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In vitro and in vivo activity of iclaprim, a diaminopyrimidine compound and potential therapeutic alternative against Pneumocystis pneumonia

  • E. M. Aliouat
  • E. Dei-Cas
  • N. Gantois
  • M. Pottier
  • C. Pinçon
  • S. Hawser
  • A. Lier
  • D. B. Huang
Original Article
  • 190 Downloads

Abstract

Pneumocystis pneumonia is a serious complication that may affect immunosuppressed patients. The absence of reliable and safe therapeutic alternatives to trimethoprim–sulfamethoxazole (TMP/SMX) justifies the search for more effective and less toxic agents. In this study, the in vitro and in vivo anti-Pneumocystis jirovecii activity of iclaprim, a diaminopyrimidine compound that exerts its antimicrobial activity through the inhibition of dihydrofolate reductase (DHFR), as does TMP, was evaluated alone or in combination with SMX. The antimicrobial activity of iclaprim was tested in vitro using an efficient axenic culture system, and in vivo using P. carinii endotracheally inoculated corticosteroid-treated rats. Animals were orally administered iclaprim (5, 25, 50 mg/kg/day), iclaprim/SMX (5/25, 25/125, 50/250 mg/kg/day), TMP (50 mg/kg/day), or TMP/SMX (50/250 mg/kg/day) once a day for ten consecutive days. The in vitro maximum effect (Emax) and the drug concentrations needed to reach 50% of Emax (EC50) were determined, and the slope of the dose–response curve was estimated by the Hill equation (Emax sigmoid model). The iclaprim EC50 value was 20.3 μg/mL. This effect was enhanced when iclaprim was combined with SMX (EC50: 13.2/66 μg/mL) (p = 0.002). The TMP/SMX EC50 value was 51.4/257 μg/mL. In vivo, the iclaprim/SMX combination resulted in 98.1% of inhibition compared to TMP/SMX, which resulted in 86.6% of inhibition (p = 0.048). Thus, overall, the iclaprim/SMX combination was more effective than TMP/SMX both in vitro and in vivo, suggesting that it could be an alternative therapy to the TMP/SMX combination for the treatment of Pneumocystis pneumonia.

Notes

Funding

This study was funded by Motif BioSciences Inc., New York, USA.

Compliance with ethical standards

Conflict of interest

DBH is an employee of Motif BioSciences. SH is an employee of IHMA.

Ethical approval

This research involved animals. All procedures in this research were in compliance with the Animal Welfare Act, the Guide for the Care and Use of Laboratory Animals, and the Office of Laboratory Animal Welfare.

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • E. M. Aliouat
    • 1
  • E. Dei-Cas
    • 1
  • N. Gantois
    • 1
  • M. Pottier
    • 1
  • C. Pinçon
    • 2
  • S. Hawser
    • 3
  • A. Lier
    • 4
  • D. B. Huang
    • 5
    • 6
  1. 1.Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 8204 – CIIL - Centre d’Infection et d’Immunité de LilleLilleFrance
  2. 2.Biomathematics Laboratory, Faculty of Pharmaceutical SciencesUniversity of LilleLilleFrance
  3. 3.IHMA Europe SàrlMontheySwitzerland
  4. 4.Stony Brook University HospitalStony BrookUSA
  5. 5.Motif BioSciencesNew YorkUSA
  6. 6.Rutgers New Jersey Medical SchoolNewarkUSA

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