OBJECTIVE: "Krokodil" is the street name for an impure homemade drug mixture used as a cheap substitute for heroin, containing desomorphine as the main opioid. Abscesses, gangrene, thrombophlebitis, limb ulceration and amputations, jaw osteonecrosis, skin discoloration, ulcers, skin infections, and bleeding are some of the typical reported signs in humans. This study aimed to understand the toxicity of krokodil using Wistar male rats as experimental model. METHODS: Animals were divided into seven groups and exposed subcutaneously to NaCl 0.9% (control), krokodil mixture free of psychotropic substances (blank krokodil), pharmaceutical grade desomorphine 1 mg/kg, and four different concentrations of krokodil (containing 0.125, 0.25, 0.5, and 1 mg/kg of desomorphine) synthesized accordingly to a "domestic" protocol followed by people who inject krokodil (PWIK). Daily injections for five consecutive days were performed, and animals were sacrificed 24 hr after the last administration. Biochemical and histological analysis were carried out. RESULTS: It was shown that the continuous use of krokodil may cause injury at the injection area, with formation of necrotic zones. The biochemical results evidenced alterations on cardiac and renal biomarkers of toxicity, namely, creatine kinase, creatine kinase-MB, and uric acid. Significant alteration in levels of reduced and oxidized glutathione on kidney and heart suggested that oxidative stress may be involved in krokodil-mediated toxicity. Cardiac congestion was the most relevant finding of continuous krokodil administration. CONCLUSIONS: These findings contribute notably to comprehension of the local and systemic toxicological impact of this complex drug mixture on major organs and will hopefully be useful for the development of appropriate treatment strategies towards the human toxicological effects of krokodil.

CIAFEL Faculty of Sport University of Porto Porto Portugal

CVO Addiction Research Centre Utrecht The Netherlands Department of Addictology 1st Faculty of Medicine Charles University General University Hospital Prague Czech Republic Freudenthal Institute for Science and Mathematics Education Utrecht University Utrecht The Netherlands

Department of Analytical Chemistry Chemistry Institute Fluminense Federal University Niterói Brazil

Department of Chemical Sciences Laboratory of Organic and Pharmaceutical Chemistry Faculty of Pharmacy University of Porto Porto Portugal

Department of Chemical Sciences Laboratory of Organic and Pharmaceutical Chemistry Faculty of Pharmacy University of Porto Porto Portugal Interdisciplinary Center of Marine and Environmental Investigation Porto Portugal

LAQV REQUIMTE Department of Chemical Sciences Laboratory of Applied Chemistry Faculty of Pharmacy University of Porto Porto Portugal

UCIBIO REQUIMTE Laboratory of Toxicology Department of Biological Sciences Faculty of Pharmacy University of Porto Porto Portugal

UCIBIO REQUIMTE Laboratory of Toxicology Department of Biological Sciences Faculty of Pharmacy University of Porto Porto Portugal IINFACTS Institute of Research and Advanced Training in Health Sciences and Technologies Department of Sciences University Institute of Health Sciences CESPU CRL Gandra Portugal Department of Public Health and Forensic Sciences and Medical Education Faculty of Medicine University of Porto Porto Portugal

UCIBIO REQUIMTE Laboratory of Toxicology Department of Biological Sciences Faculty of Pharmacy University of Porto Porto Portugal IINFACTS Institute of Research and Advanced Training in Health Sciences and Technologies Department of Sciences University Institute of Health Sciences CESPU CRL Gandra Portugal Department of Public Health and Forensic Sciences and Medical Education Faculty of Medicine University of Porto Porto Portugal EPSJV Joaquim Venâncio Polytechnic School of Health Oswaldo Cruz Foundation Rio de Janeiro Brazil

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