Historical overview of the rationale for the pharmacological use of prolonged-release fampridine in multiple sclerosis

Fernández, Ó; Berger, Thomas; Hartung, Hans‐Peter; Putzki, Norman

doi:10.1586/ecp.12.59

Cited by 9 publications

(5 citation statements)

References 71 publications

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“…Clinically useful serum levels of 4-AP, with usual doses of 15 mg to 40 mg per day, are in the range of 15 to 70 ng/mL for multiple sclerosis and spinal cord injury patients. 17,18 Discussion 4-Aminopyridine blocks voltage-gated K + (Kv) channels, which leads to prolonged depolarization and improved action potential conduction in demyelinated nerve fibers. 3,17 As a result, 4-AP facilitates neurotransmitter release.…”

Section: Case Reportmentioning

confidence: 99%

“…The C-max of dalfampridine is approximately half of immediate-release 4-AP, and the elimination half-life of dalfampridine is approximately 6.4 hours (almost twice that of immediate-release 4-AP). 18 MS patients taking chronic daily oral therapy with sustained-release 4-AP tend to show greater neurological improvement with serum levels in excess of 60 µg/L. 27 Serum protein binding is estimated to be 1% to 3%.…”

Section: Case Reportmentioning

confidence: 99%

“…The clinical presentation of 4-AP toxicity seen with the immediaterelease form, at standard doses, probably arises from the rapid absorption and relatively high serum levels, compared to the extended-release form, dalfampridine. 18,19,28 All documented 4-AP overdose cases have presented with some degree of altered mental status. [6][7][8][9][10][11][12][13][14][15][16] As in the case of AM, the family disclosed that she had suddenly become confused as to place, time, and person.…”

Section: Case Reportmentioning

confidence: 99%

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Unintentional 4-Aminopyridine Overdose in a Multiple Sclerosis Patient

Thompson

2013

Journal of Pharmacy Technology

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Objective:To discuss the clinical presentation and treatment of a 4-aminopyridine overdose resulting from a pharmacy prescription compounding error. Case Summary: A 55-year-old female with a 12-year history of multiple sclerosis is reintroduced to immediate-release 4-aminopydrine for symptom management. Four hours after the second dose, she is admitted to the emergency room with altered mental status, pulmonary edema, and seizures progressing to status epilepticus. She is intubated and managed with benzodiazepines followed by a propofol infusion. After 5 days she is discharged to home. Laboratory analysis of the capsules detected 127 mg of 4-aminopyridine, yet the prescription label indicated the contents as 12.5 mg capsules, to be taken twice a day. Discussion: There are 14 cases of previously published 4-aminopyridine toxicity in the literature. Four of those cases are due to pharmacy compounding errors. This case presents with typical and anticipated symptomatology such as acute delirium, cognitive changes, speech changes, elevated blood pressure, tachycardia, seizures, and status epilepticus. However, this case is unique in that the patient also presented with pulmonary edema, a finding not mentioned in the previous 14 cases. These adverse drug events are due to the neurotransmitter release induced through potassium channel blockade afforded by 4-aminopyridine when ingested in excessive amounts. In the context of adverse drug events, the 4-aminopyridine overdose as the causal link for the clinical findings in this case as determined by the Naranjo probability scale is ranked as definite. Conclusion: 4-Aminopyridine is a potent potassium (Kv) channel blocker and is accepted as a therapeutic agent for multiple sclerosis patients. In excess, 4-aminopyridine can produce significant adverse neurological effects most notable being status epilepticus. To date, no 4-aminopyridine overdose case reported has ended in death. Caution is advised to those pharmacists who provide compounding services.

