Maslova G. Pathogenetic substantiation of a differentiated approach to the prevention of liver injury in patients with hemoblastosis with overweight and obesity.

The dissertation is devoted to generalization and new solution to the problem, which consists in the pathogenetic substantiation for the prevention of liver injury in patients with acute and chronic hemoblastosis depending on the presence of overweight and obesity on the basis of clinical and experimental studies. The model of nonalcoholic steatohepatitis, based on the use of high-calorie diet with 42.8% fat content and 4% fructose water solution as the only source of liquid during 63 days, was firstly invented. At the first time, a method of modelling doxorubicin-induced liver injury with nonalcoholic steatohepatitis in rats was developed. The method consists in intraabdominal doxorubicin administration in the dosage of 5 mg/kg/day for 3 days. The way of doxorubicin-induced liver injury prophylaxis in rats with experimentally modelled nonalcoholic steatohepatitis in rats was proposed for the first time. It includes intraabdominal S-ademetionine injection in the dose of 100 mg/kg of mass with simultaneous doxorubicin administration during 3 days aimed to prevent anthracycline-induced liver injury. For the first time the connection between oxidative stress activation and disturbances in arginine/citrulline cycle in rats with modelled nonalcoholic steatohepatitis induced by doxorubicin administration was found and histomorphological peculiarities of liver tissue were investigated. The protective effect of S-ademetionine was firstly proved towards oxidative stress development, arginase and ornithine decarboxylase activities reduction in blood serum and liver, morphological changes in rats with modelled nonalcoholic steatohepatitis by doxorubicin injection. There was a further investigation of frequency and risk factors of liver infiltration with tumour cells and biochemical blood tests peculiarities of its manifestation in patients with acute and chronic leukemias. It was demonstrated that increased activity of alkaline phosphatase, especially in case of simultaneous rise of gamma-glutamyl transpeptidase, alanine and asparagine aminotransferases, can be effectually used as an indirect marker of tumour liver infiltration in patients with acute and chronic hemoblastosis progression. For the first time, it was proved that overweight and obesity in patients with acute myeloblastic and lymphoblastic leukemias potentiate the risk of liver injury caused by hemoblastosis. The features of prooxidant-antioxidant status in patients with acute and chronic leukemias continued to be studied. It was established that an association of acute myeloblastic anaemia and oxidative stress activation potentiates disturbances in arginine/citrulline cycle with the rise of arginase and ornithine decarboxylase activities, citrulline and arginine content in patients’ blood serum. Further investigation of chemotherapy toxicity of different schemes which are used for the treatment of patients with acute and chronic hemoblastosis was conducted. High toxicity of chemotherapy was revealed, with a powerful role of oxidative stress in its development. Prescription of S-ademetionine was firstly substantiated in patients with acute myeloblastic and lymphoblastic leukemias and chronic lymphoproliferative disorders who undergo chemotherapy and have normal weight. This measure decreases risk of hepatotoxic reactions, suppresses activity of oxidative stress, and deals with arginine/citrulline cycle disturbances. Combined prescription of S-ademetionine and ursodeoxycholic acid in patients with acute myeloblastic and lymphoblastic leukemias and chronic lymphoproliferative disorders, who undergo chemotherapy and have overweight or obesity, was substantiated for the first time. Such prescription promotes decreased frequency of hepatotoxic reactions through the influence on their main pathogenetic pathways. For the first time, the influence of L-ornithine-L-aspartate on the prominent pathogenetic mechanisms of hepatotoxic reactions occurring in the case of chemotherapy was demonstrated. Also, the prescription of L-ornithine-L-aspartate and ursodeoxycholic acid combination in patients with multiple myeloma and overweight or obesity, aimed to prevent cytostatic-induced hepatotoxic reactions, was pathogenetically substantiated.