First insight into the effect of single oral dose therapy with artemisinin –naphthoquine phosphate combination in a mouse model of Schistosoma mansoni infection Samar N. El-Beshbishi, Amira Taman, Mohamed El-Malky, Manar S. Azab, Amira K. El-Hawary, Dina A. El-Tantawy

Introduction Considerable efforts are ongoing in the development of novel drugs for the prevention and cure of schistsomiasis. As a result, many compounds with promising antischistosomal properties have been identified. The compound naphthoquine phosphate tablets (abbreviated CO-ArNp) is a new single oral dose antimalarial combination consisting of naphthoquine phosphate and artemisinin . Naphthoquine phosphate belongs to the group of antimalarial 4-aminoquinolines. The curative effects of these two drugs in combination against Plasmodium were superior to those of each drug used singly. The combination is indicated for the treatment of all forms of malaria, including multiple–drug resistant malaria

No data have been published on the use of naphthoquine phosphate combined with artemisinin in schistosomiasis. Therefore, this work aimed to investigate the potential antischistosomal activity of different artemisinin- naphthoquine phosphate combination-dosing protocols against juvenile and adult stages of S. mansoni Egyptian strain, in a mouse model, based on some parasitological and histopathological criteria. This study investigates an alternative antischistosomal drug using the compound naphthoquine phosphate tablet (CO-ArNp), which is a novel single oral dose antimalarial drug, containing a combination of naphthoquine phosphate and artemisinin.

Materials and methods Drugs Animals, parasites and infection Animal groups Study of parasitological criteria Histopathology and granuloma measurements

Control-1, 2 and 3: Infected control and received the vehicle only at days (7, 21, 42). 300 mg/kg (CO-ArNp-1A), at day 7 400 mg/kg (CO-ArNp-1B) at day 7 400 mg/kg (CO-ArNp-2A), day 21 500 mg/kg (CO-ArNp-2B ) day 21 500 mg/kg (CO-ArNp-3A), day 42 600 mg/kg (CO-ArNp-2C) day 21 600 mg/kg (CO-ArNp-3B) day 42 PZQ-1, -Infected and treated with PZQ in a dose of 500 mg/kg/day for 2 days at day 7 PZQ-2, -Infected and treated with PZQ in a dose of 500 mg/kg/day for 2 days at day 21 PZQ-3, -Infected and treated with PZQ in a dose of 500 mg/kg/day for 2 days at day 42

No. of mice investigated Table 1 Effects of artemisinin-naphthoquine phosphate and praziquantel on worm burdens in infected mice harbouring 1-week-old juvenile S. mansoni (Egyptian CD strain). Drug dose(mg/kg) No. of mice investigated No. of mice cured Worm reductions Animal groups Total worms TWR (%) vehicle 6 † 24.33±3.27 _ Control-1 CO-ArNp-1 300 8 2 4.50±3.02**1 81.51 A 400 5 1.20±1.64**1 95.07 B 500x2 9.17±1.94** 62.33 PZQ-1 Values are exposed as means ± SD. TWR=total worm reduction. CO-ArNp=compound artemisinin-naphthoquine phosphate; PZQ=praziquantel. † One mouse died during the course of infection. Significant difference from infected control at **P < 0.01. 1 Significant difference from PZQ (500x2 mg/kg) at P < 0.01.

Discussion The difference in the stage susceptibility could be explained by the presence of higher anti-oxygen free radical effect and other biochemical toxicity in adult than the juvenile worms. These make the juveniles more susceptible to the free radicals liberated after the cleavage of the endoperoxide bond by haemin or other iron compounds in schistosomes, or due to the reaction of the drug with the haemin or other iron ions causing higher mortality rate of juvenile than adult worms The difference in the sex-related susceptibility of schistosomes where female worms have been found to be more susceptible to ART than males, may be explained by the fact that female worms take more blood cells for nutrition to lay eggs, and hence they have much more haemin, haematin and iron porphyrin than males

الحمد لله Thank you