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4-AminoPyridine

  1. Phase 2 trial of sustained-release Fampridine in chronic Spinal Cord Injury
    Spinal Cord 2007 Feb;45(2):158-68

  2. 4-AminoPyridine Blocks Potassium Channels

  3. Effects of 4-AminoPyridine on DeMyelinated Axons, Synapses and muscle tension
    Brain 2000 Jan;123(Pt 1):171-184

  4. 4-AminoPyridine enhances co-ordinated movements
    J Neurol Sci 1998 Jul 15;159(1):102-106

  5. The effects of 4-Aminopyridine and TetraEthylAmmonium Ions on normal and DeMyelinated mammalian Nerve Fibers
    J Physiol (Lond) 1981;313:301-15

  1. Pharmacokinetic studies of single and multiple oral doses of Fampridine-SR (sustained-release 4-AminoPyridine) in patients with chronic Spinal Cord Injury
    Clin NeuroPharmacol 2003 Jul-Aug;26(4):185-92

  2. Fatigue in Progressive Multiple Sclerosis: results of a randomized, double-blind, placebo-controlled, crossover trial of oral 4-AminoPyridine
    Mult Scler 2001 Dec;7(6):354-8

  3. 4-AminoPyridine Eases MS Symptoms
    Neurology 1997 Apr;48(4):817-821

  4. Effects of 4-AminoPyridine on stretched mammalian Spinal Cord: the role of Potassium Channels in Axonal Conduction
    J NeuroPhysiol 2003 Oct;90(4):2334-40

  5. Pathological changes of isolated Spinal Cord Axons in response to mechanical stretch
    NeuroScience 2002;110(4):765-77

  6. Fampridine-SR in Multiple Sclerosis: a randomized, double-blind, placebo-controlled, dose-ranging study
    Mult Scler 2007 Apr;13(3):357-68

  7. Effect of 4-AminoPyridine on Gait in ambulatory Spinal Cord Injuries: a double-blind, placebo-controlled, crossover trial
    Spinal Cord 2004 Dec;42(12):674-85

  8. Dose comparison trial of sustained-release Fampridine in Multiple Sclerosis
    Neurology 2008 Oct 7;71(15):1134-41

  9. Sustained-Release Fampridine for Symptomatic Treatment of Multiple Sclerosis (October) (CE)
    Ann Pharmacother 2008 Sep 9



WWW Links

  1. Ampyra (Dalfampridine)

  2. Acorda Therapeutics Announces Positive Data from Second Phase 3 Study of Fampridine-SR on Walking Ability in People with Multiple Sclerosis
    by: Acorda Therapeutics

  3. 4-AminoPyridine and Ampyra
    by: Larry & Patricia Frieders, Compounding Pharmacists




#1

Pharmacokinetic Studies Of Single And Multiple Oral Doses Of Fampridine-SR (Sustained-Release 4-AminoPyridine) In Chronic Spinal Cord Injury

Hayes KC, Potter PJ, Hansebout RR, Bugaresti JM, Hsieh JT, Nicosia S, Katz MA, Blight AR, Cohen R
Clin NeuroPharmacol 2003 Jul-Aug;26(4):185-92
University of Western Ontario and Lawson Health Research Institute, London, Ontario, Canada
PMID# 12897638
Abstract

Fampridine (4-AminoPyridine) is a Potassium Channel blocking agent that restores Conduction in DeMyelinated Axons and improves Neurologic function in patients with chronic Spinal Cord Injury (SCI).

Based on the pharmacokinetic profile of orally administered Fampridine, multiple daily doses (4 or more) would need to be taken to sustain its therapeutic effects.

Two studies were conducted to determine the pharmacokinetics and safety profile of an oral, sustained-release (SR) formulation of Fampridine (Fampridine-SR, 10-25 mg) administered as a single dose (n = 14) and twice daily for 1 week (n = 16) in patients with chronic, incomplete SCI.

Mean plasma concentrations and area under the plasma concentration-time curve were proportional to the dose administered, whereas other pharmacokinetic parameters were independent of dose.

