Studies on the effectiveness of H1-+H2-antagonist combinations in preventing life-threatening anaphylactoid reactions in anaesthesia and surgery: Problems with selecting the animal model from clinical data and with “equi-effective” doses
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Animal models are necessary for studies on the effectiveness of histamine H1- + H2-receptor antagonists in preventing life-threatening anaphylactoid reactions in anaesthesia and surgery. Clinical data were presented here for the first time which showed a clear correlation between the severe haemodynamic changes (shock and death) and plasma histamine levels.
A dog model was developed which best resembled the clinical situation and was remarkably successful in showing the effectiveness of the H1- + H2-antagonist combination dimetindene and cimetidine compared to dimetindene (H1) alone and to low and high-dose corticosteroids. However, this model is no longer feasible after the new German Animal Protection Law in 1986.
A piglet model was developed which was handicapped from the beginning by respiratory depression induced by compound 48/80 independently of histamine release. A dose had to be chosen which mostly induced only systemic histamine release reactions (grade 2), not life-threatening reactions (grade 3) confounded by respiratory distress. In addition, basal plasma histamine levels were higher than in man by one order of magnitude. however, the advantage of the piglet model was the influence of histamine on the heart rate which is similar to that in humans.
In a randomized trial, the combination of dimetindene and cimetidine was superior to that of dimetindene and ranitidine or famotidine, respectively. The problem of “equieffective” doses in this field is discussed: separate clinical trials are necessary to demonstrate the effectiveness of each combination in preventing most sufficiently life-threatening reactions.
KeywordsHistamine Cimetidine Ranitidine Respiratory Depression Histamine Release
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