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Discovery of functionally distinct anti-C7 monoclonal antibodies and stratification of anti-nicotinic AChR positive Myasthenia Gravis patients.
Front Immunol
September 2022
Immunology Research Unit, GlaxoSmithKline Research & Development (GSK R&D), Stevenage, United Kingdom.
Myasthenia Gravis (MG) is mediated by autoantibodies against acetylcholine receptors that cause loss of the receptors in the neuromuscular junction. Eculizumab, a C5-inhibitor, is the only approved treatment for MG that mechanistically addresses complement-mediated loss of nicotinic acetylcholine receptors. It is an expensive drug and was approved despite missing the primary efficacy endpoint in the Phase 3 REGAIN study.
View Article and Find Full Text PDFInfluence of Experimental End Point on the Therapeutic Efficacy of Essential and Additional Antidotes in Organophosphorus Nerve Agent-Intoxicated Mice.
Toxics
April 2022
Chemical, Biological and Radiological Division, Defence Science and Technology Laboratory (DSTL), Salisbury SP4 0JQ, UK.
The therapeutic efficacy of treatments for acute intoxication with highly toxic organophosphorus compounds, called nerve agents, usually involves determination of LD values 24 h after nerve agent challenge without and with a single administration of the treatment. Herein, the LD values of four nerve agents (sarin, soman, tabun and cyclosarin) for non-treated and treated intoxication were investigated in mice for experimental end points of 6 and 24 h. The LD values of the nerve agents were evaluated by probit-logarithmical analysis of deaths within 6 and 24 h of i.
View Article and Find Full Text PDFInfluence of experimental end point on the therapeutic efficacy of the antinicotinic compounds MB408, MB442 and MB444 in treating nerve agent poisoned mice - a comparison with oxime-based treatment.
Toxicol Mech Methods
November 2020
Chemical, Biological and Radiological Division, Defence Science and Technology Laboratory (DSTL), Salisbury, United Kingdom.
Therapeutic efficacy of antidotal treatment of acute poisoning by nerve agents is generally assessed by the evaluation of LD values of nerve agents over 24 h following poisoning without or with a single administration of antidotal treatment. In this study, LD values of four nerve agents (sarin, soman, tabun and cyclosarin) for non-treated and treated poisoning were evaluated in mice for two experimental end points - 6 h and 24 h. While the efficacy of atropine or oxime-based antidotal treatment was the same regardless of the experimental end point, the therapeutic efficacy of all three newly developed bispyridinium non-oxime compounds (MB408, MB442, and MB444) was mostly slightly higher at the 6 h end point compared to the 24 h end point, although the therapeutic efficacy of MB compounds was not superior to oxime-based antidotal treatment.
View Article and Find Full Text PDF[Eculizumab Treatment for Refractory Generalized Myasthenia Gravis].
Brain Nerve
June 2019
Department of Neurology, Graduate School of Medicine, Chiba University.
Myasthenia gravis (MG) is an autoimmune disease of the neuromuscular junction mainly caused by anti-nicotinic acetylcholine receptor (AChR) antibodies. Complements are known to play a prominent role in the pathogenesis of MG. Long-term remission may not necessarily be achieved in MG patients with conventional therapies.
View Article and Find Full Text PDFEfficacy of antidotes and their combinations in the treatment of acute carbamate poisoning in rats.
Toxicology
September 2018
Department of Anatomy and Forensic Medicine, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia.
Background: Physostigmine and its analogues neostigmine, pyridostigmine and rivastigmine are carbamates nowadays used in many indications, including antidotal effects against antimuscarinic poisonings, reversal of competitive neuromuscular block, myasthenia gravis, Alzheimer's disease and prophylaxis against nerve agent intoxications. Use of these medicinal carbamates, but also of carbamate insecticides, created need for research into the potential and mechanisms of action of several antidotes against carbamate poisonings, including anticholinergics and oximes.
Aim: The goal of this experimental study was to ascertain the life-preserving potential of anticholinergics atropine, hexamethonium and d-tubocurarine, oxime HI-6 and their combinations in rats poisoned with physostigmine or pyridostigmine.
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