Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1997-05-19
1998-06-30
Goldberg, Jerome D.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
A61K 3800
Patent
active
057734151
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This invention relates to an anti-cardiac hypertrophic agent.
BACKGROUND ART
The interest in des-Aspartate-angiotensin I, a nine amino acid angiotensin peptide (Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu), as a peptide of the renin-angiotensin system was first generated when Blair-West and colleagues (Blair-West et al, J. Clin Endocrinol. Metab., 32:575-578 (1971)) postulated a biosynthetic pathway for the production of angiotensin III by enzymatic NH.sub.2 -terminal degradation of angiotensin I to the nonapeptide and sequential action of angiotensin converting enzyme on this nonapeptide to produce the heptapeptide. Since then des-Aspartate-angiotensin I has been shown to be an excellent substrate of plasma and pulmonary angiotensin converting enzyme (Tsai et al, J. Med Chem., 18:1 180-1183 (1975)) and that its pressor and steroidogenic actions are dependent on its conversion to angiotensin III (Campbell et al, Endocrinology, 100:46-50 (1977)). Recently we found that homogenates of rat aorta and hypothalamus degrade exogenous angiotensin I to mainly des-Aspartate-angiotensin I instead of angiotensin II and the enzyme responsible for the degradation was a specific aminopeptidase that was not inhibited by amastatin, bestatin and EDTA (Sim, Blochem. Pharmacol., 45:1524-1527 (1993); Sim et al, Blood Pressure, 3:260-264 (1994) and Sim et al, Biochem. Pharmacol., 48:1043-1046 (1994)). Des-Aspartate-angiotensin I has also been shown to attenuate the pressor action of angiotensin II and angiotensin III in the brain (Sim and Radhakrishnan, Eur. J Pharmacol., 257:R1-R3 (1994)). Peripheally, it is able to potentiate the contractile action of angiotensin II on the rabbit aortic ring but to attenuate the contractile action of angiotensin III in the same tissue (Sim and Yuan, Eur. J Pharmacol., 287:175-178 (1995)). These recent findings of ours seem to indicate that des-Aspartate angiotensin I is a functional peptide that may have undefined specific actions in ensuring the normal functioning of the cardiovascular system.
DISCLOSURE OF INVENTION
In the course of studying the cardiovascular pharmacology of des-Aspartate-angiotensin I, the nonapeptide has been found to attenuate significantly the experimentally-induced cardiac hypertrophy in rat. It has been surprisingly discovered that des-Aspartate-angiotensin I is effective in accordance with the present invention at an exceeding low dose, i.e. an i.v. dose of 180 ng (given over a period of 4 hours) per day for four days attenuates significantly the experimentally-induced cardiac hypertrophy in rats. Another significant finding is that, despite being a peptide des-Aspartate-angiotensin I is equally effective in attenuating the cardiac hypertrophy when given orally at 285 mg per day for four days. These findings show that des-Aspartate-angiotensin I is a highly specific anti-cardiac hypertrophic agent and is effective at concentrations that produce minimum or no secondary effects.
Therefore, the present invention is directed to the use of des-Aspartate-angiotensin I as an anti-cardiac hypertrophic agent or in the preparation of an anti-cardiac agent, for either the prevention or treatment of cardiac hypertrophy or a pharmaceutical composition for preventing or treating cardiac hypertrophy comprising an effective amount of des-Aspartate-angiotensin I and a pharmaceutically acceptable carrier or diluent or a method for preventing or treating cardiac hypertrophy, which comprises administering to a subject in need of treatment an effective amount of des-Aspartate-angiotensin I or a packaged pharmaceutical composition for preventing or treating cardiac hypertrophy comprising a container suitable for storing a pharmaceutical preparation, an effective amount of des-Aspartate-angiotensin I in said container, and instructions associated with said container giving instructions for hie use of said des-Aspartate-angiotensin I for preventing or treating cardiac hypertrophy.
MODES FOR CARRYING OUT THE INVENTION
In the practice of the method of the present invention,
REFERENCES:
patent: 5231083 (1993-07-01), Linz et al.
Blair-West et al, Journal of Clinical Endocrinology and Metabolism, 32:575-578 (1971).
Tsai et al, Journal of Medicinal Chemistry, vol. 18, No. 12, pp. 1180-1183 (1975).
Campbell et al, Endocrinology, vol. 100, No. 1, pp. 46-51 (1977).
Sim, Biochemical Pharmacology, vol. 45, No. 7, pp. 1524-1527 (1993).
Sim et al, Blood Pressure, 3:260-264 (1994).
Sim et al, Biochemical Pharmacology, vol. 48, No. 5, pp. 1043-1046 (1994).
Sim et al, European Journal of Pharmacology, 257:R1-R3 (1994).
Sim et al, European Journal of Pharmacology, vol. 278, pp. 175-178 (1995).
del Rio et al., "des-Asp-Angiotensin I: Its Identification in Rat Blood and Confirmation as a Substrate for Converting Enzyme", Endocrinology, vol. 108, No. 2, 1981, pp. 406-412.
Goldberg Jerome D.
National University of Singapore
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