Gen. Pharmac. Vol. 23, No. 5, pp. 853-859, 1992 Printed in Great Britain.All rights reserved
0306-3623]92 $5.00+ 0.00 Copyright© 1992PergamonPress Ltd
REPEATED TREATMENT WITH QUINOLONES POTENTIATES THE SEIZURES I N D U C E D BY AMINOPHYLLINE IN GENETICALLY EPILEPSY-PRONE RATS ANGELADE SARRO,I GIUSEPPER. TRIMARCHI,l DOMENICOAMMENDOLA2 and GIOVAMBATTISTADE SARRO3 qnstitute of Pharmacology, School of Medicine, 2Institute of Veterinary Pharmacology, School of Veterinary Medicine, University of Messina and 3Chair of Pharmacology, School of Medicine, University of Reggio, Calabria, Italy (Received 20 January 1992)
Almtraet--l. The effects of a chronic treatment with several quinolone derivatives on the aminophyUineinduced convulsions in the genetically epilepsy-prone rat have been investigated. 2. Two series of experiments have been performed: in the first one animals received the quinolone twice a day for 5 days, then were given aminophylline (80-140 mg. kg - J, i.p.); in the second series of experiments the rats were treated once a day with the quinolone plus 120 mg.kg -~ of aminophylline for 5 days. The changes induced by both treatment protocols on electrocortical activity and on the occurrance of seizures have been evaluated. 3. Enoxacin reduced the dose of aminophylline necessary for the induction of seizures in a higher degree with respect to the other quinolone derivatives. The derivatives which showed minor proconvulsant properties were ofloxacin, ciprofloxacin and cinoxacin. The potentiation of seizures induced by quinolones appeared a dose-dependent phenomenon which was more evident when high doses of quinolones were used. 4. The chronic treatment carried out daily with quinolones and aminophylline suggests that additive neurotoxic effects of both classes of drugs may contribute to the increase of severity of seizure scores. 5. The possible role of GABA-benzodiazepine, excitatory amino acid, purinergic mechanisms as well as the role of pharmacokynetic factors are discussed.
INTRODUCTION The quinolone agents are an important therapeutic class of drugs showing a great and broad spectrum of antibacterial activity. However, clinical experience has indicated a possible incidence of undesirable adverse reactions and drug interactions following their use. Side effects such as dizziness, headache and restlessness have most commonly been reported. Seizures and hallucinations have been described more frequently either in patients with underlying predisposition (i.e. epilepsy, cerebro-vascular diseases and psychosis) to central nervous system (C.N.S.) effects or in patients receiving non-steroidal antiinflammatory drugs concomitantly with quinolones (see Dimpfel et al., 1991). Many articles have also been published on the interaction of some quinolones with theophylline and, recently we described the behavioral pattern of this interaction in two different strains of rats. In this study we used normal Sprague-Dawiey rats and genetically epilepsy-prone rats. The latter have generalized clonic-tonic convulsions to loud tone and have been reported to have an increased seizure susceptibility to a variety of nonaudiogenic convulsant treatments, including pentylenetetrazoi, electroshock (Laird and Jobe, 1987; Faingold, 1988; Dailey et al., 1989), fluorothyl (Franck et al., 1989), and kindling induction to angular bundle stimulation (Savage et al., 1986). Extensive Gr 2~/~E
853
study was done on the nature of audiogenic seizures in the genetically epilepsy-prone rats; pathology was observed in both peripheral (Penny et al., 1983) and central auditory regions (Faingold et al., 1986a, b). A non-specific propensity to generalized seizures, regardless of the eliciting stimuli, enhances the value of this strain of rats as a model in the study of gene-linked generalized epilepsy. Several widespread neurotransmitter abnormalities have also been rcported in the genetically epilepsy=prone rats, including abnormal concentration of norepinephrine (NE) (Dailey and Jobe, 1986), serotonin (5-HT) (Dailey et aL, 1989; Jobe et aL, 1986), excitatory amino acids (Chapman et ai., 1986), bcnzodiazepine receptors and GABA levels (Booker et al., 1986; Tacke and Braestrup, 1984). Since aminophylline has been known for many years to induce convulsions (Johns et a/., 1951; McColl et ai., 1956; Stone and Javid, 1980; Dunwiddie and Worth, 1982) and we described that the pattern of responsiveness to this convulsant agent may be different in the genetically epilepsy-prone rats and in normal rats (De Sarro and De San'o, 1991), we decided to better clarify this phenomenon. Thus, the intent of the present study was to examine aminophylline-induced seizures in the genetically epilepsyprone rats after a chronic treatment (5 days) with doses of quinolones corresponding to one single therapeutic dose (STD) in humans.
854
ANGELADE SARROet al. MATERIALS AND METHODS
Animals Genetically epilepsy-prone susceptible rats (a strain derived from Sprague-Dawley rats) were inbred at the University of Messina vivarium facilities from progenitor stock exhibiting grade 9 seizures to audiogenic testing (GEPR-9, according to the scoring system of Jobe et al., 1973) obtained from Dr B. S. Meldrum (University of London). Rats were housed 3 or 4 per cage in stable conditions of humidity (60 + 5%) and temperature (21 + 2°C) and allowed free access to food and water until the time of the experiment. Animals were maintained on a 12 hr light and 12 hr dark cycle (light on 07:00-19:00, off 19:00-07:00). Male rats, 10-18 weeks old, 220-290 g were used. Genetically epilepsy-prone rats were tested three times at weekly intervals between 6 and 8 weeks of their life and only animals which showed an audiogenic seizure in all three exposures to sound stimulation were used for these experiments. Seizures were induced in genetically epilepsy-prone rats by exposing them to a mixed frequency sound of 12-16 kHz, 109 dB intensity under a hemispheric plexiglass dome. Chronic treatment The chronic treatment dose of each quinolone was administered twice a day, at 08:00 and 20:00 and lasted 5 days. The drugs were administered by gastric intubation (p.o.). The doses used were: ciprofloxacin hydrochloride, 5 and 10mg.kg-t; cinoxacin, 10 and 20 mg.kg-~; norfloxacin, 7.5 mg. kg- ~; rufloxacin hydroehloride, 5 mg. kg-~; enoxacin sesquhydrate, 5 and 7.5mg.kg-~; ofloxacin, 5 and 10 mg. kg-i; pefloxacin mesylate, 8 mg.kg-t; and pipemidic acid, 10 mg.kg -~. Control group received vehicle p.o. as appropriate. On day 6 seizures were induced in genetically epilepsyprone rats (average N = at least 8 for each dose of compound studied) pretreated with quinolones or vehicle orally (4ml.kg -~) lhr prior to i.p. administration of aminophylline. Genetically epilepsy-prone rats were injected with aminophylline (60, 80, 100, 120, or 140mg.kg -t, i.p.) dissolved in sterile saline (4 ml.kg -t, i.p.). Animals were placed in a plexiglass box (30 x 30 x 45 cm), were observed for 6 hr and seizure intensity was scored on the following scale: 0, no response; 1, wandering and twitching nose; 2, tremor and hind limb extension; 3, head nodding; 4, jumping and fore limb clonus; 5, forelimb clonus and rearing; 6, falling down; 7, tonic extension of all four limbs; 8, clonictonic seizures followed by post-ictal period or fatal outcome. The fraction of animals exhibiting seizures was observed for 6hr and the intensity score for each animal was recorded. In addition, another group of animals was treated once a day orally for 5 days with cinoxacin (10 and 20 mg. kg-~), ofloxacin (5mg-kg-t), enoxacin (5mg.kg -t) and aminophyiline (120 mg-kg -I, i.p.). Electrocortical activity Electrocortical (ECoG) activity was recorded (8 channel ECoG machine OTE Biomedica, Florence, Italy) through four chronically-implanted steel screw electrodes, inserted bilaterally onto the fronto-parietal area. The ground electrode was implanted epidurally over the nasal bone. At least 3 rats treated with the highest dose of quinolone derivatives + aminophylline or aminophylline alone were studied for changes in ECoG activity. Statistical analysis Data were analyzed by Mann-Whithey U-test and the CD~0 values (+95 confidence limits) for clonic component of seizure (phase 5) were calculated by Litchfield-Wilcoxon test (Litchfield and Wileoxon, 1949).
