A means with antiaggregatory activity

 

(57) Abstract:

The invention relates to medicine and can be used to treat conditions involving increased adhesion - aggregation of platelets and for preservation of platelet-rich plasma. We offer you a means with antiaggregatory activity E1characterized by the opportunity of using bolus injection, high storage stability, low capacity for biotransformation in the body. 6 table.

The invention relates to medicine and can be used to treat conditions involving increased adhesion-aggregation properties of platelets and for preservation of platelet-rich plasma.

The search for inhibitors of platelet aggregation, has a pronounced effect when bolus injected into the body, is of great interest to emergency care to patients with increased aggregation capacity of platelets (myocardial infarction, brain ischemia, and others).

The purpose of the invention means, effectively reducing aggregation activity of platelets during bolus injection, with high storage stability and low SP the funds reducing platelet aggregation, known compound 5-oxa-6-keto-prostaglandin E1. Information about biological activity in the literature are missing.

To identify in vitro antiaggregatory activity of freshly prepared solution of 5-oxa-6-keto-prostaglandin E1as progresando used ADP at concentrations of 10-5M 2 10-7M in the final mixture, the collagen at a concentration of 14 μg/ml and epinephrine at a concentration of 2.5-5 µg/ml of platelet-Rich plasma was obtained by centrifugation stable of 3.8% solution of sodium citrate blood of healthy donors for 10 min at 1000 rpm platelet Aggregation was registered on aggregometry company Chronolog Corporation (USA). The degree egregii expressed in percent drop in the optical density of the platelet-rich plasma after the reaction compared with the initial level. The results of the experiment showed that the use of the structure as preaggregate ADP at a concentration of 2 to 10-7M (PL.1) 5-oxa-6-keto-prostaglandin E1already in the amount of 0.001 μg/ml final mixture significantly reduced platelet aggregation in vitro. When the number of added prostanoid antiaggregatory effect was increased. A-keto-prostaglandin E1in an amount of 0.01 μg/ml and almost completely blocked by increasing the concentration of the studied agent to 0.1 µg/ml Adrenaline dependent aggregation (table.3) was decreased by approximately 20% when introduced into a cuvette of prostanoid in an amount of 0.01 μg/ml and twice with increasing concentrations of 5-oxa-6-keto-prostaglandin E1to 0.1 μg/ml to About the same activity possessed the substance and in the induction of aggregation ADP 10-5M (PL.4).

Thus, the results of this work showed that 5-oxa-6-keto-prostaglandin E1has a strong antiaggregatory effect in vitro.

To identify the antiaggregatory activity of 5-oxa-6-keto-prostaglandin E1ex vivo freshly prepared solution of the substance was administered to rabbits in the marginal ear vein at a rate of 1 μg/kg, 2 mg/kg or 5 mg/kg of body weight of the animal. Blood was taken by the method of free fall drops prior to the introduction of substances through 15, 30, 60, 90, 120, 150 and 180 min after injection of prostanoid and stabilized by 3.8% solution of sodium citrate in the ratio of 9:1. In data obtained from samples of platelet-rich plasma was determined aggregation activity of platelets, using as inductor ADP 10-5M

The results of landina E1as antiaggregatory funds. Thus, even when the dose of 1 mg/kg of body weight of the animal, this substance was significantly reduced platelet aggregation rabbits for 30 minutes With increasing amounts of input prostanoid up to 2 mg/kg of body weight duration of effect after a single injection was increased to two hours, and the strength of the effect, especially during the first 30 min was significantly increased. A further increase in the dose of the agent up to 5 mg/kg did not increase the duration of antiaggregatory effect of the drug, but the effect was such that platelet aggregation ex vivo in the first 30 min after injection was suppressed almost completely.

Thus, 5-oxa-6-keto-prostaglandin E1when intravenous bolus introduction had pronounced antiage - garinim action.

To assess the stability of the antiaggregatory effect of 5-oxa-6-keto-prostaglandin E1dry samples of the substance kept at a temperature of +4aboutWith in glass or plastic tubes. The starting solutions of prostanoid was prepared by adding to the hinge 96about-ethanol (0.1 ml to 5 mg), and then an equimolar amount of sodium bicarbonate and physiologyand bottles with ground stoppers at a temperature of +4aboutC. Working solutions were prepared immediately before the experiment from the source, adding saline solution in amount sufficient to obtain a desired concentration of prostanoid. Antiaggregatory activity of 5-oxa-6-keto-prostaglandin E1was assessed by its ability to block platelet aggregation in healthy donors in the presence of ADP (10-5M).

To study the stability of antiaggregatory properties of 5-oxa-6-keto-prostaglandin E1stored in dry form, from the same sample of the substance once every six months for two years, took a sample and bred them with the aforementioned method, and then studied the effect of the obtained solutions on the functional activity of platelets. The results of the experiment showed that a sample of 5-oxa-6-keto-prostaglandin E1during two years of storage in dry form have not lost their antiaggregatory activity.

The stability of samples stored in the form of solutions, were evaluated monthly for two years. The data obtained indicate that, although the activity of a solution of 5-oxa-6-keto-prostaglandin E1and decreased over time, but even 24 months after breeding the Oka stability during storage.

Antiaggregatory activity of 5-oxa-6-keto-prostaglandin E1can also be used for stabilization of platelet-rich plasma, as it is known that many of the tools with antiaggregatory effect and will not cause any damage when this enzyme system, providing functional activity of cells that can save your valuable platelets in a condition suitable for subsequent transfusion. To confirm this property of prostanoid been studied for its effect on the functional activity of human platelets during storage. For the experiment, platelet-rich human plasma was placed in equal volumes of two glass tubes, one of the portions served as a control and another was added a solution of 5-oxa-6-keto-prostaglandin E1in quantities of 1 microgram of a substance per 1 ml rich plasma. Then the investigated sample was placed in a water bath at +37aboutWith over 4 h, after which they were stored at +4aboutWith during the whole time of the experiment. The functional activity of platelets was assessed by their ability to aggregate in response to the addition of ADP (10-5M) in combination with epinephrine (5 µg/ml). The results of the study are presented in table.6, obrabatyvat, when storing plasma samples over 72 h, the presence of a mixture of 5-oxa-6-keto-prostaglandin E1significantly increased functional activity of platelets. This suggests that this substance increased the lifespan of platelets.

The use of 5-oxa-6-keto-prostaglandin E1as a means with antiaggregatory activity.

 

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