The findings of this study suggest that Fampridine administration has no serious and permeant adverse effects in patients with different types of MS. In autoimmune inflammatory diseases like MS, sudden shifts in neurological function happens and these acute inflammatory demyelination situations, clinically called as relapses, develop many clinical abnormalities in these patients by effecting highly myelinated regions of the nervous system such as spinal cord, optic nerve, brain stem ,and cerebellum (17). Among this clinical manifestation, gait dysfunction is one of the most ubiquitous, impactful, and life-limiting consequence, with a wide range of contributing factors like sensory changes, lower extremity weakness or spasticity, and cerebellar ataxia (18, 19). These clinical symptoms directly correlate with demyelination, the pathologic hallmark of MS, which causes acute functional changes by altering the impulse conduction in axons. As it was mentioned before, this conduction defect is raised by alterations in function and contribution of voltage-gated ion channels (4). There are variety types of voltage gated channels in axons, carry out a vital function in impulse conduction. Voltage-gated Na + channels (Nav), mostly located in non-myelinated parts (node of Ranvier and initial segments) of a normal axon, which are initially responsible for producing action potential. And voltage-gated K+ channels (Kv), in nodal and juxtaparanode regions cover by the myelin sheet, playing a role in neural excitability (20). Blockade of Na + channels during relapses due to cytokine release or antibody attachment, leads to a high level of intracellular Na+. This situation leads to the failure of Na+/K + ATPase pump according to lack of ATP and this failure exacerbate the intracellular Na + aggregation, causing the Na+/Ca2 + exchanger acts reversely. The extra intracellular Ca2+, initiate apoptosis and axon degeneration (4, 21) (Fig. 4). Additionally, the demyelination exposes the K + channels, leads to K + leakage. As a result, it repolarizes the cell and decreases the neural excitability. The overall impact is neuromuscular communication impairment as it is harder to initiate an action potential (4, 22) (Fig. 4). In all parts of the body, ion channels have been suggested to have attractive therapeutic potentials, and insights into the role of these channels in neurons have led to development of new high-efficacy drugs (23).
Of particular note, studies have exhibited improvements in gait and neurological function of MS patients treated with Fampridine (24). Other studies have recently shown that Prolonged-Release Fampridine has significant positive effects on cognition, and depression in MS patients and improves quality of life in these patients (25, 26). Fampridine, with generic name of dalfampridine, is an FDA approved board-spectrum lipophilic drug for MS patients, sold under name of Ampyra in US and Fampyra in Europe, Canada, and Australia (8, 9). This drug has demonstrated therapeutic effects on motor dysfunction in patients with MS, by blocking the exposed potassium channels on demyelinated axons as its main pharmacological property. However, it can also relive the conduction blocks that result in facilitation of neuromuscular and synaptic transmission and also it can affect the Voltage-activated Calcium Channel independent of potassium channels (27, 28). All these pharmacological features increase the amplitude of the action potential and this may increase the risk of seizures. Gastrointestinal tract rapidly absorbs the orally-administered dalfampridine. Complete elimination of this drug and its metabolites is carry out by kidney, making this drug harmful for patients with significant kidney diseases (14).
In a small randomized trial performed on 8 MS patients with motor deficits, immediate-release Fampridine was evaluated in high-serum and low serum concentration. All patients with high-serum concentration (greater than 60 ng/ml) experienced side effects (SEs). One patient showed a grand ma1 seizure at a serum Fampridine level of 104 ng/ml and another patient developed an acute confusional episode at s serum concentration peak of 114 ng/ml (29). In another trial performed by Schwid et al., on 10 MS patients, no serious side effect was occurred and only patients with serum concentration greater than 60 ng/ml exhibited improvements (30). Comparing these results suggest a narrow margin between therapeutic concentration and toxic concentration of Fampridine which leads to adverse effects (AEs). Goodman et al., performed a phase II multicenter randomized trial in 2008 to evaluate efficacy and side effects of three different doses of Fampridine in patients with MS (31). 206 MS patients received Fampridine 10, 15 or 20 mg or placebo in this dose-comparison study. Sever and serious side effects were seen more in high dose group (20 mg) and included urinary tract infection (16%), Headache (14%), and Paresthesia (14%). Nevertheless, no clear dose-related increase was seen in most of the side effects (31). In a dose raging study, 25 MS patients received 10 to 40 mg Fampridine. Dizziness, paresthesia, insomnia, asthenia, tremor, nausea, and headache were the most common SEs and 5 subjects were excluded from the trial at doses greater than 25 mg due to convulsions in two patients at doses of 30 and 35 mg (32). Two Phase III trials in 2009 and 2010, were performed by Goodman et al., leading to FDA approval of Fampridine (10, 33). In the first parent study, 11 patients (5%) of Fampridine-treated group were withdrawn from the study due to side effects like sepsis, ankle fracture, balance disorder, confusion state, headache, dizziness, and anxiety. Moreover, 16 patients (7%) experienced one or more serious adverse events (urinary tract infection and MS exacerbation were most common). A focal seizure occurred and it was judged as possibly related to Fampridine treatment. Besides, the death of a patient one week after the study completion was considered to be unrelated to the treatment (33). In the second parent trial, 5 patients (4.2%) in the Fampridine-treated group, experienced one or more serious AEs. The Fampridine-treated group experienced events include urinary tract infection (17.5%), fall (11.7%), insomnia (10%), headache (9.2%). Other adverse effects like asthenia, dizziness, nausea, back pain, balance disorder, upper respiratory tract infection, arthralgia, nasopharyngitis, and paresthesia were also observed in the Fampridine-treated group (10). The long-term evaluation of safety and efficacy of Fampridine which was published in 2015, were almost consistent with the two previous parent trials (34). In A 5-year (from 2010 through 2015) post marketing study on 107,000 patients treated with Fampridine in US, the most common adverse effects were dizziness (3.7%), insomnia (3.2%), balance disorder (3%), fall (2.4%), headache (2.4%), nausea (2.1%), and urinary tract infection (2%). Rare anaphylactic reactions and drug hypersensitivity reactions were seen in some patients as serious AEs (35). No epileptic condition was seen in both ENHANCE and MOBILE trial (36, 37). This study provides additional evidence on side effects of Fampridine in MS patients. Nevertheless, it has a number of limitations. First, over 70% of our study population consisted of women, which may hamper the generalizability of the findings to settings and locations where a more balanced distribution of MS between the two sexes are observed. Second, the fact that a self-administering checklist was utilized to obtain data renders our findings prone to a number of forms of bias. As such, future research is needed to further illuminate the safety and efficacy of Fampridine in individuals with MS.