Murray Weiner

Influence of Some Vasoactive Drugs on Fibrinolytic Activity

The phenomenon of fibrinolysis in thromboembolic disease is of great importance. In this communication the authors present striking evidence of fibrinolysis induced by drugs.

Pharmacological Considerations of Antithrombotic Therapy

Publisher Summary This chapter discusses the pharmacological considerations of antithrombtic therapy. The primary purpose of anticoagulant therapy is the prevention of thromboembolic phenomena without causing hemorrhage, and altered coagulability is a means to this end, and not an end in itself. Thrombosis need not occur the moment coagulability increases, and hemorrhage is not necessarily the immediate result of excessively reduced coagulability. An understanding of the physiologic disposition of antithrombotic agents is fundamental to the interpretation of the pattern of altered coagulability that they induce. Numerous factors contribute to the wide range of response to the administration of an anticoagulant: (1) the initial status of coagulability, (2) status of the mechanisms responsible for the formation and dissipation of clotting factors, (3) the physiologic disposition of the drug, (4) sensitivity of the clotting mechanisms involved to the drug, (5) presence of other chemical or physical agents that influence coagulability or the fate of the anticoagulant, and (6) status of the vascular bed.

Effect of Steroids on Disposition of Oxyphenbutazone in Man.

Summary The anabolic steroid methan-drostenolone causes an elevation in oxyphen-butazone plasma levels in man. The elevation is not due to a slowed rate of metabolism, but to an altered distribution between plasma and tissues. The glucocorticoids, prednisone and dexamethasone, do not influence the blood levels of oxyphenbutazone.

PULMONARY EMBOLISM: ITS INCIDENCE AT NECROPSY IN RELATION TO PERIPHERAL THROMBOSIS

Excerpt The most dangerous complication of venous thrombosis is pulmonary embolism, with its mortality of about 20 per cent.1Such embolism has been reported by Barnes3to be responsible for 34,000 d...

An evaluation of methods of dicumarol administration

Abstract The physiological disposition of Dicumarol by the body is reviewed and its relationship to methods of Dicumarol dosage is discussed. An illustrative case in which Dicumarol was given by both the continuous (daily) and the intermittent dosage methods is presented. The case illustrates: (1) the relationship of prothrombin response to plasma Dicumarol concentration; (2) the difficulty of recognizing promptly when a given daily dose of Dicumarol is inadequate; (3) the danger of undetected accumulation of daily doses to excessively high plasma Dicumarol concentrations; (4) the importance of knowing not only what the prothrombin time is at the moment, but also the direction in which it is changing; and (5) the better control of prothrombin response afforded by the intermittent dosage method.

The influence of the physiologic disposition of chelates on their use in medicine.

Most drugs in use today have come to the attention of the physician by way of empirical observations or chemical analogy with known active compounds. It is, however, more satisfying to the research worker to predict the potential usefulness of an untested class of compounds by a knowledge of their physicochemical properties. The chelates are such compounds. Of course, in the last analysis, the method that requires the least intelligence but is ultimately the most trustworthy, namely, trial-and-error, must be employed to determine the true worth of a chemical agent in clinical medicine. The concept of chelation, which has been developed from careful physicochemical studies of relatively controlled systems, need not be reviewed here. We propose to limit ourselves to a discussion of some N-carboxy chelates and to review the fate of these agents in the body, with a view to correlating their physicochemical properties and physiologic disposition with their potential therapeutic value. Chelate action in the living organism cannot always be explained by the simple assumption that a metal vital to some important enzyme system is removed by the agent. One need only cite the remarkable observation that adding ethylenediaminetetraacetic acid (EDTA) to an enzyme-free system of iron-ascorbic acid markedly speeds up the p-hydroxylation of many aromatic compounds, an effect which one might expect to require the presence of an iron-dependent natural enzyme. Since so many of life’s processes are fundamentally enzymatic, and since enzymes may be considered substances that alter the dynamics and specificity of relatively simple spontaneous chemical reactions involving metals and organic compounds, it is no surprise that agents that can bind and alter the disposition of metals may be considered for an extremely wide variety of uses. In fact, there have been reports on the possible application of N-carboxy chelates to almost every basic type of disease to which man falls victim. There are literature references to the application of the chelate concept to problems of allergy, cancer, infection, poisoning, degenerative diseases, inflammatory diseases, errors in metabolism, deficiency diseases-in fact, every chapter heading found in a standard textbook of medicine. Fundamental to all these potential uses of chelates is an understanding of what happens to them and to the metals they influence in the body.

The Effect of Glucagon and Insulin on the Prothrombin Response to Coumarin Anticoagulants

