Pharmacological evaluation of garenoxacin,a novel des-F(6)-quinolone antimicrobial agent: effects on the central nervous system

The effects of garenoxacin (formerly T-3811 or BMS-284756) on the central nervous system (CNS) were compared with various quinolones. Garenoxacin injected intracerebroventricularly into mice caused clonic convulsion at a higher dose (50 micrograms/body) than norfloxacin, ciprofloxacin, sitafloxacin and trovafloxacin. Additionally the convulsant activity of garenoxacin was not potentiated by biphenylacetic acid (BPAA). Garenoxacin did not induce any convulsions at intravenous doses up to 60 mg/kg in combination with 200 mg/kg oral administration of fenbufen in mice, and its convulsant activity was weaker than those of enoxacin, norfloxacin, ciprofloxacin, alatrofloxacin and ofloxacin. In addition, convulsions were not induced by combination administration of garenoxacin (60 mg/kg, i.v.) and any of 9 kinds of nonsteroidal anti-inflammatory drugs (NSAIDs) or BPAA. In a rotarod test, which was performed in order to evaluate the drug-induced dizziness, coordinated locomotor activity of mice was suppressed by alatrofloxacin at an intravenous dose of 60 mg/kg, but not by garenoxacin, ciprofloxacin and norfloxacin at up to 60 mg/kg. In an in vitro study using rat brain synaptic membrane, garenoxacin had no inhibitory effect on GABA binding in the presence or absence of NSAIDs. In conclusion, the effects of garenoxacin on CNS were weaker than those of other quinolones in experimental animals, so it might possess a low potential for CNS adverse reactions such as convulsion and dizziness in clinical use.     

Effect of Bile Duct Ligation and Unilateral Nephrectomy on Brain Concentration and Convulsant Potential of the Quinolone Antibacterial Agent Levofloxacin in Rats

To mimic the excretion route of the quinolone antibacterialagent levofloxacin (LVFX) in humans, we produced an excretion-limited(EL) model in male Sprague–Dawley rats by bile duct ligationand unilateral nephrectomy. We then examined the relationshipbetween brain levels of LVFX and its convulsant effects in controland EL animals. Serum concentrations of LVFX in EL animals (EL+ LVFX) were 2.38- and 1.59-fold and brain concentrations were1.33- and 1.19-fold those of the controls (control + LVFX) at30 min after a single intravenous injection of 10 and 100 mg/kgLVFX, respectively. Furthermore EL animals became more susceptibleto the convulsant effect of LVFX with a 1.28-fold decrease inconvulsion-inducing dose. In combination with oral pretreatmentwith 400 mg/kg 4-biphenylacetic acid (BPAA), convulsion-inducingdoses in the control (control + LVFX + BPAA) and EL (EL + LVFX+ BPAA) groups were markedly decreased by 2.25 and 9 times thatof the control + LVFX group. EL operation and BPAA pretreatmentslowed the elimination of LVFX in the serum and brain 4 hr laterin the following order: EL + LVFX + BPAA, control + LVFX + BPAA,EL + LVFX, and control + LVFX groups. This order reflects thatfor the convulsion-inducing doses. These results suggest thatEL rats may be a useful model for humans and that the convulsanteffect of LVFX with or without BPAA arises not only from theattainment of maximum brain concentration but also from delayeddisappearance from the brain.     

Kinetics of drug action in disease states. XXXVIII: Effect of body temperature on the convulsant activity of pentylenetetrazol in rats.

