EVALUATION OF ANALGESIC AND ANTI-INFLAMMATORY ACTIVITY OF 1-HYDROXY-1,1-ETHYLIDENDIPHOSPHONIC ACID ADDUCT AND BIS (2-PYRIDYL-1,2,4-TRIAZOLYL-3)PROPANE DURING COURSE ADMINISTRATION IN MALE RATS

Abstract

The article presents the results of evaluation of analgesic and anti-inflammatory activity of the adduct of 1-hydroxy-1,1-ethylidendiphosphonic acid and bis(2-pyridyl-1,2,4-triazolyl-3)propane (HEA+BPP) in male rats with a 21-day course administration. The aim of the study was to evaluate analgesic and anti-inflammatory activity in male rats with 21-day course administration of HEA+BPP course administration with 21-day course administration. The animals were divided into 7 groups of 10 individuals. Analgesic activity of HEA+BPP was tested on 40 males, and anti – inflammatory activity was tested on 30 others. In studies of analgesic activity of HEA+BPP, males of one group were control and received intraperitoneal injections of 0.2 ml of saline solution every day at 10.00 for 21 days, the others groups received 0.2 ml of intraperitoneal injections of HEA+BPP at doses of 5, 50 and 100 mg/kg at the same time for 21 days. In analgesic studies, groups of animals were similarly formed, when testing the anti-inflammatory effect of HEA+BPP, only without injecting a dose of 100 mg/kg. HEA+BPP synthesized at the Department of General and inorganic chemistry of the faculty of biology and chemistry of the Tauride Academy (structural division) of the V. I. Vernadsky Crimean Federal University. The chemical purity of HEA+BPP was at least 98 %. The analgesic activity of HEA+BPP was evaluated by the parameters of pain sensitivity of animals in the background and 1 hour after intraperitoneal injections on the 1st, 6th, 10th, 14th and 21st days of the experiment in the models of acute pain stress «tail-flick», Randall-Sellitto and «hot plate». Before the tail-flick and Randall-Sellitto tests were performed, the animals were placed in special rat retainers after injection. The anti-inflammatory activity of HEA+BPP was evaluated in the formalin paw edema test in rats. Acute inflammatory response was reproduced by subplantar injection of 0.1 ml of 2 % formalin solution in the form of an aqueous solution into the left hind leg of a rat, and then the value of limb edema was measured using the method of water plethysmometry on the 10th and 21st days of course administration of HEA+BPP in doses of 5 and 50 mg/kg. The data are presented as mean and standard error mean, statistical analysis performed using the software packages StatSoft/STATISTICA 8 and Graph Pad Prism 7.0. The significance of differences between groups was determined using one-way analysis of variance (ANOVA) with post hoc test Tukey and non-parametric criterion of multiple comparisons of Dunn, according to official methodological recommendations on statistical treatment of the results of preclinical studies of medicines, given in the literature. During course administration to male rats of HEA+BPP for 21 days in the dose range from 5 to 100 mg / kg, it was found that this compound mainly demonstrates effectiveness as an analgesic with a single injection, only for mechanical pain, this substance is effective with a course administration at a dose of 5 mg/kg: The «tail-flick» test showed, that using of HEA+BPP as an analgesic involved in the spinal mechanism of pain sensitivity regulation is advisable in doses of 5, 50 and 100 mg/kg only with a single injection: latent period of the reaction discharge of the tail increased relative to control at a dose of 5 mg/kg on the 1st day of administration of HEA+BPP by 32.7 % (p≤0.05), at a dose of 50 mg/kg on the 1st and 21st days of administration – by 40 % (p≤0.01) and 67.1 % (p≤0.001) and at a dose of 100 mg/kg on the 1st day of administration – by 80.0 % (p≤0.01), respectively. At a dose of 5 mg/kg on the 10th day of administration, on the contrary, was discovered algogenic effect of HEA+BPP (latent period of the reaction discharge of the tail was significantly decreased relative to control by 24.1 % (p≤0.01). In the test of Randall-Selitto the efficiency of single use HEA+BPP as an analgesic in mechanical pain at doses of 50 and 100 mg/kg (pain threshold was significantly increased relative to control at 25.2 % (p≤0.01) and 80 % (p≤0.01), and in course administration only at a dose of 5 mg/kg (pain threshold was significantly increased relative to control at 55.3 % (p≤0.001), 72.5 % (p≤0.001) and 49.6 % (p≤0.01) on the 6th, 14th and 21st day of the course introduction). The «hot plate» test shows the feasibility of only a single use of HEA+BPP as an analgesic in doses of 5 and 50 mg/kg, since these effects were unstable and unstable when administered on a course basis. The «formalin test» revealed the inflammatory and exudative effect of HEA+BPP at a dose of 5 mg/kg, in which HEA+BPP on the 21st day of administration increased the formalin edema of the rat paw by 70.9 % (p≤0.01).