A means of reducing the affinity of hemoglobin to oxygen

 

(57) Abstract:

A means of reducing the affinity of hemoglobin to oxygen, refers to clinical pharmacology and can be used to treat disorders of the oxygen supply. The invention consists in the application of the known compound 2,6-dimethyl-3,5-bis-(2-ethoxyacetylene)-4-(2-deformational)-1,4- -dihydropyridines for a new purpose. The aim of the invention is to increase the activity of funds, reduces the affinity of hemoglobin to oxygen. table 1.

The invention relates to medicine, specifically, pharmacology, and relates to means for reducing the affinity of hemoglobin to oxygen, can be used to treat disorders of the oxygen exchange.

Known compounds with the ability to reduce the affinity of hemoglobin (HB) to oxygen (O2): glutathione, oxides of nitrogen, benzoate, organic and inorganic phosphates (2,4). However, these compounds due to their high toxicity is not permitted for use in medical practice (5).

Known drugs that have the ability to reduce the affinity of HB for O2: reverse (prototype), cysteine, vincamine, some neuroleptics and anesthetics, acetazolamide, t considered as a side effect (2,4,5). Specific drugs that have this effect, absent (2). However, the use of drugs that reduce the affinity of HB for O2an effective way of correcting disorders of the oxygen supply to the organs. It is established that the increase in P502 mm RT.article equivalent to the increase of oxygen delivery to tissues by 30% (9) or almost two-fold increase in blood flow (10). The proofs of the high activity of substances that reduce the affinity of HB for O2when oxygen deficiency organs, particularly the brain. So, in terms of asphyxia in cats Cavinton contributes to a longer preservation of electrocorticogram and reduce recovery time parameter after termination of exposure (6).

The purpose of the invention increased activity funds, which reduces the affinity of HB for O2.

This goal is achieved by the fact that as a means of reducing the affinity of HB for O2apply 2,6-dimethyl-3,5-bis-(2-ethoxyacetylene)-4-(2-deformational)-1,4 - dihydropyridines (connection 1).

The compound 1 revealed hypotensive and vasodilator activity (1). Application connection partsto HB K O2.

These properties connection 1 not described in literature.

To establish a new connection properties 1 performed 3 series of experiments. In the first series examined the effects of compound 1 at a dose of 25 mg/kg intravenously to rats at pH NVO2and R50blood samples after saturation with a gas mixture containing 4% O2WITH 5% CO2and 91% N2(3). In the second series of experiments under similar conditions was evaluated the effect of Cavinton in a dose of 3 mg/kg intraperitoneally. The choice of doses of drugs held in prior research: drugs at these doses did not cause a significant reduction in systemic arterial pressure. In the third series of experiments, control, intravenous was infusional equiano amount of solvent compounds 1.

Example 1. Protocol experience from series 1. Rat 280 g were narcoticyou with urethane (1 g/kg intraperitoneally) were fixed in position with his back to the machine. Under local procaine anesthesia in ofpreparing carotid artery was injected Teflon catheter for blood sampling. The animal was Gaprindashvili (1500 IU/kg). A blood sample (0.5 ml) were placed in the saturator and saturated gas mixture within 10 minutes NVO2evaluated on oxigemometry OSM company Radiometer. To control for the feast upon the received results served as the source, they were: 32,8 mm RT.article 37.8 mm RT. Art. pH 7,337 NVO250.1% of Intravenously injected compound 1 at a dose of 25 mg/kg (0.025% solution of 12% dimethylacetamide was infusional intravenously over 15 min). After 1 h the newly produced blood samples (0.5 ml), the sample was placed in a saturator and repeated the whole procedure, as in the control. The obtained experimental values of 32.5 mm RT.article 37,4 mm RT.article pH 7,330 NVO236,8%

Example 2. Protocol experience from series 2. Rat 260 g were narcoticyou with urethane (1 g/kg intraperitoneally) were fixed in position with his back to the machine. Under local procaine anesthesia in ofpreparing carotid artery was injected Teflon catheter for blood sampling. The animal was Gaprindashvili (1500 IU/kg). A blood sample (0.5 ml) were placed in the saturator and saturated gas mixture within 10 minutes NVO2evaluated on oxigemometry OSM-1 firm Radiometer. To control the saturation of gases in the blood sample was determined by pH and hemoglobin content in the gas analyzer ABL-4 from the same company. The results obtained served as the original, they were: 30,3 mm RT.article 37.5 mm RT. St, pH 7,386 NVO249.1% of Intraperitoneally injected Cavinton dose of 3 mg/kg Over 1 h once again made the blood samples (0.5 ml), the sample was placed in a saturator and repeated the whole procedure, as in cantley in the table. The initial pH value, NVO2and R50in blood samples after saturation at control and experimental rats the first and second series did not differ significantly. The stability of these readings in a separate series of experiments, and no significant changes in the control series of experiments allowed us to assess the effects of the drugs as compared to the level before drug administration, and between series. Comparison of the effects of compound 1 with the prototype indicates a high activity of compound 1 as a means of reducing the binding of HB with O2. Thus, after the introduction of Cavinton at saturation of the blood sample gas mixture with fixed values OF2and CO2value NVO2decreased by 4.5% and P50increased by 1.5 mm RT. century After the introduction connections 1 value NVO2decreased by 11.7% and P50increased by 3.9 mm RT.article Therefore, the effect of compound 1 in 2.6 times the prototype (P/0,05).

Thus, the results of the experiments indicate that pronounced ability of compound 1 to reduce the affinity of HB for O2. This property of matter that leads to the relief of the impact of oxygen by red blood cells, will contribute to improving the supply of oxygen to tissues and mo is m the air, when the atmospheric pressure decreases.

2. In lung disease: enfizeme lung, bronchial asthma, pneumonia.

3. By reducing opportunities oxygen transport by red blood cells: erythropenia, anemia of all types, arterio-venous shunts.

4. When circulation disorders: ischemic organs, atherosclerosis, thromboembolism.

5. With increasing affinity of hemoglobin for oxygen: pathological forms of HB, diabetes, fermentatio erythrocytes.

6. In addition, when the shocks.

7. To improve oxygenation of tissues in radiotherapy of tumors.

8. To accelerate detoxification, improving oxygen supply to tissues.

The proposed tool will be widely used in clinical practice for the treatment of disorders of the oxygen exchange in the lung disease, disorders of function of red blood cells, organ blood flow, as well as acute conditions (shock, intoxication, hypoxia).

The use of 2,6-dimethyl-3,5-bis-(2-etoxycarbonyl)-4- (2-deformational)-1,4-dihydropyridines as a means of reducing the affinity of hemoglobin to oxygen.

 

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