Extended-release dalfampridine in the management of multiple-sclerosis-related walking impairment

Abstract

Abstract:Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system that causes neurological impairment in young adults. As part of the disease, ambulation remains one of the most disabling features of multiple sclerosis. Extendedrelease dalfampridine is a long-acting form of 4-aminopyridine that has been shown in two phase III trials to increase ambulation speed in a subset of patients with multiple sclerosis (timed walk responders). The primary endpoint of these studies was 'responder status', analyzing difference in the proportion of timed walk responders between extended-release dalfampridine and placebo groups. Extended-release dalfampridine exerts its effects by inhibiting voltage-activated K + channels and has been previously demonstrated to improve action potential propagation in demyelinated nerve fibers in vitro. Side effects of extendedrelease dalfampridine include increased urinary tract infections, insomnia, headache, asthenia, dizziness, back pain, and paresthesias. Rare seizure events are also reported on the approved dose of 10 mg every 12 h. In this review we will summarize the results of key phase II and phase III trials of extended-release dalfampridine, its safety, and potential use in patients with multiple sclerosis.

Pharmacological characterization of crotamine effects on mice hind limb paralysis employing both ex vivo and in vivo assays: Insights into the involvement of voltage-gated ion channels in the crotamine action on skeletal muscles

“…Actually, this effect seemed paradoxal to us considering the effects of the presence 4-AP in the observed crotamine-induced increase of isolated diaphragm contraction force, as the potentiation of crotamine-induced increased contraction force by 4-AP was observed only when this ion channel blocker was added after crotamine stimulation ( Fig 5 ). Blockers of voltage-activated K + channels are able to prolong the motoneuron action potential, which thereby may increase the release of neurotransmitter at the neuromuscular junction, which led to their use as inducer of seizure in mice and for the symptomatic treatment in multiple sclerosis in human [ 39 , 40 ]. Interestingly, 4-AP was described to be capable of reversing the effects of tetrodotoxin (TTX) poisoning in animals [ 41 ], and both blockers seem to affect crotamine effects ( Table 1 ).…”

Recommendations for the Use of Prolonged‐Release Fampridine in Patients with Multiple Sclerosis (MS)

“…The clinical efficacy of 4‐AP formulations is directly related to the total serum concentration, while toxicity and adverse side effects are directly related to the peak serum dose . Although the prolonged‐release formulation of fampridine has a lower risk of seizures than immediate release 4‐AP, patients treated with fampridine PR have increased seizure risk.…”

Exercise Training and Cognitive Rehabilitation

“…26 Cognitive dysfunction is a highly disabling consequence of MS. Dysfunctions of information processing speed, learning and memory, and executive functions have been associated with depression in MS. 27,28 Cognitive dysfunction further has been associated with unemployment and loss of employment in persons with MS, 24,29 as well as reduced social functioning, 26 loss of driving abilities, 30,31 and using the Internet for conducting activities of daily living (eg, purchasing an airline ticket). 32 The prevalence and burden of walking and cognitive dysfunction underscore the importance of managing these cooccurring consequences of MS. To that end, the current review develops a rationale and framework for examining the independent and combined effects of exercise training and cognitive rehabilitation on walking and cognitive functions in persons with MS. We focus on approaches for rehabilitation (ie, factors that could help a person with MS achieve and maintain maximal physical, psychological, social, and vocational potential, and quality of life, consistent with physiological impairment, environment, and life goals 33 ) as these have been identified as the best, and perhaps only, methods for restoring function in MS. 33,34 Exercise training and cognitive rehabilitation, in particular, represent the rehabilitative approaches with the largest and most convincing bodies of literature for improving, restoring, and maintaining walking and cognitive functions, respectively, in MS. We do not review pharmacological treatments as these do not fall within the classical purview of rehabilitation, and there are existing reviews on extended-release, oral administration of dalfampridine (4-aminopyridine or 4-AP) for improving walking in MS. 35,36 This article further is not a comprehensive, systematic review on the efficacy or effectiveness of exercise training and cognitive rehabilitation in MS, as there have been several recent reviews on this for exercise training 41 and cognitive rehabilitation. 58 Our rationale and framework are based on (a) evidence supporting exercise training and cognitive rehabilitation as behavioral approaches for rehabilitation of walking and cognitive function in MS, (b) cognitive-motor coupling, and (c) potential cross-modality transfer effects in this population.…”