Harry Gold

A qualitative comparison of various digitalis bodies

Abstract In the present study seventy-seven experiments were carried out with six widely different members of the digitalis group in order to ascertain whether these showed any qualitative differences in the cardiac action. Electrocardiographic criteria of digitalis action were used, and the relative intensity of action upon different cardiac structures (in relation to the fatal dose) was used to indicate qualitative differences. The results show that widely different digitalis bodies have the same qualitative cardiac actions but that there are extraordinary individual differences in response to the same preparation. This fact may be an important factor in the confusion found in the clinical literature. There are numerous references in the literature to qualitative differences in the cardiac action of different members of the digitalis group, and implications that such differences exist are common in commercial advertisements, but in no single instance are these statements substantiated by adequately controlled experiments. Examples are cited showing some of the sources of error in the interpretation of observations which appear to indicate qualitative differences in the cardiac action of different digitalis bodies.

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.

The importance of differences in the potency of digitalis in clinical practice

Abstract 1. 1. This communication deals with an analysis of the factors involved in the application of the bio-assay of digitalis by the cat method to clinical practice. 2. 2. Evidence is presented showing that body weight is a factor in digitalis dosage and that it is essential to take into account differences in potency of digitalis as determined by bio-assay. 3. 3. It is pointed out that when small doses of digitalis are used, the value of both factors (body weight and differences in potency) may escape detection. 4. 4. An analysis is made of the experience of the Committee for the study of digitalis in pneumonia at Bellevue Hospital with a well-known commercial preparation of digitalis, the potency of which was later proven to have been incorrectly labelled by the manufacturer. This analysis shows in the first place, that a specimen of digitalis which was found to be about twice as active as anticipated for man proved to be also twice as active by the cat method of assay; and secondly, it shows the dangers arising from the use of digitalis, especially in large doses, without knowing the exact potency. 5. 5. Evidence is presented showing the confusion which arises from the use of the term “standardized digitalis” without stating the exact potency because of the different standards used by the various manufactures. 6. 6. The relative merits of so-called “stronger” and “weaker” preparations of digitalis are discussed.

On the R-T interval in experimental coronary occlusion.

In 1918 Smith 1 published electrocardiographic tracings following ligation of coronary vessels in the dog. In one tracing, five minutes after tying the circumflex branch of the left coronary artery, there occurred, among other changes, marked elevation of the T-wave, with the T-wave originating on the down stroke of the R-wave, when the latter had reached about one-half the distance to the base line. In 1920 Pardee 2 published a similar electrocardiogram obtained from a patient four hours after an obstruction of a coronary vessel. More recently, Rothschild, Mann, and Oppenheimer 3 renewed the interest in the peculiar change of the R-T interval as an early diagnostic sign of coronary obstruction. They reported observations on four patients shortly after acute coronary occlusions in which among the first changes in the electrocardiogram there was the characteristic elevation of the R-T interval above the base line. In 1909 Eppinger and Rothberger 4 observed in dogs that partial or complete absence of the desecending limb of the R-wave was a relatively frequent and characteristic occurrence following the injection of silver nitrate solution into tlie muscle of the left ventricle whether at the base or apex. The T-wave became high and broad and originated either at the peak of the ascending limb of the R-wave or from the lower end of the descending limb which failed to reach the base line. They explained this effect on the basis of impaired contraction of the mass of circular muscle fibres in the structure of the left ventricle.

Depression of the vomiting reflex by the digitalis bodies

Abstract The emetic action of the digitalis bodies has been the subject of numerous experimental investigations. These have dealt mainly with its mechanism and the conditions under which these drugs induce vomiting. 1 It is a very familiar phenomenon in both animals and man that a moderately toxic dose induces one or two attacks of vomiting and as the dose is increased vomiting continues and becomes more intense. There may be remissions lasting several hours; then the vomiting recurs and may continue for a day or two after the drug has been discontinued. The drug sometimes causes death in dogs and cats without having produced vomiting. After a very large intravenous injection a convulsion and death may occur within a few seconds; this does not appear to allow sufficient time for vomiting to take place. We have, however, seen cats die even after an intramuscular injection of ouabain without vomiting. Under ordinary conditions such observations are rare. Several years ago in the course of a study of digitalis elimination, one of us 2 observed what appeared to be an interference with the vomiting mechanism after repeated injections of digitalis. It was noted that after small doses were injected daily intravenously in several cats there came a point when sufficient cumulation had taken place to induce vomiting. The next few daily doses continued to cause vomiting, but the last two or three daily doses before the animal died no longer produced emesis. In those experiments electrocardiograms were not taken. Such a change in the response of the vomiting reflex to the digitalis bodies might be of considerable practical importance in view of the fact that reliance is generally placed on nausea and vomiting as signs for discontinuing digitalis in order to avoid serious overdosage. The present study was undertaken to extend these observations and to determine whether it be possible, by the repeated injections of the digitalis bodies, to diminish or abolish the emetic action of the drugs while at the same time increasing the intensity of the cardiac poisoning.