The purpose of this investigation was to determine the effect of body temperature on the pharmacodynamics (convulsant activity) of pentylenetetrazol (PTZ). Rats received an iv infusion of PTZ until the onset of maximal seizures, at which time samples of cerebrospinal fluid (CSF), brain, and blood (for serum) were obtained for subsequent determination of PTZ concentrations by HPLC. The PTZ infusion caused a decrease in body temperature of approximately 4 degrees C within 20 min and onset of seizures in approximately 40 min. Compared with animals whose temperature was maintained in the normal range by heating pads, the hypothermic rats required significantly larger doses and higher serum, brain, and CSF concentrations of PTZ to produce seizures. Other rats received an injection of brewer's yeast to produce fever. Then, PTZ was infused 6, 12, or 24 h later when body temperature was elevated by an average of 1.3, 1.1, or 0.4 degrees C, respectively. Compared with control rats, whose temperature was maintained in the normal range by heating pads, moderate hyperthermia had no significant effect on the dose and concentrations of PTZ required to produce maximum seizures. Pentylenetetrazol exemplifies a drug that can produce hypothermia which, in turn, reduces the sensitivity of rats to its pharmacologic action. Unlike the central nervous system (CNS) depressants phenobarbital and ethanol, whose pharmacologic activity in rats is enhanced at elevated body temperature, the activity of the CNS stimulant PTZ is apparently not altered by fever.     

Isobolographic assessment of the convulsant interaction between theophylline and caffeine or pentylenetetrazol in rats

To characterize the convulsant interaction between theophylline and caffeine, male Sprague-Dawley rats received an iv infusion of one of seven different combinations of these drugs and of each drug individually until the onset of maximal seizures (which occurred within 30 to 40 min after the start of the infusion). The total infused doses of the two drugs and their respective concentrations in the serum, brain, and cerebrospinal fluid (CSF) were used for isobolographic analysis. The results are consistent with classical dose- and concentration-addition and do not suggest either antagonism or synergism. The potency ratio based on the doses or serum concentrations was appreciably different from that based on brain or CSF concentrations. The brain:serum and CSF:serum concentration ratios of caffeine were appreciably higher than those of theophylline. Similar experiments were performed with seven combinations of theophylline and pentylenetetrazol (PTZ) and with each of these drugs individually. This second set of experiments also yielded essentially linear isobolographs indicative of dose- and concentration-addition. The potency ratio based on CSF concentrations was appreciably different from ratio values based on doses, and from those based on brain or serum concentrations. These results illustrate a useful strategy for the characterization of pharmacodynamic drug interactions and highlight the importance of the choice of sampling site for determinations of the potency of drug.     

Adverse drug interactions between pyridonecarboxylic acids and nonsteroidal antiinflammatory drugs: convulsion after oral or intracerebral administration in mice

Comparing with other pyridonecarboxylic acids (PCAs), the neurotoxicity of (+/-)-7-(3-amino-1-pyrrolidinyl)-6-fluoro-1-(2,4-difluorophenyl)-1,4- dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid p-toluenesulfonate hydrate (T-3262), which is a new PCA, was investigated in mice in a combination with fenbufen (FBF). T-3262, ofloxacin (OFLX) and nalidixic acid (NA) did not produce convulsion, but enoxacin (ENX) and norfloxacin (NFLX) produced it after an oral administration with FBF. The intracerebral injection of drugs alone to mice revealed that both FBF and 4-biphenylacetic acid (BPAA), which is principally responsible for FBF's antiinflammatory action, scarcely had convulsant activity. While all the PCAs had convulsant activity and the order of potency was as follows; NFLX greater than ENX greater than OFLX greater than penicillin G potassium greater than the free base of T-3262 (T-3262 base) greater than or equal to NA. When orally pretreated with BPAA, the convulsive threshold was scarcely lowered for T-3262 base and OFLX, but for ENX and NFLX it was lowered to about 1/300 and 1/100 of the respective activity. As the result, convulsant activities of ENX and NFLX were greatly potentiated, and their potencies became almost equal. The adverse drug interactions between T-3262 and FBF were scarcely observed in mice.     

