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Effect of premedications in a murine model of asparaginase hypersensitivity.

Journal:
The Journal of pharmacology and experimental therapeutics


Issue Date:
2015


Abstract(summary):

A murine model was developed that recapitulates key features of clinical hypersensitivity to Escherichia coli asparaginase. Sensitized mice developed high levels of anti-asparaginase IgG antibodies and had immediate hypersensitivity reactions to asparaginase upon challenge. Sensitized mice had complete inhibition of plasma asparaginase activity (P =3D 4.2 * 10(-13)) and elevated levels of mouse mast cell protease 1 (P =3D 6.1 * 10(-3)) compared with nonsensitized mice. We investigated the influence of pretreatment with triprolidine, cimetidine, the platelet activating factor (PAF) receptor antagonist CV-6209 [2-(2-acetyl-6-methoxy-3,9-dioxo-4,8-dioxa-2,10-diazaoctacos-1-yl)-1-ethyl-pyridinium chloride], or dexamethasone on the severity of asparaginase-induced allergies. Combining triprolidine and CV-6209 was best for mitigating asparaginase-induced hypersensitivity compared with nonpretreated, sensitized mice (P =3D 1.2 * 10(-5)). However, pretreatment with oral dexamethasone was the only agent capable of mitigating the severity of the hypersensitivity (P =3D 0.03) and partially restoring asparaginase activity (P =3D 8.3 * 10(-4)). To rescue asparaginase activity in sensitized mice without requiring dexamethasone, a 5-fold greater dose of asparaginase was needed to restore enzyme activity to a similar concentration as in nonsensitized mice. Our results suggest a role of histamine and PAF in asparaginase-induced allergies and indicate that mast cell-derived proteases released during asparaginase allergy may be a useful marker of clinical hypersensitivity. U.S. Government work not protected by U.S. copyright.


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