Novel predictive approaches for drug-induced convulsions in non-human primates using machine learning and heart rate variability analysis.

Drug-induced convulsions are a major challenge to drug development because of the lack of reliable biomarkers. Using machine learning, our previous research indicated the potential use of an index derived from heart rate variability (HRV) analysis in non-human primates as a biomarker for convulsions induced by GABAA receptor antagonists. The present study aimed to explore the application of this methodology to other convulsants and evaluate its specificity by testing non-convulsants that affect the autonomic nervous system. Telemetry-implanted males were administered various convulsants (4-aminopyridine, bupropion, kainic acid, and ranolazine) at different doses. Electrocardiogram data gathered during the pre-dose period were employed as training data, and the convulsive potential was evaluated using HRV and multivariate statistical process control. Our findings show that the Q-statistic-derived convulsive index for 4-aminopyridine increased at doses lower than that of the convulsive dose. Increases were also observed for kainic acid and ranolazine at convulsive doses, whereas bupropion did not change the index up to the highest dose (1/3 of the convulsive dose). When the same analysis was applied to non-convulsants (atropine, atenolol, and clonidine), an increase in the index was noted. Thus, the index elevation appeared to correlate with or even predict alterations in autonomic nerve activity indices, implying that this method might be regarded as a sensitive index to fluctuations within the autonomic nervous system. Despite potential false positives, this methodology offers valuable insights into predicting drug-induced convulsions when the pharmacological profile is used to carefully choose a compound.

Cell-specific NFIA upregulation promotes epileptogenesis by TRPV4-mediated astrocyte reactivity.

BACKGROUND: The astrocytes in the central nervous system (CNS) exhibit morphological and functional diversity in brain region-specific pattern. Functional alterations of reactive astrocytes are commonly present in human temporal lobe epilepsy (TLE) cases, meanwhile the neuroinflammation mediated by reactive astrocytes may advance the development of hippocampal epilepsy in animal models. Nuclear factor I-A (NFIA) may regulate astrocyte diversity in the adult brain. However, whether NFIA endows the astrocytes with regional specificity to be involved in epileptogenesis remains elusive. METHODS: Here, we utilize an interference RNA targeting NFIA to explore the characteristics of NFIA expression and its role in astrocyte reactivity in a 4-aminopyridine (4-AP)-induced seizure model in vivo and in vitro. Combined with the employment of a HA-tagged plasmid overexpressing NFIA, we further investigate the precise mechanisms how NIFA facilitates epileptogenesis. RESULTS: 4-AP-induced NFIA upregulation in hippocampal region is astrocyte-specific, and primarily promotes detrimental actions of reactive astrocyte. In line with this phenomenon, both NFIA and vanilloid transient receptor potential 4 (TRPV4) are upregulated in hippocampal astrocytes in human samples from the TLE surgical patients and mouse samples with intraperitoneal 4-AP. NFIA directly regulates mouse astrocytic TRPV4 expression while the quantity and the functional activity of TRPV4 are required for 4-AP-induced astrocyte reactivity and release of proinflammatory cytokines in the charge of NFIA upregulation. NFIA deficiency efficiently inhibits 4-AP-induced TRPV4 upregulation, weakens astrocytic calcium activity and specific astrocyte reactivity, thereby mitigating aberrant neuronal discharges and neuronal damage, and suppressing epileptic seizure. CONCLUSIONS: Our results uncover the critical role of NFIA in astrocyte reactivity and illustrate how epileptogenic brain injury initiates cell-specific signaling pathway to dictate the astrocyte responses.

Refractory Convulsive Status Epilepticus Provoked by Intoxication with Dalfampridine in a Patient with Multiple Sclerosis and Depression Disorder: A Case Report and Literature Review.

PURPOSE: Dalfampridine (DFP) is used to improve motor functions in patients with multiple sclerosis (MS). Overdose of DFP can occur for a variety of reasons and can lead to a state of epilepsy. CASE REPORT: A 24-year-old woman with MS was admitted to hospital with severe sweating and delirium after attempting suicide by overdosing on DFP. At the time of hospitalization, she developed a tonic-clonic seizure that did not respond to immediate intravenous (IV) diazepam injection, followed by intravenous sodium valproate. Therefore, according to the hospital protocol of the neurology department, the patient was intubated and IV infusion of midazolam was started, Due to the persistence of seizures, sodium thiopental began and the patient was admitted to the intensive care unit (ICU). In the ICU, she received an infusion of sodium thiopental and intravenous sodium valproate, monitored by a daily electroencephalogram (EEG). The patient was discharged after four days due to her stable medical condition. CONCLUSION: Epilepsy in case of overuse of DFP should be considered as a life-threatening side effect and timely treatment should be done to prevent damage to the nervous system.

