Means for normalizing the energy processes in the tissues of the body in hypoxia

 

(57) Abstract:

The invention relates to medicine. It is proposed to use the extract hoods pork or fetal adrenal glands to normalize the energy processes in the tissues under hypoxic conditions. The invention allows to normalize the content of ATP, AMP and ADP, and the ratio of ATP/AMP. 3 table.

The invention relates to therapeutic drugs based on compounds of animal origin and can be used in medicine as a means of normalizing the energy processes in the body tissues under hypoxic conditions.

The use of oxygen occupies a leading place in the life of the organism, as it involved the synthesis of adenosine triphosphate (ATP), which is the most readily available source of energy in cells, without which stop all metabolic processes.

At the organism level is insufficient oxygen to tissues is manifested by stress with the mobilization of the nervous system, respiratory, circulatory, endocrine glands, especially the pituitary, adrenal, thyroid, etc. that clinically manifests with excitement. In the future, with increasing D. the Aries hypoxia is characterized by increased anaerobic glycolysis with the accumulation of lactic acid, recovery equivalents, inhibition of oxidative phosphorylation. The deficit of ATP, increase the permeability of cell membranes, excessive loss of potassium and calcium intake leads to intracellular acidosis, edema, and degeneration of cells.

There are a large number of biological substances with antihypoxic effect on the body. Antihypoxic properties have very different chemical composition of a substance with a variety of biological and physiological effects(1, 3, 4, 5, 7, 8). The mechanism of action is also different, because of the multiplicity of forms of hypoxia and their targets. Depending on the mechanism of action there are medications that improve the delivery of oxygen to tissues, normalizes metabolism, reducing the body's need for oxygen. Allocate antihypoxants direct (specific) actions that affect physiological and metabolic parameters in conditions of oxygen deficiency and do not change them when normoxia (gamma-hydroxybutyric acid, gamma-aminobutyric acid, creatine phosphate, actinolite, vitamin K3and others). Antihypoxants indirect (non-specific) actions change the tension of the functional and metabolizes the l and others ).

In terms of the entire organism hypoxic damage occur mostly as the result of an imbalance of oxygen transport and request it cells. For this reason, the first mandatory condition for the choice of the drug is its ability to enhance the blood circulation. To normalize blood pressure, which can dramatically decrease during hypoxia, widely used dopamine and corticosteroids (hydrocortisone, prednisone and others).

The second direction in the choice of means is the impact on the metabolism of the cells, reducing the energy demands of tissue hypoxia with the aim conserve oxygen. However, there is another point of view that in the correction of hypoxic conditions not favourable to suppress metabolism and energieproductie. On the contrary, it is possible to achieve a protective effect by using substances that optimize the work on limiting levels of energy metabolism or activating compensatory metabolic system.

Widely assigned in hypoxic States derivatives barbiturates, neuroleptics, tranquilizers, adrenergic and sympathomimetics. When prescribing these drugs antihypoxic effect to the decrease of basal metabolic rate and body temperature. But they are characterized by selectivity and narrow the breadth of therapeutic action, which is dangerous complications. They help to reduce functional lability, loss of adaptive capabilities of the organism.

Due to damage of cell membranes by peroxides widespread use of antioxidant protection during hypoxia, especially in the post-hypoxic period resumes when the flow of oxygen. With this purpose, apply the alpha-tocopherol, carnitine, ceruloplasmin, Essentiale, non-steroidal anti-inflammatory drugs, etc. But an antioxidant for the prevention and treatment during hypoxia may be accompanied by violations, which could exacerbate the pathological process. There is evidence of the absence of correlation between the antioxidant and antihypoxic effects.

Because hypoxia and posthypoxic period there was a violation of intracellular calcium, which is an activator of many metabolic processes, as antihypoxants have been widely used calcium channel blockers and inhibitors of phospholipases (nifedipin, verapamil, flunarizin and others). However, in these cases, not direct to the s can dramatically reduce blood pressure.

One of the widely used antihypoxants called sodium oxybutyrate (GHB-kamakshipalya acid), which reduces the sensitivity of the brain to circulatory hypoxia. The conversion of GHB in succinate allows to synthesize ATP molecules in the tricarboxylic acid cycle with low voltages of oxygen in the tissues. The disadvantages of this drug is pronounced sedative and muscle relaxant action in large doses is not only a deep sleep, and anesthesia, with the rapid introduction of non-motor stimulation, possible convulsions and respiratory arrest requiring resuscitation measures with long-term use develops hypokalemia.

The achievements of modern biochemistry and molecular biology in the study of the changes of metabolism in pathology and essence of their regulatory mechanisms indicates a promising application of endogenous substrates, enzymes and other regulators as a means of directional correction pathogenicity processes. Therefore, the objective of the invention is to develop effective tools for the normalization of the energy processes in the body tissues on the basis of endogenous substrate of animal origin. As the latter authors sokolo 60 different steroid substances, 7 of them are related to hormones (11-hypertension, 11-dehydrocorticosterone, aldosterone, 11-desoxycortisol, hydrocortisone, cortisone). The adrenal cortex also synthesized androgens, among them mainly dehydroepiandrosterone (DHEA), a precursor of sex hormones and anabolic effect. All these substances are presented in minor concentrations.

