Multiple Sclerosis Neurodegenerative Disease Human Central Nervous System Biology Essay

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Multiple sclerosis (MS) is a progressive immune-mediated neurodegenerative disease of human central nervous system (CNS), which causes irreversible disability in a large number of affected individuals. Dalfampridine (4-aminopyridine or 4-AP) is an orally administered potassium channel blocker, which was recently approved by FDA for symptomatic treatment of MS. Dalfampridine, which acts at the CNS, enhances conduction in demyelinated axons and improves walking ability of MS patients. The authors of this review paper present a comprehensive review of the pharmacology, pharmacokinetics, clinical trials, and adverse effects dalfampridine used in treatment of MS patients.

Multiple sclerosis: A brief review of pathogenesis

Multiple sclerosis (MS) is a chronic progressive inflammatory and neurodegenerative disease of human central nervous system (CNS) which usually affects young adults, with a reported median age of onset of approximately 30 years (Confavreux C NEJM 2000). In approximately 85% of patients with MS, the disease is initially recognized by a relapsing-remitting course which may eventually lead to a progressive deterioration of neurological status along with significant loss of neurological function (2-4 Rudick 2010 Archives). Neuropathologically, MS presents with various patterns, however, inflammatory demyelination and oligodendrocyte loss and neuronal and axonal degeneration (REFFF) constitute salient features of microscopic examination of MS lesions (REEFFF). Currently, the cause and cure for MS remain elusive and in many cases MS ends with significant neurological disabilities. While massive activation of the inflammatory arm of the immune system against putative CNS antigen(s) such as myelin basis protein plays a major role in pathogenesis of demyelinating process of MS, the neurodegenerative process prevails in the long run and causes significant cognitive and functional deterioration in affected patients.

Electrophysiologic examination of demyelinated lesions indicates conduction block as the predominant feature of these lesions. The pathophysiology of such conduction block in MS rests on segmental demyelination with loss of whole internodes of myelin. In fact, the impulse conduction fails specifically at the site of demyelination, while the normal segments of the axons on both sides continue their impulse conduction normally. Certain features which determine the impulse conduction block in demyelinated axon consist of the size of demyelinated area, extent of myelin loss along the internode, and the time elapsed since demyelination happened. The duration of demyelination is an important factor since myelin loss sets a number of adaptive axonal responses in motion. For example, development of a revised group of ion channels along the demyelinated membrane may result in restoration of impulse conduction. The size of the demyelinated lesion is another significant factor since axons repair centripetally inside the lesion and extensive lengths of demyelination are repaired slowly which in turn reflects the fact that the chance of functional recovery correlated inversely with the lesion size. Loss of myelin sheath is another significant factor in the process of conduction block. It appears that myelin loss involving the paranodal area is stronger factor in blocking conduction than a comparable loss of distributed along the internode.

Apart from the segmental demyelination which is associated with conduction block, histopathologic examination of MS tissue has shown that some node are inappropriately wide in MS lesions due to paranodal demyelination (or retraction of the paranodes (Wolswijk and Balesar 2003).

Another salient feature of demyelinated axons is abnormal reorganization of the ion channels. The rapid conduction velocity and successful transmission of electric signals in mammalian myelinated axons depend on the proper spatial distribution of ion-selective channels. Na+ channels are clustered at nodes of Ranvier in densities that are ~25 times that of internodal regions (Shrager, 1989). These clusters are necessary for efflux of ion currents at nodes and permit rapid saltatory conduction. In contrast, other studies have demonstrated that K+ currents appear only after loosening of the myelin sheath from the axonal membrane (Chiu and Ritchie, 1980) K+ channels are found only in paranodal and internodal regions and they normally do not contribute to the action potential (Rasband MN1998). Scientific studies which have focused on action potential propagation in normal and demyelinated axons have revealed a reorganization of axolemmal ion channels, which in turn leads to conduction impairments. Loss or decrease of sodium channels from the nodes of Ranvier (Novakovic 1998) causes the nodes to be inexcitable and leads to conduction block. Sherratt et al. (1980) demonstrated that in demyelinated regions sodium channel concentrations are reduced, while voltage-sensitive potassium channels (which are not active on normal myelinated axons) become detectable. This exposure of K channels at juxtaparanodal region leads to efflux through fast K channels and causes axonal conduction block by preventing sufficient depolarization and initiation of the action potential at the node of Ranvier (Leung G, Sun W 2011). Demyelination also exposes slow K channels, further interrupting normal hyperpolarization and blunting normal repetitive impulse release from the presynaptic area terminals (Hayes KC 2004). In 1981, Bostock et al. (Bostock 1981) demonstrated that potassium channel blockers dendrotoxin and 4-aminopyridine improved conduction impairments in experimentally demyelinated axons and laid the scientific rationale for clinical studies of potassium channel blockers in MS patients.

Pharmacology and pharmacokinetics of dalfampridine

Dalfampridine (4-aminopyridine) is one of the three isomeric amines of pyridine with chemical formula H2NC5H4N, which acts a selective potassium-channel blocker. It has been shown to bind reversibly to the cytoplasmic side of K channels, blocking the ion conductance pathway which leads to prolongation of action potentials in unmyelinated nerve fibers and enhanced neurotransmitter release at synaptic endings (Bever and Judge 2009). Dalfampridine has been studied extensively in symptomatic treatment of MS patients with walking impairment. Impairment of ambulation is a major neurological deficit in MS patients and significantly interferes with their quality of life. It is hypothesized that dalfampridine improves clinical symptoms of MS by restoring conduction in demyelinated axons through voltage-dependent potassium channel blockade (Judge SI 2006).