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Section: Case Reportmentioning

confidence: 99%

Section: Case Reportmentioning

confidence: 99%

Section: Case Reportmentioning

confidence: 99%

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Unintentional 4-Aminopyridine Overdose in a Multiple Sclerosis Patient

Thompson

2013

Journal of Pharmacy Technology

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“…8 However, such treatment strategies do not cover the broad spectrum of MS clinical manifestations; therefore, other pharmacologic agents may be used to specifically control the complications and symptoms of MS. 9 Walking impairment is a complication of MS that leads to a varied extent of disabilities that dramati-cally affect the quality of life in patients with MS. 10 Treatments of such mobility impairments are typically limited. 16 The mechanism of action of dalfampridine is based on its potassium channel blockage that prolongs action potentials and improves conduction in the demyelinated neurons. 11 Dalfampridine (also named fampridine, 4aminopyridine, 4-AP) is an organic compound that is characterized by 1 of the 3 isomeric amines of pyridine.…”

mentioning

confidence: 99%

“…15 Fampyra was also approved for clinical use in Canada in February 2012. 16 The mechanism of action of dalfampridine is based on its potassium channel blockage that prolongs action potentials and improves conduction in the demyelinated neurons. 17 Dalfampridine has been shown to improve walking speeds in approximately one-third of MS patients.…”

mentioning

confidence: 99%

Comparative Randomized, Single‐Dose, Two‐Way Crossover Open‐Label Study to Determine the Bioequivalence of Two Formulations of Dalfampridine Tablets

Bawab

Alkhalidi

Albarahmieh

et al. 2018

Clinical Pharm in Drug Dev

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Dalfampridine is a medication that is approved by the US Food and Drug Administration to improve walking impairments in patients with multiple sclerosis (MS). The branded dalfampridine is enormously expensive; hence, the availability of generic dalfampridine will provide better access to the medication, especially for uninsured patients with MS. Bioequivalence studies are demanded by the regulatory authorities to allow the marketing of new generics of dalfampridine. The aim of this study was to assess the bioavailability of the generic (test) and branded (reference) formulations of 10 mg dalfampridine of extended-release tablets after oral administration to healthy adults under fed conditions. The current report methodology was based on a comparative, randomized, single-dose, 2-way crossover open-label study design. Twenty-seven subjects were given a single dose of the test dalfampridine tablet and completed the clinical study. The pharmacokinetic parameters C and AUC K , AUC , t , and t were estimated to prove bioequivalence. The confidence intervals for the log-transformed test/reference ratios for dalfampridine 100.96% (97.09%-104.97%) and 99.77% (95.81%-103.87%) for C and AUC , respectively, were within the allowed limit specified by the regulatory authorities (80%-125%). Hence, clinically, the test tablet can be prescribed as an alternative to the reference for the indication of improving walking impairments in patients with MS.

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Restoring Axonal Function with 4-Aminopyridine: Clinical Efficacy in Multiple Sclerosis and Beyond

2018

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The oral potassium channel blocker 4-aminopyridine has been used in various neurological conditions for decades. Numerous case reports and studies have supported its clinical efficacy in ameliorating the clinical presentation of certain neurological disorders. However, its short half-life, erratic drug levels, and safety-related dose restrictions limited its use as a self-compounded drug in clinical practice. This changed with the introduction of a prolonged-release formulation, which was successfully tested in patients with multiple sclerosis. It was fully approved by the US FDA in January 2010 but initially received only conditional approval from the European Medicines Agency (EMA) in July 2011. After additional clinical studies, this conditional approval was changed to unrestricted approval in August 2017. This article reviews and discusses these recent studies and places aminopyridines and their clinical utility into the context of a broader spectrum of neurological disorders, where clinical efficacy has been suggested. In 2010, prolonged-release 4-aminopyridine became the first drug specifically licensed to improve walking in patients with multiple sclerosis. About one-third of patients across disease courses benefit from this treatment. In addition, various reports indicate clinical efficacy beyond multiple sclerosis, which may broaden its use in clinical practice.

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Historical overview of the rationale for the pharmacological use of prolonged-release fampridine in multiple sclerosis

Cited by 9 publications

References 71 publications

Unintentional 4-Aminopyridine Overdose in a Multiple Sclerosis Patient

Unintentional 4-Aminopyridine Overdose in a Multiple Sclerosis Patient

Comparative Randomized, Single‐Dose, Two‐Way Crossover Open‐Label Study to Determine the Bioequivalence of Two Formulations of Dalfampridine Tablets

Restoring Axonal Function with 4-Aminopyridine: Clinical Efficacy in Multiple Sclerosis and Beyond

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