RESUMEN
BACKGROUND: 4-Aminopyridine (4-AP) is a Food and Drug Administration-approved drug to improve motor function in people with multiple sclerosis. Preliminary results suggest the drug may act on intact neural circuits and not just on demyelinated ones. OBJECTIVE: To determine if 4-AP at clinically relevant levels alters the excitability of intact motor circuits. METHODS: In anesthetized rats, electrodes were placed over motor cortex and the dorsal cervical spinal cord for electrical stimulation, and electromyogram electrodes were inserted into biceps muscle to measure responses. The motor responses to brain and spinal cord stimulation were measured before and for 5 hours after 4-AP administration both in uninjured rats and rats with a cut lesion of the pyramidal tract. Blood was collected at the same time as electrophysiology to determine drug plasma concentration with a goal of 20 to 100 ng/mL. RESULTS: We first determined that a bolus infusion of 0.32 mg/kg 4-AP was optimal: it produced on average 61.5 ± 1.8 ng/mL over the 5 hours after infusion. This dose of 4-AP increased responses to spinal cord stimulation by 1.3-fold in uninjured rats and 3-fold in rats with pyramidal tract lesion. Responses to cortical stimulation also increased by 2-fold in uninjured rats and up to 4-fold in the injured. CONCLUSION: Clinically relevant levels of 4-AP strongly augment physiological responses in intact circuits, an effect that was more robust after partial injury, demonstrating its broad potential in treating central nervous system injuries.
Asunto(s)
4-Aminopiridina/farmacología , Fármacos del Sistema Nervioso Central/farmacología , Médula Cervical/efectos de los fármacos , Corteza Motora/efectos de los fármacos , Tractos Piramidales/efectos de los fármacos , Traumatismos de la Médula Espinal/tratamiento farmacológico , 4-Aminopiridina/sangre , 4-Aminopiridina/farmacocinética , Animales , Fármacos del Sistema Nervioso Central/sangre , Fármacos del Sistema Nervioso Central/farmacocinética , Médula Cervical/lesiones , Médula Cervical/fisiología , Médula Cervical/fisiopatología , Evaluación Preclínica de Medicamentos , Estimulación Eléctrica , Electromiografía , Potenciales Evocados Motores/efectos de los fármacos , Potenciales Evocados Motores/fisiología , Femenino , Miembro Anterior/efectos de los fármacos , Miembro Anterior/fisiología , Miembro Anterior/fisiopatología , Microelectrodos , Corteza Motora/fisiología , Corteza Motora/fisiopatología , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/fisiología , Músculo Esquelético/fisiopatología , Tractos Piramidales/lesiones , Tractos Piramidales/fisiología , Tractos Piramidales/fisiopatología , Distribución Aleatoria , Ratas Sprague-Dawley , Traumatismos de la Médula Espinal/fisiopatologíaRESUMEN
BACKGROUND: In January 2010, dalfampridine extended release tablets (dalfampridine-ER [Ampyra *]; prolonged-, modified- or sustained-release fampridine [Fampyra ] in some countries), 10 mg to be administered twice daily approximately 12 hours apart, were approved by the US Food and Drug Administration. This was the first drug indicated to improve walking in patients with MS. SCOPE: Publications describing the pharmacokinetics of dalfampridine-ER or the immediate release formulation were identified from a search of PubMed through June 2012 using the search terms 'dalfampridine OR fampridine OR 4-aminopyridine' AND 'pharmacokinetics' and were supplemented with unpublished studies made available by Acorda Therapeutics Inc. FINDINGS: Pharmacokinetic studies show dose proportionality, with dalfampridine-ER having a more favorable profile than immediate-release dalfampridine. With twice-daily dosing of dalfampridine-ER, time to peak plasma concentration (3.2-3.9 hours) and apparent terminal plasma half-life (5.6-6.4 hours) are approximately twice those of immediate-release formulations, with comparable overall exposure and peak plasma concentrations (21.6 ng/mL) that were maintained at levels approximately 50% lower than immediate release. Steady state is achieved within 39 hours; pharmacokinetics are predictable based on single dosing. Trough plasma concentrations of 13-15 ng/mL are required to maintain efficacy. Renal excretion is predominantly as unchanged compound, and renal clearance in healthy individuals exceeds the glomerular filtration rate. Since dalfampridine-ER exposure increases with renal impairment, it is contraindicated in patients with moderate or severe impairment in the US, and in patients with any renal impairment in the European Union. CONCLUSIONS: Dalfampridine-ER has low protein binding, is not a substrate for p-glycoprotein and does not affect CYP450 enzymes, suggesting a low potential for drug-drug interactions. Because of the narrow therapeutic range and risk of adverse events, including seizure, with increasing plasma concentrations, the recommended dose and regimen of dalfampridine-ER should not be exceeded and not be used with other dalfampridine formulations. A limitation of this review is that it includes some data that have not yet been published.