Ignoring Pharmacokinetics May Lead to Isoboles Misinterpretation: Illustration with the Norfloxacin-Theophylline Convulsant Interaction in Rats

Purpose. To investigate the norfloxacin-theophylline convulsant interaction in vivo, with an experimental approach distinguishing between pharmacodynamics and pharmacokinetics contributions to the observed effect. Methods. Male Sprague Dawley rats (n = 38) were infused each compound separately or in different combination ratios. Infusion was maintained until the onset of maximal seizures. Cerebrospinal fluid and plasma samples were collected for high performance liquid chromatography drug determination. The nature and intensity of the pharmacodynamics interaction between drugs was quantified with an isobolographic approach. Results. Isobolograms suggested a relatively marked antagonism between norfloxacin and theophylline at the cerebrospinal fluid (previously shown to be part of the biophase) and dose levels, but not at the plasma (free and total concentrations) levels. These apparent discrepancies could be explained by nonlinear distribution or/and distribution desequilibrium phenomenon. Conclusions. These findings showed that the quantitative isobolographic approach is appropriate to assess the nature and intensity of the pharmacodynamic interaction between two drugs when data are collected within the biophase, but that data interpretation outside the biophase can be risky due to further pharmacokinetic complexities, in particular slow or/and nonlinear diffusion into the biophase.     

Kinetics of drug action in disease states. XXXIII: Disparate effects of pentylenetetrazol in rats as a function of renal disease model and pharmacologic endpoint

The purpose of this investigation was to determine if the pharmacodynamics of the central nervous system stimulant pentylenetetrazol (PTZ) are altered in renal dysfunction. Female rats subjected to bilateral ureteral ligation (with sham-operated controls) or injected with uranyl nitrate (with saline injected controls) were infused intravenously with PTZ until the onset of either a minimal (myoclonic jerk) or maximal (tonic hindlimb extension) seizure. Neither chemically nor surgically induced renal dysfunction caused a change in the concentrations of PTZ in CSF, serum, or brain at onset of minimal seizures. When PTZ was infused to onset of maximal seizures, the rats with chemically induced renal dysfunction required higher concentrations, whereas the ureter-ligated rats convulsed at lower concentrations of PTZ than did the corresponding control animals. Thus, the effects of experimental renal dysfunction on the convulsant action of PTZ are dependent on both the disease model and the endpoint used for the pharmacodynamic measurement. Apparently, renal dysfunction did not affect the PTZ-induced seizure threshold, but inhibited the spread of seizures. The increased sensitivity of ureter-ligated rats may be due to their pronounced retention of water, since water loading is known to increase seizure susceptibility.     

Extension of the isobolographic approach to interactions studies between more than two drugs: illustration with the convulsant interaction between pefloxacin, norfloxacin, and theophylline in rats

This work proposes a model to characterize the additivity or the nonadditivity of combinations of more than two agents. Using a Bayesian framework, we modeled the variability between experimental subjects, the errors that occurred during data collection, and the relationship between effects and concentrations of agents at the effect site. The model was used to characterize the additivity (or non-additivity) of norfloxacin, pefloxacin, and theophylline in causing maximal seizures in male Sprague Dawley rats. Animals received the drugs separately or in various combinations. Drug infusion was stopped at the onset of maximal seizures, and cerebrospinal fluid samples were collected for determination of drug concentration by high-performance liquid chromatography. The model was fitted to concentration data using Markov Chain Monte Carlo techniques. Results showed that induction of seizures by mixtures of theophylline and pefloxacin were additive. Seizure induction by mixtures of norfloxacin and pefloxacin or norfloxacin and theophylline were not additive and, given the model, these drugs interacted negatively. There was no triple interaction effect between the drugs. This study demonstrates the ease with which mixtures of more than two drugs can be analyzed with the proposed model.     

The Effect of Immunosuppression by Total-Body Irradiation on the Pharmacodynamics of Centrally Active Drugs in Rats

