In Vitro and In Vivo Activities of Synthetic Trioxolanes against Major Human Schistosome Species

Abstract

Schistosomiasis is a parasitic disease that remains of considerable public health significance in tropical and subtropical environments. Since the mainstay of schistosomiasis control is chemotherapy with a single drug, praziquantel, drug resistance is a concern. Here, we present new data on the antischistosomal properties of representative synthetic 1,2,4-trioxolanes (OZs). Exposure of adult Schistosoma mansoni for 24 h to a medium containing 20 g/ml OZ209 reduced worm motor activity, induced tegumental alterations, and killed worms within 72 h. While exposure of S. mansoni to OZ78 had no apparent effect, addition of hemin reduced worm motor activity and caused tegumental damage. Administration of single 200-mg/kg of body weight oral doses of OZ78, OZ209, and OZ288 to mice harboring a juvenile S. mansoni infection resulted in worm burden reductions of 82.0 to 95.4%. In the adult infection model in mice, single 400-mg/kg doses of these compounds resulted in a maximum total worm burden reduction of 52.2%. High worm burden reductions (71.7 to 86.5%) were observed after administration of single 200-mg/kg doses of OZ78 and OZ288 to hamsters infected with either juvenile or adult S. mansoni. A single 200-mg/kg dose of OZ78 to hamsters infected with adult Schistosoma japonicum resulted in total and female worm burden reductions of 94.2 to 100%. Our results, along with the low toxicity, metabolic stability, and good pharmacokinetic properties of the OZs, indicate the potential for the development of novel broad-spectrum antischistosomal OZ drug candidates.

In vitroandin vivotrematode models for chemotherapeutic studies

“…3-4 week old worms might also be used for in vitro studies (Hobbs et al 1993) including drug sensitivity assays, as juvenile worms might show differences with regard to drug sensitivity when compared to larvae and adult worms. Following several washing steps, worms are incubated for example in DMEM, RPMI 1640 or HBSS supplemented with foetal calf serum, penicillin and streptomycin (Ramirez et al 2007 ;Xiao et al 2007). Schistosomes survive in a range of In vitro and in vivo trematode models for chemotherapeutic studies supplemented tissue culture media for periods ranging from 3-120 days (Smyth and Halton, 1983).…”

Disposition of Mefloquine and Enpiroline Is Highly Influenced by a Chronic Schistosoma mansoni Infection

“…After each PK sampling point (1,2,4,8,12,24,48,72, or 168 h posttreatment), the liver and gut, including the portal vein and mesenterial veins, were dissected from infected mice. Livers were pressed and examined under the microscope, and all worms were sexed and counted (16). In addition, worms within the portal vein and mesenterial vein system were picked and counted separately as described previously (16).…”

Morphological effects and tegumental alterations induced by mefloquine on schistosomula and adult flukes ofSchistosoma mansoni

“…Nonetheless, in spite of the lack of dedicated product development partnerships for helminth diseases, a number of compounds with interesting anti-schistosomal properties have been identified by various research groups in recent years; for example, peroxidic compounds (the semi-synthetic artemisinins and the synthetic trioxolanes (OZs)), 4-phenyl-1,2,5-oxadiazole-3-carbonitrile-2-oxide and the cysteine protease inhibitor K11777 (Abdulla et al 2007 ;Keiser and Utzinger, 2007 ;Utzinger et al 2007 ;Xiao et al 2007 ;Sayed et al 2008 ;Caffrey et al 2009). An important finding was that mefloquine (MQ), an arylamino alcohol (4-quinoline-methanol), developed by the Walter Reed Institute of Research in the early 1970s (Sweeney, 1981) and now marketed for the prophylaxis and treatment of malaria, showed promising anti-schistosomal activity in mice.…”