Drugs Aminophylline (Sigma, St Louis, Mo., U.S.A.) was dissolved in sterile saline. Pipemidic acid (Sigma), ciprofloxacin hydrochloride (Sigma and Bayer Italia, Milano, Italy), enoxacin sesquhydrate (Zambeletti, Milano, Italy), norfloxacin (Merck, Sharp & Dohme, Rome, Italy), ofloxacin (Glaxo, Verona, Italy), rufloxacin hydrochloride (Mediolanum Farmaceutici, Milano, Italy), cinoxacin (Eli Lilly Italia, Sesto Fiorentino, Italy) were dissolved in a solution containing 50% of dimethylsulfoxide in sterile saline. Pefloxacin mesylate (Rhon~Poulenc Pharma, Milano, Italy) was dissolved in sterile H20. RESULTS
Chronic treatment with quinolones in genetically epilepsy-prone rats The effects of a chronic treatment of aminophylline with pipemidic acid, enoxacin, ofloxacin, pefloxacin, cinoxacin, rufloxacin, norfloxacin or ciprofloxacin on occurrence of seizures are presented in Tables 1 and 2, whilst the relative CDs0 for clonic component of seizure (phase 5) are reported in Table 3. The concentration of aminophylline that produced a high incidence of seizures was lower after chronic treatment with enoxacin in comparison to other quinolones studied. The percentage of rats showing seizures when treated orally twice daily for 5 days with 5 or 1 0 m g ' k g -~ of enoxacin, l hr before receiving aminophylline was significantly increased (P < 0.01) in comparison to group receiving vehicle + aminophylline. Similar and less evident (P < 0.05) convulsant effects were observed in animals treated with pefloxacin, rufloxacin, norfloxacin and pipemidic acid. Whereas after a chronic treatment with ofloxacin, cinoxacin and ciprofloxacin was observed a lower increase in seizure severity score (Tables 1 and 2). Electrocorticographic epileptic signs were observed more rapidly in rats treated with enoxacin + aminophylline than in those received other quinolones + aminophylline. In addition, no significant changes were observed in the electrocorticographic pattern when genetically epilepsy-prone rats received v e h i c l e + a m i n o p h y l l i n e alone or a quinolone d e r i v a t i v e + a m i n o p h y l l i n e (results not shown).
Chronic concomitant treatment with quinolones and aminophylline Systemic administration once a day for 5 days of quinolones orally and a dose of aminophylline of 120 mg. k g - l , i.p. produced an increase on occurrence of seizures (Table 4). The concentration of aminophylline that produced a high incidence o f seizure was lower after chronic treatment with enoxacin ( 5 m g ' k g -~) in comparison to other quinolones (Table 4). In addition, cinoxacin (10 and 20 m g . k g -~) and ofloxacin (5 m g . k g -~) induced a low incidence of seizures after chronic treatment (Table 4). Some electrographic epileptic signs were observed in rats which did not show behavioral epileptic symptoms. The E C o G discharges consisted in single spikes, spike-waves or burst of spikes of brief duration. In animals showing clear epileptic symptoms such as head rearing, tremor, clonus of fore and hind limbs, tonic extension and rearing, complexes o f
Effects of quinolones on aminophylline-indueed convulsions
855
Table 1. The effectsof somequinoloneson seizuresinducedby aminophyllinein genetically epilepsy-pronerats Median seizure score time (hr) Quinolone Vehicle
Cinoxacin 10 m g ' k g -l
Cinoxacin 2 0 m g . k g -I
Ofloxacin 5 m g ' k g -I
Ofloxacin 1 0 m g ' k g -~ Pipemidic acid 10mg-kg -~ Rufloxacin 5 m g ' k g -I
Aminophylline (mg-kg -I, i.p.) 60 80 100 120 140 160 180 200 80 100 120 140 80 100 120 140 160 80 100 120 140 80 100 120 140 80 100 120 140 80 100 120 140 160
0-1 0.4 + 0.2 0.8 + 0.2 1.2 _+0.2 1.6 + 0.2 2.0_+0.2 2.2_+0.2 3.4 + 0.3 4.2 -+ 0.4 1.2 -+ 0.3* 1.5_+0.3 1.8-+0.3 2.1 _+0.4 1.5 _+0.4t 1.9 -+_0.3~" 2.2-+0.3 2.5 -+ 0.4 2.8-+0.3 1.2 _+ 0.3 1.6-+0.4 1.9_+0.4 2.2+0.3 1.6+_0.4"1" 2.0-+0.4t 2.3 -+ 0.3* 2.7 _+ 0.3 1.8 _+ 0.3t 2.4+0.4t 3.2_+0.4t 3.6 _+0.3~" 1.9 + OAt 2.3_+0.3t 3.1-+0.3t 3.4-+0.3t 3.7+0.4~-
1-2 0.4 __.0.2 1.0 __.0.2 1.6 _ 0.2 2.0 _ 0.2 2.4_+0.2 3.3+0.3 4.6 __.0.3 5.2 __.0.3 1.4 -+ 0.4 1.8+0.4 2.2-+0.4 2.6_+0.3 1.9 _+ 0.3t 2.3+0.3* 2.7+0.4 2.9 + 0.3 3.3_+0.4 1.4 _+0.3 1.9_+0.2 2.2-+0.3 2.8_+0.4 2.0+0.4t 2.5-+0.4t 2.9 _+ 0.3* 3.8 _+ 0.4t 2.3 _+ 0.4~" 2.9-+0.4t 3.6_+0.3~" 4.4 _+0.4t 2.2 + 0.2"1" 2.7+0.3~" 3.5_+0.31" 4.2+0.4t 4.8_+0.3t
2-4 0.5 __.0.2 1.2 -t- 0.2 1.7 __.0.2 2.0 + 0.2 2.8_+0.3 4.1 _+0.2 5.2 __.0.4 6.3 _ 0.4 1.7 -+ 0.3 2.1 + 0 . 4 2.6_+0.4 3.2_+0.4 2.2 _+0.4* 2.6-+0.3~" 2.9+0.3* 3.3 __.0.4 4.3_+0.4 1.8 -+ 0.3 2.2+_0.4 2.7-+0.3 3.5+0.3 2.3 __.0.4~" 2.9_+0.4t 3.8 _+ OAt 4.7 _ OAt 2.4 _+ 0.4~" 3.3-+0.3"f" 4.4_+0.4"f" 5.6 _+OAt 2.6 _+0.3~" 3.4+0.4"[" 4.4_+0.31" 5.1-+0.41" 5.6_+0.4~"
4-6 0.5 + 0.2 1.2 + 0.2 1.8 -t- 0.2 2.2 _+0.2 3.2_+0.2 4.2_+0.3 5.5 + 0.4 6.6 + 0.4 2.0 _ 0.3 2.4-+0.4 3.0_+0.4 3.8_+0.4 2.6 _+OAt 3.3-+0.5~" 3.7 -+ 0.4t 4.2 _ 0.4 4.9+0.3 2.1 -+ 0.3 2.5_+0.4 3.2-+0.3 4.0-+0.4 3.1-+0.3t 3.8_0.4~" 4.6 + 0.4~" 5.6 _+ 0.3t 2.7 -t- 0.3t 3.8_+0.4t 5.3_+0.4t 6.8 _+0.4t 2.8 _+ 0.3t 3.7+0.3t 5.2_0.4t 5.7-+0.4t 6.4-+0.3t
Groups of 8-10 animals were orally administered twice a day for 5 days with a quinolone derivative and again with one dose of the drug the day of test and 1 hr later injected i.p. with the stated doses of aminophylline and were observed for 6 hr. The incidence of each seizure phase was recorded and median seizure score + SEM, for each dose level studied, is expressed, Significant differences in the incidence of seizure phases, between concurrent aminophylline alone and quinolones plus aminophylline, are denoted by *P < 0.05 and t P < 0.01 using Mann-Whitney U-test.
spikes or spike-waves lasting from 20 to 140 sec and occurring periodically were recorded (Fig. 1). DISCUSSION
The present study demonstrates marked differences among quinolones to potentiate the convulsant activity of aminophylline in genetically epilepsyprone rats. We have recently hypothesized that (a) the pathology in auditory regions, specifically in the inferior colliculus, does not occur by itself in the genetically epilepsy-prone rats but is strongly linked to the brainstem abnormality and (b) the necessary basis of clonic-tonic seizure susceptibility in the genetically epilepsy-prone rats is a pathology in brainstem regions (De Sarro and De Sarro, 1991). The GABA and excitatory amino acids may play a primary role in various seizure models (Iadarola and Gale, 1982; De Sarro et al., 1984, 1986; McNamara et al., 1983; Millan et al., 1986) and perhaps in the seizures induced by aminophylline as recently observed in our laboratory (De Sarro et al., 1991). It is becoming increasingly apparent that genetically epilepsy-prone rats are a valuable tool in the study of the factors underlying a non-specific genetic propensity for generalized seizures.
