CHEMOTHERAPY OF TRYPANOSOME AND SPIROCHETE INFECTIONS : BIOLOGICAL SERIES. III. THE THERAPEUTIC ACTION OF N-PHENYLGLYCINEAMIDE-p-ARSONIC ACID IN EXPERIMENTAL TRYPANOSOMIASIS OF RABBITS.
In the treatment of experimental trypanosomiasis of rabbits with subsequent appraisal of the value of the therapeutic agent used, there are certain experimental factors including uniform infecting strains of trypanosomes and the observation of general procedures of method and time of inoculation conditioned by the infection itself which must be taken into account. The conspicuous and characteristic clinical signs and symptoms seen in rabbit trypanosomiasis serve as criteria of the severity and duration of the disease, and it is obvious that the infection should be well established before treatment is instituted. For the same reason, before the question of a permanent cure can be established, treated rabbits should be kept under observation for a sufficient period of time, which with the species of organisms that we have used is at least 3 months. The therapeutic results with the amide of N-phenylglycine-p-arsonic acid were obtained in rabbits which showed well marked clinical signs of a definitely established disease, and in many instances the infection was extremely advanced and of prolonged duration. The five species which we have employed, Tr. brucei, Tr.gambiense, Tr. equinum, Tr. equiperdum, and Tr. evansi, are uniformly fatal in rabbits. With the usual acute, actively progressing infection of from I to 2 weeks duration produced by our strain of Tr. brucei, the drug has a curative range of from 0.2 to 0.35 gm. per kilo of body weight, when administered intravenously in single doses, or from one-third to one-half the minimal lethal dose. Of the twenty-nine rabbits treated with doses falling within this range, twenty-five, or 86 per cent, were permanently cured and there were no relapses observed with doses above 0.3 gm. The infection produced by our strain of Tr. gambiense is controlled by a slightly lower dose, since there were no relapses with single doses of 0.3 gm. and a single dose of 0.15 gm. effected a cure in one of three rabbits so treated. The therapeutic experiments with Tr. equinum, Tr. equiperdum, and Tr. evansi are too few to admit of final conclusions, but apparently from the evidence at hand, much the same curative range is operative in Tr. evansi infections, while larger doses or a different system of treatment should have been employed in the treatment of rabbits infected with our strains of Tr. equinum and Tr. equiperdum. In addition to the ultimate curative results obtained with single doses within the curative range, it is important to consider the marked therapeutic action with smaller single doses, as shown by the rapid regression and healing of the clinical lesions of the acute infections produced by all five species of trypanosomes together with a marked improvement in the general physical state of the animal. Moreover, large single doses, above those of the so called curative range, caused no disturbance of a toxic nature and were apparently well borne. A system of repeated dose therapy may be employed with advantage in the treatment of both initial and relapsed infections in rabbits, especially in those instances in which there is induration or even necrosis of tissues with weakness and emaciation of the animal host. The factor of time of repetition or the spacing of doses is in our experience as important as that of size of the dose employed and depends upon the rate, degree, and duration of action of the particular dose of the drug in question. Since the amide of N-phenylglycine-p-arsonic add apparently possesses the power of tissue penetration to a marked degree, it is desirable to give the second dose within a short time after the first in order that it may have a full opportunity for the immediate and complete development of its action. The repetition of small doses such as 0.15 gm. per kilo of body weight on successive or alternate days has given successful results as regards both the immediate regression and healing of lesions and ultimate permanent cures in severe, chronic infections. It is possible, however, to administer increasingly large doses, if this is necessary, since infected as well as normal rabbits exhibit a remarkable tolerance to repeated large doses of the drug. The therapeutic activity of small doses administered intramuscularly is quite comparable with that observed after similar doses given intravenously, as indicated by the rate of regression and healing of clinical lesions, while such effects proceed somewhat more slowly after subcutaneous injections. Permanent cures have been obtained in Tr. brucei infection with intramuscular and subcutaneous administration of single doses of from 0.2 to 0.5 gm. of the drug per kilo of body weight and in other instances with three repeated doses of 0.1 gm. per kilo given intramuscularly. One severely infected rabbit which received 0.75 gm. per kilo per os immediately following a small dose of sodium bicarbonate was also cured. The therapeutic experiments here reported represent only a portion of those carried out with N-phenylglycineamide-p-arsonic acid and the scope of the present paper does not permit a detailed description of the many phases of the experiments or a full discussion of the various factors involved and the results obtained, all of which we hope to publish at some future time.
Laboratories of The Rockefeller Institute for Medical Research.
L
L
Pearce
W H
WH
Brown