Randomized clinical trial evaluating triazolopyridazine SLU-2633 as a treatment for gastric cryptosporidiosis in eastern indigo snakes (Drymarchon couperi).

Gastric cryptosporidiosis caused by Cryptosporidium serpentis has negatively impacted the conservation efforts for the imperiled eastern indigo snake (EIS, Drymarchon couperi). Multiple treatments, including paromomycin, nitazoxanide-azithromycin-rifabutin, clofazimine, curcumin, hydrogen peroxide gavage, and triazolopyridazine MMV665917 have proved ineffective in eliminating the parasite. In a structure-activity relationship study, a 10-fold more potent analog of MMV665917 (SLU-2633) was discovered. Additionally, greater potency of SLU-2633 improved the therapeutic index of this compound. When SLU-2633 was evaluated in mice, oral administration of 50 mg/kg twice daily for four days caused a 99% reduction in parasite burden; and the mice were Cryptosporidium-free ten days post-treatment. With these promising results, SLU-2633 was selected as a potential treatment of gastric cryptosporidiosis in EIS. Ten EISs naturally infected with C. serpentis were randomly divided into two groups of five. Group A received 50 mg/kg SLU-2633 once daily for four days, then twice weekly for six weeks, and Group B received the diluent once daily for four days, then twice weekly for six weeks. Group A had significantly lower levels of C. serpentis DNA three weeks after the initial dose (P = 0.047) through one month after cessation of drug administration (P = 0.018). However, two months after cessation of drug administration, there was no longer a difference between the two groups (P = 0.27). At this dosing regimen, SLU-2633 reduced the overall burden of C. serpentis DNA by 88% suggesting that SLU-2633 may be effective in eliminating C. serpentis infection in EIS with an optimized dosing regimen or formulation.