These studies provide further evidence that some quinolones possess pro-convulsant activity as previously described in man (Areieri et aL, 1987; Ball, 1986; Fass, 1987; Monk and Campoli-Richards, 1987) and this occurs more often in patients receiving quinolones in combination with theophylline (Maesen et al., 1984). The mechanism of decrease in theophylline clearance induced by quinolones has generally been considered to be an inhibition of theophylline metabolism: quinolones are able to competitively inhibiting cytochrome P450 activity in hepatic microsomes and theophylline is metabolized by the cytochrome P450 system. Some quinolones and their metabolite 4-oxoquinolone, seem to be the main causes of the changes in theophylline metabolic clearance due to competitive inhibition of the N-demethylation pathway of theophylline (Wijnards et al., 1986; Hasegawa et al., 1990). In addition, a recent study in rats demonstrated that ofloxacin, which does not form a 4-oxometabolite, has also an effect on seizures induced by aminophylline without affecting the pharmaeokinetic and metabolism of theophylline (De Sarro and De Sarro, 1991). However, recent results indicate that the substitution on 3' and Y-carbon atoms of piperazinyl ring at 7 position of the quinolone molecule may play
856
ANGELA DE SARRO et al. Table 2. The effects of some quinolones on seizures induced by aminophylline in genetically epilepsy-prone rats Median seizure score time (hr) Quinolone Vehicle
Ciprofloxacin 5 mg.kg -I Ciprofloxacin 10mg.kg t Norfloxacin 7.5mg.kg -~ Enoxacin 5mg.kg I
Enoxacin 7.5mg.kg -I
Pefloxacin 8 m g . k g -~
Aminophylline (mg. kg- t, i.p.)
0-1
I-2
2-4
4-6
60 80 100 120 140 160 180 200 80 100 120 140 80 100 120 140 80 100 120 140 60 80 100 120 140 60 80 100 120 140 80 100 120 140 160
0.4 + 0.2 0.8 + 0.2 1.2 _+ 0.2 1.6_+0.2 2.0 _+ 0.2 2.2_+0.2 3.4_+0.3 4.2 _+0.4 1.2 _ 0.4 1.4_+0.4 1.7 _+0.3 2.0 _+ 0.3 2.2_+0.4? 2.8_+0.4? 3.3-+0.4? 3.7 _+ 0.4? 2.0 _+0.3t 2.3_+0.4? 3.0_+0.4? 3.5 _+ 0.4t 2.8 + 0.3? 3.2_+0.4"{" 3.7 _+0.4t 4.0_+0.3? 4.4_+ 0.4f 3.0 _+0.3t 3.6_+0.4? 4.0_+0.3? 4.3 _+0.4f 5.0_+ 0.4? 2.0_+ 0.4f 2.4_+0.4f 3.0_+0.3? 3.5 _+0.3t 3.8 _+0.4't"
0.4 -+ 0.2 1.0 _+ 0.2
0.5 + 0.2 1.2 _+ 0.2 1.7 _+0.2 2.0+0.2 2.8 _+0.3 4.1 _+0.2 5.2_+0.4 6.3 _+0.4 1.7 _+0.3 2.1 _+0.4 2.7 _+0.4* 3.8 _+0.3* 3.1_+0.47 4.3_+0.3? 4.8_+0.4? 5.4_+ 0.4"t 2.4 _+0.3t 3.2_+0.4? 4.2_+0.3? 5.3 _+0.3t 3.8 + 0.3? 4.4_+0.4? 4.8 _+0.4t 5.8_+0.4t 6.4_+ 0.3f 3.8 -+ 0.4f 4.6_+0.4? 5.3_+0.3? 6.3 _+0.3f 8.0_+ 0.5f 2.7_+ 0.3f 3.5_+0.4? 4.3_+0.3t 5.0 _+0.4? 5.5 _+0.4*
0.5 -+ 0.2 1.2 -+ 0.2 1.8 + 0.2 2.2+0.2 3.2 + 0.2 4.2_+0.3 5.5_+0.4 6.6 _+0.4 2.1 _+ 0.3? 2.6_+0.4* 3.8 _+ 0.4? 4.7 _+ 0.3? 3.6-+0.4? 4.9_+0.4? 5.6_+0.3? 6.3 _+0.3t 2.6 _+0.3t 3.6_+0.4? 5.0_+0.4? 6.2 _+0.3t 4.4_+ 0.3t 5.8_+0.4? 6.4_+ 0.4t 7.2_+0.3? 7.8 -+ 0.3t 4.6 -+ 0.4? 6.2_+0.4? 7.2_+0.3? 8.0_+ 0.5? 8.0 + 0.5t 3.0 _+0.3f 3.9_+0.4? 5.2_+0.4t 5.8 _+0.4t 6.4 -+ 0.4f
1.6 + 0.2
2.0+0.2 2.4 + 0.2 3.3_+0.3 4.6_+0.3 5.2 _+0.3 1.4 _+0.4 1.7_+0.3 2.2 _+0.3 2.7 _+0.4 2.6_+0.4? 3.7_+0.4? 4.1_+0.47 4.5 _+ 0.3t 2.2_+ 0.3t 2.8_+0.4? 3.4_+0.4? 4.2_+ 0.3t 3.3 _+ 0.3t 3.8_+0.4f 4.2_+ 0.4t 4.6_+0.4t 5.0 _+0.4? 3.6 + 0.4f 4.2_+0.3? 4.8_+0.3? 5.2_+ 0.4? 6.2 + 0.3f 2.3 _+0.3f 2.8_+0.4? 3.5-+0.4? 4.3 _+0.3t 4.7 _+0.3*
Groups of 8--10 animals were administered orally twice for 5 days with a quinolone derivative and again with one dose of drug the day of test and l hr later were injected i.p. with the stated doses of aminophylline and were observed for 6 hr. The incidence of each seizure phase was recorded and median seizure score -+_SEM, for each dose level studied, is expressed. Significant differences in the incidence of seizure phases, between concurrent aminophylline alone and quinolones plus aminophylline, are denoted by *P < 0.05 and t P < 0.01 using Mann-Whitney U-test.
an important role in the inhibition of theophylline metabolism (Hasegawa et al., 1991) and, in part, in the potentiation of seizures induced by aminophylline as shown in the present study. Moreover, some investigators have demonstrated increased theo-
phylline-levels in serum, even in toxic concentrations, following the co-administration of some new quinolones (Maesen et al., 1984; Raoof et al., 1987; Wijnands et al., 1984; Neu, 1988). The differences observed after a single treatment with quinolones and
Table 3. Convulsant doses (CDm) of aminophylline alone and some quinolones plus aminophylline during chronic treatment Compounds Aminophylline alone Cinoxacin 10 mg. kg- ~+ aminophylline Cinoxacin 20 mg. kg- ] + aminophylline Ofloxacin 5 mg' kg- ~+ aminophylline Ofloxacin 10 mg. kg - ~+ aminophylline Pipemidic acid 10 mg. kg-~ + aminophylline Norfloxacin 7.5 rag. kg- ' + aminophylline Ciprofloxacin 5 rag. kg- ~+ aminophylline Ciprofloxacin 10mg-kg-' + aminophylline Enoxacin 5 mg. kg- ~+ aminophylline Enoxacin 7.5 m g . k g - ' + aminophylline Pefloxacin 8 mg. kg- ~+ aminophylline Rufloxacin 5 rag- kg- ' + aminophylline
CDs0 values (confidence limits) 184.3 (147.2-230.8) 173.6 (125.8-239.6) 158.5 (121.9-206.1) 179.4 (134.9-238.6) 127.1 (94.1-171.6) 113.6 (90.2-143.1) 119.3 (85.2-167.0) 147.2 (98.1-220.8) 108.6 (79.9-147.7) 81.8 (69.3-96.5) 72.4 (58.4-98.8) 115.3 (93.7-141.8) 116.3 (92.6-147.0)
At least 32 genetically epilepsy-prone rats were used to calculate each CDs0 value (+confidence limits), according to Linchfield and Wilcoxon (1949) as described in Methods. CD~0 is expressed in mg.kg -~, i.p.
