Investigation of cardiotoxic effect potential and mechanism of lesinurad used in gout disease

Gout is a metabolic disease that is caused by an increased serum uric acid level and accumulation of monosodium urate crystals in the intra-articular and surrounding connective tissue. The prevalence of the disease tends to increase due to rise of incidence of comorbidity, factors such as lifestyle factors, gender, age and inadequate urate-lowering therapy. Chronic gout occurs as a result of not treating recurrent acute attacks and hyperuricemia. Lesinurad is a uricosuric approved by FDA in 2015 and administered in combination therapy with a xanthine oxidase inhibitor when the targeted serum uric acid level with xanthine oxidase inhibitors cannot be reached in the treatment of chronic gout. FDA reported that cardiovascular adverse effects related to the use of lesinurad have been observed, but that a causal relationship cannot be established about the underlying causes. It determined that cardiac findings emerged within the scope of the phase III studies, however the toxic effects of lesinurad on the heart and the mechanisms of cardiovascular adverse effects have not been fully elucidated yet. Due to the inadequacy of data on lesinurad in the literature, the thesis project, which was planned to be useful in eliminating the deficiency on the subject, investigated the toxic effect potential of lesinurad, which belongs to the uricosuric drug group, on the heart cell line in in vitro conditions and the mechanisms that cause toxicity. According to the data obtained, it has been determined that lesinurad causes death of heart cells at a dose of 0,845 M, reactive oxygen derivatives and apoptosis do not play a role in the cell death, a mechanism that affect cardiac protein levels is not effective, glutathione levels decrease depending on the dose. It is expected that the obtained results will contribute to the literature as well as constitute a source for cardiotoxicity studies to be conducted on mechanical, morphological and structural investigations.