The use of aminopyridines in neurological disorders.
ABSTRACT Aminopyridines are members of a family of monoamino and diamino derivatives of pyridine, and their principal mechanism of action is dose-dependent blockade of voltage-gated potassium channels, in particular, fast voltage-gated potassium channels. To date, only 2 main broad-spectrum potassium channel blockers, 4-aminopyridine (4-AP) and 3,4-diaminopyridine (3,4-DAP), have been used as investigational new drugs in various neurological diseases. More recently, licensed versions of these compounds including dalfampridine extended release (Fampyra, Biogen Idec) for the improvement of walking in adult patients with multiple sclerosis, and amifampridine (Firdapse, Biomarin Europe Ltd) for the treatment of Lambert-Eaton myasthenic syndrome have been released, and the costs associated with using these new products highlights the importance of evaluating the clinically meaningful treatment effects of these drugs.The current review summarizes the evidence of aminopyridine use in neurological conditions and in particular presents a systematic review of all randomized trials of 3,4-DAP in Lambert-Eaton myasthenic syndrome to determine the efficacy of this treatment using meta-analysis of clinical and electrophysiological end points.
SourceAvailable from: Katja Schmitz[Show abstract] [Hide abstract]
ABSTRACT: The association between vitamin D and multiple sclerosis has (re)-opened new interest in nutrition and natural compounds in the prevention and treatment of this neuroinflammatory disease. The dietary amount and type of fat, probiotics and biologicals, salmon proteoglycans, phytoestrogens and protease inhibitor of soy, sodium chloride and trace elements, and fat soluble vitamins including D, A and E were all considered as disease-modifying nutraceuticals. Studies in experimental autoimmune encephalomyelitis mice suggest that poly-unsaturated fatty acids and their 'inflammation-resolving' metabolites and the gut microflora may reduce auto-aggressive immune cells and reduce progression or risk of relapse, and infection with whipworm eggs may positively change the gut-brain communication. Encouraged by the recent interest in multiple sclerosis-nutrition nature's pharmacy has been searched for novel compounds with anti-inflammatory, immune-modifying and antioxidative properties, the most interesting being the scorpion toxins that inhibit specific potassium channels of T cells and antioxidative compounds including the green tea flavonoid epigallocatechin-3-gallate, curcumin and the mustard oil glycoside from e.g. broccoli, sulforaphane. They mostly also inhibit pro-inflammatory signaling through NF-κB or toll-like receptors and stabilize the blood brain barrier. Disease modifying functions may also complement analgesic and anti-spastic effects of cannabis, its constituents, and of 'endocannabinoid enhancing' drugs or nutricals like inhibitors of fatty acid amide hydrolase. Nutricals will not solve multiple sclerosis therapeutic challenges but possibly support pharmacological interventions or unearth novel structures. Copyright © 2014. Published by Elsevier Inc.Pharmacology [?] Therapeutics 11/2014; 148. DOI:10.1016/j.pharmthera.2014.11.015 · 7.75 Impact Factor
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ABSTRACT: Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disease that disrupts the normally reliable neurotransmission at the neuromuscular junction (NMJ). This disruption is thought to result from an autoantibody-mediated removal of a subset of the P/Q-type Ca(2+) channels involved with neurotransmitter release. With less neurotransmitter release at the NMJ, LEMS patients experience debilitating muscle weakness. The underlying cause of LEMS in slightly more than half of all patients is small cell lung cancer, and cancer therapy is the priority for these patients. In the remaining cases, the cause of LEMS is unknown, and these patients often rely on symptomatic treatment options, as there is no cure. However, current symptomatic treatment options, such as 3,4-diaminopyridine (3,4-DAP), can have significant dose-limiting side effects; thus, additional treatment approaches would benefit LEMS patients. Recent studies introduced a novel Ca(2+) channel agonist (GV-58) as a potential therapeutic alternative for LEMS. Additionally, this work has shown that GV-58 and 3,4-DAP interact in a supra-additive manner to completely restore the magnitude of neurotransmitter release at the NMJs of a LEMS mouse model. In this review, we discuss synaptic mechanisms for reliability at the NMJ and how these mechanisms are disrupted in LEMS. We then discuss the current treatment options for LEMS patients, while also considering recent work demonstrating the therapeutic potential of GV-58 alone and in combination with 3,4-DAP.Molecular Neurobiology 09/2014; DOI:10.1007/s12035-014-8887-2 · 5.29 Impact Factor
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ABSTRACT: Aminopyridines are potassium channel blockers that increase the excitability of nerve cells and axons; therefore, they are widely used to treat different neurological disorders. Here we present a patient with idiopathic downbeat nystagmus and lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia who was treated with the sustained-release form of 4-aminopyridine (4-AP). During treatment with 4-AP, the LUTS improved. This improvement was monitored by using uroflowmetry and the International Prostate Symptom Score. A significant improvement of symptoms was observed in relation to the voided volume. This included an improved emptying of the bladder without an increase in residual urine. In animal studies, both nonselective K(+) channel blockade and selective voltage-sensitive potassium blockade by 4-AP resulted in increased contraction on rat detrusor strips. To our knowledge, this is the first clinical observation of the mode of action of 4-AP in urological symptoms in humans.International neurourology journal 12/2014; 18(4):221-5. DOI:10.5213/inj.2014.18.4.221