Recombinant human diamine oxidase prevents histamine-induced hypoxia, shock and death in guinea pigs

Abstract

Background and objective Histamine is the principal effector of anaphylaxis, and circulating levels correlate well with symptom severity in Hymenoptera venom–induced anaphylaxis. Adrenaline, the recommended first-line therapy, does not neutralize histamine and may cause relevant adverse effects. Recombinant human diamine oxidase (rhDAO), engineered with a mutated heparin-binding motif, exhibits improved pharmacokinetics and rapid histamine-degrading activity. The primary aim of this study was to evaluate whether prophylactic or particularly therapeutic rhDAO prevents or reduces histamine-induced shock compared with adrenaline in guinea pigs. Methods Guinea pigs received subcutaneous histamine (1 mg/kg) with or without intramuscular adrenaline or intravenous rhDAO (2–8 mg/kg). Mean arterial pressure, heart rate, and arterial oxygen partial pressure (PaO₂) were monitored. Plasma histamine and rhDAO levels were measured. Results Histamine injection raised plasma levels above 200 ng/ml and consistently induced shock with 42% mortality. Prophylactic and therapeutic rhDAO completely degraded circulating histamine, reduced shock incidence from 100% to 0% at the highest doses, shortened tachycardia, improved PaO₂ and decreased mortality. Intramuscular adrenaline (0.005 or 0.01 mg/kg) did not improve hemodynamics, oxygenation or survival. Conclusion Recombinant hDAO prevented and treated histamine-induced shock and hypoxia, whereas adrenaline was ineffective. These findings support clinical development of rhDAO for life-threatening histamine-mediated conditions, including anaphylaxis.

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