Fampridine-SR was absorbed slowly (peak plasma concentration shortly after dosing, 2.6-3.7 hours) and eliminated (plasma half-life, 5.6-7.6 hours).

And reached steady state after 4 days of twice-daily administration. Fampridine-SR was well tolerated, with only mild to moderate adverse events reported, and no serious adverse events.

The extended plasma half-life of Fampridine-SR allows convenient twice-daily dosing. Clinical trials designed to assess Neurologic and Functional Improvement using Fampridine-SR in patients with chronic SCI are currently underway.



#2

Fatigue In Progressive Multiple Sclerosis: Results Of A Randomized, Double-Blind, Placebo-Controlled, Crossover Trial Of Oral 4-AminoPyridine

Rossini PM, Pasqualetti P, Pozzilli C, Grasso MG, Millefiorini E, Graceffa A, Carlesimo GA, Zibellini G, Caltagirone C
Mult Scler 2001 Dec;7(6):354-8
AFaR-Ospedale San Giovanni Calibita Fatebenefratelli, Rome, Italy
PMID# 11795455
Abstract

Previous studies suggest that AminoPyridine may play a role in the symptomatic treatment of Fatigue in Multiple Sclerosis.

Although the mechanism underlying the beneficial effect on Fatigue remains unclear, it has been proposed that AminoPyridines may help to improve Conduction in DeMyelinated Central Pathways, implicating both Axonal and Synaptic mechanisms.

The objective of the present study is to determine whether 4-AP decreases daily-living Fatigue in Progressive Multiple Sclerosis.

The effect of 4-AP on other NeuroPhysiological and NeuroPsychological parameters was also considered. A 'double-blind', randomized, 'placebo-controlled', crossover trial was conducted on 54 patients with Progressive Multiple Sclerosis.

All patients received treatment with placebo and 32 mg per day of 4-AP, each for 6 months. The main outcome measure was the Fatigue Severity Scale. Secondary measures were EDSS, Cognitive Functions and NeuroPhysiological Parameters.

Forty-nine patients (91%) completed the study. Changes in Fatigue Scores, EDSS and Cognitive Functions were not significantly different between 4-AP and placebo.

However, when patients treated with 4-AP were divided into two groups according to the Serum level of 4-AP, a significant effect on Fatigue compared with placebo was observed in the 'high level' ( > 30 ng/ml) group (P = 0.05).

Synchronization of Motor Evoked Potentials improved during 4-AP with respect to placebo (P = 0.019) and this correlated positively with Fatigue reduction (P = 0.010). No relevant side effects were observed.



#3

4-AminoPyridine (sustained-release) Eases
Multiple Sclerosis Symptoms

Schwid SR, Petrie MD, McDermott MP, Tierney DS, Mason DH, Goodman AD
Neurology 1997 Apr;48(4):817-821
Univ of Rochester Medical Center, Dept of Neurology, Rochester, NY USA
UI# 97263989
Abstract

Objective
To evaluate the efficacy of 4-AminoPyridine sustained release (4-AP SR) (4-Ampridine EL-970) using quantitative measures of motor function in Multiple Sclerosis (MS) patients.

Background
In vitro 4-AP improves Conduction through DeMyelinated Axons. A previous multicenter trial of 4-AP SR using the Expanded Disability Status Scale (EDSS) as the primary outcome was unable to establish clinical efficacy.

Design & Methods
Ten MS patients with stable motor deficits (EDSS 6.0-7.5) were given 4-AP SR 17.5 mg bid and placebo for 1 week each in a double-blind, placebo-controlled, crossover trial.

Time to walk 8 meters, time to climb four stairs, Maximum Voluntary Isometric Contraction measured quantitatively (MVICT), Manual Muscle Testing (MMT), grip strength, EDSS, and the patient's global impression were measured.

