Inhibitory Effect of New Quinolones on GABAAReceptor-Mediated Response and Its Potentiation with Felbinac inXenopusOocytes Injected with Mouse-Brain mRNA: Correlation with Convulsive Potencyin Vivo

Kawakami, Junichi; Yamamoto, Keiji; Asanuma, Atsushi; Yanagisawa, Keiji; Sawada, Yasufumi; Iga, Tatsuji

doi:10.1006/taap.1997.8137

Cited by 27 publications

(21 citation statements)

References 25 publications

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“…This action is similar to that exerted in the CNS (Akaike et al 1991;Halliwell et al 1995), where it is considered partly responsible for the epileptogenic effect of these compounds (Yamamoto et al 1988;Akahane et al 1989Akahane et al & 1994Kawakami et al 1997).…”

Section: Discussionmentioning

confidence: 67%

“…Finally, the effect of enoxacin was evaluated on the contractile responses induced by the GABAA receptor agonist 3-amino-1 -propane sulphonic acid, confirming that fluoroquinolones act as antagonists at enteric GABAA receptors (Blandizzi et al 1991). This action is similar to that exerted in the CNS (Akaike et al 1991;Halliwell et al 1995), where it is considered partly responsible for the epileptogenic effect of these compounds (Yamamoto et al 1988;Akahane et al 1989Akahane et al & 1994Kawakami et al 1997).…”

Section: Discussionmentioning

confidence: 86%

“…For example, several quinolones and fluoroquinolones inhibit the specific binding of [3H]GABA, [3H]muscimol or tritiated benzodiazepines to synaptic plasma membranes from the rat brain in a concentration-dependent manner (Segev et al 1988;Yamamoto et al 1988;Tsuji et al 1988;Unseld et al 1990). This interaction, which is potentiated by NSAIDs (Tsuji et al 1988;Akahane et al 1989;Kawakami et al 1997), is believed to underlie the proconvulsive effect of fluoroquinolones (Yamamoto et al 1988;Akahane et al 1989Akahane et al & 1994Kawakami et al 1997).…”

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confidence: 99%

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Fluoroquinolone‐Induced Motor Changes in the Guinea‐Pig Isolated Ileum

Nucci

Candura

Tagliani

et al. 1998

Pharmacology & Toxicology

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Abstract:The effects of norlloxacin and enoxacin were examined on spontaneous motor activity in the guinea-pig isolated ileum. Micromolar concentrations of both compounds caused a biphasic response consisting of relaxation followed by transient contraction. Relaxation to noriloxacin, which was unaffected by phentolamine, propranolol and hyoscine (each at 1 pM), was partially sensitive to tetrodotoxin (1 pM). This indicates that the response is partly mediated by nonadrenergic non-cholinergic (NANC) inhibitory nerves, and partly related to a direct action on the smooth muscle. Apamin (0.1 pM) and suramin (300 pM) inhibited norfloxacin-induced relaxations to an extent similar to that of tetrodotoxin. Conversely, NG-nitro-L-arginine (300 pM) was ineffective. In the presence of theophylline (100 pM) and 3-isobutyl-lmethylxanthine (1 0 pM), norfloxacin caused relaxation less effective than when added alone. Based on this observation, the NANC component of the relaxation apparently depends on ATP release, whereas the direct component might be due, at least in part, to phosphodiesterase inhibition. Norfloxacin-induced contractions were neurogenic and cholinergic in nature. They were reduced by indomethacin or S-ketoprofen (both at 0.01-1 pM) and suramin (300 pM), suggesting involvement of local prostaglandin production probably induced by ATP release. Previous findings revealed that norfloxacin acted as a non-competitive antagonist at enteric GABAA receptors. In this study the same property was shared by enoxacin against the contractile response to 3-aminopropane sulphonic acid (3-APS), a GABAA receptor agonist. In conclusion, fluoroquinolones exert inhibitory and excitatory effects in the guinea-pig ileum. These are mediated by ATE prostaglandin and acetylcholine release that might underlie, at least in part, the alterations of gastrointestinal motility observed after fluoroquinolone administration. Furthermore, isolated intestinal preparations might be useful to predict the GABAA-antagonist potential of this class of compounds.

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Section: Discussionmentioning

confidence: 67%

Section: Discussionmentioning

confidence: 86%

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confidence: 99%

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Fluoroquinolone‐Induced Motor Changes in the Guinea‐Pig Isolated Ileum

Nucci

Candura

Tagliani

et al. 1998

Pharmacology & Toxicology

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“…It is most often admitted from the numerous studies conducted in vitro that this central excitatory effect should result from inhibition of ␥-aminobutyric acid (GABA) binding to its receptors (1,12,28,29). However, both in vitro electrophysiological and radioligand binding experiments demonstrated that FQs are only weak GABA A receptor antagonists and that their affinities are greatly potentiated by the active metabolite of fenbufen, biphenylacetic acid (BPAA), which does not exhibit any inhibitory action per se (2,14,16,21). Furthermore, other in vitro binding experiments suggested that FQs exert their convulsant effects in part by reducing central adenosinemediated inhibition (11).…”