Aging-associated susceptibility to stress-induced ventricular arrhythmogenesis is attenuated by tetrodotoxin.

Aging is associated with increased prevalence of life-threatening ventricular arrhythmias, but mechanisms underlying higher susceptibility to arrhythmogenesis and means to prevent such arrhythmias under stress are not fully defined. We aimed to define differences in aging-associated susceptibility to ventricular fibrillation (VF) induction between young and aged hearts. VF induction was attempted in isolated perfused hearts of young (6-month) and aged (24-month-old) male Fischer-344 rats by rapid pacing before and following isoproterenol (1 µM) or global ischemia and reperfusion (I/R) injury with or without pretreatment with low-dose tetrodotoxin, a late sodium current blocker. At baseline, VF could not be induced; however, the susceptibility to inducible VF after isoproterenol and spontaneous VF following I/R was 6-fold and 3-fold higher, respectively, in old hearts (P < 0.05). Old animals had longer epicardial monophasic action potential at 90% repolarization (APD90; P < 0.05) and displayed a loss of isoproterenol-induced shortening of APD90 present in the young. In isolated ventricular cardiomyocytes from older but not younger animals, 4-aminopyridine prolonged APD and induced early afterdepolarizations (EADs) and triggered activity with isoproterenol. Low-dose tetrodotoxin (0.5 µM) significantly shortened APD without altering action potential upstroke and prevented 4-aminopyridine-mediated APD prolongation, EADs, and triggered activity. Tetrodotoxin pretreatment prevented VF induction by pacing in isoproterenol-challenged hearts. Vulnerability to VF following I/R or catecholamine challenge is significantly increased in old hearts that display reduced repolarization reserve and increased propensity to EADs, triggered activity, and ventricular arrhythmogenesis that can be suppressed by low-dose tetrodotoxin, suggesting a role of slow sodium current in promoting arrhythmogenesis with aging.

[The effect of fampridine on gait in people with Multiple sclerosis (MS)].

INTRODUCTION: Fampridine is a drug for people with Multiple Sclerosis (MS). It is a broad-spectrum voltage-dependent potassium channel blocker that enhances synaptic transmission. The drug has been shown to be able to enhance conduction in demyelinated axons, thereby leading to improved gait in patients with MS. The purpose of this study was to examine the effect of fampridine on gait function in people with MS in the end of a 2 weeks trial drug period and to observe how many patients continued drug therapy. MATERIAL AND METHODS: Data from 41 individuals with MS was collected retrospectively for this study. Measurements were administered by physiotherapists and the results from the Timed 25-Foot Walk (T25FW) and 12-item Multiple Sclerosis Walking Scale (MSWS-12) were obtained from medical records from The National University Hospital of Iceland. RESULTS: The results showed a significant difference in walking speed before and at the end of trial period (p<0.0001). The average improvement in walking speed was 22%. Results also demonstrated a significant difference in MSWS-12 scores before and at the end of treatment (p<0.0001). The average improvement in MSWS-12 was 11.4 points. Eighteen individuals (43.9%) continued treatment after the trial period. CONCLUSION: Fampridine can have a positive effect on impaired gait function in people with MS and can be an important adjunct to treatment.

[Efficacy and safety of Kinezia (fampridine) in the complex therapy of multiple sclerosis]. / Effektivnost' i bezopasnost' preparata Kinezia (fampridin) v kompleksnoi terapii rasseyannogo skleroza.

