ON THE FORMATION OF PRECIPITATES AFTER THE INTRAVENOUS INJECTION OF SALVARSAN.
The results of these experiments are definite. There is, in the first place, a very striking difference with regard to precipitate formation between the acid and alkaline solutions of salvarsan when injected intravenously. Intravenous injections of alkaline solutions of salvarsan produce no precipitate in the blood, while injections of the acid solution nearly always give a precipitate. Furthermore, after injections of the acid solution, there is a striking difference between the blood from the right side of the heart and that from the left side. At the end of injections of an acid solution of salvarsan, a precipitate was seldom present in the arterial blood. Blood taken from the left ventricle at this time (at autopsy) also showed no precipitate in a large majority of cases; in eight experiments there was no precipitate, in three a doubtful trace of precipitate, and in one a definite small amount. On the other hand, blood obtained from the right ventricle and the lungs showed a very different condition. In ten out of twelve animals (rabbits and dogs), blood from the right ventricle contained a definite precipitate, and in a number of these cases the amount of precipitate was large. Blood squeezed from the lungs showed in eight out of ten cases at least as much precipitate as was found in the blood from the right ventricle. The results of injections of alkaline solutions of salvarsan, as pointed out before, are quite different from those produced by the acid solutions. In thirteen experiments upon dogs and rabbits, no trace of a precipitate was found in the arterial blood, the blood from the left ventricle, the right ventricle, or the lungs. There is no apparent difference in the process of precipitate formation whether salvarsan solutions and the blood are mixed in vivo or in vitro. In both mixtures the acid solutions produce a precipitate, while the alkaline solutions of salvarsan do not. These experiments have demonstrated the fact that a precipitate is present in the blood after an injection of an acid solution of salvarsan. One would expect that such a precipitate, consisting as it usually does of rather coarse particles, would, if brought to the medulla, cause immediate death by producing emboli. However, the freedom from such occurrences may be explained by the fact that the precipitate, which is abundantly present in the right ventricle, is only rarely seen in blood taken from the carotid or femoral arteries or even from the left ventricle itself. The fact itself, however, is quite difficult to interpret. It might perhaps be assumed that the precipitate is filtered out during its passage through the lung capillaries. If this is the case, we might expect intravenous injections of salvarsan to produce embolism in the pulmonary vessels with consequent fatal results. As a matter of fact, we have in the recent literature an instance which seems to point to such a result. Miessner (6) tried the effects of salvarsan in cattle which had foot and mouth disease. He used at first the acid solution, and though the dose was small, seven milligrams per kilo of body weight, all the animals (four) died in from ten hours to two days after the injection. They all showed labored respiration during or soon after the injection of salvarsan. He then decreased the dose to five milligrams per kilo of body weight, and repeated the experiments. He used also normal animals as controls upon those which had the foot and mouth disease. Both the sick and normal (control) animals showed labored respiration. One died after four days. At autopsy all organs except the lungs appeared to be normal. The lungs presented the following appearance: There were grayish yellow spots scattered irregularly over the surface. On the cut surface these were seen as grayish yellow spots the size of a pea, which appeared in groups and which sometimes filled a lobule completely. Other spots were surrounded by a small area of dark red lung parenchyma. The affected portion contained no air and felt solid. In adjacent parts the tissue seemed normal. A microscopic examination showed that the larger and smaller pulmonary arteries were filled with uniform, homogeneous, yellow masses. About the vessels there was a serous exudate. In brief, the changes seen indicated, he believed, that there was a thrombosis of the blood-vessels with inflammatory exudative changes of the lung parenchyma. Miessner states that a similar pathological condition was found in a normal control animal that died. He suggests that the acid solution of salvarsan might lead in man to a thrombosis of the pulmonary arteries. In support of this suggestion, he mentions a case reported to him by Ehrlich of a man who died following the injection of an acid solution. The lung picture in this case was somewhat similar to that which he had found in cattle. It may be mentioned in passing that Miessner found that alkaline solutions of salvarsan were far less toxic than the acid solutions. Animals (cattle) which received in an alkaline solution 400 milligrams of salvarsan per kilo of body weight did not show the least symptom of disturbance. In contrast to Miessner's results seem to stand my observations and those of Auer described in the introduction of this paper. Auer (5) found (in 8 rabbits) that no evident harmful effects followed the injections of very large doses of the acid solution, if they were given in a highly diluted form (one tenth per cent.). In my own experiments, it was found that a one fifth per cent. acid solution (3 rabbits) and even a one half per cent. solution (1 rabbit) produced no ill effects. The experiments described in this paper make it certain that the doses of the acid solution given to these last mentioned four animals must have produced a precipitate in the right ventricle and in the lungs, and yet the animals survived and showed no symptoms whatever of disturbance following the injection. This difference between our observations and those of Miessner might perhaps be explained by the assumption that the action of salvarsan in acid solution is more deleterious to cattle than to rabbits. Furthermore, Miessner seems to have injected the salvarsan in high concentrations. In one instance, in which figures are given, the drug was administered in a five per cent. solution. As mentioned before, Auer has shown the importance of the concentration. While in a one tenth per cent. solution twenty and thirty milligrams per kilo of body weight of the acid solution may be injected with impunity, even six or seven milligrams per kilo may prove rapidly fatal when injected in a one half per cent. solution. Our own results, however, leave us with two puzzling questions : First, if the acid solution of salvarsan causes such a coarse precipitate in the right ventricle and in the lungs, how does it happen that this precipitate does not bring about the death of the animal? Second, what is the real cause of the remarkable fact that this precipitate does not pass over into the arterial side of the circulation? Does the precipitate undergo a profound chemical or mechanical change while it passes through the lung capillaries? In future investigations we may try to answer these interesting questions. For the present, it is necessary to be content with the establishment of the bare facts as they are presented in the conclusions.
Joseph
D R
DR
Department of Physiology and Pharmacology of the Rockefeller Institute for Medical Research, New York.