Effects of quinolones on aminophylline-inducedconvulsions
857
Table 4. Effectsof combinedchronictreatmentof enoxacin,cinoxacinor ofloxacin and aminophylline(120rag.kg-i, i.p.) in geneticallyepilepsy-pronerats Quinolone+ Maximummedianseizurescore (day) aminophylline (dose mg) 1 2 3 4 5 Vehicle 2.2 +_0.2 2.2 _+0.2 2.5 +_0.3 2.9 + 0.3 3.1 _+0.3 Enoxacin 5 3.2 +_0.41" 4.5 _+0.4:~ 6.3 __0.4~/ 7.2 _+0.3~ 7.8 _+0.2*:[: Cinoxacin l0 2.3 __0.3 2.4 + 0.3 2.7 __0.4 3.1 + 0.3 3.4 __.0.4 Cinoxacin20 2.4 __0.3 1.3_+0.4~f 4.6 +_0.3:~ 5.2 _+0.4~ 5.8 +_0.4:~ Ofloxacin 5 2.2 _+0.3 2.4 __0.3 2.6 _+0.3 2.9 +_0.3 3.2 _+0.3 Groups of 8-10 animalswereadministeredorallywiththe quinolonederivativeand l hr later were injected i.p. with 120mg.kg-t of aminophyllineand were observed for 6 hr. The same animalswere treated with the same combined treatment for 5 days. The incidenceof each seizure phase was recorded and median seizurescore_+SEM, for each dose levelstudied, is expressed. *The medianseizurescore+ SEM for this valuesis related to 8 rats. Significant differences in the incidenceof seizure phases, between concurrent aminophyllinealone and quinolonesplus aminophylline,are indicated by tP < 0.05 and :~P< 0.01 usingMann-WhitneyU-test.
aminophylline (De Sarro and De Sarro, 1991) and also be involved in C.N.S. effects of quinolones the present study in which chronic treatment study (Dimpfel et al., 1991). In addition, quinolones possess was performed clearly show that pharmacokinetic some chemical similarities with kynurenic acids which factor may be involved when quinolones and may be an endogenous ligand for excitatory amino aminophylline were concomitantly administered for acid receptors (Stone, 1982) and we may suggest a long time. The clinical basis for this suggestion was possible interaction of these antibiotics with glutathe observation of epileptic activity in patients who mate receptor binding sites. However, the doses of received both quinolones and theophylline. On the quinolones used were similar to those used in clinical contrary, seizures were also observed in patients conditions (Wolff et al., 1987; Monk and Campoliwho did not display elevated theophylline serum Richards, 1987) whereas the doses of aminophylline levels (Ball, 1986). The chronic treatment carried were higher than those used in humans (Rail, 1985). out daily with quinolones and aminophylline The propensity of genetically epilepsy-prone rats to suggests us that additive neurotoxic effects of both seizure, similarly to that observed in epileptic classes of drugs may contribute to the increase of patients, may amplify the excitatory central nerseizure score observed during chronic treatment (for vous system side effects observed with the co-administration of aminophylline and quinolones as pre5 days). Various neurotransmitters may contribute to the viously suggested (Covelli et al., 1985; Ball, neurotoxicity of quinolones and aminophylline. 1986). The potency of inhibition of the specific binding of Recently, it has been reported that ciprofloxacin specifically binds GABAA receptors and that ICs0 of adenosine receptor agonists L-3H-N6-phenylisopropylciprofloxacin was lower than those of pefloxacin adenosine and 3H-N-ethylcarboxamidoadenosine to ofloxacin and nalidixic acid (Segev et al., 1988). rat brain synaptic membranes by some quinolones However, the concentrations needed for an inter- studied does not correspond to the convulsant acaction of quinolones and GABA are rather high and tivity of these antibiotics and suggests that other vary among the different quinolones tested by a factors are responsible of these seizures potentiated factor of --, 100. Thus, it seems questionable that a by quinolones (Dodd, 1989). Grand mal convulsions specific interaction of quinolones with GABA recep- in patients who had predisposing factors were detors can explain the C.N.S. effects observed during scribed during quinolone therapy (Paton and Reeves, 1988). The section of the quinolones which cross quinolone alone or quinolone + other drugs therapy. In the study of Segev et al. aminophylline appeared the blood brain barrier is still unknown, although more potent than ciprofloxacin in inhibiting mus- recent data suggest that ciprofloxacin and pefloxacin cimol binding and the combination of aminophylline concentrations in cerebrospinal fluid were from 5 to and ciprofloxacin showed an additive reduction of 40% of concomitant serum concentrations whilst muscimol binding to the GABAA receptor (Segev ofloxacin concentrations ranged from 5 to 25% and et al., 1988). This is in agreement with some studies higher levels being detected in presence of inflamwhich demonstrated no competition among mation (Valainis et al., 1986; Paton and Reeves, 1988; quinolones to bind GABA receptor by using synapto- Andriole, 1988; Bergan, 1988; Dimpfel et al., 1991). somes isolated from rat brain (Dette and Knothe, The possibility of different clearance among 1987). In addition, data generated by the patch clamp quinolones may be also responsible of potentiation of technique, suggest that GABA receptor binding stud- aminophylline-induced seizures. We conclude, therefore, that physicians should ies may underestimate the complexity of quinolone interaction with non-steroidal antiinflammatory consider the possible epileptogenic activity of the drugs, with xanthynes and with other compounds at simultaneous administration of aminophyUine and neurotransmitter level. Some in vivo studies indicated some quinolones when treating patients with prethat dopamine, opioid and glutamergic receptors may disposing epileptic factors.
ANGELA DE SARROel a[.
858
Control 1-3
2-4
45rain after Enox.
1--3
2-4
l h r a f t e r Aminophy.
1--3 2--4
t 1~rtl i
....
.
!,''': IL
2hr D 1--3 2--4
4hr
1-3 2--4
lO0~V
[
i I sec
Fig. 1. Electrocorticogram, before and during seizure induced by combined treatment with enoxacin (7.5 mg.kg -t, orally) and aminophylline (120 mg.kg -I, i.p.) in genetically epilepsy-prone rats. (A) Baseline activity. (B) Electrocorticogram 45 min after enoxacin. (C) Electrocorticogram during a seizure which occurred 1 hr after aminophylline. (D), (E) Electrocorticographic pattern observed 2 and 4 hr after aminophylline. Acknowledgements--Financial support from the Italian Ministry of University and Scientific and Technologic Research is gratefully acknowledged. Our thanks to Mr Antonino Giacopello for his skillful technical assistance. We are grateful to Rhone--Poulenc Pharma, Milano; Eli Lilly Italia, Sesto Fiorentino; Bayer Italia, Milano; Zambeletti, Milano; Merck Sharp & Dohme, Roma; Glaxo, Verona; Mediolanum Farmaceutici, Milano for the generous supply of quinolones.
