Walter Modell

On the significance of significant

Clinical Pharmacology and Therapeutics (1981) 30, 1–2; doi:10.1038/clpt.1981.120

Clinical pharmacology of antianginal drugs.

The problem of examining and evaluating antianginal effects is explored. Special attention is paid to the mode of action of the nitrites, which form the mainstay of the modern treatment of angina of effort. Other pharmacologic features of these drugs are also examined. Prophylactic therapy is considered, and the improbability of developing an effective long‐acting nitrite is discussed. Other drugs and therapies are also considered: alcohol, sedatives and tranquilizers, khellin, xanthines, hormones, cholesterolytic agents, tissue extracts, anticoagulants, papaverine, and antithyroid drugs. The monamine oxidase inhibitors, the probable mode of their effect in angina, and their uses and dangers are considered in some detail.

Pharmacological Evidence for the Importance of Catecholamines in Cardiac Rhythmicity

Dogs with complete heart block were used to explore the dependence of the intrinsic rhythmicity of the heart on catecholamine activity. By the use of reserpine, hexamethonium, and surgical sympathectomy, it was demonstrated that, while reduction in catecholamine activity slows both the atrial and the ventricular rates, the ventricular pace maker was always affected to a greater degree. The effect of a combination of reserpine and hexamethonium on the ventricle was greater than when either agent was administered alone, suggesting that the greater the sympathetic blockade, the greater the depression in pacemaker rhythmicity. Since the course of its action on the heart paralleled that of catecholamine depletion, it seems probable that the effect of reserpine on rhythmicity was due to its catecholamine depleting action. It was thought unlikely that prolonged hypotension contributed to the reserpine action on the heart. It is indicated that disturbances in electrolyte balance and blood pH did not play a role in the effects observed.

Clinical pharmacology: A definition

This may seem like a late date for such a statement, but clinical pharmacology, the latest portfolio in medicine, suffers from the lack of an established and recognized definition; and what is even more distressing to clinical pharmacologists is that, even to those who use the term with some assurance, it often seems to mean different things. The reason for the confusion is not newness alone; the term itself is basically unclear and to a degree even inaccurate. It seems at once to imply such diverse aspects of drugs and their nature and application as applied pharmacology, clinical trials, therapeutics, drug screening, and pharmacology in the clinic (as against the animal laboratory) as well as human pharmacology and, of course, all the methodology involved. As a result in different hands it is used differently. Yet, despite the need to consolidate the subject, there are reasons for perpetuating a title which so early in its history already seems to be a misnomer. It has gained wide acceptance; to shift to a different and more precise but unrecognized term might result in a large step backward at a critical juncture when the need for progress in the discipline is urgent and at a time when the discipline has received its initial invitations to participate on an equal basis in modern medical society.

Clinical pharmacology of digitalis materials

The pharmacologic actions of digitalis which have been observed in the laboratory animal and in man are reviewed and correlated. It is shown how, in most instances, the findings in the former have a direct bearing on the application of digitalis materials in the clinic. An attempt is made to clarify some of the more poorly understood aspects of digitalis action.

Acute Toxicity of Mercurial Diuretics.

Conclusions (1) The admixture of theophylline with salyrgan reduces the toxicity of the latter as the result of some reaction between the two compounds inasmuch as aging is required before the changed toxicity is demonstrable. (2) This influence of theophylline did not apply to mercurin. (3) In terms of mercury, non-ionizable organic mercurials are not necessarily less toxic than mercuric chloride.

To protect the American patient

The wide array of medication available to the American patient is a tribute to modern science.

A full cycle of diuretics.

On the basis of what we know of the cornmon clinical forms of edema and their treatment, in most instances the effect of a diuretic is primarily homeostatic rather than excretory. The ultimate purpose of therapy is not only to res tore the size of the intercellular fluid compartment to its normal condition but more specifically to reduce the expanded stores of the fixed base, sodium, to normal. In accomplishing this, there are the homeostatic requirements that the anions excreted with the sodium be so proportioned that no specific anionic electrolyte or blood pR disturbance ensues and that the process be so highly particularized for the cation sodium that no other negative cation balance develops. However they accomplish it, effective diuretics induce a net sodium loss, the fluid loss being obligated by the process; the extent to which they approach the other requirements and the nature of other disturbances they induce vary widely. There seems to be a compulsion to compose variations on the theme of effective diuretics already available which apparently derives from presumptions that there is need for greater natriuretic potency as well as for diuretics which cause less disturbance of other anion and cation relationships than those now in use. Beyond this, there is always the goal of developing a diuretic with no undesirable effects at all. This has resulted in the creation of a pride in new diuretics. It is interesting to examine how closely developments in diuretics during the past 40 or 50 years have approached these putative improvements. To those suffering from edema, the simplest means of inducing diuresis-the elimination of sodium from the diet to a degree which leads to effective negative sodium balance, e.g., the Karell diet-also appears to be the least acceptable of aIl possibilities. Although this procedure is Iess likely than most others to lead to homeostatic difficulties, it lacks potency. But it works and, if pursued, is sometimes eminently satisfactory. The major difficulty with it is that it is untolerable to the modern jaded palate. A modification in the direction of satiating the demand for a salty taste while removing the salt from the food ingested through the use of cation exchange res ins has been rejected after hopeful trial because of other gastrointestinal difficulties. It thus appears at the very outset that in the therapeutic approach to a negative so-

Report of the subcommittee on position and status of the clinical pharmacologist in drug research

The new F. D. A. regulations direct attention to the clinical pharmacologist and have suddenly created a broad demand for his services. Yet there is no clear‐cut de:6.nition of a clinical pharmacologist or of clinical pharmacology; there are no generally accepted standards for the education and training of clinical pharmacologists and, though a journal with such a title is now in its fourth annual volume, there exists no collected body of literature or any textbook. If only for the legal considerations, an authoritative statement on the meaning and scope of clinical pharmacology is urgently needed. Since an important public function is involved, this subcommittee puts forward the statement which follows in the hope it will lead to the establishment of appropriately high standards for clinical pharmacology and clinical pharmacologists.

Treatment of Nutritional Disturbances

The term nutrition has much broader implications than is generally appreciated. It implies not only the eating of foods, minerals, vitamins and the like, but also the food’s conversion into materials which the body can use. Finally, nutrition implies the way in which the body uses the material it digests to maintain growth, replacement, activity and good health. This includes, therefore, not only digestive processes in the intestine, but also metabolic processes all over the body, chemical and physical processes which are involved in maintaining the various physiologic activities of the organs and tissues of the body, and its constancy, or to use the presently more fashionable term, homeostasis. Nutritional diseases may be divided into dietary, electrolyte and metabolic disturbances.