OBJECTIVE: To analyze the efficacy and safety of fampridine** (Valenta Pharm, Russia) in the complex therapy of multiple sclerosis (MS). MATERIAL AND METHODS: One hundred and twenty-six patients with MS were double blind randomized to receive fampridine (n=60) or placebo (n=66). Fampridine was administered in prolonged-release form (film-coated tablets, 10 mg) at a dose of 10 mg (1 tablet) 2 times a day, for 24 weeks. The placebo group was treated in the same way. From the 12th week, all patients in the placebo group were transferred to therapy with fampridine, 10 mg 2 times a day, for another 12 weeks. Concomitant standard therapy for MS was allowed in both groups (concomitant disease-modifying medications and other treatment). The primary outcome in the study was the proportion of patients with reduced t25fw test time (determining walking speed on a 25-foot path) on at least two out of three visits compared to baseline. The mean change in Multiple Sclerosis Functional Composite (MSFC) scores from baseline was assessed at visits 4-7 (8-24 weeks). RESULTS: The proportion of patients with reduced t25fw test time compared to the baseline level was 31.7% in the fampridine group, which is higher than in the placebo group - 3.0% (p<0.001). The overall result of the Multiple Sclerosis Functional Composite (MSFC) reflected a gradual improvement in the patient's condition during treatment period. The dynamics of MSFC result relative to the baseline level significantly differed (p<0.05) between the fampridine and placebo groups in favor of the fampridine group during all treatment periods. In the fampridine group, adverse events (AE) associated with disorders of the nervous system were more common: headache, dizziness, and coordination disorders. CONCLUSIONS: Fampridine improves walking performance in MS patients. The Russian product fampridine has demonstrated a favorable safety profile.

Efficacy and safety of fampridine for walking disability in multiple sclerosis.

Fampridine is the only drug approved for the treatment of walking impairment in multiple sclerosis. Around a third of the patients on treatment obtained an improvement in walking speed during the development phase. The effects are clinically significant, appear soon after the start of the treatment and are long-lasting, but disappear soon after the drug is withdrawn. In the real-world setting, the number of patients with a significant response to the treatment seems to be higher (around 70%). The tolerance is good, with mild to moderate, and transient adverse events. The most commonly reported are insomnia, headache, fatigue, back pain, dizziness, nausea and balance disorders. The main contraindications are a history of seizures, renal impairment and concomitant treatment with OCT2 inhibitors.

The effect of fampridine on the risk of seizure in patients with multiple sclerosis.

BACKGROUND: Fampridine was first approved by the US Food and Drug Administration (FDA) to improve walking in multiple sclerosis (MS) patients, which was demonstrated by an increase in their walking speed. Nevertheless, the medication has been reported to possess an epileptogenic effect since it blocks the voltage-gated potassium channels in neural fibers. Several studies have indicated that the risk of seizure among fampridine consumers is not substantially higher than that in the general MS population, however. The objective of this study is to describe 97 MS patients for whom fampridine was prescribed and to assess the incidence of post-medication seizures. METHODS: This cohort study included 97 MS patients with gait problems who referred to the Isfahan Clinic of MS from August 2017 to September 2019. The exclusion criteria were a previous or family history of seizure or a history of renal impairment. Fampridine was prescribed for all the patients at a dose of 10 mg twice daily (12 hours apart). RESULTS: three patients (with an approximate incidence rate of 0.015 per 100 patient-years) presented with generalized tonic-clonic seizures, 7, 9, and 14 months after initiating fampridine consumption. The radiological findings revealed significant cortical and subcortical lesions in the three patients. Further, two of them consumed baclofen or fingolimod simultaneously with fampridine. CONCLUSION: The reported incidence rate is relatively higher than that in the general MS population. The extensive (sub) cortical lesions and the concomitant medications probably have an important role in the epileptogenesis, regardless of fampridine. However, the potential pro-convulsant properties of fampridine should not be overlooked.

Electrophysiological and behavioral properties of 4-aminopyridine-induced epileptic activity in mice.

4-aminopyridine (4-AP) is a widely used drug that induces seizure activity in rodents, especially in rats, although there is no consensus in the literature on the dose to be used in mice. The aim of the present study was to investigate the effect of the intraperitoneal administration of 4-AP in two doses (4 and 10 mg/kg) in vivo. EEG, movement, and video recordings were made simultaneously in male B6 mice to specify the details of the seizures and to determine whether there is a suitable non-lethal dose for seizure induction and for further molecular studies. Seizure behavior in mice differs from that seen in rats, with no characteristic stages of epileptic seizures, but with spiking and seizure activity. Seizure activity, although produced at both doses without being lethal, induced different changes of the EEG pattern. Smaller dose induced a lower amplitude seizure activity, decreased spiking activity and later onset of seizures, while higher dose induced a much more intense brain seizure activity and severe trembling. It is concluded that the intraperitoneal administration of 4-AP at a dose of 10 mg/kg induces explicit seizure activity in mice which is repeatable and can be suitable for further molecular research.