The aim of this investigation was to assess whether immunosuppression induced by total-body irradiation (TBI) affects the pharmacodynamics of centrally acting drugs. Female Sabra rats were exposed to a single dose of gamma irradiation (5.3 Gy). Four days later, when both the cellular and the humoral immune responses were impaired, they received an i.v. infusion of either phenobarbital (0.8 mg/min), ethanol (16.3 mg/min), pentylenetetrazol (PTZ; 0.618 mg/min), or theophylline (as aminophylline; 2 mg/min). The infusion was stopped at the onset of the pharmacologic end point—loss of righting reflex for the depressant agents or maximal seizures for the stimulant drugs—and the concentrations of the neuroactive drugs at that point were determined. In the ethanol experiment, blood samples were also taken upon awakening. The radiation-induced immunosuppression significantly decreased the CNS sensitivity to the depressant action of both phenobarbital and ethanol as indicated by the higher CSF phenobarbital concentrations required to induce sleep in the irradiated rats versus controls (156±4 vs 133 ±5 mg/L, respectively; P < 0.05), and the higher serum ethanol concentrations at the onset and offset of sleep in the immunosuppressed group versus control values (4.6±0.2 and 1.68±0.01 vs 3.79±0.17 and 1.32±0.9 mg/mL, respectively; P < 0.04). Exposure to TBI did not alter the pharmacodynamics of the two convulsant drugs (theophylline andPTZ).     

Effect of fenbufen on the entry of new quinolones, norfloxacin and ofloxacin, into the central nervous system in rats.

The entry of two new quinolone antibacterial agents, norfloxacin and ofloxacin, into the central nervous system (CNS) of rats, and the effect of fenbufen on this was investigated. At various times after the administration of a bolus intravenous dose of norfloxacin or ofloxacin (10 mg kg-1) with or without fenbufen (20 mg kg-1), serum and cerebrospinal fluid (CSF) samples and whole brain were collected from the rats and the concentration of norfloxacin or ofloxacin in each sample was determined. Serum concentrations of both quinolones declined biexponentially with time and were significantly elevated by coadministration with fenbufen at the terminal phase. The fractions of these quinolones bound to serum protein were not altered by coadministration with fenbufen. Coadministered fenbufen raised the brain concentrations of both quinolones but did not affect their brain to serum unbound concentration ratios. In contrast, CSF to serum unbound concentration ratios as well as CSF concentrations of norfloxacin and ofloxacin were elevated by coadministration with fenbufen. Apparent diffusional clearances between blood and CSF of norfloxacin and ofloxacin estimated by the physiological model analysis increased by 1.9 and 2.6 times, respectively, after coadministration with fenbufen. These findings suggest that coadministered fenbufen may facilitate the entry of norfloxacin and ofloxacin into the CNS.     

Effect of orally administered dextromethorphan on theophylline- and pentylenetetrazol-induced seizures in rats

Dextromethorphan, widely used as an antitussive, has recently been shown to protect animals against maximal electroshock and excitatory amino acid (N-methyl-D-aspartate)-induced convulsions. Its protective efficacy against theophylline-induced seizures was determined in this investigation in view of the limited effectiveness of presently available anticonvulsants against this manifestation of serious theophylline intoxication. Rats were pretreated with an oral dose of dextromethorphan (50 mg/kg) or saline solution. Fifteen minutes later, the rats were infused intravenously with theophylline [approximately 11 mg/(kg.min)] until the onset of maximal seizures. Pretreatment with dextromethorphan was associated with a significant decrease in the concentrations of theophylline in the cerebrospinal fluid and serum at the pharmacologic endpoint. To further explore this unanticipated effect, a similar experiment was performed with the convulsant pentylenetetrazol (PTZ), which was infused at a rate of approximately 3.4 mg/(kg.min) until the onset of maximal seizures. Dextromethorphan-pretreated animals required a significantly larger dose of PTZ than did controls to produce the first myoclonic jerk, but a significantly smaller dose of the convulsant to produce maximal seizures. Serum and cerebrospinal fluid concentrations of PTZ at onset of maximal seizures were significantly lower in dextromethorphan-treated than in control animals. The proconvulsant activity of dextromethorphan with respect to theophylline-induced maximal seizures is similar to that of phenytoin, and is consistent with other pharmacologic evidence of such similarity.     

