J. Murray Steele

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.

Simultaneous flux of sodium into and out of the dog intestine

The simultaneous unidirectional flow of sodium into and out of isolated loops of jejunum, ileum and colon of the dog, has been measured, in vivo . Four loops of bowel observed over a 5-year period did not degenerate physiologically or histologically. The variability of sodium flux, measured repeatedly over the five years, was no greater in experiments conducted 1 day apart than in those conducted over a period of years. Adrenalectomy did not reduce this inherent variability. Moderate salt loading by intravenous administration, or by dietary intake, did not alter the transfer rates of sodium across the intestine. Approximately 1 ml of water was transferred into and out of a 20-cm length of intestine/min. Sodium concentration was usually maintained at 144 mEq/l. in the lumen of the small intestine, while sodium concentration in the lumen of the large intestine usually decreased to be partially replaced by potassium. It is suggested that the rates of sodium flow across the dog intestine, in vivo , are of the same order of magnitude per unit surface area as those of sodium flux across amphibian tissues, in vitro . While water may enter the amphibian tissue 50 times as fast as sodium, water and sodium traverse the dog intestine in the ratio of their free diffusion coefficients, water moving twice as fast as sodium.

Observations on G-25671, A Phenylbutazone Analogue (4-(phenylthioethyl) −1,2-diphenyl 3,5-pyrazolidinedione).∗:

Summary and Conclusions 1. Observations were made on the physiological behavior of a compound in which the butyl side chain of phenylbutazone was replaced by a phenyl-thioethyl group. 2. Rate of biotransformation of this compound in man was greatly accelerated, with a biologic half life of only 3 hours compared to 70 hours for phenylbutazone. Such rapid disappearance might have some advantage in minimizing toxic manifestations but would pose the problem of maintaining therapeutic levels since the drug would have to be given at relatively frequent levels. 3. Like phenylbutazone, G-25671 exerted distinct antirheumatic effects but produced little or no sodium retention and consequently no hemodilution. These observations show that the antirheumatic and sodium-retaining properties in the phenylbutazone series may be dissociated. 4. The drug has a more marked uricosuric effect than phenylbutazone.

Abnormalities of the Urinary Tract in “Essential Hypertension.”

Summary Abnormalities of the urinary tract, as demonstrated in pyelograms obtained after intravenous injection of diodrast are frequently present in young persons suffering from “essential hypertension.” In 50 of 71 patients some abnormality was present. Under these circumstances it seems desirable to explore further the meaning of these phenomena.

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

Effect of Partial Clamping of Aorta in Dogs upon Diastolic Pressure in Carotid and Femoral Arteries

Summary Clamping the aorta above the orifices of the renal artery in dogs is followed by elevation of the diastolic level of arterial pressure in the hind legs as well as in the carotid arteries. Constriction of the peripheral arterioles is, therefore, a general phenomenon, just as when it follows partial clamping of the renal arteries. The hypertension which develops in coarctation of the aorta in man is on this evidence analogous to that which accompanies constriction of the renal arteries. The evidence suggests strongly that interference with the hemodynamics of the renal circulation leads to hypertension in man as well as in animals.