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From the Tice Laboratories, a detail of the Chicago Municipal Tuberculosis Sanitarium, and the Department of Pathology and Bacteriology, University of Illinois College of Medicine
Abstract
The specific antagonistic action of thymoxyethyldiethylamine on histamine and its prevention of anaphylactic shock suggests that histamine is liberated into circulating fluids during anaphylactic shock and may cause death of the guinea pig.
Thymoxyethyldiethylamine does not neutralize histamine or antigen directly but antagonizes the action of histamine. Thus, it differs from histaminase (6) and from the neutralizing serum (7) obtained from previously burned pigs or humans, which neutralizes histamine directly.
As irritation or injury to cells causes histamine to leave the cells, it follows that the excess of circulating histamine is only an indicator of the amount of irritation or injury sustained by the cells. It has been very difficult to separate the primary from the secondary effects of histamine. The action of thymoxyethyldiethylamine suggests an answer to this problem. In sensitized animals treated with this drug before the injection of antigen, respiratory difficulty, scratching, or convulsions rarely developed. These animals, however, did show signs of malaise and prostration. They rolled over on one side and appeared listless although their reflexes remained intact. They could not be made to stand or walk. This condition lasted for one to several hours after which recovery was apparent. The cause of this prostration might be due to the primary tissue-alterations, or incomplete neutralization of histamine, or to other substances leaving the injured cells.
As shown in this study, 0.5 mgm. per kilogram of histamine intracardially, or approximately 1 to 2 gamma of histamine per milliliter of blood, is fatal to the guinea pig (5). This takes into consideration dilution by body-fluids. Code (1) found, in anaphylactically shocked guinea pigs, from 0.35 to 1.2 gamma per ml.; the average was about 1 gamma or less; (the normal range is 0.08 to 0.16 gamma). The amount of thymoxyethyldiethylamine injected readily neutralized 0.5 mgm. per kilogram insofar as action on smooth muscle is concerned. Other effects of histamine were probably prevented inasmuch as the animals receiving histamine after thymoxyethyldiethylamine recovered rapidly. Thymoxyethyldiethylamine injected alone in similar amounts as above caused a decreased response to mechanical stimuli in the guinea pig. (The lethal dose of thymoxyethyldiethylamine for guinea pigs is 400 mgm. per kilogram of base.)
It has long been suspected that scratching, respiratory embarrassment, convulsions, and early death are caused by the histamine liberated during anaphylactic shock. Primary tissuedamage and substances other than histamine probably account for the prolonged malaise and prostration in the thymoxyethyldiethylamine-treated animals, and the deaths that sometimes terminate protracted anaphylactic shock.
Footnotes
1 Aided by a grant from Abbott Laboratories.
This article has been cited by other articles:
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  R. L. MAYER, C. P. HUTTRER, and C. R. SCHOLZ ANTIHISTAMINIC AND ANTIANAPHYLACTIC ACTIVITY OF SOME agr-PYRIDINOETHYLENEDIAMINES Science, July 27, 1945; 102(2639): 93 - 94. [PDF]
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