Acthar® Gel (repository corticotropin injection) dose-response relationships in an animal model of epileptic spasms.

Studies were undertaken to evaluate the effectiveness of Acthar® Gel (repository corticotropin injection [RCI]) in the tetrodotoxin (TTX) model of early-life-induced epileptic spasms. Repository corticotropin injection (RCI) is widely used in the United States to treat infantile spasms. A major component of RCI is N25 deamidated ACTH. Additionally, we hoped to provide some insight into the possible role circulating corticosteroids play in spasm cessation by comparing the RCI dose-response relationships for spasm suppression to RCI-induced corticosterone release from the adrenal gland. Spasms were induced by chronic TTX infusion into the neocortex beginning on postnatal day 11. Repository corticotropin injection (RCI) dosages were between 8 and 32 IU/kg/day. Drug titration protocols were used, and comparisons were made to injections of a vehicle gel. Video/EEG recordings (24/7) monitored the drug's effects continuously for up to 2 months. Tetrodotoxin (TTX)-infused control rats were monitored for the same period of time. In separate experiments, the same dosages of RCI were given to rats and 1 h later plasma was collected and assayed for corticosterone. A parallel study compared the effects of 1-day and 10-day RCI treatments on circulating corticosterone. Results showed that RCI was ineffective at dosages of 8, 12, and 16 IU/kg/day but eliminated spasms in 66% of animals treated with 24 or 32 IU/kg/day. Treating animals with 32 IU/kg/day alone produced the same degree of spasms suppression as observed during the titration protocols. In rats that had hypsarrhythmia-like activity, RCI eliminated this abnormal interictal EEG pattern in all rats that became seizure-free. In terms of plasma corticosterone, 1- and 10-day treatments with RCI produced similar increases in this hormone and the levels increased linearly with increasing dosages of RCI. This stood in sharp contrast to the sigmoid-like dose-response curve for decreases in spasm counts. Our results further validate the TTX model as relevant for the study of infantile spasms. The model should be useful for investigating how RCI acts to eliminate seizures and hypsarrhythmia. Dose-response results suggest that either very high concentrations of circulating corticosteroids are required to abolish spasms or RCI acts through a different mechanism.