Nerve agent poisoning in primates: antilethal, anti-epileptic and neuroprotective effects of GK-11

Abstract

Organophosphorus nerve agents are still in use today in warfare and as terrorism compounds. Classical emergency treatment of organophosphate poisoning includes the combined administration of a cholinesterase reactivator (an oxime), a muscarinic cholinergic receptor antagonist (atropine) and a benzodiazepine anticonvulsant (diazepam). However, recent experiments with primates have demonstrated that such treatment, even when administered immediately after organophosphate exposure, does not rapidly restore normal electroencephalographic (EEG) activity and fails to totally prevent neuronal brain damage. The objective of this study was to evaluate, in a realistic setting, the therapeutic benefit of administration of GK-11 (gacyclidine), an antiglutamatergic compound, as a complement to the available emergency therapy against organophosphate poisoning. GK-11 was injected at a dose of 0.1 mg/kg (i.v) after a 45-min latency period to heavily intoxicated (8 LD50) primates. Just after intoxication, man-equivalent doses of one autoinjector containing atropine/pralidoxime/diazepam were administered. The effects of GK-11 were examined on survival, EEG activity, signs of toxicity, recovery after challenge and central nervous system histology. The present data demonstrate that treatment with GK-11 prevents the mortality observed after early administration of classical emergency medication alone. EEG recordings and clinical observations also revealed that GK-11 prevented soman-induced seizures and motor convulsions. EEG analysis within the classical frequency bands (beta, theta, alpha, delta) demonstrated that central activity was totally restored to normal after GK-11 treatment, but remained profoundly altered in animals receiving atropine/pralidoxime/diazepam alone. GK-11 also markedly accelerated clinical recovery of soman-challenged primates. Lastly, this drug totally prevented the neuropathology observed 3 weeks after soman exposure in animals treated with classical emergency treatment alone. GK-11 represents a promising adjuvant therapy to the currently available emergency polymedication to ensure optimal management of organophosphate poisoning in man. This drug is presently being evaluated in a human clinical trial for a different neuroprotective indication.

Proceedings of the 2001 ECBC Scientific Conference on Chemical and Biological Defense Research, 6-8 March 2001, Marriott's Hunt Valley Inn, Hunt Valley, MD

“…Animals that had seizures controlled by the different anticonvulsant treatments (OFF) were significantly more likely to be totally free of neuropathology or, if it did occur, to have it greatly reduced in both incidence and severity. This is in agreement with previous findings in both rodents and nonhuman primates ; Lallement et al , 1998) that any treatment that can reduce or terminate seizure activity in nerve agent-exposed animals has a protective effect on the development of neuropathology. Another interesting aspect of these results was the strong association between anticonvulsant effect of the treatment and protection from the acute lethal effects of the nerve agents.…”

“…Another interesting aspect of these results was the strong association between anticonvulsant effect of the treatment and protection from the acute lethal effects of the nerve agents. Such association has been seen in previous studies from our laboratory with both anticholinergic as well as benzodiazepine drugs using soman challenge in this guinea pig model and has also been observed in nonhuman primate studies of anticonvulsant treatment of soman exposure (Lallement et al ,1998. Such an association between mortality and status epilepticus is well recognized in the clinical medical literature (Towne et al 1994; Krumholz et al 1995).…”

Animal Models That Best Reproduce the Clinical Manifestations of Human Intoxication with Organophosphorus Compounds

“…In contrast, approximately 40% of the AMN-treated animals developed seizures when challenged with 1.0Â LD 50 VX, but all guinea pigs survived the VX challenge regardless of whether they developed seizures (O'Donnell et al, 2011). Because unremitting convulsions induced by soman and sarin contribute to their lethal potency, timely treatment of soman-or sarinchallenged animals with benzodiazepines significantly improves their survival and increases the effectiveness of the standard therapy consisting of the muscarinic antagonist atropine and such AChE reactivators as pralidoxime in reducing mortality induced by these nerve agents (Lallement et al, 1997(Lallement et al, , 1998McDonough et al, 1999McDonough et al, , 2000. This is in agreement with the well reported increased risk of death associated with status epilepticus in humans (Ferlisi and Hocker, 2013;Jette and Trevathan, 2014).…”

“…The finding that the severity of the neuropathology induced by the nerve agents correlates well with the duration and severity of convulsions led to the suggestion that early management of nerve agentinduced convulsions would be sufficient to reduce the neuropathology and the accompanying neurologic deficits (Martin et al, 1985;Hayward et al, 1990;Lallement et al, 1993Lallement et al, , 1994Lallement et al, , 1997Lallement et al, , 1998McDonough and Shih, 1997;McDonough et al, 2000;Raveh et al, 2002;Shih et al, 2003). However, spontaneous recurrent motor convulsions and electrical seizures in addition to neurodegeneration have been observed in rats long after acute seizures following an exposure to nerve agents were terminated by benzodiazepines (de Araujo Furtado et al, 2010).…”

“…The genetic, anatomic, physiologic, behavioral, and metabolic similarities between humans and nonhuman primates make the nonhuman primates the most appropriate animal model of a variety of human conditions, including OP intoxication (Lallement et al, 1998;Lenz et al, 2005;Anderson, 2008;Sun et al, 2008). It is particularly noteworthy that, because the anatomy and physiology of the nonhuman primate brain are very close to those of humans, neurobehavioral tasks normally used to assess cognitive functions in humans (e.g., delayed-matchingto-sample task) have been successfully adapted for nonhuman primates, and thereby increased the translational relevance of nonhuman primates in research (Buccafusco, 2008).…”