The 45-year story of the development of an anti-aldosterone more specific than spironolactone.

Abstract

At the early stage of its development in 1957, the daily dose of spironolactone necessary to improve various pathological conditions was not precisely determined and dose-dependent sexual side effects limited its long-term use. Prescription of high daily doses and absence of selectivity for the mineralocorticoid receptor explain these limitations. The 9-11alpha epoxy group added to mexrenone by the Ciba-Geigy chemists in 1984 and improved chemical synthesis at Searle, permitted the original international clinical development of a selective antagonist for high blood pressure and congestive heart failure treatment. This review deals with the main methodological issues of a 20-year biological and clinical development of eplerenone, the second antimineralocorticoid drug. The investigation of a large range of daily doses (25-400mg) initially selected in normal volunteers by the 9alpha-fluorohydrocortisone test has led to the conclusion that 50-100mg q.i.d. doses of eplerenone offer a favorable benefit/risk ratio in various patient populations by neutralization of the aldosterone effects on blood pressure and target organ damage. The absence of sexual side-effects has confirmed the clinical relevance of the initial biological hypothesis on the need for more selectivity at the androgen and progestogen receptor sites. Widening the distance between efficacy and adverse effects of an anti-mineralocorticoid drug will facilitate the long-term maintenance of a moderately negative sodium balance and a slightly positive potassium balance, while minimizing the direct effects of salt and aldosterone on the heart, vessels, brain, and kidneys. Wide use in unselected patients and additional controlled clinical trials are necessary to confirm the benefits expected from animal and clinical research given that a 45-year interval also characterizes the story of the Na-Cl cotransporter (NCC) blocker, chlorthalidone, from its initial clinical use to the demonstration of its beneficial effects on cardiovascular morbidity and mortality.

• Authors: Joël Ménard
• Journal: Molecular and cellular endocrinology (Mol Cell Endocrinol) Vol. 217 Issue 1-2 Pg. 45-52 (Mar 31 2004) ISSN: 0303-7207 [Print] Ireland
• PMID: 15134800 (Publication Type: Historical Article, Journal Article)

Chemical References

• Antihypertensive Agents
• Mineralocorticoid Receptor Antagonists
• Receptors, Mineralocorticoid
• Spironolactone
• SC 25152
• Chlorthalidone

Topics

• Antihypertensive Agents (adverse effects, chemical synthesis, history, pharmacology)
• Cardiovascular Diseases (drug therapy, metabolism, mortality)
• Chlorthalidone (history, pharmacology)
• Clinical Trials as Topic
• Erectile Dysfunction (chemically induced)
• Female
• Gynecomastia (chemically induced)
• History, 20th Century
• Humans
• Male
• Mineralocorticoid Receptor Antagonists (chemical synthesis, history, pharmacology)
• Pain (chemically induced)
• Receptors, Mineralocorticoid (metabolism)
• Spironolactone (analogs & derivatives, chemical synthesis, history, pharmacology)