III IIII US005529992A United States Patent (19) 11 Patent Number: 5,529,992 Weber 45) Date of Patent: Jun
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III IIII US005529992A United States Patent (19) 11 Patent Number: 5,529,992 Weber 45) Date of Patent: Jun. 25, 1996 54 METHOD FOR INHIBITING MYOCARDIAL Brilla, C. G., et al, abstract, "Myocardial fibrosis in experi FBROSS BY ADMINISTERING AN mental hypertension: potential role of fibroblast corticoid ALDOSTERONE ANTAGONST WHICH receptors,” J. Hypertension 8: S8 (1990). SUPPRESSES ALDOSTER ONE RECEPTORS Weber, K. T., and Brilla, C. G., "Pathological hypertrophy and cardiac interstitium: fibrosis and renin-angiotensin-al 75 Inventor: Karl T. Weber, Columbia, Mo. dosterone system." Circulation 83: 1849-1865 (Jun. 1991). Weber, K. T., and Brilla, C. G., “Myocardinal fibrosis and 73) Assignee: Curators of the University of elevations in plasma aldosterone in arterial hypertension,” Missouri, Columbia, Mo. Aldosterone: Fundmental Aspects 215: 117-120 (1991). Brilla, C. G., and Weber, K. T., "Prevention of myocardial 21 Appl. No.: 160,236 fibrosis in hypertension: role of fibroblast corticoid receptors and spironolactone' Proceedings of the 75th Annual Meet 22). Filed: Dec. 2, 1993 ing of the Fed of Amer: Societies for Exper. Biology, 1991, abstract No. A1256, published Apr. 21, 1991. Related U.S. Application Data American Journal of Cardiology, Klug et al., "Role of 63 Continuation-in-part of Ser. No. 871,390, Apr. 21, 1992, Mechanical and Hormonal Factors in Cardiac Remodeling abandoned. and the Biologic Limits of Myocardial Adaptation," Jan. 21, 1993, vol. 71, No. 3, pp. 46A-54A. (51) Int. Cl. .................. A61K 31/71 Journal of Molecular and Cellular Cardiology, Brilla et al., (52) ... 514/175; 514/173 "Anti-Aldosterone Treatment and the Prevention of Myo 58) Field of Search ...................................... 514/173, 175 cardial Fibrosis in Primary and Secondary Hyperaldoster onism,” May 1993, vol. 25, No. 5, pp. 563-575. 56 References Cited American Journal of Cardiology, Brilla et al., "Antifibrotic Effects of Spironolactone in Preventing Myocardial Fibrosis U.S. PATENT DOCUMENTS in Systemic Arterial Hypertension.” Jan. 21, 1993, vol. 71, 4,003,996 1/1977 Pappo et al............................. 514/175 No. 3, pp. 12A-16A. Journal of Pharmacology and Experimental Therapeutics, OTHER PUBLICATIONS "Three New Epoxy-Spirolactone Derivatives: Characteriza Remington's Pharmaceutical Sciences, 15th edition 1975, tion in vivo and in vitro,'Feb. 1987, vol. 240, No. 2, pp. pp. 867-868, 650-656. Doering, C. W., et al., "Collagen network remodeling and Bundesverbrand D. Pharm. Ind. E. V., “Rote Liste,' 1987 diastolic stiffness of the rat left ventricle with pressure Editio Cantor, Aulendorf/Wortt. overload hypertrophy,” Cardiovasc. Res. 22: 686-695 Primary Examiner-Rebecca Cook (1988). Attorney, Agent, or Firm-Senniger, Powers, Leavitt & Brilla, C. G., et al., “Remodeling of the rat right and left Roedel ventricle in experimental hypertension," Circ. Res, 67: 1355-1364 (1990). (57) ABSTRACT Weber, K. T., et al., "Structural remodeling of myocardial This invention discloses a method of using an aldosterone collagen in systemic hypertension: functional consequences antagonist such as spironolactone, at a dosage which does and potential therapy.' Heart Failure 6: 129-137 (1990). not disrupt a patient's normal electrolyte and water-retention Weber, K.T., et al., “Myocardial remodeling and pathologic balance, to inhibit myocardial fibrosis, including left ven hypertrophy.” Hospital Practice 26(4): 73–80 (1991). tricular hypertrophy (LVH). Andreoli, T. E., "Introduction: Modern aspects of congestive heart failure.” Hospital Practice 26(4): 7-8 (1991). 4 Claims, No Drawings 5,529,992 1 2 METHOD FOR NHIBITING MYOCARDIAL sure). In patients with edema or hypertension, an excess of FBROSS BY ADMINISTERNG AN ALDO promotes salt and water retention and potassium ALDOSTERONE ANTAGONST WHCH loss, which are detrimental. Certain drugs, most notably SUPPRESSES ALDOSTER ONE RECEPTORS spironolactone (discussed below), can be used to suppress activity of elevated circulating ALDO, or to suppress the GOVERNMENT SUPPORT synthesis of ALDO. This invention was supported in part by grant R01-31701 ALDO secretion is influenced by various signals involv from the National Institutes of Health. Accordingly, the ing adrenocorticotropin hormone (ACTH), melanocyte federal government has certain rights in this invention. stimulating hormone, atrial natriuretic peptide, and plasma 10 concentrations of sodium and potassium, and by a multi-step RELATED APPLICATION pathway called the renin-angiotensin-aldosterone (RAA) system. In response to certain signals which indicate low This application is a continuation-in-part of U.S. patent blood pressure, the kidneys secrete renin, which cleaves a application Ser. No. 07/871,390, filed on Apr. 21, 1992 precursor peptide called angiotensinogen to release a peptide abandoned. 