Discovery of an Effective Ricin Antidote: An Old Drug for a New Use
Pp. 182-196 (15)
Junfei Yin, Michael Fung and John W. Cherwonogrodzky
A cell-based high throughput screening assay (HTS) was established to
screen the Prestwick Chemical Library for candidates that acted against ricin. Of 1120
compounds screened, only 7 were identified as ricin inhibitors. Secondary screening
with cell cultures identified only ethotoin as a dose-dependent inhibitor against ricin
induced toxicity. Ethotoin was further evaluated in two in vivo studies. Study 1: When
mice were given intra-peritoneal injections of 5×LD50 ricin (1 μg) pre-incubated with
ethotoin (1 mg), all mice survived (monitored for 14 days). In contrast, control mice
without ethotoin died within 2 days. Study 2: When mice were given 2×LD50 ricin (0.2
μg) by the intranasal route and then given ethotoin by multiple oral/gavage deliveries
(at 1, 2, 4, 6, 8 and 10 hr after intoxication) 40% of the mice were alive at day 14. In
contrast, all control mice (those that received sterile saline instead) died between days
3-9. Hence ethotoin, given by one route (oral) could rescue some mice from ricin given
by another route (intra-nasal). Our findings suggest that ethotoin, although now an
abandoned anti-convulsant drug, deserves further investigation and development as a
potential antidote against the ricin biothreat.
Ricin, antidote, repurposing, drug, ethotoin, anticonvulsant, rescue.
Defence Research and Development Canada (DRDC), Suffield Research Centre, P.O. Box 4000, Station Main, Medicine Hat, AB, T1A 8K6, Canada.