Novel Drug Combination Treatment for Nerve Agent and Organophosphate Poisoning in Children - (HJF 447-16)

Organophosphates (OP) which include pesticides and nerve agents are a common source of poisoning with approximately 3 million worldwide exposures each year and around 300,000 resulting deaths. Researchers at the Uniformed Services University of the Health Sciences (USUHS) have developed a novel treatment formulation to treat CNS symptoms including status epilepticus (SE), with a special emphasis on pediatric patients. The effectiveness of this drug combination has been demonstrated in vivo.

Applications and Advantages

Studies in rats have shown that the formulation is effective treating short-term and long-term CNS symptoms from poisoning
Both drugs have been demonstrated to be safe to use in humans
Tailored for pediatric patients but animal data suggest the treatment should be similarly effective in adults
Far superior to benzodiazepines for suppressing SE and protecting against brain damage

Innovation Description

Organophosphate (OP) pesticides are a common source of poisoning with approximately 3 million worldwide exposures each year and around 300,000 resulting deaths. OP pesticides and OP nerve agents such as sarin, VX, and soman cause toxicity via the same primary mechanism. These nerve agents have been used in terrorist attacks in Japan and more recently in attacks in Syria which killed 1,429 people including 426 children. In addition to deaths, exposure to OP can result in long-term morbidity. Central nervous system (CNS) symptoms and injury including seizures and status epilepticus (SE) are associated with and are drivers of significant morbidly and mortality from OP exposure. Existing countermeasures, including benzodiazepines are inadequate in treating many of the symptoms from poisoning, including SE and in preventing resulting brain damage and chronic neuropsychiatric disease. As such there is a need for new therapies to treat exposed patients; especially children who are more susceptible to the harmful effects of these toxins.

Researchers at USUHS have developed a novel treatment formulation to treat CNS symptoms including SE, with a special emphasis on pediatric patients. This formulation consists of a kainate/AMPA receptor antagonist, LY293558 and an antimuscarinic compound which also antagonizes NMDA receptors, Caramiphen. Both drugs have previously been shown to be safe for use in humans. Using a juvenile animal model for acute soman nerve agent exposure, the researchers have demonstrated that this formulation is effective in terminating seizures and in preventing brain damage. The included figure exemplifies the dramatic difference between the benzodiazepine midazolam (MDZ) and the combination of LY293558 with caramiphen (CRM) in reducing the total duration of SE within the time period of 24 hours after acute exposure to soman. This difference between the two treatments in the total duration of SE plays a pivotal role in the extent of acute and long-term brain damage.

test results

Treatment of soman-exposed postnatal-day-21 rats with either MDZ or LY293558+CRM stopped the initial SE induced by soman however, recurrence of seizures within 24 h post-exposure was significantly less after LY293558+CRM administration. (A) Overview image corresponding to compressed EEG for a 24 h period from a representative animal from each of the two treatment groups. Arrows show the time points of soman and anticonvulsant administration. (B) Representative sample EEG traces from a rat treated with MDZ (left set of traces) and a rat treated with LY293558+CRM (right set of traces) at baseline during soman-induced SE, as well as 30 min and 8 h after anticonvulsant administration. (C) Group data for the duration of the initial SE and the total duration of SE within 24 h after soman exposure. Sample size is n = 5 for the MDZ-treated group and n = 7 for the LY293558+CRM-treated group. ***P < 0.001 (Student’s t-test).