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THE STEROIDAL ACTIONS OF DIGITALIS EDWARD B. Le WINN* William Withering's reintroduction of digitalis to medicine in 1785 marked the first time in the long history of diat drug diat it was shown unequivocally to be of value in the treatment of a specific clinical problem , namely, "die dropsy" [I]. In order to temper the reputation as a treacherous and dangerous medicine which digitalis had acquired through centuries ofabuse, Withering, in the section onEffects, Rules and Cautions of his classic, An Account of the Foxglove, wrote, "Let the medicine [digitalis] . . . be continued until it either acts on Ike kidneys, the stomach, the pulse, or the boweL·; let it be stopped upon thefirst appearance ofany one ofthese effects, and I will maintain diat the patient will not suffer from its exhibition , nor the practitioner be disappointed in any reasonable expectation" (Withering's emphasis). In time diis cautionary note became generally heeded, and it was the accepted practice to prescribe digitalis in courses lasting at most only a week or two at a time. It was not until some 60 years ago that this practice was abandoned in favor of continuous administration over longer periods [2]. It was probably for this reason diat 165 years were to elapse from Withering's account ofthe foxglove to first reports in 1950 [3] and 1953 [4] suggesting that the pharmacodynamics of digitalis include a steroidal action, namely, gynecomastia, elicited clinically during relatively long-term use (months or years), in addition to and in contrast with its long-known cardiotonic effects, which may appear within hours or days. In the 3 decades since the first reports of the steroidal behavior of digitalis [3, 4], sufficient additional information concerning the clinical and laboratory aspects of the effects has been acquired to engage the attention not only of the cardiologist and pharmacologist but of the gynecologist, endocrinologist, urologist, surgeon, oncologist, and Work supported by funds from the Institutes for the Achievement of Human Potential, Philadelphia, Pennsylvania.»Senior attending physician, medicine, emeritus, Albert Einstein Medical Center, Philadelphia, Pennsylvania. Address: Box 439, Upper Black Eddy, Pennsylvania 18972.© 1984 by The University of Chicago. All rights reserved. 0031-5982/84/2702-0380101.00 Perspectives in Biology and Mediane, 27, 2 ¦ Winter 1984 | 183 pathologist as well. A review of the developments on which diis information is based may be ofvalue to these and odier areas ofmedicine. Structural Characteristics ofDigitalis Digitalis, primarily a horticultural term, has in recent years acquired a specific pharmacological meaning, referring to any steroid or steroidglycoside compound that exerts a typical, positive, inotropic, and electrophysiological effect on die heart [5, pp. 945-952]. More than 300 such substances are known to exist in nature, occurring mostly in a wide variety of herbs, flowers, shrubs, and trees but also in the animal kingdom , notably in the skin of the common toad. All digitalis glycosides combine three components: (1) a steroid nucleus to which is attached, at the Cl 7 position, (2) an unsaturated five- or six-member lactone ring, and (3), at the C3 position, a chain of one or more monosaccharide molecules (fig. 1). Chen and Henderson [6] concluded from their study of the pharmacology of 64 cardiac glycosides and aglycones that, although one could not expect complete correlation of structure with biologic behavior , the importance of the spatial arrangements in the molecules ofdiese substances was demonstrated repeatedly. The structural arrangements in some glycosides and aglycones endow them not only with cardiotonic and apparently steroidal but also with convulsive capabilities. It is noteworthy that similar specific relationships exist in the various structural features and the physiological actions of the steroidal hormones , whether those of the glucocorticoids, the mineralocorticQids, or the sex hormones, which have in common with the cardiac glycosides essentially the same steroid nucleus. It is these specific structural relationships that endow each steroidal hormone and each cardiac glycoside with its special biological characteristics. THE STEROID NUCLEUS Through their steroid portion the glycosides are chemically related to cholesterol, bile acids, sterols, and the sex and adrenocortical hormones. The steroid moiety consists of a cyclopentanoperhydrophanthrene nucleus with its C and D rings in the eis or "chair-shaped" configuration. This arrangement is one of the characteristics contributing...


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