Evaluating dalfampridine for the treatment of relapsing-remitting multiple sclerosis: does it add to the treatment armamentarium?

Introduction: Multiple sclerosis (MS) is a demyelinating disease, causing axonal damage and disability. Dalfampridine (DAL) is an extended-release formulation of 4-aminopyridine (4AP) and broad-spectrum voltage-dependent potassium channel blocker that is reported to improve motor, visual and cognitive functions. Furthermore, it is presently the only approved drug for walking impairment in MS. Areas covered: Herein, the authors evaluate DAL as a relapsing-remitting MS treatment, reporting and commenting on all aspects of the drug including its chemistry, safety, pharmacokinetics, and cost-effectiveness. A bibliographic search was performed on PubMed using the terms 'dalfampridine OR fampridine OR 4-aminopyridine'. Expert opinion: Evidence from post-marketing studies suggests that DAL, consistent with the effects of 4AP, may not only improve walking speed, but also arm function, fatigue, mood and cognition through restored nerve conduction in central nervous system demyelinated areas. Long-term safety data confirm that the approved dose of 10 mg twice daily is generally well tolerated. However, despite the reported efficacy, the extent of the benefits is limited in real life activities, although significant improvements have been demonstrated in the clinical setting. Patients often complain of side effects (such as cramps and painful paraesthesia) or lack of efficacy. Also, its considerably higher pricing in comparison to 4AP represents an important limitation.

Astrocytic endfoot Ca2+ correlates with parenchymal vessel responses during 4-AP induced epilepsy: An in vivo two-photon lifetime microscopy study.

Neurovascular coupling (NVC) underlying the local increase in blood flow during neural activity forms the basis of functional brain imaging and is altered in epilepsy. Because astrocytic calcium (Ca2+) signaling is involved in NVC, this study investigates the role of this pathway in epilepsy. Here, we exploit 4-AP induced epileptic events to show that absolute Ca2+ concentration in cortical astrocyte endfeet in vivo correlates with the diameter of precapillary arterioles during neural activity. We simultaneously monitored free Ca2+ concentration in astrocytic endfeet with the Ca2+-sensitive indicator OGB-1 and diameter of adjacent arterioles in the somatosensory cortex of adult mice by two-photon fluorescence lifetime measurements following 4-AP injection. Our results reveal that, regardless of the mechanism by which astrocytic endfoot Ca2+ was elevated during epileptic events, increases in Ca2+ associated with vasodilation for each individual ictal event in the focus. In the remote area, increases in Ca2+ correlated with vasoconstriction at the onset of seizure and vasodilation during the later part of the seizure. Furthermore, a slow increase in absolute Ca2+ with time following multiple seizures was observed, which in turn, correlated with a trend of arteriolar constriction both at the epileptic focus and remote areas.

Pulmonary arterial hypertension in patient treated for multiple sclerosis with 4-aminopyridine.

4-Aminopyridine (4-AP) is a recent treatment indicated to improve walking in patient with multiple sclerosis. We report the first case of pulmonary arterial hypertension (PAH) that we attribute to the use of 4-AP. A 64-year-old woman with multiple sclerosis presented with dyspnea. After excluding other secondary causes of pulmonary hypertension, a diagnosis of severe PAH due to 4-AP was made based on right heart catheterization. History revealed that the dyspnea began with the initiation of 4-AP. After discontinuation of 4-AP therapy and initiation of ambrisentan and tadalafil, dyspnea and pulmonary arterial pressure have improved significantly and one specific PAH treatment was stopped. 4-AP is an outward rectifying potassium channel blocker with a vasoconstrictor effect in animal's pulmonary artery. According to the chronological sequence of events, the lack of other etiology, and its pharmacological plausibility, 4-AP is highly suspected to have induced our patient's PAH.

De novo convulsive status epilepticus in patients with multiple sclerosis treated with dalfampridine.

