Theodore Greiner

Human assay of three new mercurial diuretic agents; a promising preparation for oral use.

Conclusions Three organic mercurial preparations possessing diuretic activity were assayed by the oral route against the Standard, mercuhydrin solution given intramuscularly, in patients with congestive failure. Of the three materials, the 3-chloro-mercuri-2-methoxy propylurea proved to be the most effective, producing with oral doses a diuretic response equivalent to results obtained by the conventional doses of intramuscular mercuhydrin. The diuretic potency of this compound when given orally is somewhat more than one-fourth of its potency by intramuscular injection, and by the latter route 4.3 times (in milligrams) as potent as intramuscular mercuhydrin. We are not aware of any mercurial diuretic with such a favorable ratio of intramuscular to oral potency, namely 4:1. In the case of the thiol compound we tested in this study, the ratio was 11.1. In another study(7) in which mercuhydrin was tested by the intramuscular and oral routes, this ratio was 24:1. There still remains the problem of gastrointestinal irritation. By the method employed in the bioassay, it was necessary to give the total dose at one time, in the case of the larger doses as many as 9 tablets. This, therefore, subjected the local irritant action to a rigorous test. As the results stand, it appears that approximately one-half of the population with congestive heart failure might be able to tolerate by the oral route doses of this compound which produce highly effective diuretic responses. This is as far as the investigation in clinical pharmacology has carried the problem. It is now necessary to establish the most satisfactory dosage plans for the use of this material by the oral route. If approximately one-half of the population can tolerate as many as 9 tablets given at one time without gastrointestinal distress, it may well turn out that by dividing this amount into several fractions taken at intervals during the day, satisfactory diuretic effects may be obtained with less interference from gastrointestinal symptoms. The protracted use of the material over periods of weeks and months may disclose other problems which are not revealed by the single dose bioassay method. It remains for clinical trials to decide these matters.

Intramuscular Administration of Digoxin in Propylene Glycol.

Summary Digoxin in 40% propylene glycol and 10% ethanol was injected intramuscularly in 7 patients with auricular fibrillation. Its full cardiac effect was reached in 8 hours, while intravenous digoxin in the same patients reached full effect in 2 hours. Intensity and persistence of action were the same for both routes. Additional intramuscular injections in 26 patients revealed pain but no permanent tissue damage.

A method for evaluation of laxative habits in human subjects

Abstract 1. 1. A method is described for detecting laxative action in normal human subjects and for measuring the potency of laxative agents in constipated patients. 2. 2. Since the subjects record all observations on a daily report card, one physician can apply the method, retaining most of the advantages of the “double-blind” test. Dosage is constant over 1- or 2-week intervals. 3. 3. Both frequency and consistency of stool are measured, for the correlation between these two responses is only +0.5. The subjective categorical judgments of consistency are converted to a single numerical value by the ridit transformation. 4. 4. The laxative potency of an unknown agent emerges from the comparison of its results with those of placebo. The sensitivity of the method is calibrated by a standard laxative, USP fluid extract cascara sagrada in daily doses of 2 c.c. to normal subjects and 4 c.c. to constipated patients. 5. 5. With this method the unknown preparation, a beverage containing an extract of bran, was not distinguished from placebo by a group of 40 normal subjects nor by a group of 20 constipated patients. 6. 6. Dosage-response curves in constipated patients indicate that greatest sensitivity to dosage change lies below 0.5 Gm. daily of powdered USP cascara sagrada.