THE STUDY OF THE ANTIHYPOXIC ACTION OF 1-PHENETHYL-5,7-DIHYDRO-1H-PYRROLO- [2,3-d]PYRIMIDIN-2,4,6-TRIONE (DEZAPUR) ON DIFFERENT MODELS OF HYPOXIA

Extension of hypoxic states is a consequence of disorder of cerebral, coronary and peripheral circulation, and it requires further search for substances that can reduce the negative effect of hypoxia on tissues, and increase their resistance to hypoxia. The study of the antihypoxic activity of 1-phenethyl5,7-dihydro-1H-pyrrolo-[2,3-d]pyrimidin-2,4,6-trione under the conditional name of Dezapur on different models of hypoxia (hemic, hypercapnic, histotoxic and hypobaric) has been presented. The reference drug is Mexidol. Dezapur in the dose of 10 mg/kg and Mexidol in the dose of 100 mg/kg show the expressed antihypoxic activity on all models of hypoxia compared to the control group: hemic hypoxia in 2.09 and 1.82 times, hypercapnic hypoxia – in 2.35 and 2.29 times, on histotoxic hypoxia – in 2.04 and 1.9 times, hypobaric hypoxia – in 3.06 and 2.72 times, respectively.

Hypoxia is a pathological process, which is characterized by decrease of the oxygen content in the blood and tissues, development of the complex of the secondary non-specific metabolic and functional disorders, as well as the reaction of adaptation [1]. Extension of hypoxic states is a consequence of disorder of cerebral, coronary and peripheral circulation, and it requires further search for substances that can reduce the negative effect of hypoxia on tissues, and increase their resistance to hypoxia. Therefore, the search of such substances that would increase the resistance of tissues to hypoxia, bind free radicals formed as a result of hypoxia, i.e. having the antioxidant effect and reducing inflammatory edema, is a topical issue of medical chemistry [2,5].

Materials and Methods
The antihypoxic activity was studied on nonlinear white male mice weighing 20±2g. The test substance in the dose of 1/10 of its LD 50 and the reference drug Mexidol in the dose of 100 mg/kg (ED 50 ) were introduced intragastrically 30 min prior to the experiment. Control and experiments were performed simultaneously and recorded the life time in minutes [7]. All animals were divided into 3 groups, each group of 6 animals: group 1 -intact animals received distilled water in the volume of 1 ml; group 2 -animals received Dezapur in the effective dose of 10 mg/kg; group 3 -animals received the reference drug Mexidol [6,9].
The acute hypobaric hypoxia was created by raising animals to the height of 11.000 m and with the speed of 50 m/s in the Komovsky apparatus; the acute hypoxic hypoxia -by placing animals in a 200 ml airtight chamber; the hemic acute hypoxia -by subcutaneous injection of sodium nitrite in the dose of 225 mg/kg; the histotoxic hypoxia -by intraperitoneal introduction of sodium nitroprusside in the dose of 25 mg/kg. The antihypoxic action was assessed by duration of the animals' life. The results of the study were compared with the reference drug Mexidol widely known in medical practice as an antihypoxant and antioxidant drug [4,8,10].

Results and Discussion
According to the results obtained Dezapur exhibited a stable antihypoxic activity by the life expectancy of the animals on all experimental models (Table, Fig.). Its prophylactic introduction prolonged the life of mice in 2.0-3.1 times compared to the control group.
On the experimental models of the acute normobaric hypoxia and the acute histotoxic hypoxia the antihypoxic activity of Dezapur and Mexidol was almost identical. When introducing Dezapur on these models of hypoxia the life of animals was 2.5 and 2.1 times longer, and it was not significantly different from the indicators of Mexidol (2.4 and 2.0 times, respectively). The results obtained are statistically unreliable (p>0.05).
In the acute hemic hypoxia the efficiency of Dezapur exceeded the similar effect of the reference drug in 1.19 times. The life of animals was 1.97 times longer when introducing Dezapur and 1.65 times longer when introducing Mexidol.
Dezapur and Mexidol showed the highest antihypoxic activity in relation to the control group on the model of the acute hypobaric hypoxia. At the same time the efficiency of Dezapur was 1.13 times higher than that of Mexidol by the life expectancy in mice.
The data obtained concerning Mexidol coincide with the results of other authors [6,9].
The data obtained indicate that Dezapur in the dose of 10 mg/kg and Mexidol in the dose of 100 mg/kg show the expressed antihypoxic activity on all models of hypoxia compared to the control group: hemic hypoxia in 2.09 and 1.82 times, hypercapnic hypoxia -in 2.35 and 2.29 times, on histotoxic hypoxia -in 2.04 and 1.9 times, hypobaric hypoxia -in 3.06 and 2.72 times, respectively.

CONCLUSIONS
Under conditions of hemic, normobaric, histotoxic and hypobaric hypoxia (in white mice) Dezapur (10 mg/kg, single intragastric introduction) significantly prolongs the life of animals in 2.1; 2.0; 2.4; 3.1 times, respectively, and in this respect it is not inferior to the reference drug Mexidol. It indicates the presence of significant antihypoxant properties in the compound. Notes: * -р<0.05 compared to the control group. The survival of control animals is taken as 100%.