In addition, dalfampridine has also been used for treatment of Lambert-Eaton myasthenic syndrome. As a potassium channel blocker, dalfampridine prolongs action potentials and thereby prolongs neurotransmitter release at the neuromuscular junction. Studies involving animal models have demonstrated that can reverse tetrodotoxin toxicity.

Dalfampridine, which is a sustained-release oral form of fampridine, is rapidly and completely absorbed from the gastrointestinal tract, however, its absolute bioavailability has not been determined. Compared to an aqueous oral solution, the extended release tablet shows a relative bioavailability of 96%, with a delayed absorption pattern which provides a less rapid rise to a lower maximum plasma concentration. In healthy volunteers who took a single 10 mg dose of dalfampridine, peak serum concentrations were reached 3 to 4 hours following oral administration and it was almost completely and rapidly eliminated by urinary excretion. Elimination of dalfampridine and its metabolites are almost complete after 24 hours. The elimination half-life of dalfampridine is 6.4 hours in healthy individuals. Vollmer et al. (Vollmer 2009) studied the pharmacokinetics of dalfampridine in clinical trials of MS patients and found that multiple dosing of this medication was associated with its accumulation. In addition, the investigators noted that the steady-state pharmacokinetic profile of fampridine sustained-release 20 mg BID administered for 2 weeks appeared to support the administration of twice-daily dosing in this population. This dosage was generally well tolerated by study participants.

Dosage of dalfampridine and administration

Dalfampridine which is marketed as Ampyra is available as 10 mg extended release tablets with relative bioavailability of 96%, peak of plasma concentration of 3-4 hours and half life of 5.2-6.5 hours. Dalfampridine is excreted in urine so it is contraindicates in patients with moderate or severe renal impairment (CrCL <50 mL/min) or history of seizures.

Clinical trials of dalfampridine in multiple sclerosis

In January 2010, dalfampridine was approved by the FDA for symptomatic treatment of MS patients with specific indication for improving walking. In the past 4-aminopyridine has been used as an experimental agent which presumably enhances nerve conduction of demyelinated axons through its effects on potassium channels for treatment of fatigue in MS. Sheean et al. (Sheean 1998) reported that use of fampridine in MS patients was associated with improvements in fatigue as well motor and visual symptoms. In addition, dalfampridine has been assessed and studied in other cohorts of MS patients in the context of various clinical trials to determine its efficacy in improving MS patients’ ambulation.

In 2002, Goodman et al. (Goodman 2002) reported the results of a four-center randomized, double-blind placebo-controlled study of controlled release aminopyridine in 31 MS patients. The study participants were treated with increasing doses of 20 to 80 mg of aminopyridine daily in divided doses. A total of 25 participants received the active medication and 11 participants were treated with placebo. Outcome measures of this clinical trial consisted of timed ambulation, manual testing of leg strength, paced auditory serial addition task, 9-hole peg test, and a fatigue diary. The results of this clinical trial indicated a statistically significant and dose-related enhancement of timed ambulation in AP-treated patients compared to those who received placebo. A significant enhancement of leg strength was also observed in approximately 11% of AP-treated participants compared with a 4% worsening of placebo-treated participants, P=0.01. The reported side effects consisted of dizziness, insomnia, paresthesia, nausea, headache, tremor, pain and anxiety. On daily doses of 60 and 70 mg two MS patients seized. A phase 2, multi-center, randomized, double-blind, placebo-controlled, parallel-group, dose-comparison (10, 15, or 20 mg twice daily orally) clinical trial of sustained-release fampridine in MS patients demonstrated significantly more consistent responders as determined by improvement in ambulation as compared to the placebo-group: 36.7% versus 8.5% (Goodman 2008). Fampridine was generally well tolerated and serious and severe adverse effects were more common in those patients who received the highest dose.

Another phase 3 multicenter clinical trial of dafampridine included 301 MS patients (27% with relapsing-remitting MS and 73% with progressive MS), during which participants were assigned in a ratio of 3 to 1 to be treated with dalfampridine 10 mg or placebo orally twice daily for a period of 14 weeks (Goodman Lancet 2009). A recently published phase 3 multi-center double-blind clinical trial of extended-release dalfampridine in patients with definite MS of any course type assessed the efficacy, safety, and pharmacodynamics of extended release oral dalfampridine in these patients. The participants of this clinical trial which included 39 centers were randomized to 9 weeks of treatment with dalfampridine (10 mg twice daily; n=120) or received placebo (n=119). The primary outcome of this clinical trial consisted of consistent improvement on the Timed 25-Foot Walk, with percentage of time walk responders (TWRs) in each treatment group. The last on-treatment assessment collected information from 8 to 12 hours postdose, to assess and determine maintenance of effect. The results of this clinical trial indicated that the proportion of TWRs was higher in the dalfampridine group (51/119 or 42.9%) compared to the placebo group 11/118 or 9.3%. p<0.0001). The average enhancement of walking speed among the dalfampridine-treated TWRs during the 8-week efficacy assessment period was 24.7% from baseline; the mean enhancement at the last on-treatment visit was 25.7%, reflecting maintenance of effect over the interdosing period. The investigators did not find any new safety issues. The authors concluded that this clinical trial provided class 1 evidence that dalfampridine extended-release tablets provided meaningful enhancement of walking ability in a subset of MS patients, with the effect maintained between doses.

Adverse effects and drug interactions

The side effects of dalfampridine consist of dizziness, nausea, and seizures (Stork and Hoffman 1994; Potter 1998; Pena and Tapia 1999, 2000; Korenke 2008). Dalfampridine is contraindicated in patients with history of epilepsy or history of severe renal insufficiency (Smith 2010).