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Torantil (histaminase) in urticaria following serum administration
TORANTIL ( H I S T A M I N A S E ) IN URTICARIA FO L L O WIN G SERUM ADMINISTRATION J O H N A . TOOMEu M.D., FREDERIC M. KRIETE, M.D., •N1) HAROLD C. EPSTEIN, M . D . CLEVELAND, OHIO
ST and McHenry, 1 in 1930, reported ttmt histaminase could be B Eneutralized in vitro by a substance extracted from certain viscera, particularly the gastrointestinal tract and kidney. Since this substance displayed the properties of an enzyme, they called it histaminase. They prepared it as a stable powder and defined 1 unit as the amomlt necessary to neutralize 1 mg. of histamine after twenty-four hours of incubation at 37 ~ C. at a pH of 7.2. tIistaminase was subsequently manufactured ior clinical use from porcine gastrointestinal tract. It was given the trade name of Torantil and distributed in the form of tablets or capsules, each containing 5 units. It has been frequently suggested that a sudden release of histamine might be the mechanism whereby the various clinical signs of an allergic state are produced. Were this true, it would be logical to assume that a substance capable of destroying histamine in the body might be of therapeutic value. A number of investigators have, therefore, tested histaminase experimentally and clinically in a wide variety of conditions. The results have been diverse and difficult to interpret. The only reports pertinent to our work were those concerned with use of histaminase in serum sickness after antitoxin or antiserum administration. Foshay and Hagebusch 2 reported "marked relief in twenty of twenty-two cases," with prevention of serum sickness in six of eight patients treated prophylactically. Roth and Horten 3 noted relief in from twelve to thirty-six hours in fourteen of seventeen patients; and Vaisberg ~ had good results in one patient. Cherry and Prickman 5 used Torantil to prevent and treat selann sickness in twentytwo patients with good results. Many patients treated with serums and antitoxins develop serum sickness. It was decided to note the effect of Torantil in such patients i n the Division of Contagious Diseases, City Hospital, Cleveland, following the administration of" scarlet fever antitoxin, diphtheria antitoxin, pneumococcus antiserum or meningococcus antitoxin. In the first clinical experiment, thirteen patients who developed urticaria were given four tablets of Torantil four times a day until the serum sickness had subsided. This procedure seemed worthless, since From the Division of Contag'ious Diseases City Hospital and the Department of Pediatrics, Western Reserve University. 29O
TOOMEY ET AL. :
TORANTIL (HISTAMINASE)
291
by a n y s t a n d a r d of comparison, the thirteen treated seemed no better t h a n the thirteen u n t r e a t e d control patients. I t was thought at the time that the amount of Torantil given had been inadequate. I n the next clinical experiment, 10 patients with urticaria were given six Torantil tablets four times a day for as long as ten days. When infants were to be treated, the tablets were crushed and placed in the formula. A t no time was the medication administered parenterally. Again our results, when compared with ten u n t r e a t e d control patients, were inconclusive. Our t h i r d clinical experiment was done a f t e r it was pointed out by the m a n u f a c t u r e r s t h a t the earlier p r e p a r a t i o n s of histaminase were sometimes unstable. New material was obtained. Forty-one patients were given 120 units daily, starting just as soon as urticaria a p p e a r e d and continuing until it disappeared. The treated were compared with forty-one u n t r e a t e d patients with urticaria. Comparisons were difficult to make. The normal as well as the t r e a t e d individuals lost their urticaria between one and seven to eight days. There was no striking direc* tive tendency noticed when cases were analyzed and grouped according to the time of recovery of the patients, nor were there any startling improvements noticed in any individual patient. This experience ran counter to t h a t r e p o r t e d in the literature. Alexander 6 collected case reports of over 150 patients with urticaria who were beneficially treated with Torantil. He mentions one report where histaminase failed to benefit twenty-nine patients. The reports in the literature were again examined. They seemed to us at times v a r y i n g and vague. The especial recommendation t h a t in severe types of serum sickness 25 units be given f r o m f o u r to six times daily until there is i m p r o v e m e n t meant nothing, since most pa9tients begin to recover a n y w a y within forty-eight hours. Since it was difficult f o r us to detect any difference between our control and t r e a t e d patients, a fourth a n d more conclusive clinical experiment was planned. I n epidemic meningitis, u r t i c a r i a is one of the complications of serum t h e r a p y in nearly 100 per cent of the patients treated. I n brief, here we had a disease which, when treated with serum intravenously, is always followed by serum sickness. I t was decided to determine whether Torantil (histaminase) would prevent or modify this serum sickness. I t was thought that; if we gave Torantil as soon as the patient was given antitoxin, we could determine whether it prevented serum sickness and whether it modified its course. The meningococcic antitoxin was given intravenously to sixty-five patients, sixty-three of whom received 100,000 or more units. The two exceptions received 60,000 and 70,000 units, respectively. Thirty-six of the patients were treated with histaminase; twenty-nine were not. The d r u g was given ora]]y daily for ten days, s t a r t i n g either on the day of antitoxin administration if admitted early in the day or the day following if admitted late at night. The dose was at ]east sixteen
