RU2618622C1 - Method for skeletal muscle experimental ischemia pharmacological correction using vardenafil and pentoxifylline in combined therapy - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: for skeletal muscle ischemia correction on the background of skeletal muscle ischemia simulation, its correction is performed by daily intragastric administration of a combination of vardenafil at a dose of 0.09 mg kg and pentoxifylline at a dose of 30 mg/kg 1 time a day, for 7 days.

EFFECT: method provides good rheological effect in the ischemia hearth at lower drugs doses and safety of their use in terms of side effects of treatment.

1 tbl, 1 ex

Description

The invention relates to medicine, in particular to experimental pharmacology and surgery, and can be used to correct skeletal muscle ischemia.

A known method of pharmacological correction of skeletal muscle ischemia with sildenafil, including with L-name-induced deficiency of nitric oxide (RF patent No. 2497203).

The main disadvantage of this method is the use of sildenafil, which is less selective and less safe than the drug of the same group of vardenafil. In vitro studies on the selectivity of action on PDE-5, it was proved that, unlike other representatives of its pharmacological group, vardenafil is 10 times superior to sildenafil. The effect on PDE-6, which is contained in the retina of the eye and is responsible for visual disturbances, is 6 times less pronounced in vardenafil than in sildenafil. This explains the lowest frequency of visual disturbances among all PDE inhibitors during treatment with vardenafil. Vardenafil has a lesser effect than sildenafil on PDE-1 contained in the testes, therefore, does not inhibit spermatogenesis. The effectiveness of vardenafil does not depend on the intake, the nature of food, alcohol and approaches 75-80%.

A limited pathogenetic orientation associated only with the endothelium-dependent vasodilating effect during monotherapy with sildenafil. The mechanism of action of sildenafil and vardenafil is based on the blockade of hydrolysis of cyclic guanosine monophosphate (cGMP), as a result of which the concentration of cGMP increases and the cGMP-dependent protein kinase is activated, followed by phosphorylation of ion channels. As a result, the concentration of calcium in smooth muscle vascular cells decreases, which leads to their relaxation. PDE-5 inhibitors promote the development of vasodilation under the action of endogenous nitric oxide (NO), which is secreted from nerve endings and endothelial cells, stimulating the synthesis of cGMP using the enzyme guanylate cyclase. The relaxation of smooth muscle cells leads to the expansion of the arteries, which provides the necessary flow of arterial blood to the tissues. According to recent studies, drugs of this group, by affecting the metabolic pathway of nitric oxide, have a pronounced endothelioprotective effect, are able to activate protein kinase G and ATP-dependent potassium channels.

The mechanism of action of pentoxifylline (trental) is based on the accumulation of cyclic adenosine monophosphate in the smooth muscles of the vascular wall, blood cells, and other body tissues. In addition, the drug blocks the action of the enzyme phosphodiesterase. The combined therapy of vardenafil with pentoxifylline allows you to achieve the following pharmacological effects: some myotropic vasodilating effect, normalization of erythrocyte elasticity, decreased platelet aggregation, decreased blood viscosity, decreased plasma fibrinogen concentrations, improved fibrinolysis. In this regard, the proposed dose of pentoxifylline in combination was 30 mg / kg.

Monotherapy with sildenafil at a dose of 2.2 mg / kg is less safe from the point of view of side effects, and is also pharmacoeconomically impractical. Whereas the dose of vardenafil that we have proposed is 0.09 mg / kg (based on published data, the effect of the effect on neoangiogenesis in small doses, that is, a 10-fold reduction in them, allows achieving practically the same level of microcirculation).

Thus, the combined use of vardenafil and pentoxifylline for ischemia of the limb, which act on different pathogenesis links, is quite justified. This non-competitive interaction allows us to achieve the maximum physiological response, provide a good rheological effect in the focus of ischemia and reduce the dose of each of the drugs in our combination, which, in turn, increases the safety of this combination from the point of view of side effects, and is also pharmacoeconomically more profitable .

An object of the invention is to develop a method for pharmacological correction of skeletal muscle ischemia with vardenafil and pentoxifylline in combination therapy.