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Arcieri G., Grit~th E., Gruenwaldt G., Heyd A., O'Brien B., Becker N. and August R. (1987) Ciprofloxacin: an update on clinical experience. Am. J. Med. 82, 381-386. Ball P. (1986) Ciprofloxacin: an overview of adverse experiences. J. Antimicrob. Chemother. 18, 187-193. Bergan T. (1988) Pharmacokinetics of fluorinated quinolones. In The Quinolones (Edited by Andriole V. T.), pp. 199-154. Academic Press, New York. Booker J. G., Dailey J. W., Jobe P. C. and Lane J. D. (1986) Neurobiology of seizure predisposition-the genetically epilepsy-prone rat--V. Cerebral cortical GABA and benzodiazepine binding sites in genetically seizure prone rats. Life Sci. 39, 799-806. Chapman A. G., Faingold C. L., Hart G. P., Bowker H. M. and Meldrum B. S. (1986) Brain regional amino acid levels in seizure susceptible rats: changes related to soundinduced seizures. Neurochem. Int. 8, 273-279.
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0306-3623]92 $5.00+ 0.00 Copyright© 1992PergamonPress Ltd
REPEATED TREATMENT WITH QUINOLONES POTENTIATES THE SEIZURES I N D U C E D BY AMINOPHYLLINE IN GENETICALLY EPILEPSY-PRONE RATS ANGELADE SARRO,I GIUSEPPER. TRIMARCHI,l DOMENICOAMMENDOLA2 and GIOVAMBATTISTADE SARRO3 qnstitute of Pharmacology, School of Medicine, 2Institute of Veterinary Pharmacology, School of Veterinary Medicine, University of Messina and 3Chair of Pharmacology, School of Medicine, University of Reggio, Calabria, Italy (Received 20 January 1992)
Almtraet--l. The effects of a chronic treatment with several quinolone derivatives on the aminophyUineinduced convulsions in the genetically epilepsy-prone rat have been investigated. 2. Two series of experiments have been performed: in the first one animals received the quinolone twice a day for 5 days, then were given aminophylline (80-140 mg. kg - J, i.p.); in the second series of experiments the rats were treated once a day with the quinolone plus 120 mg.kg -~ of aminophylline for 5 days. The changes induced by both treatment protocols on electrocortical activity and on the occurrance of seizures have been evaluated. 3. Enoxacin reduced the dose of aminophylline necessary for the induction of seizures in a higher degree with respect to the other quinolone derivatives. The derivatives which showed minor proconvulsant properties were ofloxacin, ciprofloxacin and cinoxacin. The potentiation of seizures induced by quinolones appeared a dose-dependent phenomenon which was more evident when high doses of quinolones were used. 4. The chronic treatment carried out daily with quinolones and aminophylline suggests that additive neurotoxic effects of both classes of drugs may contribute to the increase of severity of seizure scores. 5. The possible role of GABA-benzodiazepine, excitatory amino acid, purinergic mechanisms as well as the role of pharmacokynetic factors are discussed.
INTRODUCTION The quinolone agents are an important therapeutic class of drugs showing a great and broad spectrum of antibacterial activity. However, clinical experience has indicated a possible incidence of undesirable adverse reactions and drug interactions following their use. Side effects such as dizziness, headache and restlessness have most commonly been reported. Seizures and hallucinations have been described more frequently either in patients with underlying predisposition (i.e. epilepsy, cerebro-vascular diseases and psychosis) to central nervous system (C.N.S.) effects or in patients receiving non-steroidal antiinflammatory drugs concomitantly with quinolones (see Dimpfel et al., 1991). Many articles have also been published on the interaction of some quinolones with theophylline and, recently we described the behavioral pattern of this interaction in two different strains of rats. In this study we used normal Sprague-Dawiey rats and genetically epilepsy-prone rats. The latter have generalized clonic-tonic convulsions to loud tone and have been reported to have an increased seizure susceptibility to a variety of nonaudiogenic convulsant treatments, including pentylenetetrazoi, electroshock (Laird and Jobe, 1987; Faingold, 1988; Dailey et al., 1989), fluorothyl (Franck et al., 1989), and kindling induction to angular bundle stimulation (Savage et al., 1986). Extensive Gr 2~/~E
853
study was done on the nature of audiogenic seizures in the genetically epilepsy-prone rats; pathology was observed in both peripheral (Penny et al., 1983) and central auditory regions (Faingold et al., 1986a, b). A non-specific propensity to generalized seizures, regardless of the eliciting stimuli, enhances the value of this strain of rats as a model in the study of gene-linked generalized epilepsy. Several widespread neurotransmitter abnormalities have also been rcported in the genetically epilepsy=prone rats, including abnormal concentration of norepinephrine (NE) (Dailey and Jobe, 1986), serotonin (5-HT) (Dailey et aL, 1989; Jobe et aL, 1986), excitatory amino acids (Chapman et ai., 1986), bcnzodiazepine receptors and GABA levels (Booker et al., 1986; Tacke and Braestrup, 1984). Since aminophylline has been known for many years to induce convulsions (Johns et a/., 1951; McColl et ai., 1956; Stone and Javid, 1980; Dunwiddie and Worth, 1982) and we described that the pattern of responsiveness to this convulsant agent may be different in the genetically epilepsy-prone rats and in normal rats (De Sarro and De San'o, 1991), we decided to better clarify this phenomenon. Thus, the intent of the present study was to examine aminophylline-induced seizures in the genetically epilepsyprone rats after a chronic treatment (5 days) with doses of quinolones corresponding to one single therapeutic dose (STD) in humans.
854
ANGELADE SARROet al. MATERIALS AND METHODS
Animals Genetically epilepsy-prone susceptible rats (a strain derived from Sprague-Dawley rats) were inbred at the University of Messina vivarium facilities from progenitor stock exhibiting grade 9 seizures to audiogenic testing (GEPR-9, according to the scoring system of Jobe et al., 1973) obtained from Dr B. S. Meldrum (University of London). Rats were housed 3 or 4 per cage in stable conditions of humidity (60 + 5%) and temperature (21 + 2°C) and allowed free access to food and water until the time of the experiment. Animals were maintained on a 12 hr light and 12 hr dark cycle (light on 07:00-19:00, off 19:00-07:00). Male rats, 10-18 weeks old, 220-290 g were used. Genetically epilepsy-prone rats were tested three times at weekly intervals between 6 and 8 weeks of their life and only animals which showed an audiogenic seizure in all three exposures to sound stimulation were used for these experiments. Seizures were induced in genetically epilepsy-prone rats by exposing them to a mixed frequency sound of 12-16 kHz, 109 dB intensity under a hemispheric plexiglass dome. Chronic treatment The chronic treatment dose of each quinolone was administered twice a day, at 08:00 and 20:00 and lasted 5 days. The drugs were administered by gastric intubation (p.o.). The doses used were: ciprofloxacin hydrochloride, 5 and 10mg.kg-t; cinoxacin, 10 and 20 mg.kg-~; norfloxacin, 7.5 mg. kg- ~; rufloxacin hydroehloride, 5 mg. kg-~; enoxacin sesquhydrate, 5 and 7.5mg.kg-~; ofloxacin, 5 and 10 mg. kg-i; pefloxacin mesylate, 8 mg.kg-t; and pipemidic acid, 10 mg.kg -~. Control group received vehicle p.o. as appropriate. On day 6 seizures were induced in genetically epilepsyprone rats (average N = at least 8 for each dose of compound studied) pretreated with quinolones or vehicle orally (4ml.kg -~) lhr prior to i.p. administration of aminophylline. Genetically epilepsy-prone rats were injected with aminophylline (60, 80, 100, 120, or 140mg.kg -t, i.p.) dissolved in sterile saline (4 ml.kg -t, i.p.). Animals were placed in a plexiglass box (30 x 30 x 45 cm), were observed for 6 hr and seizure intensity was scored on the following scale: 0, no response; 1, wandering and twitching nose; 2, tremor and hind limb extension; 3, head nodding; 4, jumping and fore limb clonus; 5, forelimb clonus and rearing; 6, falling down; 7, tonic extension of all four limbs; 8, clonictonic seizures followed by post-ictal period or fatal outcome. The fraction of animals exhibiting seizures was observed for 6hr and the intensity score for each animal was recorded. In addition, another group of animals was treated once a day orally for 5 days with cinoxacin (10 and 20 mg. kg-~), ofloxacin (5mg-kg-t), enoxacin (5mg.kg -t) and aminophyiline (120 mg-kg -I, i.p.). Electrocortical activity Electrocortical (ECoG) activity was recorded (8 channel ECoG machine OTE Biomedica, Florence, Italy) through four chronically-implanted steel screw electrodes, inserted bilaterally onto the fronto-parietal area. The ground electrode was implanted epidurally over the nasal bone. At least 3 rats treated with the highest dose of quinolone derivatives + aminophylline or aminophylline alone were studied for changes in ECoG activity. Statistical analysis Data were analyzed by Mann-Whithey U-test and the CD~0 values (+95 confidence limits) for clonic component of seizure (phase 5) were calculated by Litchfield-Wilcoxon test (Litchfield and Wileoxon, 1949).
