The thesis aimes at expanding the possibilities of influence on the pathogenesis of diabetus mellitus (DM) and metabolic syndrome (MS), gout and asymptomatic hyperuricemia, as well as increase in thiazide diuretics efficacy and safety. In search of this solution the necessity arises to correct simultaneously the disorders of carbohydrate, lipid, purine metabolism interrelated with shifts of electrolyte homeostasis as well as to normalize the functional state of the central nervous system (CNS) which is often disturbed in the beforementioned states and undergoes changes depending on purine metabolism state. Polytropic action on the processes mentioned above is inherent in multicomponent herbal drugs, especially those containing hydroxicinnamic acids and flavonoids as well as potassium compounds. Pharmacological preparations (PhP) of goutweed (GW, Aegopodium podagraria L., Apiaceae) aerial part belong to such drugs. The thesis summarizes the results experimentally substantiating the expediency of GW extract and GW tincture use as antidiabetic preparations possessing concomitant organoprotective, metabotropic, and favourable psychotropic properties.
The tincture after extractant removal moderately decreased glycemia in the intact rat (at doses of 0.5; 1.0: 5.0 ml/kg intragastrically after single administration, 5.0 ml/kg – after course administration), against the background of hydrochlorothiazide (HCTZ) with excess fructose as well as dexamethasone (DEX)-induced insulin resistance (IR, at a dose of 1 ml/kg) and caused the antihyperglycemic action in mice with alloxan-induced diabetes (AD, at doses of 1.0 and 5.0 ml/kg) exceeding herbal collection “Arphasetin” (infusion, 18 ml/kg). The antihyperglycemic and beneficial nephrotropic effects on this model were also inherent in GW extract (1 g/kg). The antihyperglycemic action of GW PhP is advantageously complemented with the normolipidemic properties.
After course administration of the studied GW PhP there were no signs of the CNS functional state worsening, while the moderate advantageous psychotropic effects were seen. The antidepressive action of GW extract (realized at a dose of 100 mg/kg in female mice) was accompanied with the decrease in anxiety signs as well as the prolongation of the exhaustive swimming time. The favourable type of interaction with the CNS stimulants and depressants was established in mice, including the counteraction of the tincture (1 ml/kg) to the inhibitory effect of thiopental sodium and of the extract – to the inhibitory effect of ethanol. The extract at the effective dose mentioned above (100 mg/kg) contributed to the furher reduction in depression signs against the background of caffeine-sodium benzoate (120 mg/kg), while the tincture ability to decrease the level of depression was realized only against the background of this adenosine receptors antagonist.
Favourable intaraction of GW tincture with METF was confirmed by the decrease in acute toxicity of METF in mice, while the effect of the latter on basal glycemia in the intact rats was neither blocked, nor excessively enhanced. The possibility of decrease in METF effective dose was proven in the intact rat (after glucose loading), in rats with DEX-induced IR, metabolic disorders caused by DEX at high dose of 5 mg/kg, hyperlipidemia with lipoprotein lipase inhibition (in this case the normalizing influence of the components on the lipid composition of the liver was maintained, as well as normouricaemia and inhibition of xanthine oxidase (XOD) in the liver and kidneys). The moderate pancreas-protective effect of GW tincture combination with METF was confirmed in the period of maximum damage to the pancreatic β-cells induced by alloxan in rats. On the different models after the use of the combination there were neither signs of hepatotoxicity, nor negative influence on nitrogen and purine metabolism, while the antiproteinuric effect was seen. It showed neutrality to the CNS state against the background of neurotoxic DEX, and in the late stages of AD the regulatory influence on uric acid metabolism (counteraction to hypouricemia) and on the CNS were realized.
GW tincture is more effective on the models of carbohydrate metabolism disorders than GW extract. At the same time, the extract possessing the favourable combination of potassium compounds high content with hypoazotemic and uricosuric activity is able to increase the thiazide diuretics safety. When HCTZ at a dose causing metabolic disorders in rats (80 mg/kg for 16 days) was combined with the extract (100 mg/kg and 1 g/kg), normokalemia and an adequate potassium excretion were maintained, the changes in Na+ excretion depended on dose and regimen of the excretory renal function (ERF). During the prolonged (10 weeks) intake of excess fructose and HCTZ (20 mg/kg) the hypouricemic effect of the extract was realized together with nephroprotective action.