Pentylenetetrazol-induced seizure is not mediated by benzodiazepine receptors in vivo

The selective benzodiazepine antagonist RO 15-1788, labelled with carbon 11 [11C] RO 15-1788, as a specific marker, together with positron emission tomography, allows the in vivo study of benzodiazepine receptors in primates. In addition, when coupled with recordings of electroencephalographic activity, this method offers the feasibility of studying the correlation between occupancy of benzodiazepine receptors and the convulsant action of drugs acting at the benzodiazepine-GABA receptor complex in vivo. The present study showed that convulsant doses of pentylenetetrazol (PTZ) could affect the binding of [11C] RO 15-1788 in vivo in two ways, depending on the doses tested: at concentrations of 20 and 30 mg/kg, pentylenetetrazol increased the binding of [11C] RO 15-1788 whereas larger concentrations displaced the binding of [11C] RO 15-1788. The direct correlation between the occupancy of respective benzodiazepine receptors, afforded by increasing convulsant doses of pentylenetetrazol, revealed that competitive interaction with benzodiazepine receptors was not necessary for pentylenetetrazol to induce the appearance of seizures in vivo.     

Kinetics of drug action in disease states. XXVI: Effect of fever on the pharmacodynamics of theophylline-induced seizures in rats

This investigation was designed to determine the effect of fever on the neurotoxicity of theophylline as reflected by the concentrations of this drug that cause convulsions in experimental animals. Fever was produced in male, inbred, adult Lewis rats (approximately 180 g) by sc injection of brewer's yeast; an elevation of body temperature of 1.2 +/- 0.4 degrees C (mean +/- SD) was achieved at the time of the pharmacodynamic measurements. Theophylline was infused iv at a rate of 1.03 mg/min until the onset of maximal seizures. Drug concentrations in serum, serum water, brain, and cerebrospinal fluid (CSF) at that time were determined by high-performance liquid chromatography. Compared with the control group, the group of febrile rats had statically significantly lower serum protein concentrations, decreased serum protein binding of theophylline, and slightly increased theophylline concentrations in the CSF at the onset of seizures. Inasmuch as theophylline concentrations in the CSF reflect the concentrations of this drug in the biophase, the results of this study show that fever does not increase the sensitivity of the central nervous system to the neurotoxic effects of theophylline in rats. In fact, a statistically significant positive correlation between theophylline concentrations in the CSF and body temperature was found in this investigation, suggesting a decreased sensitivity of the animals to the neurotoxic effects of theophylline at higher body temperature.     

Effect of fluoroquinolones on the expression of matrix metalloproteinase in debrided cornea of rats

Matrix metalloproteinases (MMPs) are implicated in regenerative and healing processes in corneal injuries. Based upon reports that topical fluoroquinolones (FQs) may cause perforations during corneal healing by modulating MMPs, this study evaluated the comparative effects of commercially available FQs eye drops on the expression of MMP-2 and MMP-9 in the cornea after ethanol injury. Uniform corneal epithelial defects were created using 70% ethanol in the right eye of the rats (n?=?6). The groups studied were (I) sham, (II) normal saline with benzalkonium chloride (NS-BKC), (III) norfloxacin 0.3%, (IV) ciprofloxacin 0.3%, (V) lomefloxacin 0.3%, (VI) sparfloxacin 0.3%, (VII) gatifloxacin 0.3%, and (VIII) moxifloxacin 0.5%. Each treatment was instilled six times/day up to 48?h and rats were sacrificed using excess of anesthesia. The corneas were excised to study the expression of MMP-2 and MMP-9 using gelatin zymography and real-time PCR. All the FQs significantly increased the expression of MMP-2 and MMP-9 as compared to the sham and NS-BKC-treated group. NS-BKC did not show a significant effect on MMPs expression compared to the sham group. Among the studied FQs, ciprofloxacin was observed to exhibit maximal induction of MMP-2 and MMP-9, whereas lomefloxacin exhibited an equivocal effect on both MMP-2 and MMP-9 expression. Findings of the present study demonstrate that topical application of FQs may induce the expression of MMP-2 and MMP-9 in debrided corneal epithelium and, therefore, may delay corneal wound healing. Thus, it can be concluded that selecting a FQ for ophthalmic use having minimal effect on MMPs may impact wound healing in injured or vulnerable cornea.     

