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Research ArticleArticle

Is Hydroxylamine-Induced Cytotoxicity a Valid Marker for Hypersensitivity Reactions to Sulfamethoxazole in Human Immunodeficiency Virus-Infected Individuals?

Timothy P. Reilly, Rodger D. MacArthur, Marti J. Farrough, Lawrence R. Crane, Patrick M. Woster and Craig K. Svensson
Journal of Pharmacology and Experimental Therapeutics December 1999, 291 (3) 1356-1364;
Timothy P. Reilly
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Rodger D. MacArthur
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Marti J. Farrough
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Lawrence R. Crane
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Patrick M. Woster
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Craig K. Svensson
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Abstract

Hypersensitivity (HS) reactions to sulfonamides and sulfones continue to limit their use in human immunodeficiency virus (HIV)-infected individuals. In vitro cytotoxicity of hydroxylamine metabolites toward peripheral blood mononuclear cells (PBMCs) has been proposed as a marker for these HS reactions. To test the validity of this in vitro system, we determined the selective susceptibility of PBMCs from HIV-infected patients to the cytotoxic effects of hydroxylamine metabolites of sulfamethoxazole (SMX) and dapsone (DDS). Concentration-cytotoxic response data were collected using PBMCs from 12 sulfa-HS (10 SMX-HS and 2 SMX/DDS-HS) and 10 sulfa-tolerant HIV-infected individuals. Although sulfamethoxazole hydroxylamine (SMX-NOH) and dapsone hydroxylamine (DDS-NOH) both caused concentration-dependent increases in cell death, DDS-NOH was significantly more potent in each subject (P < .0001). A comparison of a variety of mean data for sulfa-HS and -tolerant patient populations failed to demonstrate the increased susceptibility of PBMCs from HS patients, noted by others, to either SMX-NOH or DDS-NOH. Moreover, any trend toward an increased susceptibility of PBMCs from HS patients was eliminated when adjusted for control cell death. PBMCs from sulfa-HS patients showed significantly greater susceptibility to the stress of short term in vitro incubation (P < .02). Mean (S.D.) vehicle control cell death values were 24.1% (7.6%) for HS patients and 17.1% (4.4%) for tolerant patients. No significant correlation was observed between hydroxylamine-induced or control cell death and any of the recorded clinical parameters. Although several potential reasons are proposed to explain the disparity with past investigations, the data suggest that in vitro cytotoxicity is not a valid marker for HS reactions in HIV-infected individuals using currently accepted experimental procedures.

Footnotes

  • Send reprint requests to: Craig K. Svensson, Pharm.D., Ph.D., Department of Pharmaceutical Sciences, Wayne State University, Detroit, MI 48202. E-mail:cks{at}wizard.pharm.wayne.edu

  • Abbreviations:
    ADR
    adverse drug reaction
    DDS
    dapsone
    DMSO
    dimethyl sulfoxide
    MTT
    3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
    HBSS
    Hanks' balanced salt solution
    HIV
    human immunodeficiency virus
    HS
    hypersensitivity
    LC50
    concentration causing 50% cell death
    PBMC
    peripheral blood mononuclear cell
    TMP
    trimethoprim
    SMX
    sulfamethoxazole
    NOH
    hydroxylamine
    • Received May 11, 1999.
    • Accepted September 3, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 291 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 291, Issue 3
1 Dec 1999
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Research ArticleArticle

Is Hydroxylamine-Induced Cytotoxicity a Valid Marker for Hypersensitivity Reactions to Sulfamethoxazole in Human Immunodeficiency Virus-Infected Individuals?

Timothy P. Reilly, Rodger D. MacArthur, Marti J. Farrough, Lawrence R. Crane, Patrick M. Woster and Craig K. Svensson
Journal of Pharmacology and Experimental Therapeutics December 1, 1999, 291 (3) 1356-1364;

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Research ArticleArticle

Is Hydroxylamine-Induced Cytotoxicity a Valid Marker for Hypersensitivity Reactions to Sulfamethoxazole in Human Immunodeficiency Virus-Infected Individuals?

Timothy P. Reilly, Rodger D. MacArthur, Marti J. Farrough, Lawrence R. Crane, Patrick M. Woster and Craig K. Svensson
Journal of Pharmacology and Experimental Therapeutics December 1, 1999, 291 (3) 1356-1364;
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