. (1997). Fundam. Appl. Toxicol 38,[75][76][77][78][79][80][81][82][83][84][85][86][87][88] The extent to which cardiorespiratory infirmity and other sublethal effects of saxitoxin (STX) and tetrodotoxin (TTX) can be reversed by 4-aminopyridine (4-AP) was investigated in guinea pigs chronically instrumented for the concurrent electrophysiological recordings of electrocorticogram (ECoG), diaphragmatic electromyogram (DEMG), Lead II electrocardiogram, and neck skeletal muscle electromyogram. Animals were intoxicated with either STX or TTX (2 and 3 /xg/kg, im) to produce a state of progressive cardiorespiratory depression (depicted by decreasing DEMG amplitude, bradypnea, and bradycardia). At the point where cardiorespiratory performance was most seriously compromised («30 min posttoxin), 4-AP (1 or 2 mg/kg, im) was administered. The therapeutic effect of 4-AP was striking in that, within minutes, the toxin-induced diaphragmatic blockade, bradypnea, bradycardia, and depressed cortical activity were all restored to a level either comparable to, or surpassing, that of control. The optimal 4-AP dose level was determined to be 2 mg/kg (im) based on analyses of cardiorespiratory activity profiles throughout the course of intoxication and 4-AP treatment. At the dose levels (either 1 or 2 mg/ kg) used to restore ventilatory function and cardiovascular performance, 4-AP produced no sign of seizures and convulsions. Although less serious secondary effects such as cortical excitant/arousal effect (indicated by ECoG power spectral analysis) and transient periods of skeletal muscle fasciculation were observed, these events were of minor concern particularly in view of the remarkable therapeutic effects of 4-AP. © i»»7 society of Toxicology.Saxitoxin (STX) and tetrodotoxin (TTX) are among the deadliest nonprotein neurotoxins known (lethal dose in guinea pigs «*5 ^g/kg, im; unpublished observations).
The selective blockade of potassium channels on excitable membranes by 4-aminopyridine (4-AP) leads to facilitation of neurotransmitter release at a wide variety of synapses. This compound has been shown to be efficacious against lethality induced by saxitoxin (STX) and tetrodotoxin (TTX) in guinea pigs. To characterize the actions of 4-AP in guinea pigs we have investigated its pharmacokinetics (PK) and pharmacodynamics following a 2 mg/kg, intramuscular (im) dose in awake chronically instrumented (IN) animals. Animals were chronically instrumented for electrophysiologic recordings of diaphragmatic electromyogram (DEMG), lead II electrocardiogram (ECGII) and electrocorticogram (ECoG). Also, PK studies were carried out in uninstrumented (UN) guinea pigs. Blood and electrophysiologic data were collected at predetermined time intervals up to 4 hours post 4-AP administration. High performance liquid chromatography was used to determine plasma 4-AP concentrations. For IN and UN animals, plasma concentration-time data best fit a one-compartment model, and PK parameter estimates were similar for both groups. Peak plasma levels were found to occur between 16 and 17 min, and the half-lives of elimination were 65 and 71 min for IN and UN animals respectively. Heart and respiratory rates were elevated as early as 5 and 15 min respectively in response to 4-AP administration. The duration of action was approximately 1-1.5 half-lives of elimination beyond peak plasma levels. Maximum ECoG responses were observed between 12-15 min after 4-AP injection; some residual drug effects were still apparent at 240 min. The difference between the heart and respiratory rates and ECoG profiles suggests that these different physiological systems respond with varying degrees of sensitivity to plasma 4-AP concentrations. The stimulation of these systems is consistent with the action of 4-AP in reversing STX- and TTX-induced cardiorespiratory depression and decreased ECoG power in guinea pigs.
Managing organophosphorus nerve agent poisoning involves pyridostigmine (PYR) pretreatment followed by post‐exposure oxime/anticholinergic therapy. For military/civilian populations not enrolled in the PYR pretreatment program, however, the post‐exposure therapy offers little, if any, protection. To eliminate the need for pretreatment, we have developed, and efficacy evaluated, a post‐exposure therapy mix consisting of scopolamine (0.5 mg/kg, im), methyl‐atropine (2 mg/kg, im), physostigmine (0.015 mg/kg, im), MMB4 (a bispyridinium oxime; 26.1 mg/kg, im) and phenobarbital (25 mg/kg, ip) against a lethal dose (2×LD50) of either soman (GD), sarin (GB), cyclo‐sarin (GF) or VX in unanesthetized guinea pigs instrumented for concurrent recordings of CNS and cardiorespiratory activities. Results showed that none of the animals tested exhibited seizures, convulsions or signs of anomalous cardiorespiratory activities. Only mild acute cholinergic effects (salivation, dystonia) and phenobarbital's sedative effects were seen during the first 20 min post‐agent. Animals were typically asymptomatic within 20–30 min. All animals survived 24 hrs post nerve agent exposure. Our findings indicate that the therapy mix used in this study was effective not only in antagonizing nerve agent‐induced lethality, but also in protecting the functional integrity of the CNS and cardiorespiratory system.
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