Effect of fluoroquinolones on the expression of matrix metalloproteinase in debrided cornea of rats

Matrix metalloproteinases (MMPs) are implicated in regenerative and healing processes in corneal injuries. Based upon reports that topical fluoroquinolones (FQs) may cause perforations during corneal healing by modulating MMPs, this study evaluated the comparative effects of commercially available FQs eye drops on the expression of MMP-2 and MMP-9 in the cornea after ethanol injury. Uniform corneal epithelial defects were created using 70% ethanol in the right eye of the rats (n = 6). The groups studied were (I) sham, (II) normal saline with benzalkonium chloride (NS-BKC), (III) norfloxacin 0.3%, (IV) ciprofloxacin 0.3%, (V) lomefloxacin 0.3%, (VI) sparfloxacin 0.3%, (VII) gatifloxacin 0.3%, and (VIII) moxifloxacin 0.5%. Each treatment was instilled six times/day up to 48 h and rats were sacrificed using excess of anesthesia. The corneas were excised to study the expression of MMP-2 and MMP-9 using gelatin zymography and real-time PCR. All the FQs significantly increased the expression of MMP-2 and MMP-9 as compared to the sham and NS-BKC-treated group. NS-BKC did not show a significant effect on MMPs expression compared to the sham group. Among the studied FQs, ciprofloxacin was observed to exhibit maximal induction of MMP-2 and MMP-9, whereas lomefloxacin exhibited an equivocal effect on both MMP-2 and MMP-9 expression. Findings of the present study demonstrate that topical application of FQs may induce the expression of MMP-2 and MMP-9 in debrided corneal epithelium and, therefore, may delay corneal wound healing. Thus, it can be concluded that selecting a FQ for ophthalmic use having minimal effect on MMPs may impact wound healing in injured or vulnerable cornea.     

Application of serial sampling of cerebrospinal fluid in pharmacodynamic studies with a drug active in the CNS: heptabarbital concentrations at onset and offset of loss of righting reflex in rats

As cerebrospinal fluid (CSF) possesses unique characteristics in order to explore concentration-pharmacological response relationships of drugs active in the CNS, the practicability of serial sampling of CSF was tested in a study with heptabarbital. Concentrations in CSF and plasma were measured simultaneously in individual rats during and after an intravenous infusion for 30 min. At the end of the infusion, the distribution equilibrium was attained with a CSF/plasma concentration ratio of 0.38, roughly equal to the fraction unbound to protein. When concentrations in blood and CSF were determined at the onset and offset of loss of righting reflex concentrations in blood were significantly greater at onset (146 +/- 19 mg/l) than at offset (108 +/- 16 mg/l, n = 6), whereas concentrations in CSF were identical (39 +/- 5 and 38 +/- 5 mg/l, respectively). This confirmed the earlier observation that the CSF is pharmacokinetically indistinguishable from the site of action. When the duration of the loss of righting reflex was varied, concentrations of heptabarbital in CSF at onset and offset were similar, independent of the duration of the loss of righting reflex (1-5 hr). These findings demonstrate the absence of the development of acute tolerance and confirmed that no (inter)active metabolites interfered with the pharmacological response. In a total number of 26 rats the concentrations in CSF at onset and offset of loss of the righting reflex were compared. The interindividual variation was 13-15% and the intra-individual variation was only 4-6%. The results demonstrate the usefulness of serial sampling of CSF in pharmacodynamic studies with centrally acting drugs.     

