Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Patent
1998-02-19
1999-01-12
Spicack, Phyllis G.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
514565, A61K 31205, A61K 31195
Patent
active
058590560
DESCRIPTION:
BRIEF SUMMARY
The invention relates to pharmaceutical compositions, namely, to pharmaceutical compositions for the treatment of such heart and blood vessel diseases, which are connected with blood circulation disturbances of various genesis and localization, stenocardia, myocardium infarction, arrhythmias, hypertension, myocarditis as well as low heart potency.
The proposed therapeutic composition contains known chemical substances, the use of which gives unexpected pharmacological effects. Namely, there is offered a pharmaceutical composition which contains .gamma.-butyrobetaine in a combination with 3-(2,2,2-trimethyl-hydrazinium)propionate as an active system and pharmaceutically acceptable fillers or solvents.
In the treatment of cardiovascular diseases, 3-(2,2,2-trimethyl-hydrazinium)propionate is a known preparation (Mildronate, Quaterine) (UK patent GB 2105992), the mechanism of action of which is based on the limitation of carnitine biosynthesis rate and the related long-chain fatty acid Transport limitation through mitochondria membranes (Simkhovich B. Z., Shutenko Z. V., Meirena D. V. et al. 3-(2,2,2-trimethylhydrazinium)-propionate (THP)--a novel .gamma.-butyrobetaine hydroxylase inhibitor with cardioprotective properties. Biochem.Pharmacol. 1988, 37, 195-202).
BACKGROUND ART
.gamma.-Butyrobetaine (actinine), from which the mammalian organism synthesises carnitine, was primarily characterised as a toxic substance which accelerates respiration, causes salivation and lacrimation, pupil dilation, vasoconstriction and heart stop in diastole (W. Linneweh, Z. Physiol. Chem., 42, 181, 1929). At the same time, in later papers other authors ascertained that .gamma.-butyrobetaine is extremely low toxic (LD.sub.50 >7000 mg/kg, s.c.). (W. Rotzsch, I. Lorenz, E. Strack, Acta biol. med. ger. 1959,3,28-36).
In the literature data on nonsubstituted .gamma.-butyrobetaine cardiovascular effects are missing, though it was reported (Hosein E. A., McLennan H. Pharmacological action of .gamma.-butyrobetaine. Nature, 1959, 183, 328-329) that .gamma.-butyrobetaine is a substance similar to acetyl choline with a prolonged action. However, later the same authors reported that by an error the experiments involved, instead of .gamma.-butyrobetaine, its methyl ester which in fact possesses cholinergic properties. Contrary to the former nonesterified .gamma.-butyrobetaine was characterised as a pharmacologically inert substance (E. A. Hosein, P. Proulx, Isolation and probable functions of betaine esters in brain metabolism, Nature, 1960, 187, 321-322. A. S. V. Burgen, F. Hobiger. Brit. J. Pharmacol., 4, 229 (1949), E. Strack, K. Foesterling. Z. Physiol. Chem., 1953, 295, 377).
.gamma.-Butyrobetaine administration increases the level of carnitine biosynthesis in the organism serving as a substrate in this process. Thus, it would be natural to anticipate that in the organism at a simultaneous administration of camitine biosynthesis blocker 3-(2,2,2-trimethyl-hydrazinium)propionate and .gamma.-butyrobetaine, the pharmacological effect of 3-(2,2,2-trimethylhydrazinium)propionate should decrease because carnitine biosynthesis is activated if .gamma.-butyrobetaine concentration increases. On the contrary, it was now unexpectedly discovered that the opposite effect is observed, i.e. .gamma.-butyrobetaine intensifies the effect of 3-(2,2,2-trimethylhydrazinium)propionate on the cardiovascular system.
DISCLOSURE OF THE INVENTION
The experiments were performed on male and female (2.9-3.8 kg) anaesthetized cats (urethane 200 mg/kg and chloralose 50 mg/kg, both i.p.).
The chest was opened in the experimental animals, which were artificially respirated, and blood pressure in the carotid artery as well as general aorta blood flow were measured on physiograph DMP-46 "Narco Bio-Systems" USA.
It was detected that the pharmaceutical composition which contains .gamma.-butyrobetaine in combination with 3 -(2,2,2-trimethylhydrazinium)-propionate possesses a marked effect on blood vessel tonus and blood circulation, which exceeds every separate active
REFERENCES:
patent: 4451485 (1984-05-01), Kalvinsh
Simkhovich, B Z et al.; Biochem. Pharmacol. vol. 37, No. 2, 1988, pp. 195-202.
W. Rotzsch et al, Acta biol. med. germ., 1959, Band 3, pp. 28-36.
Hosein E.A. et al, Nature, 1960, vol. 187, pp. 321-322.
Hosein E.A. et al, Nature, 1959, vol. 183, pp. 328-329.
Burgen A.S.V. et al, Brit. J. Pharmacol., 1949, 4, pp. 229-233.
Simkhovich, B Z et al, Vopr. Med. khim. vol. 32, No. 4, 1986, pp. 72-75.
Chemical Abstracts, vol. 105, 15, Nr. 127077, 13 Oct. 86, pp. 45-46.
Kalvinsh Ivars
Veveris Maris
Abrahams Colin P.
Spicack Phyllis G.
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