In hypoxia violated adrenal function, primarily hemodynamic disorders and abnormalities in metabolic processes, as corticosteroid hormones affect the genetic apparatus of cells, control the synthesis of proteins on ribosomes and activate enzymes.

It is easy to imagine that the application for correction of dysfunction of the adrenal glands, one semi-synthetic drug (e.g., hydrocortisone) may not replace the ensemble compounds in metabolic processes. You must bear in mind not only the fact of the presence in all cells of the body of corticosteroid receptors, but also the diversity in the degree of their affinity to the concentrations of hormones, which can detect differences in the effects of low and high concentrations. In the first case monpolies orientation, typical stress. Using extract extract of bark pork and fetal adrenal glands, we expected to get the anabolic effects that are possible only with sufficient ATP synthesis.

The efficacy of the study drug was performed by the classical method of estimating the content of adenosine monophosphate (AMP), adenosine diphosphate (ADP), adenosine triphosphate (ATP) and the ratio of ATP/AMP, the value of which is a sensitive indicator of energy balance reactions utilization and ATP synthesis. Means for stimulation of energy processes in the tissues was prepared as follows: frozen in liquid nitrogen adrenal glands of pigs and newborn (died in childbirth) were crushed with the help of the top and subjected to extraction with ethyl alcohol. Water-soluble compounds were removed by freezing. The extract obtained was transferred into the alcohol, and then in a physiological solution with a 10% concentration of ethyl alcohol. 3 g of tissue of the adrenal received 1 ml of the extract. Technological scheme of production of the extract the extract of the adrenal cortex are described in the literature (6).

Animals were injected with the extract of extract of bark pork and fetal (human)nadmocan the risk of hypoxia. Carried rise to a height of 9000 meters flowing in the chamber with the speed of 1000 meters per minute. Hypobaric hypoxia lasted for 40 minutes and then the animals at the same speed fell to the ground. Injections were made subcutaneously in the morning (9-10 hours). Animals were selected equal mass (150-180 g) and sex (males). The control were 4 groups of animals: the first group (I) are not subjected to any stress (intact), the second group (II) were exposed to hypobaric hypoxia without prior administration of drugs, a third group (III) received two injections of 10% ethanol in isotonic salt to hypobaric hypoxia; the fourth group (IV) was administered in two injections of hydrocortisone on the same basis as the extracts of the adrenal glands, in an amount of 5 mg/kg animal mass; the fifth group (V) was the animals that were administered the extract of porcine adrenal, and sixth group (VI) animals, which were injected extract the fetal adrenal. Thus, all experimental animals were divided into 6 groups.

The control group with the introduction of hydrocortisone is due to the extensive use of the latest in clinical practice is neither liver, brain and heart, taken when slaughtering animals, researched content Denisovich phosphates (ATP, ADP, AMP).

In the study of adenosine compounds pieces of the extracted tissue was immersed in liquid nitrogen. The sample tissue was ground in a mortar in the presence of liquid nitrogen, and then placed in buxy containing chilled 10% trichloroacetic acid (0.005 M EDTA) at a rate of 10 ml/g of tissue. Samples were extracted for 20 minutes, filtered and THU were removed three times by shaking (for 2 minutes) with two volumes of sulphuric ether saturated with water. Traces of ether were removed by aeration and the extract was neutralized to pH 7.0 to 7.4 with 0.1 NaOH. All operations were carried out at a temperature of from 0 tooC. In the neutralized extracts were determined by the content of free nucleotides by the method of column chromatography on aktuala-cellulose (ET-30) according to the described method (I.e. Ivanova and N. Rubel, 4). All studies subjected to statistical processing to calculate the confidence coefficient t-test.

Studies have shown liver tissue (table 1), in animals exposed to hypobaric hypoxia (group II) without the prior tread injection decreased ATP (2,4960,576 mmol/g) and the 0.9% normal. In animals that received two injections of extracts of the bark of the porcine adrenal gland and underwent hypobaric hypoxia (group V), the content of the AMF (0,3480,049 mmol/g) corresponded to the normative values, and the ATP content (2,9290,465 mmol/g) was close to the target and the ratio of ATP/AMP (8,654) exceeded the guideline values, indicating favorable for energy processes in the tissues of the liver.

Similar results were obtained in the study of adenosintriphosphate in animals exposed to hypobaric hypoxia and received two injections of extracts of fetal adrenal glands (group VI). As in animals of group V, the content of the AMF were below guideline values (0,3720,082 mmol/g), the ATP content was equivalent to the intact animals (2,9170,328 mmol/g) and the ratio of ATP/AMP was $ 8,232, which is higher than that of intact animals.