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PEDIATRICS
a n d usually t w e n t y tablets daily in t w e n t y - f o u r patients. E i g h t patients received f r o m twelve to fifteen tablets dM]y. The drug was given as long as the serum sickness lasted. Thus, the t r e a t m e n t was both prophylactic and therapeutic. No patients was treated for less t h a n eight days, a total of at least f r o m 128 to ]60 tablets ( f r o m 640 to 800 units). Of the thirty-six patients receiving histaminase, thirty-four, or 94 per cent, had serum sickness; of the twenty-nine patients receiving no histaminase, twenty-three, or 79 p e r cent, had serum sickness. Conversely, two, or 6 per cent, of those treated escaped a serum reaction as contrasted with six, or 21 per cent, of those untreated. There was actually a higher percentage of serum reactions among the patients who received histaminase, although this is not of great statistical significance. I n the patients receiving histaminase, the reactions lasted, f r o m one to ten days, the average being 4.6 days; in those in the control group, they lasted f r o m one to twelve days, the average being 4.8. Thus, there was no essential difference in the duration of the serum sickness in the patients in the two series. COMMENT
One investigator considered results to be good when symptoms disappeared in f r o m one to four days a f t e r the onset of t r e a t m e n t but presented no evidence as to the duration of serum sickness in u n t r e a t e d patients. Similarly, in those reports in which histaminase was credited with having p r e v e n t e d serum sickness, no controls were included; t h a t is, no data were given as to the incidence o3 reactions to be expected with the p a r t i c u l a r types of sera used. Until such controlled studies are made, it must, perhaps, be admitted t h a t the reactions caused b y the various types of horse and goat sera used in the previous reports m a y be more amenable to histaminase t h a n the reactions following the use of meningococcic antitoxin. This, however, does not seem-likely. CONCLUSION
ttistaminase neither prevents nor ameliorates the serum sickness which follows the administration of meningococcus antitoxin (horse). REFERENCES
1. Best, C. I{., and McI-Ienry, E. W.: Y. Physiol. 70: 349, 1930. 2. :F'oshay, Lee, a~d ]~Iagebusch, O. E.: 5. A. M. A. 112: 2398, 1939. 3. l~oth~ G. M., and tIorten, ]~. T.: (a) Proc. Staff Meet., Mayo Clinic 12: 129, 1937; (b) J. A. IV[. A. 110: 686, 1938; (e) Bull. :New York Acad. 1Y[ed. 16: 570, 1940. 4. Yaisberg, lVL: Rrew York State J. Med. 39: 2199, 1939. 5. Cherry, J. H., and Priekman, L. E.: Unpublished data cited by Roth and iorten.aa 6. Alexander, H. L.:
J. Lab. & Clin. lKed. 26: 110, 1940.
ST and McHenry, 1 in 1930, reported ttmt histaminase could be B Eneutralized in vitro by a substance extracted from certain viscera, particularly the gastrointestinal tract and kidney. Since this substance displayed the properties of an enzyme, they called it histaminase. They prepared it as a stable powder and defined 1 unit as the amomlt necessary to neutralize 1 mg. of histamine after twenty-four hours of incubation at 37 ~ C. at a pH of 7.2. tIistaminase was subsequently manufactured ior clinical use from porcine gastrointestinal tract. It was given the trade name of Torantil and distributed in the form of tablets or capsules, each containing 5 units. It has been frequently suggested that a sudden release of histamine might be the mechanism whereby the various clinical signs of an allergic state are produced. Were this true, it would be logical to assume that a substance capable of destroying histamine in the body might be of therapeutic value. A number of investigators have, therefore, tested histaminase experimentally and clinically in a wide variety of conditions. The results have been diverse and difficult to interpret. The only reports pertinent to our work were those concerned with use of histaminase in serum sickness after antitoxin or antiserum administration. Foshay and Hagebusch 2 reported "marked relief in twenty of twenty-two cases," with prevention of serum sickness in six of eight patients treated prophylactically. Roth and Horten 3 noted relief in from twelve to thirty-six hours in fourteen of seventeen patients; and Vaisberg ~ had good results in one patient. Cherry and Prickman 5 used Torantil to prevent and treat selann sickness in twentytwo patients with good results. Many patients treated with serums and antitoxins develop serum sickness. It was decided to note the effect of Torantil in such patients i n the Division of Contagious Diseases, City Hospital, Cleveland, following the administration of" scarlet fever antitoxin, diphtheria antitoxin, pneumococcus antiserum or meningococcus antitoxin. In the first clinical experiment, thirteen patients who developed urticaria were given four tablets of Torantil four times a day until the serum sickness had subsided. This procedure seemed worthless, since From the Division of Contag'ious Diseases City Hospital and the Department of Pediatrics, Western Reserve University. 29O
TOOMEY ET AL. :
TORANTIL (HISTAMINASE)
291
