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Pyridostigmine Protection from Nerve Agent Intoxication: Concept to FDA Approval *
Published in Brian J. Lukey, James A. Romano, Salem Harry, Chemical Warfare Agents, 2019
Michael Adler, James P. Apland, Sharad S. Deshpe, Irwin Koplovitz, David E. Lenz
Tetanic tension recorded at 100 Hz in the control hemidiaphragm had peak amplitudes ranging from 61 to 79 g and plateaus that were well maintained during the train (Figure 18.3, Control). In contrast, tetanic tensions in diaphragms from GD-challenged animals were markedly depressed, and the waveforms exhibited a characteristic “tetanic fade,” even though the stimulation parameters were unchanged from those used to elicit control responses (Dirnhuber and Green, 1978; French et al., 1979) (Figure 18.3, GD). At PB doses >1 µg/kg, hemidiaphragms from pretreated animals exhibited a dose-dependent increase in tetanic tension amplitudes, a slower rate of tetanic fade, and higher plateau tensions. Tetanic fade stems from desensitization of nAChRs as a result of the prolonged synaptic residence time of ACh, especially during high-frequency repetitive stimulation (Eccles and MacFarlane, 1949; Katz and Miledi, 1973; Kasprzak and Salpeter, 1985). ACh accumulation in turn arises from the inability of transmitter to be cleared from the synapse when AChE activity is reduced below a critical level, generally considered to be 25–30% of control (Heffron and Hobbiger, 1979; Laskowski and Dettbarn, 1979). Removal of transmitter by diffusion, which is adequate for most synapses, is not effective at the NMJ, because this process is impeded by close apposition of the pre- and post-junctional membranes as well as by the high density of nAChRs (Anglister et al., 1998; Katz and Miledi, 1973). The latter interferes with free diffusion of ACh by promoting multiple successive transmitter–receptor binding events, thus slowing the removal of ACh (Katz and Miledi, 1973). The desensitization of respiratory muscles during repetitive stimulation renders these muscle unable to contract, leading to respiratory collapse. By contrast, single twitches are generally potentiated by AChE inhibitors (Clark and Hobbiger, 1983), even at near-lethal doses (see Figure 18.7).
Impaired neuromuscular function by conjoint actions of organophosphorus insecticide metabolites omethoate and cyclohexanol with implications for treatment of respiratory failure
Published in Clinical Toxicology, 2021
Kosala N. Dissanayake, Robert Chang-Chih Chou, Adrian Thompson, Filip Margetiny, Charlotte Davie, Scott McKinnon, Vishwendra Patel, Lester Sultatos, Joseph J. McArdle, Richard E. Clutton, Michael Eddleston, Richard R. Ribchester
In sum, in isolated preparations omethoate-induced inhibition of AChE resulted in prolonged nerve-evoked muscle contractures, focused on neuromuscular junctions. Differences in the amount of passive compliance of extrajunctional muscle in long and short muscle fibres (pig pelvic limb and mouse diaphragm or TS muscles, compared with mouse FDB) are likely to have determined whether overall muscle force during these localised contractures are registered by a force transducer as tetanic fade or prolonged tetanic aftercontraction. None the less, as in recordings from pigs (Figure 3), normal or near-normal functional responses were restored by increasing extracellular (or circulating) [Mg2+].