    Results
  • Timed gait was improved on 4-AP SR compared with placebo in 9 of 10 subjects (p =0.02)
  • Timed stair climbing, MVICT, MMT, grip strength, and EDSS showed nonsignificant improvements on 4-AP SR
      • Based on their global impressions:
      • seven subjects preferred 4-AP SR over placebo
      • one preferred placebo
      • There were no serious side effects

Conclusion
4-AP SR improved motor function in MS patients. The quantitative outcomes used in this study, permit more sensitive evaluation of the therapeutic effect, and promise to be useful in future trials of symptomatic MS treatments.





#4

Effects of 4-AminoPyridine On Stretched Mammalian Spinal Cord: The Role Of Potassium Channels In Axonal Conduction

Jensen JM, Shi R
J NeuroPhysiol 2003 Oct;90(4):2334-40
Purdue University, Center for Paralysis Research, Department of Basic Medical Sciences, West Lafayette, Indiana 47907, USA
PMID# 12853442
Abstract

Axonal conduction deficit is a major contributor to various degrees of disability after Spinal Cord Injury.

4-AminoPyridine (4-AP), a Potassium Channel blocker, has been shown to restore some Conduction and improve Neurological function in both animal and human studies.

Using a double sucrose-gap recording device, we have examined the effects of 4-AP on isolated guinea pig Spinal Cord White Matter after stretch injury.

At a concentration of 100 microM, 4-AP increased the amplitude of the compound action potential by 100% while 1 microM 4-AP increased it by 43%, a larger response than seen following compression injury.

The length of affected tissue is suggested as a potential explanation of this differential sensitivity to 4-AP.

Plastic sections taken from the injury site revealed severe Myelin damage, especially in the ParaNodal Area, which may also partially explain why 4-AP has more effect on Conduction after stretch injury than compression.

In addition, we have shown that while enhancing Conductivity in some Axons, 4-AP significantly reduced the overall responsiveness to multiple stimuli.

As evidenced by increase of the refractory period in response to dual stimuli and the decreased ability to follow repetitive stimuli.

This increased refractoriness may be largely attributed to residual deficits in fibers newly recruited by 4-AP treatment.



#5

Pathological Changes Of Isolated Spinal Cord Axons In Response To Mechanical Stretch

Shi R, Pryor JD
NeuroScience 2002;110(4):765-77
Purdue University, School of Veterinary Medicine, Department of Basic Medical Sciences, Institute for Applied Neurology, Center for Paralysis Research, West Lafayette, IN 47907-1244, USA
PMID# 11934483
Abstract

White Matter strips extracted from adult guinea-pig Spinal Cords were maintained in vitro and studied physiologically using a double sucrose gap technique and anatomically using a horseradish peroxidase assay.

The amplitude of compound Action Potentials was monitored continuously before, during, and after elongation. Three types of Conduction Blocks resulting from stretch injury were identified:

  1. An immediate, spontaneously reversible component, which may result from a transient increase in membrane permeability and consequent disturbance of Ionic distribution
  2. A second component that was irreversible within 30-60 min of recording, perhaps resulting from profound Axolemmal disruption
  3. A third component, which may be due to perturbation of the Myelin Sheath, that was reversible with application of 100 microM of the Potassium Channel blocker, 4-AminoPyridine (4-AP)

The intensity of the Conduction deficits correlated with the extent of initial stretch over a full range of severity.

Stimulus-response data indicate that mechanical damage to Axons in stretch was evenly distributed across the caliber spectrum.

Morphological examinations revealed that a small portion of Axons exhibited membrane damage at 2 min following stretch and appeared to be largely sealed at 30 min after injury.

Further, in the entire length of the Cord strip subjected to stretch, Axons closer to the surface were found to be more likely to suffer membrane damage, which distinguished stretch injury from compression injury.

In summary, we have developed an in vitro model of Axonal stretch that provides the ability to monitor changes in the properties of Central Myelinated Axons following stretch injury in the absence of pathological variables related to Vascular damage.

This initial investigation found no evidence of secondary deterioration of Axons in the first 30 min after stretch in vitro, although there was evidence of both transient and lasting physiological and anatomical damage to Axons and their Myelin Sheaths.