BACKGROUND: Dalfampridine extended release (DAL) is a broad-spectrum voltage-gated potassium channel blocker that is indicated in multiple sclerosis to improve the nerve conduction of demyelinated axons. Seizures are a known side effect of DAL, which is contraindicated in patients with a history of epilepsy. OBJECTIVE: Three cases of multiple sclerosis (MS) with de novo convulsive status epilepticus (CSE) probably related to dalfampridine administration are described. METHODS: No patients had a history of seizures or renal impairment. Biological tests were normal. A brain magnetic resonance imaging (MRI) showed diffuse cortical and subcortical atrophy without active inflammatory lesions. RESULTS: All three patients presented with CSE that was attributed to DAL and so was discontinued. CONCLUSION: These case reports illustrate that, aside from seizures, de novo CSE is a potential complication of MS patients treated with DAL.

Effects of 4-aminopyridine on attention and executive functions of patients with multiple sclerosis: Randomized, double-blind, placebo-controlled clinical trial. Preliminary report.

BACKGROUND: A high percentage of patients with multiple sclerosis present cognitive alterations. Because 4-aminopyridine improves nerve conduction and efficient synaptic connection could improve cognitive dysfunction. OBJECTIVE: To evaluate the efficacy on cognitive performance and safety of 4-aminopyridine administered to patients with relapsing-remitting multiple sclerosis. METHODS: A randomized, double-blind, placebo controlled clinical trial was conducted in patients with relapsing-remitting multiple sclerosis diagnosis according to the McDonald criteria. At the beginning and at the end of the treatment different tests were used to assess cognitive performance. Subsequently, patients were randomized 1:1 to receive treatment or placebo. A bootstrap-t test was proposed to test the effectiveness of cognitive performance, considering a p-value < 0.05 as statistically significant. RESULTS: Twenty-four patients were recruited of which 21 completed the trial, 11 with 4-aminopyridine and 10 with placebo treatment. No significant differences between groups in the initial assessments were observed. In terms of efficacy, the experimental group achieved significantly higher scores in attention span, verbal fluency, planning and graphics and constructive motion. CONCLUSIONS: 4-aminopyridine proved to be an effective treatment on cognitive aspects in patients with relapsing-remitting multiple sclerosis. Drug doses were shown to be safe with mild to moderate adverse events (ClinicalTrials.gov number, NCT02280096).

Thalidomide protects against acute pentylenetetrazol and pilocarpine-induced seizures in mice.

Thalidomide was originally developed to treat primary neurological and psychiatric diseases. There are reports of anticonvulsant effects of thalidomide in rats and antiepileptic effects in patients. Hence, thalidomide (100, 200 and 400 mg/kg) was herein administered to mice to evaluate possible protection against seizures induced by the systemic administration of neurotoxins: 10 mg/kg of 4-aminopyridine (4-AP), 90 mg/kg of pentylenetetrazol (PTZ), or 380 mg/kg of pilocarpine. The effect of an NO and COX inhibitor (7-NI and ibuprofen, respectively) was also examined. The results show that thalidomide (1) induces the typical sedative effects, (2) has no anticonvulsant effect in mice treated with 4-AP, and (3) has anticonvulsant effect (400 mg/kg) in mice treated with PTZ and pilocarpine. It was found that 7-NI has an anticonvulsant effect in the pilocarpine model and that thalidomide's effect is not enhanced by its presence. However, thalidomide (200 mg/kg) plus 7-NI or ibuprofen tend to have a toxic effect in PTZ model. On the other hand, the combination of thalidomide and 7-NI or ibuprofen protects against pilocarpine-induced seizures. In conclusion, thalidomide did not exert an anticonvulsant effect for clonic-tonic type convulsions (4-AP), but it did so for seizures induced by PTZ and pilocarpine (representing absence seizures and status epilepticus, respectively). NO and prostaglandins were involved in the convulsive process elicited by pilocarpine.

[A retrospective study of the effects of 3,4-diaminopyridine treatment in Lambert-Eaton myasthenic syndrome].

