Assessment of the Effects of Combination Therapy with Ciprofloxacin and Fenbufen on the Central Nervous Systems of Healthy Volunteers by Quantitative Electroencephalography

Abstract

The potential effects of concurrent administration of fenbufen and ciprofloxacin on central nervous system activity in healthy young subjects were investigated by electroencephalography (EEG). Visual analog scales (VAS) were used to assess subjective measures of concentration, vigilance, tension, and irritability. When ciprofloxacin was administered in combination with fenbufen, none of the EEG parameters or VAS ratings measured were significantly different from those measured when the drugs were administered alone.

The most common adverse effects associated with quinolone use include gastrointestinal, skin, and central nervous system (CNS) reactions (1, 8). The CNS adverse effects, including headache, dizziness, confusion, insomnia, and agitation, are usually mild to moderate in severity, occurring in 0.4 to 4.4% of patients (1, 3, 4, 12). Epileptic seizures and hallucinations, which are very rare, have been observed more frequently when quinolones are administered in combination with either theophylline or nonsteroidal anti-inflammatory drugs (NSAIDs) (1).

The excitatory effects of quinolones on the CNS may possibly be related to their inhibition of γ-aminobutyric acid (GABA) from binding to the GABA receptor (14, 19, 20). It is possible that concomitant administration of quinolones with NSAIDs further reduces GABA binding in the brain, resulting in the adverse CNS effects occasionally observed. In this study we investigated the electroencephalographic (EEG) and subjective effects in healthy young volunteers of combined administration of single oral doses of the carboxyfluoroquinolone derivative ciprofloxacin and the NSAID drug fenbufen and compared these results to those for each drug administered separately.

Twelve healthy volunteers (six females) aged 19 to 39 years gave their informed consent to take part in an open study which was approved by the Joint University/Health Authority Ethics Committee. No subject had a history of alcohol or drug abuse, was taking any medication that acts on the CNS, or had a history of epilepsy. Hematology, serum biochemistry, and full liver function tests were performed prior to the start of the study, and the results were normal for all participants. Subjects were asked to abstain from consuming alcohol or caffeine-containing foods and beverages for 24 h prior to each study day. Following an overnight fast, volunteers were randomized to receive fenbufen (300 mg per os) and ciprofloxacin (500 mg per os) separately and in combination on three different occasions. There was a minimum period of 7 days between the treatments.

For EEG, several measures which have been shown to be sensitive to the effects of CNS-stimulatory drugs were selected. These included the contingent negative variation (CNV), an evoked potential related to arousal and attention (2, 15) which is increased in magnitude by a large number of CNS-stimulatory drugs (16), and auditory and visual evoked potentials (AEP and VEP, respectively), which show increased amplitude and reduced latency in response to CNS stimulants (2, 16). Background EEG activity was also recorded to monitor changes in rhythmic activity. Changes in power spectra which are indicative of CNS stimulation, such as increased beta (13- to 35-Hz) activity, decreased alpha (8- to 12-Hz) activity with an increase in peak alpha frequency, and decreased delta slow-wave (0- to 4-Hz) activity (5, 9), were also measured. Epileptogenic activity was monitored by inspection of the EEG traces for increased theta (5- to 7-Hz) activity and sharp waves or spikes, especially over the temporal lobes, which are very sensitive to paroxysmal activity. Details of the EEG measurements have been described elsewhere (18). Subjective ratings of concentration, vigilance, tension, and irritability were assessed with visual analog scales (VAS) (11). The EEG and VAS measurements were made at 0 (baseline measurement), 30, 60, 90, 120, and 180 min postdose in the following order: VAS, CNV, AEP, VEP, resting EEG with eyes open, and resting EEG with eyes closed. Each series of measurements took about 15 min to complete.

The study apparatuses were sufficiently sensitive to detect a 15% change in the EEG measures and the VAS, with an alpha activity value of 0.05 and a beta activity value of 0.2.

Changes in levels of concentration, vigilance, tension, and irritability at each assessment time were calculated by subtracting the measurement on the VAS from baseline (predose values). Statistical analysis of the EEG and VAS data was carried out by two-way analysis of variance for comparing differences between treatments and by analysis of variance with repeated measures for comparing differences within each treatment. Fisher and Scheffe tests were used for multiple paired comparisons of the data. A P value of <0.05 was considered statistically significant. Data are shown as means ± standard deviations.