by a n y s t a n d a r d of comparison, the thirteen treated seemed no better t h a n the thirteen u n t r e a t e d control patients. I t was thought at the time that the amount of Torantil given had been inadequate. I n the next clinical experiment, 10 patients with urticaria were given six Torantil tablets four times a day for as long as ten days. When infants were to be treated, the tablets were crushed and placed in the formula. A t no time was the medication administered parenterally. Again our results, when compared with ten u n t r e a t e d control patients, were inconclusive. Our t h i r d clinical experiment was done a f t e r it was pointed out by the m a n u f a c t u r e r s t h a t the earlier p r e p a r a t i o n s of histaminase were sometimes unstable. New material was obtained. Forty-one patients were given 120 units daily, starting just as soon as urticaria a p p e a r e d and continuing until it disappeared. The treated were compared with forty-one u n t r e a t e d patients with urticaria. Comparisons were difficult to make. The normal as well as the t r e a t e d individuals lost their urticaria between one and seven to eight days. There was no striking direc* tive tendency noticed when cases were analyzed and grouped according to the time of recovery of the patients, nor were there any startling improvements noticed in any individual patient. This experience ran counter to t h a t r e p o r t e d in the literature. Alexander 6 collected case reports of over 150 patients with urticaria who were beneficially treated with Torantil. He mentions one report where histaminase failed to benefit twenty-nine patients. The reports in the literature were again examined. They seemed to us at times v a r y i n g and vague. The especial recommendation t h a t in severe types of serum sickness 25 units be given f r o m f o u r to six times daily until there is i m p r o v e m e n t meant nothing, since most pa9tients begin to recover a n y w a y within forty-eight hours. Since it was difficult f o r us to detect any difference between our control and t r e a t e d patients, a fourth a n d more conclusive clinical experiment was planned. I n epidemic meningitis, u r t i c a r i a is one of the complications of serum t h e r a p y in nearly 100 per cent of the patients treated. I n brief, here we had a disease which, when treated with serum intravenously, is always followed by serum sickness. I t was decided to determine whether Torantil (histaminase) would prevent or modify this serum sickness. I t was thought that; if we gave Torantil as soon as the patient was given antitoxin, we could determine whether it prevented serum sickness and whether it modified its course. The meningococcic antitoxin was given intravenously to sixty-five patients, sixty-three of whom received 100,000 or more units. The two exceptions received 60,000 and 70,000 units, respectively. Thirty-six of the patients were treated with histaminase; twenty-nine were not. The d r u g was given ora]]y daily for ten days, s t a r t i n g either on the day of antitoxin administration if admitted early in the day or the day following if admitted late at night. The dose was at ]east sixteen
292
THE
JOURNAL
OF
PEDIATRICS
a n d usually t w e n t y tablets daily in t w e n t y - f o u r patients. E i g h t patients received f r o m twelve to fifteen tablets dM]y. The drug was given as long as the serum sickness lasted. Thus, the t r e a t m e n t was both prophylactic and therapeutic. No patients was treated for less t h a n eight days, a total of at least f r o m 128 to ]60 tablets ( f r o m 640 to 800 units). Of the thirty-six patients receiving histaminase, thirty-four, or 94 per cent, had serum sickness; of the twenty-nine patients receiving no histaminase, twenty-three, or 79 p e r cent, had serum sickness. Conversely, two, or 6 per cent, of those treated escaped a serum reaction as contrasted with six, or 21 per cent, of those untreated. There was actually a higher percentage of serum reactions among the patients who received histaminase, although this is not of great statistical significance. I n the patients receiving histaminase, the reactions lasted, f r o m one to ten days, the average being 4.6 days; in those in the control group, they lasted f r o m one to twelve days, the average being 4.8. Thus, there was no essential difference in the duration of the serum sickness in the patients in the two series. COMMENT
One investigator considered results to be good when symptoms disappeared in f r o m one to four days a f t e r the onset of t r e a t m e n t but presented no evidence as to the duration of serum sickness in u n t r e a t e d patients. Similarly, in those reports in which histaminase was credited with having p r e v e n t e d serum sickness, no controls were included; t h a t is, no data were given as to the incidence o3 reactions to be expected with the p a r t i c u l a r types of sera used. Until such controlled studies are made, it must, perhaps, be admitted t h a t the reactions caused b y the various types of horse and goat sera used in the previous reports m a y be more amenable to histaminase t h a n the reactions following the use of meningococcic antitoxin. This, however, does not seem-likely. CONCLUSION
ttistaminase neither prevents nor ameliorates the serum sickness which follows the administration of meningococcus antitoxin (horse). REFERENCES
1. Best, C. I{., and McI-Ienry, E. W.: Y. Physiol. 70: 349, 1930. 2. :F'oshay, Lee, a~d ]~Iagebusch, O. E.: 5. A. M. A. 112: 2398, 1939. 3. l~oth~ G. M., and tIorten, ]~. T.: (a) Proc. Staff Meet., Mayo Clinic 12: 129, 1937; (b) J. A. IV[. A. 110: 686, 1938; (e) Bull. :New York Acad. 1Y[ed. 16: 570, 1940. 4. Yaisberg, lVL: Rrew York State J. Med. 39: 2199, 1939. 5. Cherry, J. H., and Priekman, L. E.: Unpublished data cited by Roth and iorten.aa 6. Alexander, H. L.:
J. Lab. & Clin. lKed. 26: 110, 1940.