In this independent clinical study, we analyzed retrospectively the clinical features of 9 cases (6 male and 3 female) of Lambert-Eaton myasthenic syndrome that were administered 3,4-diaminopyridine (3,4-DAP). Four cases showed no cancer and 5 cases had small cell lung carcinoma. Seven cases were positive for anti voltage-gated calcium channel antibodies. Activities of daily living (ADL) were improved by 3,4-DAP in 8 cases that showed mainly weakness of the extremities, but did not improve ADL in 1 case with cerebellar ataxia of paraneoplastic cerebellar degeneration (PCD). Seven cases showed autonomic symptoms, and 6 cases were improved with 3,4-DAP. The maintenance dose varied widely among individuals, with a single dose ranging from 10 to 40 mg. Each patient was prescribed a maintenance dose 3 to 7 times a day. The daily dosage ranged from 36 to 100 mg. Two cases showed adverse effects to the treatment. Of those 2 cases, 1 case treated at 45 mg/day discontinued treatment, but another case treated at 100 mg/day reduced the dosage and continued treatment. The administration period was 1 to 149 months. Three cases have continued 3,4-DAP for more than 10 years. Four cases have discontinued 3,4-DAP, with 2 cases discontinuing due to death, 1 case discontinuing due to progression of cancer, and 1 case discontinuing due to an adverse reaction. Our results suggest that 3,4-DAP treatment is effective for weakness and autonomic symptoms, but may be ineffective for ataxia of PCD. Treatment with 3,4-DAP can be tolerated for a long period, but the optimal dosage varies widely among individuals.

Fampridine Prolonged Release: A Review in Multiple Sclerosis Patients with Walking Disability.

Oral fampridine prolonged release (PR) [Fampyra®] is a lipid-soluble selective potassium channel blocker that is approved in the EU for the improvement of walking in adult multiple sclerosis (MS) patients with walking disability (expanded disability status scale score of 4-7). In clinical trials (MS-F203 and MS-F204) using an objective measure of walking improvement [the timed 25-foot walk (T25FW)], more than one-third of patients receiving fampridine PR achieved a consistent on-treatment improvement in walking speed (i.e. became TW responders) over 9-14 weeks of treatment. Fampridine PR recipients who fulfilled the definition of TW responder had mean improvements of ≈25% from baseline in T25FW walking speed. In a clinical trial (ENHANCE) that used a patient-rated measure of walking improvement [12-item MS walking scale (MSWS-12)], a significantly greater proportion of fampridine PR recipients than placebo recipients achieved a ≥8-point improvement on the MSWS-12 with 24 weeks of treatment. Where reported, adverse events were mostly mild or moderate in severity, and generally consistent with the underlying disease or mechanism of action of fampridine PR. Fampridine PR is a useful treatment option to consider in adult MS patients with walking disability.

Acetylator Status Impacts Amifampridine Phosphate (Firdapse™) Pharmacokinetics and Exposure to a Greater Extent Than Renal Function.

PURPOSE: The purpose of this study is to evaluate safety, tolerability, and pharmacokinetic (PK) properties of amifampridine phosphate (Firdapse™) and its major inactive 3-N-acetyl metabolite in renally impaired and healthy individuals with slow acetylator (SA) and rapid acetylator (RA) phenotypes. METHODS: This was a Phase I, multicenter, open-label study of the PK properties and safety profile of amifampridine phosphate in individuals with normal, mild, moderate, or severely impaired renal function. Amifampridine phosphate was given as a single 10 mg (base equivalent) dose, and the plasma and urine PK properties of amifampridine and its 3-N-acetyl metabolite were determined. The safety profile was evaluated by monitoring adverse events (AEs), clinical laboratory tests, and physical examinations. FINDINGS: Amifampridine clearance was predominantly metabolic through N-acetylation, regardless of renal function in both acetylator phenotypes. In individuals with normal renal function, mean renal clearance represented approximately 3% and 18% of the total clearance of amifampridine in RA and SA, respectively. Large differences in amifampridine exposure were observed between acetylation phenotypes across renal function levels. Mean amifampridine exposure values of AUC0-∞ and Cmax were up to 8.8-fold higher in the SA group compared with the RA group across renal function levels. By comparison, mean AUC0-∞ was less affected by renal function within an acetylator group, only 2- to 3-fold higher in individuals with severe renal impairment (RI) compared with those with normal renal function. Exposure to amifampridine in the SA group with normal renal function was higher (AUC0-∞, approximately 1.8-fold; Cmax, approximately 4.1-fold) than the RA group with severe RI. Exposure to the inactive 3-N-acetyl metabolite was higher than amifampridine in both acetylator groups, independent of renal function level. The metabolite is cleared by renal excretion, and exposure was clearly dependent on renal function with 4.0- to 6.8-fold increases in AUC0-∞ from normal to severe RI. No new tolerability findings were observed. IMPLICATIONS: A single dose of 10 mg of amifampridine phosphate was well tolerated, independent of renal function and acetylator status. The results indicate that the PK profile of amifampridine is affected by metabolic acetylator phenotype to a greater extent than by renal function level, supporting Firdapse™ administration in individuals with RI in line with current labeling recommendations. Amifampridine should be dosed to effect per the individual patient need, altering administration frequency and dose in normal through severe RI. The therapeutic dose of amifampridine phosphate should be tailored to the individual patient needs by gradual dose titration up to the present maximum recommended dose (60-80 mg/day) or until dose-limiting AEs intervene to avoid overdosing and underdosing. EudraCT identifier: 2013-005349-35.

