SCHISTOACT: a protocol for an open-label, five-arm, non-inferiority, individually randomized controlled trial of the efficacy and safety of praziquantel plus artemisinin-based combinations in the treatment of Schistosoma mansoni infection.

BACKGROUND: Schistosomiasis control relies on praziquantel for preventive chemotherapy. Alternative drugs are needed for the treatment and control of schistosomiasis. Praziquantel is effective against adult schistosome worms but ineffective against larval stages of the parasite and cannot prevent re-infection or interrupt the transmission of infection. Continued reliance on praziquantel for wide-scale schistosomiasis control will likely accelerate the emergence of drug resistance. Artemisinin derivatives are effective against the juvenile stages but ineffective against adult worms. The SCHISTOACT study aimed to evaluate the efficacy and safety of praziquantel plus one of four artemisinin-based combinations in treating Schistosoma mansoni infection in Kenya. METHODS: The SCHISTOACT study is an open-label, head-to-head, five-arm, proof-of-concept, non-inferiority, individually randomized controlled trial with a follow-up of 12 weeks. A total of 540 primary school-aged children from the Mwea area, Kirinyaga County in central Kenya, diagnosed with S. mansoni infection (by Kato-Katz method) are randomly allocated (1:1:1:1:1) to a single dose of praziquantel plus a 3-day course of artesunate-sulfalene/pyrimethamine, or artesunate-amodiaquine, or artesunate plus mefloquine, or dihydroartemisinin-piperaquine, or praziquantel control arm. The primary endpoints are efficacy (cure rate, assessed by microscopy) and safety (adverse events) of each study arm 6 weeks after treatment. Secondary endpoints include cumulative cure rate, egg reduction rate, and re-infection 12 weeks after treatment. The non-inferiority margin is set at - 10 for the risk difference in cure rates between praziquantel and the combined treatment. DISCUSSION: This study assesses a strategy for repurposing artemisinin-based combination therapies (ACTs) for treating schistosomiasis. It adopts a head-to-head comparison of four different ACTs to test a non-inferiority hypothesis and to strengthen local capacity to conduct clinical trials for interventions against neglected tropical diseases. TRIAL REGISTRATION: Pan-African Clinical Trials Registry PACTR202001919442161 . Retrospectively registered on 6 January 2020.

Carbohydrates detection in the hepatic egg - granuloma system using lectin histochemistry

This study aims to evaluate the egg-granuloma system in hepatic tissues using lectin histochemistry in experimental Schistosomiasis. Eight Swiss mice were infected with a local strain of Schistosoma mansoni, being submitted forty days later to a perfusion after which slices of liver were prepared. The tissue samples were incubated with the following peroxidase conjugated lectins: Peanut agglutinin (PNA), Wheat Germ agglutinin (WGA), and Concanavalin A (Con A). All lectins recognized the glycoconjugates in the adult worm tegument. In the hepatic tissue, WGA presented the highest staining followed by PNA and Con A. The PNA presented the most intense staining of the egg-granuloma system while WGA stained the hepatic sinusoid cells and Con A bound preferentially the fibrosis rings of granuloma and the surrounding hepatic parenquima. WGA and PNA indicated the presence of residues of N-acetyl-glucosamine and galactose in the surface of Schistosoma mansoni eggs in the hepatic granulomas. In conclusion, using PNA, Con A and WGA our study presented different aspects of the egg-granuloma and Tegument of Schistosoma mansoni as well as indicated differences in the peri-ovular granulomas indicating alterations in the cellular mechanism of expression of surface carbohydrates during progression of the Schistosomiasis.

El objetivo del estudio fue evaluar el sistema de los huevos de los granulomas en los tejidos hepáticos, utilizando histoquímica de lectinas esquistosomiasis. Ocho ratones suizos experimentales fueron infectados con una cepa local de Schistosoma mansoni y luego a los cuarenta días fueron sometidos a la perfusión y se prepararon cortes de hígado. Las muestras de los tejidos fueron incubadas con las siguientes peroxidasas lectinas conjugadas: aglutinina de maní (PNA), aglutinina de germenn de trigo (WGA), Concanavalin A (Con A). Todas las lectinas reconocieron las glicoconjugadas en el tegumento del gusano adulto. El tejido hepático con WGA presentó mayor coloración seguido de PNA y Con A. El PNA presentó la más intensa tinción de los huevos mientras el granuloma del sistema WGA tiñó las células hepáticas sinusoides y las Con A estuvieron siempre presentes en los anillos de la fibrosis y alrededor de los granulomas hepáticos del parénquima. WGA y PNA indicaron la presencia de residuos de N - acetil - glucosamina y galactosa en la superficie de los huevos de Schistosoma mansoni en los granulomas hepáticos de esquistosomiasis.