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confidence: 99%

Convulsant and Subconvulsant Doses of Norfloxacin in the Presence and Absence of Biphenylacetic Acid Alter Extracellular Hippocampal Glutamate but Not Gamma-Aminobutyric Acid Levels in Conscious Rats

Smolders¹,

Gousseau²,

Marchand³

et al. 2002

Antimicrob Agents Chemother

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Fluoroquinolones are antibiotics with central excitatory side effects. These adverse effects presumably result from inhibition of ␥-aminobutyric acid (GABA) binding to GABA A receptors. This GABA antagonistic effect is greatly potentiated by the active metabolite of fenbufen, biphenylacetic acid (BPAA). Nevertheless, it remains questionable whether GABA receptor antagonism alone can explain the convulsant activity potentials of these antimicrobial agents. The present study was undertaken to investigate the possible effects of norfloxacin, both in the absence and in the presence of BPAA, on the extracellular hippocampal levels of GABA and glutamate, the main central inhibitory and excitatory amino acid neurotransmitters, respectively. This in vivo microdialysis approach with conscious rats allows monitoring of behavioral alterations and concomitant transmitter modulation in the hippocampus. Peroral administration of 100 mg of BPAA per kg of body weight had no effect on behavior and did not significantly alter extracellular GABA or glutamate concentrations. Intravenous perfusion of 300 mg of norfloxacin per kg did not change the rat's behavior or the concomitant neurotransmitter levels in about half of the experiments, while the remaining animals exhibited severe seizures. These norfloxacin-induced convulsions did not affect extracellular hippocampal GABA levels but were accompanied by enhanced glutamate concentrations. Half of the rats receiving both 100 mg of BPAA per kg and 50 mg of norfloxacin per kg displayed lethal seizures, while the remaining animals showed no seizure-related behavior. In the latter subgroup, again no significant alterations in extracellular GABA levels were observed, but glutamate overflow remained significantly elevated for at least 3 h. In conclusion, norfloxacin exerts convulsant activity in rats, accompanied by elevations of extracellular hippocampal glutamate levels but not GABA levels, even in the presence of BPAA.

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“…Quinolones function as weak, dosedependent GABA A receptor antagonists [350,351,354,356]. Quinolones vary in their potencies as receptor antagonists [350][351][352][353][354][355][357][358][359][360][361], probably at least partly because of differences in the degree to which their 7-piperazine substituents look like GABA [352]. In one study, the rank order of quinolones in terms of potency as inhibitors of ( 3 H)-muscimol binding to murine GABA synaptic receptors was prulifloxacin = norfloxacin > ciprofloxacin ³ enoxacin > gatifloxacin ³ ofloxacin = tosufloxacin = lomefloxacin > levofloxacin ³ sparfloxacin ³ pazufloxacin = fleroxacin [362].…”

Section: Quinolones and Nsaidsmentioning

confidence: 99%

Quinolones

Guay¹

2011

Drug Interactions in Infectious Diseases

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Fluoroquinolone (FQ) antimicrobials are among the most commonly used agents in the outpatient and institutional patient care environments. Due to this high frequency of utilization, the potential for deleterious drug-drug interactions with nonantimicrobials is also high. The majority of interactions with the FQs involve deleterious effects on the FQ component. These are also the most clinically-important interactions with these agents. Multivalent cations such as Mg , and other minerals as well as drugs such as sucralfate, lanthanum, sevelamer, and didanosine (the cation-supplemented version of the latter) can substantially reduce FQ bioavailability, leading the subtherapeutic drug concentrations at the infection site and clinical failure. Separation of dose administrations may or may not reduce the magnitude of these interactions. Ciprofloxacin, norfloxacin, and two experimental FQs in clinical trials (pazufloxacin and prulifloxacin) act as moderate cytochrome P450 enzyme inhibitors and may increase serum concentrations of theophylline and caffeine. Warfarin pharmacodynamics are variably affected by the FQs. The pharmacodynamic interactions between NSAIDs and FQs are only relevant if fenbufen is used concurrently with enoxacin or, possibly, prulifloxacin. Caution is warranted if sparfloxacin or moxifloxacin is used concurrently with other medications prolonging the QTc interval or if patients have other risk factors for prolongation of the QTc interval (e.g. abnormal QTc interval pre-treatment, electrolyte abnormalities, use of starvation-liquid diets, or history of heart disease). Fluoroquinolone antimicrobials can be used effectively and safely in the vast majority of patients if the clinician remembers those few drug-drug interactions that are clinically-important.

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Inhibitory Effect of New Quinolones on GABAAReceptor-Mediated Response and Its Potentiation with Felbinac inXenopusOocytes Injected with Mouse-Brain mRNA: Correlation with Convulsive Potencyin Vivo

Cited by 27 publications

References 25 publications

Fluoroquinolone‐Induced Motor Changes in the Guinea‐Pig Isolated Ileum

Fluoroquinolone‐Induced Motor Changes in the Guinea‐Pig Isolated Ileum

Convulsant and Subconvulsant Doses of Norfloxacin in the Presence and Absence of Biphenylacetic Acid Alter Extracellular Hippocampal Glutamate but Not Gamma-Aminobutyric Acid Levels in Conscious Rats

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