The main results from measuring evoked potentials are shown in Fig. 1. There were no significant changes from the predrug baseline (time zero) over the 3-h study period in CNV magnitude and reaction time or in the latency and amplitude of any of the components of the VEP or AEP for any of the drug conditions. Similarly, there were no significant differences in these measurements when ciprofloxacin and fenbufen were used separately or in combination.

FIG. 1.

Mean changes in levels of CNV, reaction time (RT), auditory P300 wave amplitude (Amp) and latency (Lat), and VEP (N₁P₂ wave amplitude [18]) following administration of ciprofloxacin and fenbufen alone and in combination. The data for power frequency spectra are not shown.

In the power spectral measurements, there were no significant differences in delta, theta, alpha, or beta activities between treatments. Visual inspection of ongoing EEG activity showed no spikes or sharp waves suggesting paroxysmal activity from any of the recording sites.

Regarding the VAS ratings (Fig. 2), there were again no significant changes over time in concentration, vigilance, tension, or irritability and there were no differences in results between the drug treatments.

FIG. 2.

Mean changes in VAS scores following administration of ciprofloxacin and fenbufen alone and in combination.

Ciprofloxacin has a broad spectrum of activity against a number of microorganisms and is used in the treatment of upper respiratory and urinary tract infections. Fenbufen is frequently used as an anti-inflammatory, analgesic, and antipyretic agent, because of its relatively low risk of gastric toxicity. The concurrent administration of these drugs rarely causes severe CNS adverse effects such as epileptic seizures and hallucinations (1). We have previously demonstrated that concurrent administration of fenbufen does not alter ciprofloxacin pharmacokinetics in humans (10). Since no cases of neurotoxic side effects have been reported for fenbufen, it is reasonable to assume that the severe CNS adverse effects observed are due to a pharmacodynamic interaction between fenbufen and ciprofloxacin in the brain.

In vitro studies have demonstrated that the CNS-excitatory effects of quinolones are, at least in part, due to concentration-dependent inhibition of GABA from binding to its receptor, thus restricting GABA-mediated inhibition of transmission in the brain (19, 20). The effect of quinolones on GABA binding in vitro is also augmented by the addition of theophylline and NSAIDs (14, 20). The in vitro work by Unseld et al. (21) also suggests that quinolone-induced CNS-stimulatory responses are mediated by the benzodiazepine-GABA_A-receptor complex. Using EEG, Unseld and coworkers (21) also showed that a single intravenous dose of ofloxacin had CNS-stimulatory effects in healthy young volunteers. The effects were only slightly augmented by the benzodiazepine antagonist flumazenil but were reversed by coadministration with the benzodiazepine midazolam.

The results of the present study, however, showed no significant changes in any of the EEG parameters or the VAS ratings when ciprofloxacin was administered in combination with fenbufen. This study was not placebo controlled, as its main purpose was to compare the effects of combination therapy with ciprofloxacin and fenbufen on CNS activity with the effects of each drug alone. Although ciprofloxacin penetrates well into the CSF, our findings suggest that the levels achieved after a single oral dose may not be sufficient to cause CNS excitation detectable by EEG recordings, perhaps due to insufficient occupancy of the GABA receptors. However, Thorsteinsson et al. (17) have reported that ciprofloxacin alone does not change EEG responses in healthy young volunteers, even after multiple doses.

Disease and age may contribute to the severe CNS adverse effects sometimes observed when quinolones and NSAIDs are coadministered. The presence of disease may increase the penetration of drugs into the CSF (6). Fluoroquinolones may also accumulate in the elderly following chronic dosing (7), due to the drugs’ reduced renal and hepatic clearances (13). These possibilities and our finding that the combination of ciprofloxacin with fenbufen into a single oral dose has no effect on CNS activity in healthy young volunteers indicate that further EEG evaluations of the neurological adverse effects associated with combination therapy with ciprofloxacin and fenbufen may require investigations with patients receiving chronic treatment with either drug.