ETI‐385 as a Novel Anti‐emetic Against Drug Induced Emesis

Abstract

Drugs currently used to prevent emesis (nausea and vomiting) target only one or a few of the pathways used by emetic stimuli to trigger the reflex. Thus, an anti-emetic drug will only be effective against some stimuli. Prior work determined that 8-OH-DPAT (DPAT, a 5-HT1A agonist) was a universally effective anti-emetic. Although DPAT prevented emesis, it also elicited an extreme anxiety response making it unsuitable for therapeutic use. Presently, there exists no universal anti-emetic drug. We tested a proprietary drug developed from DPAT, ETI-385, which successfully prevented emesis in musk shrews against chemotherapy, drug and motion stimuli. For FDA purposes, we are required to test ETI-385 in another species before taking the drug into clinical trials. Work at Epiomed Therapeutics used ETI-385 to successfully prevent emesis in cats using motion stimuli. Currently, ETI-385 is being tested in cats against a drug stimulus, Xylazine, which is a common veterinary sedative. We determined a dose response curve for ETI-385 against Xylazine over the range of 0.0225mg/kg to 0.36mg/kg. The animals received an ETI-385 pretreatment injected subcutaneously (SC) followed by an injection of Xylazine (also SC). During observation the animals were scored for symptoms of both emesis and anxiety. The dose 0.0225mg/kg was unsuccessful in preventing emesis and produced a higher symptom score than Xylazine alone, suggesting nausea. The dose 0.045mg/kg was 66.7% effective against vomiting but had an increase in symptom score while 0.09mg/kg was 83.4% effective against vomiting with a marked decrease in symptom score. At the 0.36 mg/kg dose we achieved 100% efficacy and a complete eradication of emetic symptoms. Unlike DPAT, only the highest dose produced any defensive behavior.