Oral adaptogens with antihypoxic, anti-shock and analgesic activity

 

(57) Abstract:

The invention relates to medicine and veterinary medicine, particularly to pharmacology. Found adaptogenic effect known water-soluble copolymers of N-vinylpyrrolidone and N, N, N,N-Triethylenetetramine iodide, as well as complex specified copolymer with sodium dodecyl sulfate. Adaptogenic effect of aqueous solutions of these substances detected after intragastric administration at a dose of 10-100 mg/kg of body weight. table 1.

The invention relates to biologically active synthetic macromolecular compounds, have found a new activity, or rather to the new usage of polymeric compounds on the basis of water-soluble copolymers of N-vinylpyrrolidone and N,N,N,N,- Triethylenetetramine iodide.

The claimed technical solution can be used for the development of drugs used in medicine and veterinary medicine, for example in therapy of acute hypoxic conditions, ischemia of the brain and heart, shock and stress.

Described is a water-soluble copolymers of N-vinylpyrrolidone and N,N,N,N Triethylenetetramine iodide of General formula:

< / BR>
is exist /2/, as well as membrane-substances /3/ and activators of the enzyme trypsin /4/.

Also described is a water-soluble complexes of copolymers of N-vinylpyrrolidone in N, N, N,N-Triethylenetetramine iodide with sodium dodecyl sulfate of General formula:

< / BR>
with MM from 20 to 120 thousand D, n = 83,0 - 93,0 mol.%, m = 7,0 - 17,0 mol.%, when the molar ratio m:x = 1:3,6 - 4,2, were previously described antimicrobial activity /5/, the ability to stimulate the growth of farm animals with the introduction of the feed at doses of 2 to 4 mg/kg body weight /6/ and to normalize the variances of metabolic processes in cattle /7,8/, as well as to have a modulating effect on the barrier function of membranes and the activity of the enzyme trypsin /3,4/.

Known adaptogens natural origin, derived from both vegetable and animal raw materials /9/, such as preparations of ginseng, Eleutherococcus, Rhaponticum carthamoides, zamanihi, Chinese Magnolia and others, pantocrine, etc. that are used for pharmacological correction of hypoxic States /10/, have analgesic action /11/ and antishock activity /12/.

The main disadvantage of the known adaptogens adenosine series is that they manifest their adaptogenic d the m they cause unwanted side effects: sharply reduce blood pressure, depress cardiovascular activity and function of the Central nervous system, which limits their potential use in medical practice.

The present invention was to overcome the disadvantages of the known drugs for urgent adaptation, i.e. the creation of substances that protect the body from extreme factors when simpler and physiological enteral method of introduction into the body and do not cause side adenosinergic effects. The problem was solved by the use of previously known polymeric substances /14/ from the series comprising the copolymer of N-vinylpyrrolidone and N,N,N,N-Triethylenetetramine iodide formula:

< / BR>
where

n = 83,0 - 93,0 mol.%, m = 7,0 - 17,0 mol.%; MM from 23 to 120 thousand D, and the complex of the specified copolymer with sodium dodecyl sulfate of General formula:

< / BR>
where

n = 83,0 - 93,0 mol.%, m = 7,0 - 17,0 mol.%; MM from 23 to 120 thousand L, a molar ratio of m : x = 1 : 3,6 - 4,2, as oral adaptogens with antihypoxic, anti-shock and analgesic activity.

These types of pharmacological activity are manifested after intragastric administration of polymeric substances by means of the probe in doses of 10 to 100 mg/kg of body weight.

The invention the core is howling functions of polymeric substances, and from the mode of their introduction.

As shown by additional research, applied polymer substance is practically non-toxic when enteral introduction: for white rats LD50more than 16000 mg/kg body weight for copolymers and LD50= 7200 mg/kg body weight for complexes. With a long introduction into the body in doses of 0.1 LD50these substances do not cause apparent side effects unlike adaptogene on the basis of adenosine.