The blood pressure and the size of a cardiac infarct

Abstract In the cat with an otherwose normal circulation, the blood pressure is almost invariably normal three weeks after the ligation of a large coronary artery (left circumflex). This applies to infarcts of widely different sizes, ranging from a relatively small area involving the upper third of the left ventricle posteriorly to a very large one including nearly all of the left ventricle posteriorly, together with adjacent strips of the right ventricle and interventricular septum.

The Depression of the Vomiting Mechanism by Digitalis

The vomiting produced by toxic doses of the digitalis bodies has been studied chiefly from the point of view of its mechanism and the conditions under which such vomiting occurs. Some time ago the fact was noted that in some instances toxic doses of digitalis which at first caused vomiting, when repeated, failed to cause emesis. The present experiments were planned to extend this observation and to determine under what circumstances the digitalis bodies might produce a depression of the vomiting mechanism. Observations were made on cats and dogs following the repeated intravenous injection of various members of the digitalis group. Each experiment lasted several days, and in the series of dogs some of the changes produced in the heart by the drug were recorded by frequent electrocardiograms. It was found that there was a progressive elevation of the threshold of the vomiting mechanism to digitalis. Thus the initial dose of the drug which induced vomiting, when repeated often failed to produce this result, and increasingly larger doses were required to cause vomiting. It was found that the cumulation of digitalis after repeated injections might produce very severe poisoning of the heart as indicated by the development of such toxic rhythms as ventricular tachycardia, while at the same time vomiting did not occur. In fact, in 3 dogs the final increment of digitalis which was fatal failed to cause vomiting, though sufficient time elapsed before death for vomiting to have occurred. It was found that there was a progressive elevation of the threshold of the vomiting mechanism to digitalis. Thus the initial dose of the drug which induced vomiting, when repeated often failed to produce this result, and increasingly larger doses were required to cause vomiting.

Pupillary Reactions During Ether and Chloroform Anesthesia After Morphine.

In the course of anesthesia by ether and chloroform in the dog, the pupil dilates at 2 stages, in the period of excitement and in the period of deep narcosis. If there is violent excitement the intermediary constriction is not observed. It is commonly held that the primary dilatation is a reflex phenomenon (inhibition of the oculomotor or stimulation of the sympathetic or both). There is no clear statement, however, whether the dilatation of the pupil in the stage of deep narcosis is the result of asphyxia or the direct effect of the anesthetic. While studying the response of the vagus nerve to morphine during ether and chloroform anesthesia, it was observed that in deep ether narcosis, the pupils of the dog under the influence of morphine were widely dilated, while in deep chloroform narcosis under the same conditions, the pupils were constricted. These observations seemed of interest in their bearing upon the mechanism of the pupillary changes produced by ether and chloroform. Twelve experiments were then performed to check and extend these observations and the results are the subject of the present report. Ether and chloroform were administered by inhalation with the open cone method. The pupils were measured under constant conditions of light for any given experiment. Both eyes were examined; the pupils were found equal in all except one instance. Electrocardiographic records of the heart rate were taken at frequent intervals, making it possible in this way to correlate simultaneous effects upon the vagus and oculomotor nerves. The condensed protocols of the experiments with 2 dogs serve to illustrate the general results. The size of the pupils is expressed in percentage of the diameter of the iris. The stage of anesthesia is designated as “light” when voluntary movements as well as corneal conjunctival reflexes are present; as “deep” when these have disappeared; as “partial recovery” when the eye reflexes have reappeared; as “recovery” when voluntary movements begin.