Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1997-02-19
1999-11-09
Tsang, Cecilia J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
530328, 530329, 530330, 530332, 514 16, 514 17, 514 18, 514 19, 435219, 548535, A61K 3800
Patent
active
059814705
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND
This invention relates to uterine fibroid treatment.
Cellular proliferation and differentiation in uterine tissue is considered to be regulated by ovarian steroids as fibroids appear in the reproductive years and regress after the menopause. Uterine fibroids are most commonly treated by surgery, usually by full or partial hysterectomy, although removal of individual fibroids (myomectomy) is also undertaken at rather greater risk on women who have not completed child bearing. As far as medical treatment is concerned, agonist analogues of LHRH (luteinizing hormone-releasing hormone) such as Buserilin (GnRH analogue) have been employed to suppress oestrogen-progesterone as fibroids are ovarian steroid dependent. Such medical treatments, however, suffer from a variety of side effects such as predisposition to osteopetrosis and are not recommended for long term use.
SUMMARY
It is an object of the present invention to provide an alternative medical treatment for uterine fibroids which, it is believed, may have potential for use in situations where the above-mentioned medical treatments are inadvisable.
The present invention is based on the discoveries by the present inventor that angiotensin II (Type II) receptor (AT.sub.2) is highly expressed in fibroid tissue compared to normal myometrium (see attached FIGS. 1(A) to 1(E)), and that angiotensin II stimulates myometrial cell proliferation (see FIGS. 3(A) and 3(B).
The present invention, in a first aspect, resides in the use of an angiotensin-converting enzyme (ACE) inhibitor for the manufacture of a medicament for the treatment of uterine fibroids.
The present invention, in a second aspect, resides in the use of an angiotensin II-receptor antagonist for the manufacture of a medicament for the treatment of uterine fibroids.
The present invention, in a third aspect, resides in the use of a renin inhibitor for the manufacture of a medicament for the treatment of uterine fibroids. In this connection, it is to be appreciated that, in the renin-angiotensin system (RAS), renin synthesized by the kidneys and secreted into the circulation cleaves the decapeptide angiotensin I from angiotensinogen. Angiotensin I is converted by ACE to the octapeptide angiotensin II which is the biologically active hormone. Accordingly, the use of a renin inhibitor will also have the effect of inhibiting angiotensin II.
In a fourth aspect, the present invention resides in the use of an angiotensin II receptor (AT.sub.1 and/or AT.sub.2) expression inhibitor (including an antisense oligonucleotide directed against the angiotensin II receptor (AT.sub.1 and/or AT.sub.2) expression gene) in the manufacture of a medicament for the treatment of fibroids.
With regard to said first aspect of the present invention, namely the use of an ACE inhibitor to suppress angiotensin II expression, it is considered that any ACE inhibitor can potentially be used, including those which are known and which have been used or proposed to be used for ACE inhibition in the treatment of hypertension and congestive heart failure.
For example, ACE inhibitors such as Captopril (very soluble in water) and Enalapril (CAS 75847-73-3) (sparingly soluble in water) have relatively few side effects and are very effective in the treatment of hypertension.
Other ACE inhibitors which may be suitable are: 1992, 42(9), pages 1109-14), 1993, pages 233-235), and for other enzymes in the renin-angiotensin system.
With regard to angiotensin II receptor antagonists, it is considered that suitable antagonists can be found amongst the following:
As far as renin inhibitors are concerned, it is considered that suitable renin inhibitors may be: ACHPA-isoleucylamino]-2-methyl-2-dihydroxy-1,3-propane (Arzneim. Forsch./Drug Res., Feb 1993 43(2A), pages 255-259).
Other renin inhibitors may be C1-992 (J. Pharmacol. Exp. Ther., 268:372-9, 1994); non-peptide renin inhibitors containing 2-(((3-phenylpropyl)phosphoryl)oxy)alkanoic acid moieties as P.sub.2 -P.sub.3 replacements (J. Med. Chem. 37:486-97, 1994) and antisense oligonucleotid
REFERENCES:
patent: 5407955 (1995-04-01), Bryant et al.
Nagasawa, K. et al., "Extracellular Matrix Deposition In Hypertensive Hearts. Antifibrotic Effects of Ramipril", European Heart Journal, vol. 16, Suppl. C, 1995 United Kingdom, pp. 33-37.
Campbell-Boswell, M. et al., "Effects of Angiotensin II and Vasopressin On Human Smooth Muscle Cells In Vitro", Experimental And Molecular Pathology, vol. 35, No. 2, 1981 USA, pp. 265-276.
Christiansen, JK, "The Facts About Fibroids, Presentation and Latest Management Options", Postgraduate Medicine, vol. 94, No. 3, 1993 USA, pp. 129-134.
Lumbers, E R et al., "Acute Effects of Captopril, An Angiotensin-Convertin Enzyme Inhibitor, On The Pregnant Ewe And Fetus", American Journal of Physiology, vol. 31, No. 5, 1992 USA, pp. R754-R760.
Lukton David
The University of Birmingham
Tsang Cecilia J.
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