Lessons from the Discovery of Modern Diuretic Therapy

LESSONS FROM THE DISCOVERY OF MODERN DIURETIC THERAPY* KARL H. BEYER, fR., M.D., Ph.DA I present here a few generalizations—I hesitate to call them principles—generalizations that have helped me in an ongoing career devoted to the designed discovery of new therapy. To give these comments some basis whereby you mayjudge their credibility, I have chosen to illustrate how they applied to our role in the development of modern diuretic therapy. The few generalizations I shall relate, four actually, did not arise de novo in my thinking nor were they as clearly evident at the time of inception as I should like to present them to you. They derive from an experience with the introspection of research leadership, of awareness of the relationship between fact and opinion that goes to make up what we use as knowledge, of observations on the way people and groups of people tend to think and work, of the impact of discernment on success. They evolved as inductions which, if true and applicable to the circumstance , might make the difference in the way toward accomplishment between "no way" and "somehow." They were among the useful bits of inductive reasoning that served to motivate and even to guide research productivity where the limits and use of knowledge were inadequate or may not have been applied adequately or appropriately. You may find that the generalizations or some of them are more familiar to you than the wondrous ways ofthe kidney to which they have been applied. On the other hand, there is not a statement among the four that is not controverted by common practice. There is not one of these to which you might not offer exception. ?This lecture was written while a scholar-in-residence at the John E. Fogarty International Center for Advanced Study in the Health Sciences, and was first presented at an assembly, on September 11, 1974, at the National Institutes of Health, Bethesda, Maryland . At the invitation of Dr. George Mandel and the Department of Pharmacology, the text as set forth herein was adapted for presentation as the Fourteenth Annual Paul K. Smith Lecture, George Washington University Medical Center, Washington, D.C., February 14, 1975. !Department of Pharmacology, Milton S. Hershey Medical Center, Pennsylvania State University, Hershey, Pennsylvania 17033. 500 J Karl H. Beyer, Jr. · Modern Diuretic Therapy In effect, then, we shall relate to the use of knowledge and how to work beyond the limits ofknowledge or the limits to which it would seem applicable. This is a favorite preoccupation of mine. None of us is very good at working beyond what seem to be the limits of knowledge. I suppose many scientists consider such meditation fanciful and a waste of time. On the other hand, such rumination has served me well. For instance , the first generalization. The more closely one can approximate under controlled laboratory conditions the physiological correlates ofclinically defined disease, the more likely he will be able to modulate it effectively. Without further amplification, this statement is bound to mean different things to many people. Hence, I shall draw on the example cited in the title of this paper in order to be more explicit. In the minds of most physicians and in Dorland, edema is the "presence of abnormally large amounts of fluid in the intercellular tissue spaces of the body." In the dictionary, there are 70 italicized qualifying terms for edema, only one of which mentions salt and that refers to edema caused by an increase of sodium chloride in the diet—rather an inadequate qualification at best. To go back a bit, fluid restriction and an occasional intramuscular injection of an organomercurial diuretic were standard therapy, along with digitalis or other rational drugs where indicated, long after I finished medical school. The pharmacologist's best efforts to advance the therapeutic relief of edema were no better founded, for unusally he measured the effect of a compound on the volume of urine a rat excreted in a given period of time after having been drenched with water—tap water. The stage really was not set for the discovery and development of modern diuretic therapy until the physiologist could define and quantify the...