Hepatic regeneration after partial hepatectomy in mice infected with Schistosoma mansoni, at the acute and chronic phases of the disease.

Outbred male albino mice normal or infected with 30 cercariae of Schistosoma mansoni (LE strain) were submitted to 65% hepatectomy during the acute (70 days) and chronic phase (160 days) phases of the disease. A group of the infected animals was treated with 400 mg/kg of oxamniquine during the acute phase before hepatectomy. Non-infected, infected and treated but not hepatectomized animals were kept as controls. Hepatic regeneration was evaluated by incorporation of tritiated thymidine, intraperitoneally injected into non-hepatectomized and hepatectomized animals, 24 hours after surgery. The results showed that removal of 65% of the hepatic parenchyma, during the acute phase, led to a statistically significant increase of thymidine incorporation, when compared with the uninfected hepatectomized controls. This phenomenon was not observed at the chronic phase. Treatment with oxamniquine administered during the acute phase led to a decrease in thymidine incorporation rate 160 days after infection (90 days after treatment) and 24 hours after hepatectomy. The data suggest that infection with S. mansoni represents a considerable stimulus for the regenerative capacity of the liver during the acute, but not the chronic phase of disease.

Hepatic regeneration after partial hepatectomy in mice infected with Schistosoma mansoni, at the acute and chronic phases of the disease

Outbred male albino mice normal or infected with 30 cercariae of Schistosoma mansoni (LE strain) were submitted to 65 percent hepatectomy during the acute (70 days) and chronic phase (160 days) phases of the disease. A group of the infected animals was treated with 400 mg/kg of oxamniquine during the acute phase before hepatectomy. Non-infected, infected and treated but not hepatectomized animals were kept as controls. Hepatic regeneration was evaluated by incorporation of tritiated thymidine, intraperitoneally injected into non-hepatectomized and hepatectomized animals, 24 hours after surgery. The results showed that removal of 65 percent of the hepatic parenchyma, during the acute phase, led to a statistically significant increase of thymidine incorporation, when compared with the uninfected hepatectomized controls. This phenomenon was not observed at the chronic phase. Treatment with oxamniquine administered during the acute phase led to a decrease in thymidine incorporation rate 160 days after infection (90 days after treatment) and 24 hours after hepatectomy. The data suggest that infection with S. mansoni represents a considerable stimulus for the regenerative capacity of the liver during the acute, but not the chronic phase of disease

Fecal alpha-1-antitrypsin concentration in patients with schistosomal hepatic fibrosis.

Using fecal alpha-1-antitrypsin (FA-1-AT) as an endogenous marker of enteric protein loss, measurements on random non-dried stool samples were carried out in 20 normal healthy subjects and 30 patients with schistosomal hepatic fibrosis (SHF); 12 of them had intestinal polyposis (IP) and better hepatic functions than the others. FA-1-AT concentrations were significantly higher in schistosomal patients with or without IP than in normal subjects. Excluding those with IP, increased enteric protein loss was detected in 11 patients (61.1%) with SHF and there were definite relationship between FA-1-AT concentration and serum albumin level (r = 0.475), prothrombin activity (r = -0.625), Child-Pugh score (r = 0.614) and the presence of ascites. On the other hand, patients with IP had significantly higher FA-1-AT concentration and serum albumin level than other schistosomal patients. This excessive enteric protein loss did not correlate with serum albumin level or severity of liver disease. The cause-and-effect relationship between enteric protein loss and hypoalbuminemia has been discussed in the light of these findings. It can be concluded that protein-losing enteropathy (PLE) in patients with SHF appears to represent a paraphenomenon associated with the progress of liver disease and only becomes of major clinical significance when the hepatic synthetic activity is compromised. Determination of FA-1-AT concentration proved to be an inexpensive, rapid, convenient, nonisotopic screening test that eases diagnosis of PLE.