#6

Fampridine-SR In Multiple Sclerosis: A Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Study

Goodman AD, Cohen JA, Cross A, Vollmer T, Rizzo M, Cohen R, Marinucci L, Blight AR
Mult Scler 2007 Apr;13(3):357-68
University of Rochester, Department of Neurology, Rochester, NY 14642, USA
PMID# 17439905
Abstract

Objective
To determine the safety of sustained-release 4-AminoPyridine in subjects with Mutiple Sclerosis (MS) and to examine dose-related efficacy up to 40 mg twice daily.

Method
Multicenter, randomized, double-blind, placebo-controlled, study. Following a 4-week baseline peroid, subjects were randomly assigned to receive Fampridine-SR (n=25, doses from 10 to 40 mg twice daily, increasing in 5 mg increments weekly) or placebo (n=11).

A battery of assessments was performed weekly, including the MS Functional Composite (MSFC), fatigue questionnaires, and lower extremity manual muscle testing.

Results
The most common adverse events were Dizziness, Insomnia, Paresthesia, Asthenia, Nausea, Headache, and Tremor.

Five subjects were discontinued from Fampridine-SR because of adverse events at doses greater than 25 mg, and these included Convulsions in two subjects at doses of 30 and 35 mg twice daily.

Improvement were seen in lower extremity muscle strength (prospective analysis) and walking speed (post-hoc analysis) in the Fampridine-SR group compared to placebo (unadjusted p-values of 0.01 and 0.03, respectively).

There were no significant differences in other MSFC measure or fatigue scores.

Conclusions
Future studies should employ doses up to 20 mg twice daily with lower extremity strength and walking speed as potential outcome measures.



#7

Effect Of 4-AminoPyridine On Gait In Ambulatory Spinal Cord Injuries: A Double-Blind, Placebo-Controlled, Crossover Trial

DeForge D, Nymark J, Lemaire E, Gardner S, Hunt M, Martel L, Curran D, Barbeau H
Spinal Cord 2004 Dec;42(12):674-85
University of Ottawa, Division of Physical Medicine and Rehabilitation, Ottawa, Ontario, Canada
PMID# 15356676
Abstract

Animal and human research have shown that the drug 4-AminoPyridine (4-AP) may improve Gait in Spinal Cord lesions by enhancing nerve transmission to affected muscles.

Study Design
Prospective, randomized, double-blind, placebo-controlled, crossover trial.

Objectives
To determine the efficacy of 4-AP in improving lower limb muscle strength and biomechanical Gait patterns of Chronic Spinal Cord Injuries (SCI).

Setting
The Rehabilitation Centre (Ottawa, Canada).

Methods
In all, 15 chronic, ambulatory SCI persons were randomized to an initial 2 weeks of 40 mg/day, oral medication of either placebo or immediate-release, 4-AP.

And, subsequently crossed over to the alternate medication for the following 2 weeks.

Evaluations were conducted at baseline (before starting 4-AP or placebo medication), 2 weeks, and 4 weeks.

Measures included Dynamometer Lower Limb Isometric Muscle Force and BioMechanical Gait Measures including Temporal-Spatial Parameters, ElectroMyographic Activation Patterns, Joint Kinematics and Kinetics.

Subjective impressions of the drug by the participants were obtained from an exit survey.

Results
Despite some positive comments from subjects:

Statistical and clinical analyses showed no within-subject differences between placebo and 4-AP measures of lower limb muscle force and Objective Gait Analyses (ANOVA statistic P > 0.05).

Conclusion
Results demonstrated the importance of placebo-controlled trials and quantitative outcome measures for the evaluation of 4-AP aimed to enhance Gait for Chronic, Ambulatory SCI persons.

Energy expenditure measures and mood may relate more to subjective comments and is suggested for future investigations.



