The effects of quinolones and NSAIDs upon GABA-evoked currents recorded from rat dorsal root ganglion neurones

R. F. Halliwell, P. G. Davey, J. J. Lambert

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Abstract

Recent animal studies have demonstrated a proconvulsant effect of certain quino-lone and non-steroidal anti-inflammatory drug combinations. Radioligand binding experiments have indicated that these actions may be mediated by antagonism of the GABAA receptor. The present study has further investigated this hypothesis ina functional assay by examining the effects of the quinolones ciprofloxacin and ofloxacin alone and in combination with either fenbufen or biphenyl acetic acid (BPAA) upon GABA-evoked currents recorded from voltage-clampedrat dorsal root ganglion neurones (DRG) maintained in cell culture.GABA-evoked whole cell currents were weakly but dose-dependently (30 μM-1 mM) reduced in the presence of ciprofloxacin and ofloxacin. The IC50 for ciprofloxacin was 100 μm but greater than 1 mM for ofloxacin. Application of either fenbufen (100 μm) or BPAA (100 μm) alone produced little effect on the GABA-evoked currents. However, the inhibitory action of ciprofloxacin was enhanced in the presence of 100 μm fenbufen by approximately five-fold whereas the antagonism of GABA responses by ofloxacin was unaffected. In contrast, BPAA (100 μm) had a dramatic effect on the inhibitory actions of both antibiotics such that the IC50 for ciprofloxacin and ofloxacin was reduced to 0.03 and 0.3 μM respectively.The present results support earlier binding studies and extend them by demonstrating electrophysiologically a potent quinolone/NSAID drug interaction at the GABAA receptor. The mechanism(s) of this novel interaction remains to be determined. These results are commensurate with clinical observations of an increased risk of fits in patients prescribed certain quinolones together with certain NSAIDs.

Original languageEnglish
Pages (from-to)209-218
Number of pages10
JournalJournal of Antimicrobial Chemotherapy
Volume27
Issue number2
DOIs
Publication statusPublished - 1 Feb 1991

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Ofloxacin
Quinolones
Spinal Ganglia
Non-Steroidal Anti-Inflammatory Agents
Ciprofloxacin
gamma-Aminobutyric Acid
Neurons
Acetic Acid
GABA-A Receptors
Inhibitory Concentration 50
Drug Combinations
Drug Interactions
Anti-Inflammatory Agents
Cell Culture Techniques
Anti-Bacterial Agents
fenbufen
diphenyl

Cite this

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abstract = "Recent animal studies have demonstrated a proconvulsant effect of certain quino-lone and non-steroidal anti-inflammatory drug combinations. Radioligand binding experiments have indicated that these actions may be mediated by antagonism of the GABAA receptor. The present study has further investigated this hypothesis ina functional assay by examining the effects of the quinolones ciprofloxacin and ofloxacin alone and in combination with either fenbufen or biphenyl acetic acid (BPAA) upon GABA-evoked currents recorded from voltage-clampedrat dorsal root ganglion neurones (DRG) maintained in cell culture.GABA-evoked whole cell currents were weakly but dose-dependently (30 μM-1 mM) reduced in the presence of ciprofloxacin and ofloxacin. The IC50 for ciprofloxacin was 100 μm but greater than 1 mM for ofloxacin. Application of either fenbufen (100 μm) or BPAA (100 μm) alone produced little effect on the GABA-evoked currents. However, the inhibitory action of ciprofloxacin was enhanced in the presence of 100 μm fenbufen by approximately five-fold whereas the antagonism of GABA responses by ofloxacin was unaffected. In contrast, BPAA (100 μm) had a dramatic effect on the inhibitory actions of both antibiotics such that the IC50 for ciprofloxacin and ofloxacin was reduced to 0.03 and 0.3 μM respectively.The present results support earlier binding studies and extend them by demonstrating electrophysiologically a potent quinolone/NSAID drug interaction at the GABAA receptor. The mechanism(s) of this novel interaction remains to be determined. These results are commensurate with clinical observations of an increased risk of fits in patients prescribed certain quinolones together with certain NSAIDs.",
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AU - Davey, P. G.

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N2 - Recent animal studies have demonstrated a proconvulsant effect of certain quino-lone and non-steroidal anti-inflammatory drug combinations. Radioligand binding experiments have indicated that these actions may be mediated by antagonism of the GABAA receptor. The present study has further investigated this hypothesis ina functional assay by examining the effects of the quinolones ciprofloxacin and ofloxacin alone and in combination with either fenbufen or biphenyl acetic acid (BPAA) upon GABA-evoked currents recorded from voltage-clampedrat dorsal root ganglion neurones (DRG) maintained in cell culture.GABA-evoked whole cell currents were weakly but dose-dependently (30 μM-1 mM) reduced in the presence of ciprofloxacin and ofloxacin. The IC50 for ciprofloxacin was 100 μm but greater than 1 mM for ofloxacin. Application of either fenbufen (100 μm) or BPAA (100 μm) alone produced little effect on the GABA-evoked currents. However, the inhibitory action of ciprofloxacin was enhanced in the presence of 100 μm fenbufen by approximately five-fold whereas the antagonism of GABA responses by ofloxacin was unaffected. In contrast, BPAA (100 μm) had a dramatic effect on the inhibitory actions of both antibiotics such that the IC50 for ciprofloxacin and ofloxacin was reduced to 0.03 and 0.3 μM respectively.The present results support earlier binding studies and extend them by demonstrating electrophysiologically a potent quinolone/NSAID drug interaction at the GABAA receptor. The mechanism(s) of this novel interaction remains to be determined. These results are commensurate with clinical observations of an increased risk of fits in patients prescribed certain quinolones together with certain NSAIDs.

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