Article

The Use of Aminopyridines in Neurological Disorders

Department of Clinical Neurology, Queen's Medical Centre, Nottingham, UK.
Clinical neuropharmacology (Impact Factor: 1.84). 07/2012; 35(4):191-200. DOI: 10.1097/WNF.0b013e31825a68c5
Source: PubMed

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.

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    • "101 symptoms in MS patients such as paresthesia, palsy, vertigo, and bladder disturbances. 4-Aminopyridine (4-AP) blocks a wide range of voltage-gated K + channels and the resulting improvement of action potential conduction (Sedehizadeh et al., 2012) emends the walking capability in MS patients (Goodman et al., 2010). Accordingly, dalfampridine, an extended-release formulation of 4-AP, was approved in 2010 by the FDA for the symptomatic treatment of walking difficulties in patients with MS (Espejo & Montalban, 2012). "
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    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
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    • "contactin and Caspr2) [Gu and Gu, 2011; Horresh et al. 2008; Ivanovic et al. 2012] accompanied by a drift of K V channels to other sites of the axon, inducing a reduction in resistance, slowing of conduction velocity and conduction failure [Boyle et al. 2001]. Pharmacological inhibition of exposed K V channels at demyelinating axons was hypothesized as an attractive strategy to improve action potential generation in demyelinating disorders [Sedehizadeh et al. 2012]. Consequently 4-aminopyridine (4-AP), a well-known potassium channel blocker, was improved by providing a sustained release formulation and tested for mobility improvement in patients with MS versus placebo. "
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    ABSTRACT: Pharmacological targeting of ion channels has long been recognized as an attractive strategy for the treatment of various diseases. Multiple sclerosis (MS) is an autoimmune disorder of the central nervous system with a prominent neurodegenerative component. A multitude of different cell types are involved in the complex pathophysiology of this disorder, including cells of the immune system (e.g. T and B lymphocytes and microglia), the neurovascular unit (e.g. endothelial cells and astrocytes) and the central nervous system (e.g. astrocytes and neurons). The pleiotropic expression and function of ion channels gives rise to the attractive opportunity of targeting different players and pathophysiological aspects of MS by the modulation of ion channel function in a cell-type and context-specific manner. We discuss the emerging knowledge about ion channels in the context of autoimmune neuroinflammation. While some pharmacological targets are at the edge of clinical translation, others have only recently been discovered and are still under investigation. Special focus is given to those candidates that could be attractive novel targets for future therapeutic approaches in neuroimmune autoinflammation.
    Therapeutic Advances in Neurological Disorders 09/2013; 6(5):322-36. DOI:10.1177/1756285613487782
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    • "These demyelination-associated mechanisms cause exposure of paranodal and internodal voltage-sensitive potassium channels (K V channels) that are distributed in the axonal membrane resulting in abnormal potassium outward currents associated with slow action potential conduction, conduction failure or changes in the axon's capacity for repetitive discharges (Dunn and Blight, 2011). Blockade of K V channels exposed at demyelinated axons has been suggested as mechanism of action of 4-aminopyridine (4-AP) leading to improved action potential conduction (Sedehizadeh et al., 2012). This improvement in conduction translates into clinical benefit as measured by objectively and subjectively assessed walking abilities relative to placebo in a proportion of MS patients (Goodman et al., 2009, 2010). "
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    ABSTRACT: Neuropathological changes following demyelination in Multiple Sclerosis (MS) lead to a reorganization of axolemmal channels that causes conduction changes including conduction failure. Pharmacological modulation of voltage-sensitive potassium channels (KV) has been found to improve conduction in experimentally induced demyelination and produces symptomatic improvement in MS patients. Here we used an animal model of autoimmune inflammatory neurodegeneration, namely experimental autoimmune encephalomyelitis (EAE), to test the influence of the KV-inhibitor 4-aminopyridine (4-AP) on various disease and immune parameters as well as mobility in MOG35-55 immunized C57Bl/6 mice. We challenged the hypothesis that 4-AP exerts relevant immunomodulatory or neuroprotective properties. Neither prophylactic nor therapeutic treatment with 4-AP altered disease incidence or disease course of EAE. Histopathological signs of demyelination and neuronal damage as well as MRI imaging of brain volume changes were unaltered. While application of 4-AP significantly reduced the standing outward current of stimulated CD4(+) T cells compared to controls, it failed to impact intracellular calcium concentrations in these cells. Compatibly, KV channel inhibition neither influenced CD4(+) T cell effector functions (proliferation, IL17 or IFNγ production). Importantly however, despite equal disease severity scores 4-AP treated animals showed improved mobility as assessed by 2 independent methods, 1) foot print and 2) rotarod analysis (0.332 ± 0.03, n = 7 versus 0.399 ± 0.08, , n = 14, p < 0.001, respectively). Our data suggest that 4-AP while having no apparent immunomodulatory or direct neuroprotective effects, significantly ameliorates conduction abnormalities thereby improving gait and coordination. Improvement of mobility in this experimental model supports trial data and clinical experience with 4-AP in the symptomatic treatment of MS.
    Experimental Neurology 06/2013; 248. DOI:10.1016/j.expneurol.2013.05.016
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