Organophosphate-based chemical agents (OPs), including nerve agents and certain neurotoxic pesticides such as paraoxon, are potent acetylcholinesterase inhibitors that cause severe convulsions and prolonged seizures, including progression to status epilepticus, potentially leading to irreversible central nervous system (CNS) damage if not treated promptly. Henry M. Jackson Foundation (HJF) and Uniformed Services University of the Health Sciences (USUHS) researchers have developed a novel anti-convulsant and neuroprotective method for treating OP poisoning by using brief administration of halogenated anesthetics in therapeutically effective doses in preclinical models.

Applications and Advantages

• Single dose, short duration (5 min) administration of FDA-approved anesthetic isoflurane by inhalation or intravenous (IV) routes for treating OP poisoning from occupational and environmental exposures.
• In vivo studies in rats demonstrate that isoflurane-based methods can rapidly stop paraoxon (POX) induced convulsions, prevent subsequent brain edema and neuronal loss.
• Provides neuroprotection without the need for re-administration.
• Provides greater neuroprotection than benzodiazepines and can also serve as adjunct treatment.
• Injectable isoflurane negates the need for vaporizer equipment, enabling intravenous therapy in austere settings.
• Existing treatment methods require multiple doses, provide little or no neuroprotection and are less effective (benzodiazepines) while agents like atropine sulfate combined with oximes do not effectively prevent convulsions.

Innovation Description

OP poisoning remains a critical global health issue, resulting in thousands of deaths annually due to both accidental and intentional pesticide exposures. In addition to its public health burden, the potential misuse of OP-based agents in chemical terrorism scenarios further underscores the urgent need for effective countermeasures. OP based chemical threat agents (CTA) initially exert toxicity through excessive stimulation. If treatment is delayed, this progresses to a glutamatergic phase often resulting in status epilepticus (SE), irreversible neuronal degeneration and long-term CNS damage. The prognosis for post-exposure treatment is poor, largely because most current therapeutics fail to effectively target the secondary, non-cholinergic phase of OP-induced neurotoxicity. The efficacy of delayed treatments against OP-CTA toxicity is limited due to the fact that most drugs fail to inhibit the later phase of non-cholinergic activation. For example, diazepam—the current FDA approved anticonvulsant for OP poisoning— rapidly loses efficacy when administered beyond the acute phase.

Researchers at HJF and USUHS have demonstrated that the FDA-approved anesthetic isoflurane can be repurposed as a post-exposure intervention to terminate seizures and protect the CNS in OP poisoning models. In vivo studies in rats showed that 5% isoflurane dose, delivered in 100% oxygen for 5 min— even when administered up to one hour post paraoxon (POX) exposure—produced robust anticonvulsant effects and significantly mitigated CNS injury. To address logistical limitations of inhalation delivery, researchers developed an injectable formulation consisting of 10% isoflurane dissolved in an IV-compatible lipid-water emulsion. This formulation demonstrated equivalent efficacy in terminating seizures and protecting the brain in a rat model of POX poisoning. The relevance of these studies to organophosphate poisoning is that the effectiveness of the current treatment regimen of oxime, atropine sulfate and benzodiazepine is time-dependent and may not fully control convulsions and seizures or sufficiently protect the brain from neuronal loss. The ability to repurpose isoflurane as a rapid, single-dose intervention—distinct from its traditional use as a long-duration anesthetic—presents a promising therapeutic avenue not only for OP poisoning but also for broader applications in neuroprotection and potentially cardioprotection.

Inventors

• Aryan M. A. Namboodiri, Ph.D., USUHS
• John Moffett, Ph.D., HJF
• Jishnu Krishnan, Ph.D. HJF

Innovation Status

Proof-of principle studies have been completed in rats for POX and studies are underway for nerve gas agents. Please see Neurotoxicology 63, 84–89 and Front. Pharmacol. 14:1293280 for studies in rats using isoflurane administration via inhalation and Front. Pharmacol. 15:1466351 for administration via IV route.

Intellectual Property Status

A U.S. patent application 11,291,637 has been issued and another U.S. provisional application has been filed.