Rutin (quercetin-3-rutinoside) administered orally after experimental Bothrops jararaca envenomation prevents hemostatic, inflammatory and hemorrhagic disturbances

Bites caused by Bothrops snakes represent a major public health problem in South America and are associated with severe systemic and local clinical manifestations. Bothrops venom induces marked hemostatic and inflammatory disturbances that may result in hemorrhage, thrombocytopenia, tissue necrosis, and kidney injury. The recommended treatment for snakebite envenomation is intravenous administration of anti- Bothrops antivenom (SAB); however, this therapy has limited efficacy against venom-induced local tissue injury mediated by the release of inflammatory mediators. In this context, adjunct pharmacological strategies capable of delaying or attenuating envenomation effects before antivenom administration may be clinically valuable, particularly in remote settings. Rutin and its derivative, rutin succinate, are flavonoids with anti-inflammatory, antioxidant, and vasoprotective properties, and have been previously shown to mitigate venom-induced damage when administered parenterally prior to Bothrops jararaca (Bj) envenomation. Herein, we evaluated the efficacy of orally administered rutin, formulated for rapid gastrointestinal absorption (nano-rutin), used alone or in combination with SAB, in a murine model of Bj snakebite envenomation. Mice received nano-rutin by gavage 10 min after venom injection and were subsequently treated with or without SAB after 1 hour. Envenomed mice developed thrombocytopenia, leukocytosis, fibrinogen consumption, elevated levels of IL-6 and cell-free DNA (cfDNA), reduced DNAse activity, hypoalbuminemia, and marked local hemorrhage and dermonecrosis. Oral nano-rutin restored most evaluated systemic parameters, and significantly reduced local hemorrhage and dermonecrosis, even in the absence of SAB. These findings support nano-rutin as an effective complementary therapy to antivenom, particularly for mitigating local tissue damage induced by Bothrops venoms.