Assessment of the efficacy and safety of fampridine.

OBJECTIVE: Assessment of the efficacy and safety of fampridine for walking improvement in adult patients with multiple sclerosis. METHOD: A descriptive retrospective study of all patients who initiated treatment with fampridine between March, 2014 and February, 2015. Efficacy was assessed through the 25-foot walk test and the 12-item walking scale for multiple sclerosis. It was reviewed whether patients had suffered any of the most frequent adverse effects described in the pivotal clinical trial. RESULTS: Six patients were included, with a 66.7% response rate. At 3-6 months, the mean change in walking speed (compared to baseline) was 39.32% and there was a mean improvement of 15 points in the walking scale. Only one patient presented adverse effects. CONCLUSIONS: The results obtained are encouraging, particularly when fampridine is the only drug currently approved to control such a disabling symptom as instability while walking.

Objetivo: Evaluación de la efectividad y seguridad de la fampridina en la mejoría de la marcha de pacientes adultos con esclerosis múltiple.Método: Estudio descriptivo retrospectivo de todos los pacientes que iniciaron tratamiento con fampridina entre marzo de 2014 y febrero de 2015. Se evaluó la efectividad utilizando el test de marcha de los 25 pies y la escala de movilidad de 12 ítems de la esclerosis múltiple. Se revisó si los pacientes habían sufrido alguno de los efectos adversos más frecuentes descritos en el ensayo pivotal.Resultados: Se incluyeron 6 pacientes, con una tasa de respuesta del 66,7%. A los 3-6 meses, el cambio medio en la velocidad de la marcha (comparado con el basal) fue del 39,32% y hubo una mejora media de 15 puntos en la escala de movilidad. Solo uno de los pacientes presentó efectos adversos. Conclusiones: Los resultados obtenidos son esperanzadores, sobre todo cuando la fampridina es el único fármaco autorizado actualmente para controlar un síntoma tan discapacitante como es la inestabilidad de la marcha.

Effect of fampridine on axonal excitability in multiple sclerosis.

OBJECTIVE: To investigate the effects of fampridine on nerve excitability, the present study utilized peripheral axonal excitability techniques in 18 MS patients receiving treatment with fampridine. METHODS: Studies were performed at baseline and repeated 3months after institution of fampridine at standard dosing. RESULTS: Following treatment with fampridine there were significant changes in axonal excitability for those parameters associated with fast K(+) channels that shifted towards normal control values. Specifically, increases were noted in the peak superexcitability of recovery cycle (fampridine, -25.6±1.6%; baseline -22.8±1.7%; p<0.004), peak depolarizing threshold electrotonus (fampridine, 69.1±1.0%; baseline 67.0±1.4%; p<0.004), and depolarizing threshold electrotonus between 40 and 60ms after onset of depolarization (fampridine, 52.8±1.3%; baseline 49.9±1.4%; p=0.02). CONCLUSION: The present study has established that fampridine at standard doses exerts effects on peripheral nerve function that may be mediated by reduction of fast K(+) conductances. SIGNIFICANCE: Modulation of fast K(+) conductances by fampridine may contribute to the improvement observed in MS symptoms including motor fatigue.