In vivo effects of metformin against Echinococcus granulosus larval stage

JULIA A. LOOS; DANIELA DRAGO; CLAUDIA MELUCCI GANZARAIN; VALERIA DÁVILA; CHRISTIAN RODRIGUES RODRIGUEZ; ANDREA C. CUMINO

Mar del Plata

Congreso; LX Reunión Científica Anual de la Sociedad Argentina de Investigación Clínica (SAIC); 2015

Sociedad Argentina de Investigación Clínica

Cystic echinococcosis is a zoonotic infection caused by the larvalstage of the cestode Echinococcus granulosus. Chemotherapycurrently employs benzimidazoles, however 40% of cases do notrespond favorably. With regard to these difficulties, novel therapeuticaltools are needed to optimize treatment in humans. Theaim of this work was to explore in vivo the effect of metformin (Met)against E. granulosus, due to the fact that in vitro the drug inhibitsthe survival of E. granulosus protoscoleces and metacestodes.We demonstrated the chemotherapeutic and chemopreventivepharmacological effects of the drug. At a dose rate of 50 mg/kg/day, Met induces protection against the infection in mice. In theclinical efficacy studies, a reduction in cyst weight was observedafter the administration of 50 mg/kg to mice with cysts developedduring four months (0.54 ± 0.10 g), compared to those collectedfrom control mice (1.75 ± 0.2 g). In vitro synergic therapeuticeffects were observed in presence of Met plus albendazole (0.07± 0.01 g) at low doses (5mg/kg day of ABZSO), suggesting theimportance of chemoprophylactic and clinical efficacy studiescombining Met with conventional anti-echinococcal agents to testthe potential use of this drug in hydatidosis therapy. P-glycoproteinexpression was investigated and since Met was detected intomurine cysts (0.2 to 0.5 μg Met/g wet weight of cyst), we analyzedthe genome occurrence OCT1/OCTN1 orthologs in Echinococcussp. We identified five putative OCT1/OCTN1 of which OCT A,B, D and E were expressed in protoscoleces and metacestodesallowing the accumulation of the drug in parasitic tissues. Possiblemechanisms for the susceptibility of metformin are discussed inrelation to dual metabolic control of parasite and host.