The technical result is achieved by the fact that in the known method of pharmacological correction of experimental skeletal muscle ischemia, including experimental modeling of skeletal muscle ischemia, according to the invention, against the background of modeling this pathology, it is corrected by intragastric administration of a combination of vardenafil at a dose of 0.09 mg / kg and pentoxifylline 30 mg / kg 1 time per day daily for 7 days.

The method is as follows.

The experiments are carried out on white rats of the Wistar line weighing 220-250 g.

Acute ischemia is modeled on the muscles of the rat's left lower leg by operative removal of a section of the great vessels, including the femoral, popliteal, anterior and posterior tibial arteries.

The level of microcirculation in the calf muscles is determined using Biopac systems equipment: MPT00 polygraph with LDF100C laser Doppler flowmetry module and TSD144 invasive needle probe. The registration and processing of laser Doppler flowmetry (LDF) results is performed using the AcqKnowledge version 3.8.1. Program, the microcirculation values are expressed in perfusion units (PE). The microcirculation level is recorded at five points (the middle of the muscle length, points 3-5 mm above and below, lateral and medial of the first).

The microcirculation level is recorded in groups of falsely operated animals, with modeling of ischemia of the calf muscles and in groups of animals that underwent correction of ischemia of the calf muscles of vardenafil + pentoxifylline.

Vardenafil (Levitra, Bayer) at a dose of 0.09 mg / kg + pentoxifylline at a dose of 30 mg / kg are administered intragastrically 1 time per day daily for 7 days.

When statistical data processing is calculated, the average value, the standard deviation. Differences are considered significant at p <0.05.

Concrete example

The average microcirculation level in the intact muscle of the tibia of rats is 527 ± 13 PE. Experimental animals were divided into the following groups:

1) intact (n = 20);

2) false-operated animals (n = 20);

3) modeling of ischemia of the leg muscles (n = 20);

4) modeling of shin muscle ischemia + vardenafil + pentoxifylline (n = 20).

Ischemia of the muscles of the left leg was simulated under anesthesia (chloral hydrate 300 mg / kg ip) by surgical removal of a section of the great vessels, including the femoral, popliteal, anterior and posterior tibial arteries. Correction of muscle ischemia was performed in animals of the 4th group by intragastric administration of vardenafil at a dose of 0.09 mg / kg and pentoxifylline at a dose of 30 mg / kg once a day daily for 7 days.

The microcirculation level in the calf muscles was determined using Biopac systems equipment: an MP100 polygraph with an LDF100C laser Doppler flowmetry module and an TSD144 invasive needle probe on days 21 and 28. The registration and processing of laser Doppler flowmetry (LDF) results was performed using the AcqKnowledge software version 3.8.1., Microcirculation values were expressed in perfusion units (PE). The microcirculation level curve was recorded at five points (the middle of the muscle length, points 3-5 mm above and below, lateral and medial of the first) for 30 seconds at each point. From the five values obtained, the average was deduced, which was entered into the protocol and was taken as the level of microcirculation in the calf muscles in this animal. From the 10 obtained values, the average was calculated, which was taken as the level of microcirculation in this group of animals at a given study period.

The results of assessing the level of microcirculation in animals of the experimental groups are presented in table 1.

In the group of false-operated animals, the average value of the level of microcirculation in the muscles of the left tibia at all periods does not significantly differ from the indicators in the group of intact animals (527 ± 13 PE) (p = 0.66; p = 0.77, respectively). In the shin muscle ischemia modeling group, the microcirculation level at all periods was significantly lower than the value in the intact muscle (p <0.05).

Correction with a combination of vardenafil and pentoxifylline significantly increased the level of regional blood flow in the ischemic muscle of the tibia of rats compared with the indicators in the second group at the corresponding time period (day 21 p <0.05; day 28 p <0.05). The level of microcirculation in this group on the 21st day approaches the indicator in the group of intact animals, and on the 28th day significantly exceeds it.

Thus, the results obtained allow us to ascertain the pharmacological correction of skeletal muscle ischemia with a combination of vardenafil and pentoxifylline due to the stimulation of neoangiogenesis.

Claims (1)

A method of pharmacological correction of experimental skeletal muscle ischemia, including experimental modeling of skeletal muscle ischemia, characterized in that, against the background of modeling this pathology, it is corrected by intragastric administration of a combination of vardenafil at a dose of 0.09 mg / kg and pentoxifylline 30 mg / kg once a day daily for 7 days.