Sustained Deterioration of Hepatic Oxygenation After Nafamostat Mesilate‐Induced Anaphylactic Shock During Hemodiafiltration

Ookawara, Susumu; K, Ito; Morishita, Yoshiyuki

doi:10.1111/aor.13097

Cited by 5 publications

(1 citation statement)

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“…Several reports of nafamostat-induced anaphylactic reactions have been published in patients undergoing hemodiafiltration (Maruyama et al, 1996;Ookawara et al, 2018;Kim et al, 2016;Kim et al, 2021). When compared with that demonstrated by heparin, the adverse reaction profile during leukocytapheresis showed increased rates of "typical" histaminemediated symptoms such as headache, nausea, rash, itching, palpitations, dyspnea, and anaphylactic shock (Sawada et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Nafamostat is a Potent Human Diamine Oxidase Inhibitor Possibly Augmenting Hypersensitivity Reactions during Nafamostat Administration

Boehm

Alix

Petroczi

et al. 2022

J Pharmacol Exp Ther

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Nafamostat is an approved short-acting serine protease inhibitor. However, its administration is also associated with anaphylactic reactions. One mechanism to augment hypersensitivity reactions could be inhibition of diamine oxidase (DAO). The chemical structure of nafamostat is related to the potent DAO inhibitors pentamidine and diminazene. Therefore, we tested whether nafamostat is a human DAO inhibitor. Using different activity assays, nafamostat reversibly inhibited recombinant human DAO with an IC 50 of 300-400 nM using 200 mM substrate concentrations. The K i of nafamostat for the inhibition of putrescine and histamine deamination is 27 nM and 138 nM, respectively For both substrates, nafamostat is a mixed mode inhibitor with P values of <0.01 compared with other inhibition types. Using 80-90% EDTA plasma, the IC 50 of nafamostat inhibition was approximately 360 nM using 20 mM cadaverine. In 90% EDTA plasma, the IC 50 concentrations were 2-3 mM using 0.9 mM and 0.18 mM histamine as substrate. In silico modeling showed a high overlap compared with published diminazene crystallography data, with a preferred orientation of the guanidine group toward topaquinone. In conclusion, nafamostat is a potent human DAO inhibitor and might increase severity of anaphylactic reaction by interfering with DAO-mediated extracellular histamine degradation. SIGNIFICANCE STATEMENTTreatment with the short-acting anticoagulant nafamostat during hemodialysis, leukocytapheresis, extracorporeal membrane oxygenator procedures, and disseminated intravascular coagulation is associated with severe anaphylaxis in humans. Histamine is a central mediator in anaphylaxis. Potent inhibition of the only extracellularly histamine-degrading enzyme diamine oxidase could augment anaphylaxis reactions during nafamostat treatment.

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