Thus, the above newly discovered properties demonstrate compliance of the claimed invention "in use" requirements of "novelty" and "inventive step". To assess antihypoxic properties of substances used two models of hypoxia - canned hypoxia with hypercapnia in mice /15/ and gemicescuu hypoxia in rats induced by injection of sodium nitrite /16/. In the first case recorded lifespan of animals under conditions of oxygen starvation, and in the second case, the proportion of rats surviving through the days after hypoxia.

Antishock effect of the substance has been evaluated in models of severe hypoglycemic shock /17/ by lengthening the lifetime of the rats and the percentage survival through day after vnutrimyshechnogo is sposobnosti to lengthen the duration of the latent period of reflex otdergivanija tail of rats when it is immersed in hot water /18/.

For a better understanding of the nature and confirmation industrial applicability of the invention provide examples of its specific implementation.

Example 1 (control jar hypoxia in mice). White mice (20 animals) weighing 18 to 20 g introduced intragastrically (W/W) using a probe 0.3 ml of distilled water. After 30 min, animals were placed in a closed airtight jar with a capacity of 100 cubic see Through 1,31,6 min all mice died from lack of oxygen.

Example 2. In the conditions of example 1 for 30 min before hypoxia mice instead of water was injected into/W copolymer of N-vinylpyrrolidone and N,N,N,N-Triethylenetetramine iodide with MM 88 thousand D of the n=83,0 mol.%, m=17,0 mol.% in the dose of 10 mg/kg of body weight in aqueous solution. Observed increase in the lifespan of mice under conditions of oxygen starvation to 14,31,5 min, i.e. by 25.7% compared to control.

Example 3. In the conditions of example 2, the animals were injected at a dose of 10 mg/kg of body weight complex of a copolymer with sodium dodecyl sulfate MM 120 thousand D, n-93,0 mol.%, m=7,0 mol.%, when a molar ratio of m:x=1:4,2. Observed increase in the lifespan of mice in hypoxia to 13.5 1.6 minutes, i.e. by 19.7% compared to control.

Example 4 (control Himicheskaya TKA is at a dose of 85 mg/kg of body weight. Through 82,09,7 min on the background of pronounced tissue hypoxia 90,01,0% of the animals died, I have survived 10,01,0% of rats.

Example 5. In the conditions of example 4 for 30 minutes before injection of sodium nitrite animals in a/W in aqueous solution was injected into a copolymer with 120 MM TIC.D. composition n= 93,0 mol.%, m=7,0 mol.% in the dose of 10 mg/kg of body weight. One day after injection of sodium nitrate survived 17,62,5% of rats.

Example 6. In the conditions of example 5, the animals were injected in a/W aqueous solution of the complex with 88 MM th. D, n = 83,0 mol.%, m = 17,0 mol.%, m:x = 1:3,6, at a dose of 100 mg/kg of body weight. One day after injection of sodium nitrite survived 52,66,6% of rats.

Example 7 (control and severe insulin shock in rats). White outbred rats (100 animals) weighing 170-190 g were injected intraperitoneal insulin at a dose of 2.5 IU/100 g body weight. After 3-4 hours after injection of insulin killed 100% of the animals (survival rate of 0%).

Example 8. For 30 min before the injection of insulin to rats (100 animals) in the conditions of example 7 was inserted in the/g at the dose of 100 mg/kg of body weight of the copolymer composition specified in example 2. One day after injection of insulin survived 45,76,2% of the animals.

Example 9. In the conditions of example 8, the animals were injected in a/W aqueous solution of the complex with 23 MM th. E composition n = 83,0 mol.%, m = 17,0 mol.%, m:x = 1:4,0 dose of 100 mg/kg mA is ergomania tail of rats when it is overheating). Rats-males (20 animals) weighing 160-180 g were injected in a/W 0.3-0.5 ml of distilled water and after 30 min test conducted on pain sensitivity, as measured by the duration of the latent period of reflex otdergivanija tail when it is immersed in water with a temperature of 56oC. This duration was 3,500,42 sec.

Example 11. In the conditions of example 10 white rats were administered an aqueous solution of a copolymer of the composition specified in example 2, at a dose of 10 mg/kg of body weight. Observed an increase in the duration of the latent period of reflex otdergivanija tail when its overheating to 14,42,0 sec.

