New calcium channel agonists as potential therapeutics in Lambert-Eaton myasthenic syndrome and other neuromuscular diseases

Department of Neuroscience Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania.
Annals of the New York Academy of Sciences (Impact Factor: 4.38). 12/2012; 1275(1):85-91. DOI: 10.1111/nyas.12001
Source: PubMed


Lambert-Eaton myasthenic syndrome (LEMS) causes neuromuscular weakness as a result of an autoimmune attack on the calcium channels that normally regulate chemical transmitter release at the neuromuscular junction. Currently there are limited treatment options for patients with this and other forms of neuromuscular weakness. A novel, first-in-class calcium channel agonist that is selective for the types of voltage-gated calcium channels that regulate transmitter release at neuromuscular synapses has recently been developed. This compound (GV-58) slows deactivation (closing) of the channel, resulting in a large increase in total calcium entry during motor nerve action potential activity. This new calcium channel agonist is currently being evaluated for the treatment of neuromuscular weakness. Potential applications include development as single therapeutics, or for combination treatments.

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    ABSTRACT: Besides antitumor therapy for patients with the paraneoplastic form of Lambert-Eaton myasthenic syndrome (LEMS), the mainstay of symptomatic treatment in LEMS is 3,4-diaminopyridine (3,4-DAP). Data from four randomized, placebo-controlled trials have revealed that muscle strength scores increased significantly with 3,4-DAP. A limited meta-analysis performed on two trials using the Quantitative Myasthenia Gravis score indicated that the clinical benefits seen were modest. Meta-analysis of the mean change in compound muscle action potential amplitude following 3,4-DAP treatment revealed a significant improvement compared to placebo. However, most patients with noncancer LEMS require long-term immunosuppression, usually with prednisolone and azathioprine. A single crossover study has previously shown significant short-term benefit in limb strength following intravenous immunoglobulin, and there are isolated case reports of medium term benefit from rituximab. Overall, a combination of symptomatic treatment with 3,4-DAP and immunosuppression, with or without antitumor therapy, is often successful for most LEMS patients, with other more aggressive regimens rarely needed.
    No preview · Article · Dec 2012 · Annals of the New York Academy of Sciences
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    ABSTRACT: A long-held tenet of neuromuscular transmission is that calcium-dependent neurotransmitter release is mediated by N-type calcium channels in frog but P/Q-type channels in mammals. The N-type assignment in frog is based principally on pharmacological sensitivity to ω-conotoxin GVIA. Our studies show that zebrafish neuromuscular transmission is also sensitive to ω-conotoxin GVIA. However, positional cloning of a mutant line with compromised neuromuscular function identified a mutation in a P/Q- rather than N-type channel. Cloning and heterologous expression of this P/Q-type channel confirmed a block by ω-conotoxin GVIA raising the likelihood that all vertebrates, including frog, use the P/Q-type calcium channel for neuromuscular transmission. In addition, our P/Q defective mutant line offered a means of testing the ability of roscovitine, known to potentiate frog neuromuscular transmission, to mediate behavioral and functional rescue. Acute treatment led to rapid improvement of both, pointing to potential therapeutic benefit for myasthenic disorders involving calcium channel dysfunction.
    Full-text · Article · Apr 2013 · The Journal of Neuroscience : The Official Journal of the Society for Neuroscience
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    ABSTRACT: Introduction: Lambert–Eaton myasthenic syndrome (LEMS) is a rare autoimmune disorder of the neuromuscular junction. Antibody-mediated functional loss of voltage-gated calcium channels (VGCCs) on the presynaptic surface results in reduced neurotransmitter release. Muscle weakness starts in the proximal limbs and is accompanied by autonomic failure and areflexia. About 50 – 60% of the patients have small-cell lung cancer (SCLC), with antibodies produced in reaction to VGCC on tumor cells. In non-tumor LEMS, an autoimmune reaction causes antibody production. Knowledge of the pathophysiology of antibody production in SCLC-LEMS and non-tumor LEMS and a detailed understanding of the neuromuscular junction and its dysfunction in LEMS is needed for drug development. Areas covered: This review gives an overview of the clinical symptoms, diagnosis and pathophysiology of LEMS. Current treatment options and results of recent research on newly developed symptomatic treatment are described. Expert opinion: Extensive search for SCLC is needed in LEMS patients. Appropriate tumor treatment should be started in SCLC-LEMS. In both SCLC-LEMS and non-tumor LEMS, symptomatic treatment consists of 3,4-diaminopyridine. If insufficient, pyridostigmine can be added, although a small trial failed to prove its benefit in LEMS and it is probably only efficient in a subset of patients. In moderate-to-severe disease, immunosuppressive treatment with prednisolone and azathioprine should be started. Research on drugs in LEMS is complicated by the infrequency of the disorder. Future developments are mainly expected in the field of symptomatic treatment. Possibly, further studies on immunosuppression in myasthenia gravis will be meaningful for the therapeutic strategy in LEMS as well.
    No preview · Article · Jan 2014 · Expert Opinion on Orphan Drugs
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