1. Academic Validation
  2. Effect of premedications in a murine model of asparaginase hypersensitivity

Effect of premedications in a murine model of asparaginase hypersensitivity

  • J Pharmacol Exp Ther. 2015 Mar;352(3):541-51. doi: 10.1124/jpet.114.220780.
Christian A Fernandez 1 Colton Smith 1 Seth E Karol 1 Laura B Ramsey 1 Chengcheng Liu 1 Ching-Hon Pui 1 Sima Jeha 1 William E Evans 1 Fred D Finkelman 1 Mary V Relling 2
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Sciences (C.A.F., C.S., S.E.K., L.B.R., C.L., W.E.E., M.V.R.) and Department of Oncology (S.E.K., C.-H.P., S.J.), St. Jude Children's Research Hospital, Memphis, Tennessee; Department of Medicine, Cincinnati Veterans Affairs Medical Center, Cincinnati, Ohio (F.D.F.); Department of Internal Medicine, Division of Immunology, Allergy and Rheumatology, University of Cincinnati College of Medicine, Cincinnati, Ohio (F.D.F.); and Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (F.D.F.).
  • 2 Department of Pharmaceutical Sciences (C.A.F., C.S., S.E.K., L.B.R., C.L., W.E.E., M.V.R.) and Department of Oncology (S.E.K., C.-H.P., S.J.), St. Jude Children's Research Hospital, Memphis, Tennessee; Department of Medicine, Cincinnati Veterans Affairs Medical Center, Cincinnati, Ohio (F.D.F.); Department of Internal Medicine, Division of Immunology, Allergy and Rheumatology, University of Cincinnati College of Medicine, Cincinnati, Ohio (F.D.F.); and Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (F.D.F.) mary.relling@stjude.org.
Abstract

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 = 4.2 × 10(-13)) and elevated levels of mouse mast cell Protease 1 (P = 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 = 1.2 × 10(-5)). However, pretreatment with oral dexamethasone was the only agent capable of mitigating the severity of the hypersensitivity (P = 0.03) and partially restoring asparaginase activity (P = 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.

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