Discussion and Summary The response to drugs such as the coumarin anticoagulants may be altered by factors which either affect the physiologic disposition of the drug, or the site at which the drug acts. Clues as to the nature of the drug action may be obtained by studying the factors which influence sensitivity to the drugs without altering the fate of the drug. The effect of Vitamin K in blocking the action of coumarin anticoagulants is well documented, and is not correlated with changes in the physiologic disposition of coumarins as reflected in plasma levels of the drug. In contrast, the effect of barbiturates is mediated through altered disposition of the coumarins (1,4). The tranquilizers chlorpromazine and reserpine exaggerate prothrombin response while not influencing plasma levels of the coumarin drug. This effect may be correlated with the action of these agents on NAD synthesis (5). The mechanism by which starvation causes an exaggerated response to coumarins is not known. Elements of protein origin are probably involved (2). The finding of a similar effect by glucagon suggests that the metabolic fate of tyrosine and/or tryptophan may be important to prothrombin synthesis. The fact that saline diluted plasma demonstrates the glucagon effect at least as well as undiluted plasma indicates an exaggerated prothrombin deficiency rather than a superimposed heparin-like effect. The observation that insulin has no detectable effect on sensitivity to acenocoumarin, but can block the sensitizing effect of glucagon may have clinical significance in helping to explain the “unpredictable” manner in which sensitivity to anticoagulants may be altered by an agent under one set of conditions, and not under another. It remains to be determined whether the effect of starvation on sensitivity to coumarin anticoagulants is mediated through a stimulation of endogenous glucagon production during starvation.

An Evaluation of a New Anticoagulant, Acenocoumarin (Sintrom)

A new coumarin anticoagulant, acenocoumarin (Sintrom) is compared with other hypoprothrombinemic agents in the same human subjects. Comparing doses which result in the same peak prothrombin time, both speed of onset and duration of effect are found to be a function of the rate of biotransformation. Rapid biotransformation results in fast onset and short duration of action and vice versa. Sintrom is intermediate between the slow, long-acting compounds (Dicumarol, Warfarin, Coumopyrin) and the fast, short-acting Tromexan. One 16 to 32 mg. dose of Sintrom rapidly results in a desirable hypoprothrombinemia which is maintained by a single daily dose of 2 to 10 mg.

Transitory variations in serum prothrombin activity.

When blood clots in the test tube, only a portio of the prothrombin is consumed. The amount of prothrombin activity remaining in the serum has recently been shown to have considerable clinical significance(1). Deficiencies in the the anti-hemophilic globulin (thromboplatinogen) or the platelet-tissue thromboplastic enzyme result in less consumption of prothrombin and consequently more residual serum prothrombin activity. Quick (1) has demonstrated that serum prothrombin activity can be estimated by using deprothrombinized plasma as a source of fibrinogen. His data indicate that incubation of the whole clot may alter serum prothrombin activity quite differently from similar incubation of the separated serum. This fact is probably responsible for much of the difficulties and multipliticy of technics suggested for the estimation of prothrombin consumption(3). Quick suggests that prothrombin consumption be determined by incubating 3 aliquots of blood for various time intervals before separation of the serum and doing 7 estimations of prothrombin activity of these 3 sera after various periods of further incubation. This paper presents data describing serially the pattern of serum prothrombin activity following varying periods of incubation before and after separation of the serum from the clot. These data are sought in order to determine the conditions which will best reflect the prothrombin-consuming property of a specimen of blood. Knowledge of these conditions may make it possible to estimate prothrombin consumption reliably and reproducibly by a single determination on one aliquot of blood. Data are also presented on the use of fibrinogen in place of “prothrombin-free” rebbit plasma for determining serum prothrombin activity. A standardized, dry preparation containing fibrinogen, thromboplastin, CaCI2, and NaCI in optimal amounts is employed.∗ The preparation is free from prothrombin, oxalate, and citrate(2) and is stable at 5° for at least several months. The authors wish to thank Dr. R. Kroc and E. White of Chilcott Labrotaries, Morris Plains, N. J., for preparing this reagent.

Factors Influencing the Clinical use of Chelates in Iron Storage Disease

Introduction Many sufferers of Cooleys anemia owe their survival to repeated blood transfusions. One important complication of such therapy relates to the parenteral introduction of quantities of iron which exceed the bodys excretion mechanism, resulting in abnormal stores of the metal. Elimination of excess iron by the simple expedient of phlebotomy is, of course, not possible in these severely anemic patients. I t is therefore necessary to seek some means of augmenting the bodys meager metal excreting capacity. Heavy metals, including iron, exist in physiologic material almost wholly in the form of colloidal complexes. There are considerable differences in the stability of these various complexes. Many are insoluble tissue components, and those capable of being carried in body fluids are not subject to renal or other excretion. Thus, the daily body loss of iron rarely exceeds one mg., although the body pool is about 4,000 mg. normally, and considerably more in iron storage diseases. Normally, the body content of essential heavy metals such as iron is controlled by selective absorption. Of the polyvalent metals only calcium and magnesium are known to be readily excreted in urine, and not primarily dependent on limited absorption to control balance. Increased iron stores built up by parenteral administration or absorption dysfunction can be eliminated by enhanced excretion, only if special measures are taken to alter the bound state of the metal. This is the clinical objective of the therapeutic use of chelating agents. The ideal chelating agent for this clinical purpose would be a nontoxic substance which would form a stable, water soluble iron complex which can be readily excreted. It should be able to reach the abnormal iron stores, and succeed in competitive binding only with the iron in those stores and not with iron in essential systems such as hemoglobin or cytochrome. Fortunately, these properties are now being approached by some of the currently available N-carboxy chelates. One of the most popular of these substances, EDTA, has the desired solubility and renal excretion properties, but under in vivo conditions, has little success in competing with natural iron binding substances. A related chelating agent, DTPA, is considerably more effective than EDTA in removing iron from some storage disease patients, but not from normal subjects. In order to relate this fact to some physical-chemical characteristics, it is first necessary to review