Evaluating and Reevaluating Drugs

EVALUATING AND REEVALUATING DRUGS MARTIN A. RIZACK* Throw out opium, which tL· creator himselfseems to prescribe; for we see the scarlet poppy growing in tL· cornfields, as if it wereforeseen that wherever there is hunger to befed there must be pain to be sooûied; throw out afew specifics which our art did not discover and is hardly needed to apply; throw out wine, which is afood, and the vapors which produce tL· miracle of anesthesia, and Ifirmly believe that if tL· whole materia medica, as now used, could be sunk to tL· bottom of tL· sea, it would be all the betterfor mankind—and all the worsefor thefisL·s. The above quotation, from Oliver Wendell Holmes's address to the Massachusetts Medical Society on May 30, 1860, emphasizes the constant need for réévaluation in therapeutics. Opium, probably overused and increasingly abused by generations following Holmes, has come into disuse in our time, even for patients in severe pain who would derive far greater benefit from it than the many imitations currently in vogue. Of Holmes's specifics, digitalis was most important and stood alone as the treatment for congestive heart failure. With the advent of potent diuretics , digitalis is often prescribed when not required or in the face of potassium deficiency; essential fine adjustments in dosage tend to be neglected. The net result is frequently the extremes of underdigitalization and toxicity. Osier, in the first edition of his Principles and Practice ofMedicine, published in 1892, considered as specifics—other than digitalis and opium— only mercury for syphilis, iron for anemia, quinine for malaria, and iodine for some forms of goiter [1, p. 14]. Of these, all but mercury are still important to some degree. Although specifics have appeared in large numbers since, the need for pruning the pharmacopoeia still remains . When a new drug appears, what does the practitioner need to know?»The Rockefeller University, 1230 York Avenue, New York, New York 10021.© 1987 by The University of Chicago. AU rights reserved. 0031-5982/87/3004-0534$01.00 Perspectives in Biology and Medicine, 30, 4 ¦ Summer 1987 \ 581 The first consideration is its safety. Once this is established, one has to know whether the agent has unusual properties filling a special therapeutic niche and displacing other drugs available for the same indication , or whether there are merely minor changes in the properties ofthe new drug that will make it useful only in special situations. Let me discuss a few examples gleaned from my experience as an editor of The Medical Letter. First, let me discuss desmopressin, an analog of the antidiuretic hormone arginine vasopressin. Two changes were made in the structure of the natural hormone: a d-arginine was substituted for an 1-arginine, largely eliminating pressor effects, and an amino group was eliminated, increasing antidiuretic activity and decreasing the affinity of the hormone for degradative enzymes, thereby increasing duration of action [2]. The net result was a long-acting drug with minimal adverse effects, clearly superior to the natural hormone [S]. The benefits of L-DOPA in Parkinson's disease far outweigh any adverse effects, and the drug is clearly superior to anticholinergics. The benefits diminish with time, however; whether this is because the disease progresses or because there is a loss of response to the drug is not clear. Whether the use of L-DOPA should be postponed and the less effective anticholinergics used initially is controversial [4]. The availability of the dopaminergic ergot alkali analogs, which are most effective when used with L-DOPA, provides an alternate approach to the problem [5]. Captopril was another innovative development that opened a new and promising approach to the treatment of hypertension. The drug was designed to occupy the active site of the angiotensin converting enzyme but cannot be split and therefore acts as an inhibitor [6]. Although effective, Captopril causes serious adverse effects: agranulocytosis and membranous nephritis. The incidence of about 1.5 percent is appreciable , although some of it may be due to aggravation of previously existing disease. This drug is clearly indicated for patients with severe hypertension unresponsive to other agents [7]. At lower dosage than used initially , it appears that it can be...