI (J Neurol 8(8), 2001).

    9) Segal et al (Long Beach, California) compared the effects of a single 10-mg, 4AP dose on heart-rate variability – as a measure of the autonomic nervous system – in 13 subjects with SCI with 13 able-bodied controls. The difference in pre-test heart-rate variability between subjects with SCI and able-bodied controls disappeared in the 24 hours immediately after 4AP administration (Am J Ther 9(1) 2002).

    10) Grijalva and colleagues (Mexico City, Mexico) randomized 27 patients with SCI to receive an escalating 4AP dose or placebo for 12 weeks, after which treatments were reversed. Compared to placebo controls, improved motor function, sensation and independence were observed in 4AP-treated patients. The investigators noted persistent 4AP effects on sensation and independence 12 weeks after subjects were switched to placebo. Fifty-six percent of patients had adverse reactions (Pharmacotherapy 23(7), 2003).

    11) Hayes and colleagues (London, Ontario) studied pharmacokinetics in 16 patients with incomplete SCI (ASIA grade B-D) after dosing with 25-60 mg of Fampridine–SR twice daily for one week. Peak plasma concentration occurred 2.2-3.0 hours after dosing and drug half life was 5.7-6.9 hours. The investigators concluded that 1) adverse effects were mild or moderate and not dosage related and 2) this sustained release formulation was slowly absorbed and eliminated (Arch Phys Med Rehabil 85(1), 2004).

    12) Acorda Therapeutics sponsored a phase-2 clinical trial comparing subjects treated with high- or low-dose, sustained-released 4AP formulations (i.e., Fampridine SR) with placebo-treated subjects (Cardenas DD, et al, Spinal Cord 45, 2007). Each group contained ~30 subjects. Subjects had sustained incomplete injuries at least 18 months earlier (i.e., chronic injuries), ranged in age from 18 to 70 years, and had injuries between the cervical C4 and thoracic T10 levels. Eighty percent were men, and 92% were Caucasian.

    High and low-dose subjects received 40 and 25 milligrams of the drug, respectively, twice daily for four weeks. Forty-three percent of the high-dose subjects dropped out mostly due to a variety of adverse side effects. The low-dose regimen seemed to be better tolerated with an attrition rate of only 13% compared to 10% for placebo-treated subjects, respectively.

    Outcomes were evaluated by a variety of measurements, including, patient-diary questionnaires, quality-of-life assessments, erectile function, bladder and bowel management, spasticity, and clinician views of overall improvement. Although the study lacked the statistical robustness to draw firm conclusions for many of the outcome variables, some improvements seemed to accrue for quality of life, spasticity, and erectile function.

    13) Segal and colleagues (USA) evaluated 4AP’s effects on glucose tolerance in 31 individuals with injuries sustained at least a year earlier (ref). In general, individuals with SCI are prone to impaired glucose tolerance or diabetes. After fasting, subjects ingested 75 grams of glucose and completed a five-hour glucose-tolerance test, an assessment which basically measures how effectively the body can clear glucose from the blood. Before treatment, 29 of the 31 subjects had impaired glucose tolerance. In contrast, after six months of treatment with an oral, immediate-release 4AP formulation, only 12 had impaired glucose tolerance.

    14) Grijalva and associates (Mexico) evaluated the impact of 4AP on gastric emptying in patients with chronic injuries (ref). SCI can adversely affect the gastrointestinal tract, slowing the movement of solids though the stomach and colon. Signs of a neurogenic bowel include fecal impaction, constipation, abdominal distention, prolonged bowel care, and delayed colonic transit. It has been estimated that 41-86% of individuals with SCI have some of these problems, and 41% spend at least one hour daily on bowel care.

    In this specific study, 18 subjects with chronic SCI (9 with cervical injuries and 9 with thoracic injuries) were given daily oral doses of 4AP for 12 weeks. Gastric emptying was measured before and after this period. The results indicated that “4AP intake in patients with chronic spinal cord injury significantly slowed gastric emptying regardless of level and ASIA score of injury.”

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