Murray Weiner

Observations on the antirheumatic and physiologic effects of phenylbutazone (butazolidin) and some comparisons with cortisone

Abstract 1. 1. Phenylbutazone exhibits antirheumatic effects in rheumatoid arthritis which are comparable to those shown by cortisone and corticotropin. 2. 2. Like cortisone and corticotropin the drug causes urinary retention of sodium, chloride and water, and may reactivate peptic ulcers; but unlike cortisone it does not affect the excretion of potassium nor does it cause eosinopenia or increased ketosteroid excretion. It is concluded that the action of phenylbutazone is not mediated, directly or indirectly, through the adrenal cortex. 3. 3. During phenylbutazone therapy there is often a fall in red cell count, hemoglobin and hematocrit which is primarily the result of hemodilution and not of depression of the hematopoietic system. 4. 4. Plasma levels of phenylbutazone approach a limiting concentration as dosage is increased. This limiting concentration varies widely from patient to patient. Most subjects achieve plasma levels on 400 to 600 mg. daily that are only slightly lower than when 800 mg. are given.

Time-dependent changes in the density and hemoglobin F content of biotin-labeled sickle cells.

Sickle red blood cells (RBC) are subject to a number of important cellular changes and selection pressures. In this study, we validated a biotin RBC label by comparison to the standard 51Cr label, and used it to study changes that occur in sickle cells as they age. Sickle RBC had a much shorter lifespan than normal RBC, but the two labels gave equivalent results for each cell type. A variable number of sickle, but not normal, RBC disappeared from the circulation during the first few hours after reinfusion. The number of biotinylated sickle reticulocytes was decreased by 50% after 24 h and 75% after 48 h, with a gradual decrease in the amount of reticulum per cell. The labeled sickle cells exhibited major density increases during the first 4-6 d after reinfusion, with smaller changes thereafter. A small population of very light, labeled sickle RBC was essentially constant in number after the first few days. Fetal hemoglobin (HbF) content was determined in isolated biotinylated sickle RBC after reinfusion, allowing an estimate of lifespan for RBC containing HbF (F cells) and non-F cells. The lifespan of sickle biotinylated RBC lacking HbF was estimated to be approximately 2 wk, whereas F cells survived 6-8 wk.

Incorporation of inositol hexaphosphate into red blood cells mediated by dimethyl sulfoxide

Inositol hexaphosphate (IHP) binds to deoxyhemoglobin and markedly decreases the affinity of hemoglobin for oxygen. We introduce here a method for incorporating this polyphosphate into erythrocytes, thus preparing very low affinity cells for use in respiration research. The method uses dimethyl sulfoxide (DMSO) to facilitate entry of IHP. The cells are exposed to a high concentration of DMSO which is rapidly diluted with IHP solution. During this dilution the cells become leaky and IHP enters. The influence of several variables at each step of the process has been investigated and the data support a transient osmotic gradient mechanism for IHP incorporation.

Effect of Centrally Active Drugs on the Action of Coumarin Anticoagulants

PREVIOUS investigations have shown that pretreatment with barbiturates reduces the prothrombin response to coumarin anticoagulants, presumably by stimulating the metabolic breakdown of the coumarin drugs1. Hrdina, who was interested in the effect of centrally active drugs on the response to anticoagulants, confirmed this effect of barbiturates2. On the other hand, compounds of the morphine type were found to enhance the response to coumarins (Hrdina, personal communication), and to inhibit enzymes which metabolize drugs in the liver3. The present experiments were designed to determine whether tranquillizers or antidepressants exert an effect on the coumarin response which might correlate with the nature of their central effects.

A simply prepared, standardized, and relatively stable thromboplastin extract for estimation of prothrombin time

Abstract A standardized preparation of thromboplastin which becomes ready for use after the addition of only distilled water and which is reliable and of optimum sensitivity is described. It is believed that this should add considerably to the safety of Dicumarol therapy, so that the goal of adequate therapeutic effect with minimum danger of hemorrhage can be achieved.

The control of prothrombin activity with tromexan therapy

D IFFICULTIES in the control of the hypothrombinemic effect of dicumarol@ in the treatment of thromboembolic diseases have led to the investigation of other coumarin derivatives. With one of these, tromexan@)t (3,3’-carboxymethylenbis [4-hydroxycoumarin] ethyl ester), the therapeutic effects take place more rapidly after administration of the drug and disappear more rapidly after discontinuance of the drug than is the case with dicumarol. These characteristics of tromexan are potential advantages in that they might be expected to permit more predictable control of induced hypoprothrombinemia. There was some confirmation of the early expectations1-5 but this has not been borne out in later studies.6*7 Previous works indicates that tromexan is rapidly and completely absorbed from the gastrointestinal tract, compared to the slow and sometimes incomplete absorption of dicumarol. Its biotransformation is rapid, the plasma concentration falling at an average rate of 25 per cent per hour, compared to dicumarol which falls at an average rate of about 40 per cent per day.g As with dicumarol the rate of metabolic transformation of tromexan varies widely in different subjects. The rapid disappearance of tromexan from the body is accompanied with a rapid return of the prothrombin time to pretreatment levels on discontinuing therapy. After a single dose the drug has almost disappeared from the body before the prothrombin response becomes evident, eight to twelve hours after drug administration.1 Single daily doses of the drug