Example 12. In the conditions of example 10 animals were injected with an aqueous solution of the compound specified in example 9 at a dose of 100 mg/kg of body weight. After 30 min in the test for overheating of the tail in rats observed a complete inhibition of the reflex otdergivanija tail. The latent period of the reflex was more than 40 seconds.

The results of the evaluation of adaptogenic properties declared polymeric substances are summarized in table summarizes the adaptogenic activity examples of specific performance, and adaptogenic activity of such similar as adenosine at its intraperitoneal administration in the minimum and maximum dose.

the x2">

2. Danilov, A. R., Vasiliev S. C. // New biologically active polymers and immobilized them steroids /Sat. proceedings of the Leningrad pediatric med.in-TA./Edited Nejentsev M. C.-L.: 1988, S. 26.

3. Kopeikin centuries of Biological membranes. 1988, T. 5, N 7, S. 728 to 734.

4. Kopeikin Centuries, Afanasiy N. A. Bioorganic chemistry. 1988, so-14, N 6, S. 802-809.

5. Solowski M. C., Afinogenov, E., Panarin E. F., Kovtun, M. Chem.-Pharm. log. 1980, No. 11, S. 51.

6. Panarin E. F., Grooms C. N., Kopeikin Centuries, Ahmetov So M /Vestnik St.Petersburg University. agricultural Sciences. - 1991. - 417 so. - N-6. - S. 108-112.

7. DOKSAN and DOKSAN-M specifications. THE 9291-002-02698594-94, appr. 06.07.1994 the Department. veterinary medicine of the Ministry of agriculture of the Russian Federation.

8. Guidance on the application of DARSANA and DARSANA-M in veterinary medicine N 13-5-2/113, reg. N 10.07.152-94 OVRI, approved by the Department. veterinary medicine of the Ministry of agriculture of the Russian Federation 06.07.94.

9. Durdymov I. C., Hasina E. I./Siberian Ginseng. Secrets of a "panacea". - S.-Pb. Science, 1993, S. 8-11.

10. Pharmacological correction of hypoxic States /Sat. proceedings of the Institute of pharmacology of the medical Sciences of the USSR, edited by Professor L. D. Lukyanova, M - 1989. - S. 89.

11. Herrick-Lavis K. et all./ Europ/Journ. of Pharmacology. - 1989. - v. - 162. - N 2. - P 365-369.

12. Serdyuk S. K., Giro C. E. Physiologically. log them. I. M. Sechenov. - 1995, so the body naturally. - M.: Nauka, 1991.

14. Kopeikin Centuries, Afanasiy N. A., Fazil, A., Santurian Y., / Vysokomol. connect. 1987, 29 so.And, No. 2, S. 37-376.

15. The Tsyrlin Century A. // Mechanisms of regulation baroreceptor reflex. Mechanisms of adaptive reactions of the cardiovascular system. The results of science and technology. VINITI. Ser. "Human and animal physiology". 1990, T. 41, S. 159-186.

16. Burbelo A. T., Denisenko, p. P., Slesarev Century. And. To the mechanism of the protective action of antioxidants in himicheskoi hypoxia caused by sodium nitrite/ Results of science and technology. Ser. Pharmacology. Chemotherapeutic agents. So 27 "Antioxidants". - M.: 1991, S. 89-99.

17. Hazura centuries, Saratikov A. S. Pharmacological agents in experimental medicine and biology. -Tomsk, 1977, S. 154.

18. Kharkevich D. A. Manual for laboratory exercises in pharmacology - M., 1988, S. 88-98.

The use of polymeric substances from the series comprising the copolymer of N-vinylpyrrolidone and N,N,N,N-Triethylenetetramine iodide of the General form

< / BR>
where

n = 83,0 - 93,0 mol.%;

m = 7,0 - 17,0 mol.%;

MM from 23 to 120 thousand and complex copolymer of this structure with sodium dodecyl sulfate of General formula

< / BR>
where

n = 83,0 - 93,0 mol.%;

m = 7,0-17,0 mol.% for y:x = 1 : (3 is but a dose of 10 100 mg/kg of body weight.

 

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