Drugs Aminophylline (Sigma, St Louis, Mo., U.S.A.) was dissolved in sterile saline. Pipemidic acid (Sigma), ciprofloxacin hydrochloride (Sigma and Bayer Italia, Milano, Italy), enoxacin sesquhydrate (Zambeletti, Milano, Italy), norfloxacin (Merck, Sharp & Dohme, Rome, Italy), ofloxacin (Glaxo, Verona, Italy), rufloxacin hydrochloride (Mediolanum Farmaceutici, Milano, Italy), cinoxacin (Eli Lilly Italia, Sesto Fiorentino, Italy) were dissolved in a solution containing 50% of dimethylsulfoxide in sterile saline. Pefloxacin mesylate (Rhon~Poulenc Pharma, Milano, Italy) was dissolved in sterile H20. RESULTS
Chronic treatment with quinolones in genetically epilepsy-prone rats The effects of a chronic treatment of aminophylline with pipemidic acid, enoxacin, ofloxacin, pefloxacin, cinoxacin, rufloxacin, norfloxacin or ciprofloxacin on occurrence of seizures are presented in Tables 1 and 2, whilst the relative CDs0 for clonic component of seizure (phase 5) are reported in Table 3. The concentration of aminophylline that produced a high incidence of seizures was lower after chronic treatment with enoxacin in comparison to other quinolones studied. The percentage of rats showing seizures when treated orally twice daily for 5 days with 5 or 1 0 m g ' k g -~ of enoxacin, l hr before receiving aminophylline was significantly increased (P < 0.01) in comparison to group receiving vehicle + aminophylline. Similar and less evident (P < 0.05) convulsant effects were observed in animals treated with pefloxacin, rufloxacin, norfloxacin and pipemidic acid. Whereas after a chronic treatment with ofloxacin, cinoxacin and ciprofloxacin was observed a lower increase in seizure severity score (Tables 1 and 2). Electrocorticographic epileptic signs were observed more rapidly in rats treated with enoxacin + aminophylline than in those received other quinolones + aminophylline. In addition, no significant changes were observed in the electrocorticographic pattern when genetically epilepsy-prone rats received v e h i c l e + a m i n o p h y l l i n e alone or a quinolone d e r i v a t i v e + a m i n o p h y l l i n e (results not shown).
Chronic concomitant treatment with quinolones and aminophylline Systemic administration once a day for 5 days of quinolones orally and a dose of aminophylline of 120 mg. k g - l , i.p. produced an increase on occurrence of seizures (Table 4). The concentration of aminophylline that produced a high incidence o f seizure was lower after chronic treatment with enoxacin ( 5 m g ' k g -~) in comparison to other quinolones (Table 4). In addition, cinoxacin (10 and 20 m g . k g -~) and ofloxacin (5 m g . k g -~) induced a low incidence of seizures after chronic treatment (Table 4). Some electrographic epileptic signs were observed in rats which did not show behavioral epileptic symptoms. The E C o G discharges consisted in single spikes, spike-waves or burst of spikes of brief duration. In animals showing clear epileptic symptoms such as head rearing, tremor, clonus of fore and hind limbs, tonic extension and rearing, complexes o f
Effects of quinolones on aminophylline-indueed convulsions
855
Table 1. The effectsof somequinoloneson seizuresinducedby aminophyllinein genetically epilepsy-pronerats Median seizure score time (hr) Quinolone Vehicle
Cinoxacin 10 m g ' k g -l
Cinoxacin 2 0 m g . k g -I
Ofloxacin 5 m g ' k g -I
Ofloxacin 1 0 m g ' k g -~ Pipemidic acid 10mg-kg -~ Rufloxacin 5 m g ' k g -I
Aminophylline (mg-kg -I, i.p.) 60 80 100 120 140 160 180 200 80 100 120 140 80 100 120 140 160 80 100 120 140 80 100 120 140 80 100 120 140 80 100 120 140 160
0-1 0.4 + 0.2 0.8 + 0.2 1.2 _+0.2 1.6 + 0.2 2.0_+0.2 2.2_+0.2 3.4 + 0.3 4.2 -+ 0.4 1.2 -+ 0.3* 1.5_+0.3 1.8-+0.3 2.1 _+0.4 1.5 _+0.4t 1.9 -+_0.3~" 2.2-+0.3 2.5 -+ 0.4 2.8-+0.3 1.2 _+ 0.3 1.6-+0.4 1.9_+0.4 2.2+0.3 1.6+_0.4"1" 2.0-+0.4t 2.3 -+ 0.3* 2.7 _+ 0.3 1.8 _+ 0.3t 2.4+0.4t 3.2_+0.4t 3.6 _+0.3~" 1.9 + OAt 2.3_+0.3t 3.1-+0.3t 3.4-+0.3t 3.7+0.4~-
1-2 0.4 __.0.2 1.0 __.0.2 1.6 _ 0.2 2.0 _ 0.2 2.4_+0.2 3.3+0.3 4.6 __.0.3 5.2 __.0.3 1.4 -+ 0.4 1.8+0.4 2.2-+0.4 2.6_+0.3 1.9 _+ 0.3t 2.3+0.3* 2.7+0.4 2.9 + 0.3 3.3_+0.4 1.4 _+0.3 1.9_+0.2 2.2-+0.3 2.8_+0.4 2.0+0.4t 2.5-+0.4t 2.9 _+ 0.3* 3.8 _+ 0.4t 2.3 _+ 0.4~" 2.9-+0.4t 3.6_+0.3~" 4.4 _+0.4t 2.2 + 0.2"1" 2.7+0.3~" 3.5_+0.31" 4.2+0.4t 4.8_+0.3t
2-4 0.5 __.0.2 1.2 -t- 0.2 1.7 __.0.2 2.0 + 0.2 2.8_+0.3 4.1 _+0.2 5.2 __.0.4 6.3 _ 0.4 1.7 -+ 0.3 2.1 + 0 . 4 2.6_+0.4 3.2_+0.4 2.2 _+0.4* 2.6-+0.3~" 2.9+0.3* 3.3 __.0.4 4.3_+0.4 1.8 -+ 0.3 2.2+_0.4 2.7-+0.3 3.5+0.3 2.3 __.0.4~" 2.9_+0.4t 3.8 _+ OAt 4.7 _ OAt 2.4 _+ 0.4~" 3.3-+0.3"f" 4.4_+0.4"f" 5.6 _+OAt 2.6 _+0.3~" 3.4+0.4"[" 4.4_+0.31" 5.1-+0.41" 5.6_+0.4~"
4-6 0.5 + 0.2 1.2 + 0.2 1.8 -t- 0.2 2.2 _+0.2 3.2_+0.2 4.2_+0.3 5.5 + 0.4 6.6 + 0.4 2.0 _ 0.3 2.4-+0.4 3.0_+0.4 3.8_+0.4 2.6 _+OAt 3.3-+0.5~" 3.7 -+ 0.4t 4.2 _ 0.4 4.9+0.3 2.1 -+ 0.3 2.5_+0.4 3.2-+0.3 4.0-+0.4 3.1-+0.3t 3.8_0.4~" 4.6 + 0.4~" 5.6 _+ 0.3t 2.7 -t- 0.3t 3.8_+0.4t 5.3_+0.4t 6.8 _+0.4t 2.8 _+ 0.3t 3.7+0.3t 5.2_0.4t 5.7-+0.4t 6.4-+0.3t
Groups of 8-10 animals were orally administered twice a day for 5 days with a quinolone derivative and again with one dose of the drug the day of test and 1 hr later injected i.p. with the stated doses of aminophylline and were observed for 6 hr. The incidence of each seizure phase was recorded and median seizure score + SEM, for each dose level studied, is expressed, Significant differences in the incidence of seizure phases, between concurrent aminophylline alone and quinolones plus aminophylline, are denoted by *P < 0.05 and t P < 0.01 using Mann-Whitney U-test.
