Anaphylactic shock, protection from

Historically, antibodies have been obtained from the serum of animals. The serum contains a mixture of polyclonal antibodies. In 1890, Emil Behring immunized rabbits and mice against tetanus and diphtheria and reported that the antitoxin serum could protect against a lethal dose of the toxin. Since then, antisera have been used to protect from pathogens and toxins, but serum sickness was a major drawback for their clinical use. Antisera may produce immune responses, which could cause severe allergic reactions, and may even lead to anaphylactic shock and death. 

The results obtained in the guinea-pig anaphylaxis test after oral oxatomide administration are presented in Fig. 1. A dose-dependent increase in the number of animals protected from the acute anaphylactic shock was observed and the histamine-induced paw oedema was similarly reduced by increasing doses of oxatomide. As previously found with cinnarizine, protection from anaphylactic shock was a more sensitive measure of the activity of oxatomide than was the reduction of paw oedema. In comparison with cinnarizine, however, oxatomide was considerably more potent. The calculated ED5o s, 2 h after oral administration, were 0. 16(0. 081 - 0. 31) mg/kg for protection from anaphylactic shock and 0. 30(0. 18 - 0. 50) mg/kg for inhibition of histamine oedema. 

For the oxatomide-analogues the results of histamine antagonism in vitro, together with the EDsq s for protection from anaphylactic shock and the values of histamine oedema at a standard dose of 2. 5 mg/k.g are summarized in Table III a and b. 

In no case total protection from anaphylactic shock was found at 0. 16 mg/)s.g and the ED50 values for oxatomide (compound 8) and some of the most active compounds, namely R 35 918,R 37 280 and R 37 281 (compounds 23, 61, 25) are presented in Table IV. These compounds were not superior to oxatomide in affording protection from anaphylactic shock, whereas their antihistamine activity tended to be somewhat more pronounced. 

Compound to challenge (h) Protection from Anaphylactic shock hihibition of Histamine Oedema... 

Because of the frequent occurrence of a less violent, protracted shock phase, despite protection of the animals from the acute bronchospasm, EDsq s were calculated for protection from both the acute anaphylactic shock (survival at 15 min) and the delayed phase (survival for at least 4 h). 

With respect to the lowest ED5Q for protection from anaphylactic shock (0. 11 mg/kg) the safety margin (LD50/ED50) for orally administered oxatomide is 3,000. 

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