A novel drug sequestrant-based therapeutic candidate reverses methamphetamine-induced hyperthermia and hypermetabolism and abates multiorgan toxicity in rats.

Abstract

Methamphetamine (meth) is a central nervous system stimulant associated with many fatalities. Meth can cause agitation and psychosis, hyperthermia, and multiple organ damage. Medical treatment of meth toxicity is challenged because of meth's prolonged clinical duration of action and the lack of targeted therapy. CS-1103 is an acyclic cucurbit[n]uril-type sequestrant that binds meth with high affinity, and sequestration is a pharmacologic method of reversing a target drug effect through binding, inactivation, and elimination. We hypothesized that high-dose meth would cause multiple toxicities and that CS-1103 would reduce meth-induced toxicities. We administered (+)-methamphetamine [(+)-meth; 10 mg/kg, i.v.] followed by saline or CS-1103 (400 mg/kg, i.v.) after 15 minutes to conscious, restrained rats. (+)-Meth effects were quantified for 60 minutes by continuous physiologic monitoring and by premeth (-5 minutes) and postmeth (+60 minutes) blood analysis. (+)-Meth administration caused transient agitation and death or the need for euthanasia; however, with CS-1103, agitation resolved, and obtundation and death were prevented. Select (+)-meth toxicities with saline and CS-1103 posttreatments, respectively, were as follows (mean ± SEM; P < .02 for each): hyperthermia (peak Δtemperature: 4.0 ± 0.6 vs 2.0 ± 0.5 °C), acidemia (ΔpH: -0.2 ± 0.1 vs 0.0 ± 0.0), hypoxia (Δoxygen: -35 ± 7 vs -6 ± 4 mm Hg), nephrotoxicity (Δcreatinine: 0.5 ± 0.1 vs 0.0 ± 0.1 mg/dL), hyperkalemia (Δpotassium: 2.5 ± 0.6 vs -0.4 ± 0.1 mM), and rhabdomyolysis (Δcreatine kinase: 2353 ± 624 vs 1210 ± 492 U/L). CS-1103 is a viable therapy to abort (+)-meth toxicities and to promote survival in this novel rat model of (+)-meth toxicity. SIGNIFICANCE STATEMENT: Methamphetamine is a common drug of abuse associated with broad toxicity and fatality in humans. An animal model that replicates many of these toxicities was developed and this model was used to demonstrate that CS-1103, a methamphetamine-binding sequestrant, has efficacy in preventing toxicity and death.