spikes or spike-waves lasting from 20 to 140 sec and occurring periodically were recorded (Fig. 1). DISCUSSION
The present study demonstrates marked differences among quinolones to potentiate the convulsant activity of aminophylline in genetically epilepsyprone rats. We have recently hypothesized that (a) the pathology in auditory regions, specifically in the inferior colliculus, does not occur by itself in the genetically epilepsy-prone rats but is strongly linked to the brainstem abnormality and (b) the necessary basis of clonic-tonic seizure susceptibility in the genetically epilepsy-prone rats is a pathology in brainstem regions (De Sarro and De Sarro, 1991). The GABA and excitatory amino acids may play a primary role in various seizure models (Iadarola and Gale, 1982; De Sarro et al., 1984, 1986; McNamara et al., 1983; Millan et al., 1986) and perhaps in the seizures induced by aminophylline as recently observed in our laboratory (De Sarro et al., 1991). It is becoming increasingly apparent that genetically epilepsy-prone rats are a valuable tool in the study of the factors underlying a non-specific genetic propensity for generalized seizures.
These studies provide further evidence that some quinolones possess pro-convulsant activity as previously described in man (Areieri et aL, 1987; Ball, 1986; Fass, 1987; Monk and Campoli-Richards, 1987) and this occurs more often in patients receiving quinolones in combination with theophylline (Maesen et al., 1984). The mechanism of decrease in theophylline clearance induced by quinolones has generally been considered to be an inhibition of theophylline metabolism: quinolones are able to competitively inhibiting cytochrome P450 activity in hepatic microsomes and theophylline is metabolized by the cytochrome P450 system. Some quinolones and their metabolite 4-oxoquinolone, seem to be the main causes of the changes in theophylline metabolic clearance due to competitive inhibition of the N-demethylation pathway of theophylline (Wijnards et al., 1986; Hasegawa et al., 1990). In addition, a recent study in rats demonstrated that ofloxacin, which does not form a 4-oxometabolite, has also an effect on seizures induced by aminophylline without affecting the pharmaeokinetic and metabolism of theophylline (De Sarro and De Sarro, 1991). However, recent results indicate that the substitution on 3' and Y-carbon atoms of piperazinyl ring at 7 position of the quinolone molecule may play
856
ANGELA DE SARRO et al. Table 2. The effects of some quinolones on seizures induced by aminophylline in genetically epilepsy-prone rats Median seizure score time (hr) Quinolone Vehicle
Ciprofloxacin 5 mg.kg -I Ciprofloxacin 10mg.kg t Norfloxacin 7.5mg.kg -~ Enoxacin 5mg.kg I
Enoxacin 7.5mg.kg -I
Pefloxacin 8 m g . k g -~
Aminophylline (mg. kg- t, i.p.)
0-1
I-2
2-4
4-6
60 80 100 120 140 160 180 200 80 100 120 140 80 100 120 140 80 100 120 140 60 80 100 120 140 60 80 100 120 140 80 100 120 140 160
0.4 + 0.2 0.8 + 0.2 1.2 _+ 0.2 1.6_+0.2 2.0 _+ 0.2 2.2_+0.2 3.4_+0.3 4.2 _+0.4 1.2 _ 0.4 1.4_+0.4 1.7 _+0.3 2.0 _+ 0.3 2.2_+0.4? 2.8_+0.4? 3.3-+0.4? 3.7 _+ 0.4? 2.0 _+0.3t 2.3_+0.4? 3.0_+0.4? 3.5 _+ 0.4t 2.8 + 0.3? 3.2_+0.4"{" 3.7 _+0.4t 4.0_+0.3? 4.4_+ 0.4f 3.0 _+0.3t 3.6_+0.4? 4.0_+0.3? 4.3 _+0.4f 5.0_+ 0.4? 2.0_+ 0.4f 2.4_+0.4f 3.0_+0.3? 3.5 _+0.3t 3.8 _+0.4't"
0.4 -+ 0.2 1.0 _+ 0.2
0.5 + 0.2 1.2 _+ 0.2 1.7 _+0.2 2.0+0.2 2.8 _+0.3 4.1 _+0.2 5.2_+0.4 6.3 _+0.4 1.7 _+0.3 2.1 _+0.4 2.7 _+0.4* 3.8 _+0.3* 3.1_+0.47 4.3_+0.3? 4.8_+0.4? 5.4_+ 0.4"t 2.4 _+0.3t 3.2_+0.4? 4.2_+0.3? 5.3 _+0.3t 3.8 + 0.3? 4.4_+0.4? 4.8 _+0.4t 5.8_+0.4t 6.4_+ 0.3f 3.8 -+ 0.4f 4.6_+0.4? 5.3_+0.3? 6.3 _+0.3f 8.0_+ 0.5f 2.7_+ 0.3f 3.5_+0.4? 4.3_+0.3t 5.0 _+0.4? 5.5 _+0.4*
0.5 -+ 0.2 1.2 -+ 0.2 1.8 + 0.2 2.2+0.2 3.2 + 0.2 4.2_+0.3 5.5_+0.4 6.6 _+0.4 2.1 _+ 0.3? 2.6_+0.4* 3.8 _+ 0.4? 4.7 _+ 0.3? 3.6-+0.4? 4.9_+0.4? 5.6_+0.3? 6.3 _+0.3t 2.6 _+0.3t 3.6_+0.4? 5.0_+0.4? 6.2 _+0.3t 4.4_+ 0.3t 5.8_+0.4? 6.4_+ 0.4t 7.2_+0.3? 7.8 -+ 0.3t 4.6 -+ 0.4? 6.2_+0.4? 7.2_+0.3? 8.0_+ 0.5? 8.0 + 0.5t 3.0 _+0.3f 3.9_+0.4? 5.2_+0.4t 5.8 _+0.4t 6.4 -+ 0.4f
1.6 + 0.2
2.0+0.2 2.4 + 0.2 3.3_+0.3 4.6_+0.3 5.2 _+0.3 1.4 _+0.4 1.7_+0.3 2.2 _+0.3 2.7 _+0.4 2.6_+0.4? 3.7_+0.4? 4.1_+0.47 4.5 _+ 0.3t 2.2_+ 0.3t 2.8_+0.4? 3.4_+0.4? 4.2_+ 0.3t 3.3 _+ 0.3t 3.8_+0.4f 4.2_+ 0.4t 4.6_+0.4t 5.0 _+0.4? 3.6 + 0.4f 4.2_+0.3? 4.8_+0.3? 5.2_+ 0.4? 6.2 + 0.3f 2.3 _+0.3f 2.8_+0.4? 3.5-+0.4? 4.3 _+0.3t 4.7 _+0.3*
Groups of 8--10 animals were administered orally twice for 5 days with a quinolone derivative and again with one dose of drug the day of test and l hr later were injected i.p. with the stated doses of aminophylline and were observed for 6 hr. The incidence of each seizure phase was recorded and median seizure score -+_SEM, for each dose level studied, is expressed. Significant differences in the incidence of seizure phases, between concurrent aminophylline alone and quinolones plus aminophylline, are denoted by *P < 0.05 and t P < 0.01 using Mann-Whitney U-test.
