The thesis is devoted to theoretical generalization and a new practical solution of the scientific problem of optimization of the chronic kidney disease (CKD) treatment. The dissertation substantiates the possibility to increase efficacy and safety of CKD treatment by using combinations of glucosamine (GA) derivatives with quercetin in dosage forms for oral and injectable administration (depending on the stage of CKD) and proves expediency of development and clinical implementation of nephroprotective drugs based on these substances.
The study determined that the combination of GA hydrochloride, N-acetylglucosamine (N-aGA) and quercetin in the ratio of 3:3:2 is the most expedient for oral use in CKD treatment. A comparative efficacy study of this combination in different dosage forms for intragastric (i.g.) administration showed that, in capsules (as medication "Gluquamine"), it shows a pronounced nephroprotective effect in minimal change disease and chronic renal failure (CRF) in a magnitude that significantly exceeds the activity of the tablet form of this combination and the reference drugs Quertin and Lespefril. Also, it was shown that N-aGA is the most appropriate component for the development of an injectable drug for CKD treatment because it was superior to GA hydrochloride at intramuscular (i.m.) administration in terms of efficacy in minimal change disease, showed a significant nephroprotective effect in acute kidney injury (AKI) without differences from intravenous (i.v.) administration, as well as in CRF with a pronounced antioxidant effect. This amino sugar should be combined with Corvitin (COR) (which has a prolonged pharmacokinetic profile at i.m. administration relative to i.v. use and a bioavailability of 93%) in a ratio of 1:1, as was confirmed by the highest efficacy of the N-aGA/COR (1:1) combination in AKI, which significantly exceeded the activity of other combinations. The studies concluded that ED50 of Gluquamine is 79.7 mg/kg (19 mg/kg or 1330 mg/day for a human) and ED50 of N-aGA/COR combination is 30.2 mg/kg (7.2 mg/kg or 503 mg/day for a human). Safety studies of Gluquamine and the N-aGA/COR combination as treatment for renal pathology showed that, when used in doses 3 times higher than ED50, they did not show any toxic effects in rats of both sexes, contributed to increasing kidney functional reserve and reduced azotemia. The studies demonstrated that it increases the kidney content of endogenous N-aGA and its free blood fraction, which indicated the recovery of the damaged kidneys membranes. The results of enzyme immunoassays showed that Gluquamine improved vascular endothelium function, reduced hypoxia, normalized the balance of vasodilatation and vasoconstriction factors, as well as reduced kidney content of eicosanoids. In addition, Gluquamine had a significant nephroprotective effect, preserving kidney ultra- and histostructure as well as reducing the degree of glomerulosclerosis and tubular injury. The immunohistochemical study revealed that Gluquamine had a pronounced antiproliferative effect and reduced the intensity of apoptosis. Moreover, taking in account all the studied data set, Gluquamine exceeded (p<0.05) the efficacy of the reference drugs Quertin and Lespefril.
Generalization of the obtained data concludes that important links in the mechanism of nephroprotection of the studied objects include: compensation of plastic insufficiency of kidney membranes; inhibition of proinflammatory mediators and factors of leukocyte activation and adhesion; recovery of vascular endothelial function; suppression of renal vasoconstriction; an increase of renal hemodynamics due to the endothelial mechanism of regulation; improvement of blood rheological properties; slowing down proliferative processes, prevention of nephrocyte apoptosis, inhibition of renal oxidative stress; restoration of the balance in renal regulation of renin-angiotensin-aldosterone system.
The results of the dissertation substantiate the expediency of using the combined drugs containing GA derivatives with quercetin to optimize treatment of renal pathology: while Gluquamine (capsules) is a promising drug for treatment of I-III stages of CKD (especially latent form), the N-aGA/COR combination is appropriate for treatment of III-V stages of CKD, especially in cardiovascular complications (N-aGA/COR can be used in combination with Gluquamine as well), and as an emergency treatment for ARI and CKD exacerbations. These results need to be confirmed in appropriate clinical trials.
