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Regul Toxicol Pharmacol. 2016 Feb;74:161-9. doi: 10.1016/j.yrtph.2015.11.002. Epub 2015 Nov 26.

Safety study of Ciprofloxacin in newborn mice.

Author information

1
Inserm, U1141, Robert Debré Hospital, APHP, 75019, Paris, France; Denis Diderot-Paris 7 University, Robert Debré Hospital, Paris, France.
2
Inserm, U1141, Robert Debré Hospital, APHP, 75019, Paris, France; Denis Diderot-Paris 7 University, Robert Debré Hospital, Paris, France; Department of Developmental Biology, Robert Debré Hospital, APHP, Paris, France.
3
Inserm, Clinical Investigation Center CIC 1426, Robert Debré Hospital, APHP, Paris, France; Department of Pediatric Pharmacology and Pharmacogenetics, Robert Debré Hospital, APHP, Paris, France.
4
Inserm, U1141, Robert Debré Hospital, APHP, 75019, Paris, France; Denis Diderot-Paris 7 University, Robert Debré Hospital, Paris, France; Department of Pathology, Lariboisière Hospital, APHP, 75010, Paris, France.
5
Inserm, U1141, Robert Debré Hospital, APHP, 75019, Paris, France; Denis Diderot-Paris 7 University, Robert Debré Hospital, Paris, France; PhenoPups SAS, Evry, France.
6
Department of Pharmacy, Robert Debré Hospital, APHP, Paris, France.
7
EA4245, Faculté de Médecine, Université François Rabelais, Tours, France.
8
Department of Clinical Pharmacology and Clinical Trials, Louis Pradel Hospital, EPICIME, Lyon, France; CNRS, UMR, 5558, Lyon, France; Lyon-1 University, Lyon, France; Inserm, Clinical Investigation Center CIC1407, Louis Pradel Hospital, Lyon, France.
9
Department of Women's and Children's Health, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
10
Denis Diderot-Paris 7 University, Robert Debré Hospital, Paris, France; Inserm, Clinical Investigation Center CIC 1426, Robert Debré Hospital, APHP, Paris, France; Department of Pediatric Pharmacology and Pharmacogenetics, Robert Debré Hospital, APHP, Paris, France.
11
Inserm, U1141, Robert Debré Hospital, APHP, 75019, Paris, France; Denis Diderot-Paris 7 University, Robert Debré Hospital, Paris, France. Electronic address: boris.matrot@inserm.fr.

Abstract

Ciprofloxacin, a broad-spectrum antimicrobial agent belonging to the fluoroquinolone family, is prescribed off-label in infants less than one year of age. Ciprofloxacin is included in the European Medicines Agency priority list of off-patent medicinal products requiring evaluation in neonates. This evaluation is undergoing within the TINN (Treat Infections in Neonates) FP7 EU project. As part of the TINN project, the present preclinical study was designed to assess the potential adverse effects of Ciprofloxacin on neurodevelopment, liver and joints in mice. Newborn mice received subcutaneous Ciprofloxacin at 10, 30 and 100 mg/kg/day from 2 to 12 postnatal days. Peak plasma levels of Ciprofloxacin were in the range of levels measured in human neonates. We examined vital functions in vivo, including cardiorespiratory parameters and temperature, psychomotor development, exploratory behavior, arthro-, nephro- and hepato-toxic effects. We found no effect of Ciprofloxacin at 10 and 30 mg/kg/day. In contrast, administration at 100 mg/kg/day delayed weight gain, impaired cardiorespiratory and psychomotor development, caused inflammatory infiltrates in the connective tissues surrounding the knee joint, and moderately increased extramedullary hematopoiesis. The present study pleads for careful watching of cardiorespiratory and motor development in neonates treated with Ciprofloxacin, in addition to the standard surveillance of arthrotoxicity.

KEYWORDS:

Arthrotoxicity; Fluoroquinolone; Hepatotoxicity; Neonate; Nephrotoxicity; Neurodevelopment

PMID:
26627140
DOI:
10.1016/j.yrtph.2015.11.002
[Indexed for MEDLINE]
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