Other changes in the content Denisovich nucleotides was observed in animals that received two injections of hydrocortisone before exposure to hypobaric hypoxia (group IV). The content of AMF increased to 0,7220,136 mmol/g, which was 17.85% of total Denisovich nucleotides, whereas with the introduction of the bark extract of porcine adrenal share the values of ATP content (2,3120,142 mmol/g) (group III), only the control with the introduction of alcohol ATP was below this value (2,0030,205 mmol/g).

In the brain tissue of animals (table 2), which previously entered the bark extract of porcine adrenal, after hypobaric hypoxia ATP content (2,3050,134 mmol/g) exceeded the standard value (2,1850,349 mmol/g) was significantly higher than in the control animals (group II) did not receive protective drugs (1,7320,216 mmol/g). The highest concentrations of ATP detected in brain tissues of animals, which to conduct hypobaric hypoxia was introduced extract of fetal adrenal (2,4980,109 mmol/g). Differences with the data of the previous group (which received the extract of porcine adrenal glands) were statistically significant (P<0,005). With the introduction of extracts of fetal adrenal and was the highest ratio of ATP/AMP (10,637). As in the study of the liver tissue, the introduction of hydrocortisone has not had a positive impact on the energy processes in the brain. The ratio of ATP/AMP was $ 5,485.

A distinctive feature of the energy processes in the tissues of the heart (table 3) in the conditions of hypobaric hypoxia are contiguous values Denisovich nucleotides in the introduction extracts of nadpochechnika is CE, uses mainly fatty acids. But the introduction of hydrocortisone on the same alcohol-based, as in the control (III), has not increased ATP content in these animals (2,0390,008 mmol/g), consistent with the values of control II hypobaric hypoxia (1,8280,187 mmol/g). Accordingly, the ratio of ATP/AMP with the introduction of hydrocortisone (5,382) was equal to the coefficient of hypobaric hypoxia (5,343).

Thus, a comparative study of the biological effects of various hormone-active substances during hypobaric hypoxia revealed a protective effect of extracts of bark pork and fetal human adrenal glands in the liver, brain and heart, resulting in the activation energy of the processes of preservation in tissue ATP. The introduction of hydrocortisone had an inhibitory effect on the energy formation.

The results of the research allow us to offer the product-based extract of extract of bark pork and fetal adrenal glands as a means of objectively normalizing the energy processes in the tissues under conditions of hypoxia, as evidenced by a sufficient content of ATP and a high ratio of ATP/AMP.

The authors of the present invention is not weavile means for normalizing the energy processes in the body tissues under hypoxic conditions.

Sources of information

1. Serdinov A. Z. search Strategy and possible pharmacological optimization of adaptation to hypoxia. The results of science and technology. Pharmacology. Chemical means. Moscow, 1991, T. 27, 71-82.

2. Ivanov, I. N., Rubel L. N. Some aspects of energy metabolism in rat brain in terms of the increased partial pressure of oxygen. Journal of evolutionary biochemistry and physiology. 1969, So Y, 3, 279-287.

3. Lukyanova L. D. Bioenergetic mechanisms of formation of hypoxic conditions and approach to their pharmacological correction. Pharmacological correction of hypoxic conditions. Moscow, 1989, 11-44.

4. Mashkovsky M. D. Medicines. M.: Medicine, 1986, T. 1, 568-570.

5. Maes P. the Role of high-energy phosphates in bioenergy and the capture of energy. Biochemistry of human rights. Translation from English. Moscow, Mir, 1993, T. 1, 113-116.

6. Rosenzweig P. E., sander J. K. Technology of drugs and galenical preparations (a Guide for pharmacists). Medicine, Leningrad div, 1967, 695-696.

7. Ryabinina H. A., Kirpichnikov M. M., Suzdaltsev A. A., Dakine N. N. The effect of the purine derivatives on regeneration and immunological reactivity in animals (liver). Bureacracies phosphates as an indicator of the assessment of the severity of brain hypoxia. Modeling, pathogenesis and therapy of hypoxic conditions. Bitter, 1989, S. 4-9.

9. Hazura centuries Pharmacological correction of energy metabolism in ischemic myocardium. Moscow, 1993, page 220.

10. Khvatova E. M., Sidorkin, A. N., Mironov, C. Contents Denisovich nucleotides as an indicator of energy metabolism in tissues in normal and hypoxia. The nucleotides of the brain. Moscow, 1978, 131-179.

The use of the extract of extract of bark pork or fetal adrenal glands as a means to normalize the energy processes in the body tissues under hypoxic conditions.

 

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FIELD: veterinary science.

SUBSTANCE: one should apply combined introduction of T-activin at the dosage of 5 mcg/kg once daily along with a single introduction of phenbendasol at the dosage of 5 mg/kg. Moreover, T-activin should be introduced for 3 d, and phenbendasol should be introduced simultaneously with the last injection of T-activin. Conditions for injecting immunomodulating agent and certain sequence of its injection along with antihelminthic preparation provide increased resistance to repeated infectioning in animals.

EFFECT: higher efficiency of combined therapy.

2 ex, 2 tbl

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