an important role in the inhibition of theophylline metabolism (Hasegawa et al., 1991) and, in part, in the potentiation of seizures induced by aminophylline as shown in the present study. Moreover, some investigators have demonstrated increased theo-
phylline-levels in serum, even in toxic concentrations, following the co-administration of some new quinolones (Maesen et al., 1984; Raoof et al., 1987; Wijnands et al., 1984; Neu, 1988). The differences observed after a single treatment with quinolones and
Table 3. Convulsant doses (CDm) of aminophylline alone and some quinolones plus aminophylline during chronic treatment Compounds Aminophylline alone Cinoxacin 10 mg. kg- ~+ aminophylline Cinoxacin 20 mg. kg- ] + aminophylline Ofloxacin 5 mg' kg- ~+ aminophylline Ofloxacin 10 mg. kg - ~+ aminophylline Pipemidic acid 10 mg. kg-~ + aminophylline Norfloxacin 7.5 rag. kg- ' + aminophylline Ciprofloxacin 5 rag. kg- ~+ aminophylline Ciprofloxacin 10mg-kg-' + aminophylline Enoxacin 5 mg. kg- ~+ aminophylline Enoxacin 7.5 m g . k g - ' + aminophylline Pefloxacin 8 mg. kg- ~+ aminophylline Rufloxacin 5 rag- kg- ' + aminophylline
CDs0 values (confidence limits) 184.3 (147.2-230.8) 173.6 (125.8-239.6) 158.5 (121.9-206.1) 179.4 (134.9-238.6) 127.1 (94.1-171.6) 113.6 (90.2-143.1) 119.3 (85.2-167.0) 147.2 (98.1-220.8) 108.6 (79.9-147.7) 81.8 (69.3-96.5) 72.4 (58.4-98.8) 115.3 (93.7-141.8) 116.3 (92.6-147.0)
At least 32 genetically epilepsy-prone rats were used to calculate each CDs0 value (+confidence limits), according to Linchfield and Wilcoxon (1949) as described in Methods. CD~0 is expressed in mg.kg -~, i.p.
Effects of quinolones on aminophylline-inducedconvulsions
857
Table 4. Effectsof combinedchronictreatmentof enoxacin,cinoxacinor ofloxacin and aminophylline(120rag.kg-i, i.p.) in geneticallyepilepsy-pronerats Quinolone+ Maximummedianseizurescore (day) aminophylline (dose mg) 1 2 3 4 5 Vehicle 2.2 +_0.2 2.2 _+0.2 2.5 +_0.3 2.9 + 0.3 3.1 _+0.3 Enoxacin 5 3.2 +_0.41" 4.5 _+0.4:~ 6.3 __0.4~/ 7.2 _+0.3~ 7.8 _+0.2*:[: Cinoxacin l0 2.3 __0.3 2.4 + 0.3 2.7 __0.4 3.1 + 0.3 3.4 __.0.4 Cinoxacin20 2.4 __0.3 1.3_+0.4~f 4.6 +_0.3:~ 5.2 _+0.4~ 5.8 +_0.4:~ Ofloxacin 5 2.2 _+0.3 2.4 __0.3 2.6 _+0.3 2.9 +_0.3 3.2 _+0.3 Groups of 8-10 animalswereadministeredorallywiththe quinolonederivativeand l hr later were injected i.p. with 120mg.kg-t of aminophyllineand were observed for 6 hr. The same animalswere treated with the same combined treatment for 5 days. The incidenceof each seizure phase was recorded and median seizurescore_+SEM, for each dose levelstudied, is expressed. *The medianseizurescore+ SEM for this valuesis related to 8 rats. Significant differences in the incidenceof seizure phases, between concurrent aminophyllinealone and quinolonesplus aminophylline,are indicated by tP < 0.05 and :~P< 0.01 usingMann-WhitneyU-test.
aminophylline (De Sarro and De Sarro, 1991) and also be involved in C.N.S. effects of quinolones the present study in which chronic treatment study (Dimpfel et al., 1991). In addition, quinolones possess was performed clearly show that pharmacokinetic some chemical similarities with kynurenic acids which factor may be involved when quinolones and may be an endogenous ligand for excitatory amino aminophylline were concomitantly administered for acid receptors (Stone, 1982) and we may suggest a long time. The clinical basis for this suggestion was possible interaction of these antibiotics with glutathe observation of epileptic activity in patients who mate receptor binding sites. However, the doses of received both quinolones and theophylline. On the quinolones used were similar to those used in clinical contrary, seizures were also observed in patients conditions (Wolff et al., 1987; Monk and Campoliwho did not display elevated theophylline serum Richards, 1987) whereas the doses of aminophylline levels (Ball, 1986). The chronic treatment carried were higher than those used in humans (Rail, 1985). out daily with quinolones and aminophylline The propensity of genetically epilepsy-prone rats to suggests us that additive neurotoxic effects of both seizure, similarly to that observed in epileptic classes of drugs may contribute to the increase of patients, may amplify the excitatory central nerseizure score observed during chronic treatment (for vous system side effects observed with the co-administration of aminophylline and quinolones as pre5 days). Various neurotransmitters may contribute to the viously suggested (Covelli et al., 1985; Ball, neurotoxicity of quinolones and aminophylline. 1986). The potency of inhibition of the specific binding of Recently, it has been reported that ciprofloxacin specifically binds GABAA receptors and that ICs0 of adenosine receptor agonists L-3H-N6-phenylisopropylciprofloxacin was lower than those of pefloxacin adenosine and 3H-N-ethylcarboxamidoadenosine to ofloxacin and nalidixic acid (Segev et al., 1988). rat brain synaptic membranes by some quinolones However, the concentrations needed for an inter- studied does not correspond to the convulsant acaction of quinolones and GABA are rather high and tivity of these antibiotics and suggests that other vary among the different quinolones tested by a factors are responsible of these seizures potentiated factor of --, 100. Thus, it seems questionable that a by quinolones (Dodd, 1989). Grand mal convulsions specific interaction of quinolones with GABA recep- in patients who had predisposing factors were detors can explain the C.N.S. effects observed during scribed during quinolone therapy (Paton and Reeves, 1988). The section of the quinolones which cross quinolone alone or quinolone + other drugs therapy. In the study of Segev et al. aminophylline appeared the blood brain barrier is still unknown, although more potent than ciprofloxacin in inhibiting mus- recent data suggest that ciprofloxacin and pefloxacin cimol binding and the combination of aminophylline concentrations in cerebrospinal fluid were from 5 to and ciprofloxacin showed an additive reduction of 40% of concomitant serum concentrations whilst muscimol binding to the GABAA receptor (Segev ofloxacin concentrations ranged from 5 to 25% and et al., 1988). This is in agreement with some studies higher levels being detected in presence of inflamwhich demonstrated no competition among mation (Valainis et al., 1986; Paton and Reeves, 1988; quinolones to bind GABA receptor by using synapto- Andriole, 1988; Bergan, 1988; Dimpfel et al., 1991). somes isolated from rat brain (Dette and Knothe, The possibility of different clearance among 1987). In addition, data generated by the patch clamp quinolones may be also responsible of potentiation of technique, suggest that GABA receptor binding stud- aminophylline-induced seizures. We conclude, therefore, that physicians should ies may underestimate the complexity of quinolone interaction with non-steroidal antiinflammatory consider the possible epileptogenic activity of the drugs, with xanthynes and with other compounds at simultaneous administration of aminophyUine and neurotransmitter level. Some in vivo studies indicated some quinolones when treating patients with prethat dopamine, opioid and glutamergic receptors may disposing epileptic factors.
ANGELA DE SARROel a[.
858
Control 1-3
2-4
45rain after Enox.
1--3
2-4
l h r a f t e r Aminophy.
1--3 2--4
t 1~rtl i
....
.
!,''': IL
2hr D 1--3 2--4
4hr
1-3 2--4
lO0~V
[
i I sec
Fig. 1. Electrocorticogram, before and during seizure induced by combined treatment with enoxacin (7.5 mg.kg -t, orally) and aminophylline (120 mg.kg -I, i.p.) in genetically epilepsy-prone rats. (A) Baseline activity. (B) Electrocorticogram 45 min after enoxacin. (C) Electrocorticogram during a seizure which occurred 1 hr after aminophylline. (D), (E) Electrocorticographic pattern observed 2 and 4 hr after aminophylline. Acknowledgements--Financial support from the Italian Ministry of University and Scientific and Technologic Research is gratefully acknowledged. Our thanks to Mr Antonino Giacopello for his skillful technical assistance. We are grateful to Rhone--Poulenc Pharma, Milano; Eli Lilly Italia, Sesto Fiorentino; Bayer Italia, Milano; Zambeletti, Milano; Merck Sharp & Dohme, Roma; Glaxo, Verona; Mediolanum Farmaceutici, Milano for the generous supply of quinolones.
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