5 having ten amino acid residues, called angiotensin I. This peptide is cleaved by another enzyme called angiotensin BACKGROUND OF THE INVENTION converting enzyme (ACE) to generate angiotensin II, which This invention relates to drugs such as spironolactone has eight amino acid residues. In addition to being a potent which block the activity of the hormone aldosterone, and to vasoconstrictor (which increases blood pressure), angio the use of aldosterone-blocking drugs to prevent or treat 20 tensin II functions as a hormone to stimulate the release of myocardial fibrosis, a disease condition. ALDO by zona glomerulosa cells in the adrenal cortex. The In a medical context, fibrosis refers the creation offibrotic RAA system is described in more detail in articles such as tissue (i.e., tissue characterized by an abnormally high Weber and Brilla 1991 (full citations are provided below). quantity of fibrous material, primarily strands of collagen). 25 ALDO receptors (also called mineralocorticoid receptors In some situations, fibrosis is useful and necessary, such as (MCR or MinR, or mineralosteroid receptors) are proteins in the healing of wounds, but in other situations, fibrosis can that initially reside in the cytoplasm of certain types of cells, such as smooth muscle cells and fibroblasts in the aorta (see, be harmful, especially when it interferes with the function e.g., Meyer and Nichols 1981). When an ALDO receptor is ing of internal organs. As one example, liver cirrhosis is activated by ALDO, the receptor/ALDO complex (or least usually characterized by high levels of fibrosis. That con 30 some portion thereof) is transported into the cell nucleus, dition, discussed in the above-cited parent application, Ser. where it binds to nuclear chromatin and presumably causes No. 07/871,390, is not directly relevant to this invention. an alteration in the transcription of genes that encode This invention relates to the use of mineralocorticoid proteins which are involved in the retention of sodium and antagonists (such as spironolactone) in inhibiting myocar water by the body (see, e.g., Kornel et al 1983). For more dial fibrosis. 35 information on ALDO receptors, see Agarwal and Lazar The correlation between mineralocorticoids and fibrosis 1991 and additional references cited therein. Chemical was not recognized prior to the work of the Applicant. methods of synthesizing aldosterone are described in articles However, a great deal was known about mineralocorticoids such as Barton et al 1975 and Miyano 1981. and about fibrosis, as separate fields in medicine and physi ology. Accordingly, the following sections provide back 40 ground information on each of those topics. Fibrosis Fibrosis (the generation of fibrotic tissue) is important in Mineralocorticoids a number of processes in adult mammals. In some processes, The adrenal glands, which sit on top of the kidneys in the 45 such as wound healing, fibrosis is highly beneficial and human body, are divided into two portions: the adrenal essential to survival. When one or more blood vessels, which medulla (which secretes epinephrine and norepinephrine), function as barriers to separate the intravascular and extra and the adrenal cortex. The adrenal cortex secretes a number cellular spaces, are cut or otherwise broken or disrupted, an of hormones known as corticoids, which are divided into orderly wound healing process is initiated. Certain types of two categories. Glucocorticoids (primarily hydrocortisone, 50 blood cells such as platelets release fibrinogen, plasminogen, also known as cortisol) exert their primary effects on the and fibronectin into the cellular interstitium; these molecules metabolism of glucose and other carbohydrates; they can react with other molecules to generate an extravascular also secondarily retard wound healing, by interfering with coagulation and the formation of a hydrophilic fibrin-fi inflammatory cell and fibrous tissue responses. The primary bronectingel. Various growth factors are believed to orches effects of mineralocorticoids (MC's) involve the retention of 55 trate the subsequent entry of immune and inflammatory cells certain minerals, particularly sodium, and the elimination of and fibroblasts into the gel and the formation of new blood potassium. vessels within its interstices. The most important and potent MC is aldosterone During the early stages, the gel is considered granuloma (ALDO); another naturally occurring MC which is less tous tissue. It is gradually resorbed and replaced by fibrous potent is deoxycorticosterone (DOC). If ALDO is present at 60 tissue. One of the important components of such tissue is abnormally high quantities (such as following hemorrhage,