#8

Dose Comparison Trial Of Sustained-Release Fampridine In Multiple Sclerosis

Goodman AD, Brown TR, Cohen JA, Krupp LB, Schapiro R, Schwid SR, Cohen R, Marinucci LN, Blight AR; For the Fampridine MS-F202 Study Group
Neurology 2008 Oct 7;71(15):1134-41
University of Rochester, Department of Neurology, NY; Evergreen Hospital Medical Center, Department of Neurology, Seattle, WA; Cleveland Clinic Foundation, Department of Neurology, OH; Stony Brook University Hospital, Department of Neurology, NY; Minneapolis Clinic of Neurology, MN; and Acorda Therapeutics, Inc., Hawthorne, NY
PMID# 18672472
Abstract

Objective
To examine the efficacy and safety of three different doses of sustained-release Fampridine in people with Multiple Sclerosis (MS).

Method
This multicenter, randomized, double-blind, placebo-controlled, parallel-group study recruited 206 participants at 24 centers in the United States and Canada.

After a single-blind, 2-week placebo run-in, participants were randomly assigned to receive Fampridine (10, 15, or 20 mg twice daily) or placebo for 15 weeks.

The primary efficacy variable was percent change in walking speed based on the timed 25-foot walk.

Results
Trends for increased walking speed were consistent across dose groups vs placebo, but not significant, on the prospective analysis.

An increase from baseline in lower extremity strength during the 12-week stable-dose period was seen in the groups receiving 10- and 15-mg doses, compared with placebo (p = 0.018 and 0.003).

There were no significant changes in other secondary assessments.

Post hoc analysis revealed subsets of participants in each dose group with walking speeds during the treatment period that were consistently faster than during the nontreatment period.

There were significantly more "consistent responders" in the drug-treated groups than in the placebo group (36.7% compared with 8.5%).

Consistent responders showed significantly greater improvement in self-assessed ambulation on the 12-Item MS Walking Scale than did nonresponders. Fampridine was generally well tolerated.

Severe and serious adverse events were more frequent at the highest dose.

Conclusions
This phase 2 study suggests that a subgroup of patients, when treated with Fampridine, experiences a clinically relevant improvement in walking ability:

Which is sustained for at least 14 weeks.



#9

Sustained-Release Fampridine For Symptomatic Treatment Of Multiple Sclerosis (October) (CE)

Korenke AR, Rivey MP, Allington DR
Ann Pharmacother 2008 Sep 9
The University of Montana, Pharmacy Practice Resident, Skaggs School of Pharmacy; Community Medical Center, Missoula, MT; now, Assistant Professor, College of Pharmacy, Nursing, and Allied Health, North Dakota State University, Fargo, ND
PMID# 18780812
Abstract


Objective
To review the pharmacology, pharmacokinetics, clinical trials, and adverse effects of Sustained-Release (SR) Fampridine in patients with Multiple Sclerosis (MS).

Data Sources
An English-language human data search was done using PubMed/MEDLINE (1966-August 2008) to retrieve relevant material using the search terms Fampridine-SR, 4-AminoPyridine, and Multiple Sclerosis.

References of selected articles and information from the drug developer were used to further identify pertinent trials.

Study Selection And Data Extraction
Article selection was based primarily on studies that evaluated the pharmacokinetics, safety.

And, efficacy of Fampridine-SR in patients with MS. Relevant meeting abstracts were also included as part of the analysis.

Data Synthesis
Fampridine-SR is a sustained-release, orally administered Potassium-Channel Blocker acting in the Central Nervous System to enhance Conduction in DeMyelinated Axons.

Several small trials have evaluated the safety and efficacy of Fampridine-SR in patients with MS to improve their walking ability.

Data from a recent large Phase 3 trial indicated that walking speed improved in 42.9% of patients with MS who were treated with Fampridine-SR compared with 9.3% of those who received placebo (p < 0.001).

Treatment-related adverse events associated with the use of Fampridine-SR include Dizziness, Insomnia, Nausea, and Paresthesia.

More severe adverse events, such as Seizure, have occurred in patients receiving doses higher than those currently recommended.

Conclusions
Positive results from 2 Phase 3 clinical trials have put Fampridine-SR on the path toward approval as a medication for improving walking speed and lower extremity strength in patients with MS.



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