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Antimicrobial Agents and Chemotherapy, July 1998, p. 1831-1836, Vol. 42, No. 7
BAYER AG, Institute of Toxicology, 42096 Wuppertal, Germany
Received 29 December 1997/Returned for modification 25 February
1998/Accepted 6 May 1998
Fluoroquinolones have been reported to induce central nervous
system side effects, including seizures and psychiatric events. Although relatively rare in patients up to now, the proconvulsant activity depends on the chemical structure and might be a critical endpoint of some new representatives of this valuable class
of antimicrobials. The electrophysiological determination of
field potentials in the CA1 region of the rat
hippocampus slice allowed an assessment of the excitatory
potential of fluoroquinolones and might be predictive for their
neurotoxic potency in vivo. An optimization of this method and its
extension to other fluoroquinolones resulted in a defined rank order.
Well-known already-marketed quinolones as well as some fluoroquinolones
under evaluation and development were used. The dose range
tested was between 0.5 and 4 µmol/liter, which was
comparable to the therapeutic concentration in the brain. All
tested compounds increased the population spike amplitude in a
concentration-dependent manner, and the resulting excitatory potency
was highly dependent on the chemical structure, with compounds ranging
from least to most excitatory as follows: ofloxacin, ciprofloxacin,
nalidixic acid, moxifloxacin (= BAY × 8843), fleroxacin,
lomefloxacin, enoxacin, clinafloxacin (much more excitatory than
enoxacin), tosufloxacin, trovafloxacin, BAY 15-7828, and BAY × 9181 (much more excitatory than BAY 15-7828). The proposed hippocampus
slice model not only is suitable for giving valuable alerts as to
convulsive potential during candidate selection but also enables
mechanistic investigations. These investigations pointed to the
N-methyl-D-aspartate receptor as the probable
target of the fluoroquinolone effects.
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Determination of the Excitatory Potencies of
Fluoroquinolones in the Central Nervous System by an In Vitro
Model
*
Corresponding author. Mailing address: BAYER AG,
Institute of Toxicology, Aprather Weg, 42096 Wuppertal,
Germany. Phone: 49-(0)202-368830. Fax: 49-(0)202-364137.
E-mail: GABRIELE.SCHMUCK.GS{at}bayer-ag.de.
Antimicrobial Agents and Chemotherapy, July 1998, p. 1831-1836, Vol. 42, No. 7
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
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