Use of water-soluble beta-cyclodextrin derivatives as carriers of anti-inflammatory drug biphenylylacetic acid in rectal delivery]

To improve the rectal delivery of an anti-inflammatory drug, biphenylylacetic acid (BPAA), the use of 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CyD) and heptakis (2,6-di-O-methyl)-beta-cyclodextrin (DM-beta-CyD) was investigated. Inclusion complex formations of BPAA with both beta-CyDs in a molar ratio of 1:1 in water were ascertained, and their stability constants were determined. The dissolution of BPAA in water and the release of BPAA from an oleaginous suppository (Witepsol H-5) were significantly increased by beta-CyDs, depending on the magnitude of the stability constants of the water-soluble complexes. However, the serum levels of BPAA after rectal administration of the suppositories containing BPAA or its beta-CyDs complexes in rats increased in the order of BPAA alone much less than DM-beta-CyD less than or equal to HP-beta-CyD complex. The in situ recirculation study revealed that the greater the stability constant of the complex, the lesser was the absorption of BPAA from the rectal lumen of rats under the solution state. Both in vivo and in situ studies demonstrated that rather high amount of HP-beta-CyD (about 20% of dose) was absorbable from the rat's rectum, compared with DM-beta-CyD (less than 5% of dose), suggesting the possibility of the permeation of BPAA through the rectal membrane in the form of HP-beta-CyD complex. Furthermore, DM-beta-CyD and HP-beta-CyD significantly reduced the irritation of the rectal mucosa caused by BPAA after the administration of the suppositories to rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Differential effects of petit mal anticonvulsants and convulsants on thalamic neurones: calcium current reduction.

1. Succinimide derivatives can be either convulsant (tetramethylsuccinimide (TMS)), or anticonvulsant (ethosuximide (ES); alpha-methyl-alpha-phenylsuccinimide (MPS)). ES, an anticonvulsant succinimide, has previously been shown to block calcium currents of thalamic neurones, while the convulsant succinimide TMS blocks gamma-aminobutyric acid (GABA) responses in a similar fashion to the convulsant pentylenetetrazol (PTZ). 2. Using voltage-clamp techniques, we analysed the effects of the anticonvulsant succinimides ES and MPS and the convulsants TMS and PTZ on calcium currents of acutely isolated thalamic relay neurones of the rat. 3. MPS and ES reduced low-threshold calcium current (LTCC) in a voltage-dependent manner, without affecting steady-state inactivation. MPS was less potent than ES (IC50 of 1100 vs 200 microM) but greater in efficacy (100% maximal reduction vs 40% for ES). 4. PTZ had no effect on calcium currents, and TMS only reduced LTCC at very high concentrations, and did not occlude MPS effects when applied concurrently. 5. These results, which demonstrate that anticonvulsant, but not convulsant, succinimides block LTCC, provide additional support for the hypothesis that LTCC reduction is a mechanism of action of the anticonvulsant succinimides related to their effects in petit mal epilepsy.     

Non-competitive inhibition of GABAA responses by a new class of quinolones and non-steroidal anti-inflammatories in dissociated frog sensory neurones.

1. The interaction of a new class of quinolone antimicrobials (new quinolones) and non-steroidal anti-inflammatory agents (NSAIDs) with the GABAA receptor-Cl- channel complex was investigated in frog sensory neurones by use of the internal perfusion and 'concentration clamp' techniques. 2. The new quinolones and the NSAIDs (both 10(-6)-10(-5) M) had little effect on the GABA-induced chloride current (ICI) when applied separately. At a concentration of 10(-4) M the new quinolones, and to a lesser degree the NSAIDs, produced some suppression of the GABA response. 3. The co-administration of new quinolones and some NSAIDs (10(-6)-10(-14) M) resulted in a marked suppression of the GABA response. The size of this inhibition was dependent on the concentration of either the new quinolone or the NSAID tested. The inhibitory potency of new quinolones in combination with 4-biphenylacetic acid (BPAA) was in rank order norfloxacin (NFLX) much greater than enoxacin (ENX) greater than ciprofloxancin (CPFX) much greater than ofloxacin (OFLX), and that of NSAIDs in combination with ENX was BPAA much greater than indomethacin = ketoprofen greater than naproxen greater than ibuprofen greater than pranoprofen. Diclofenac, piroxicam and acetaminophen did not affect GABA responses in the presence of ENX. 4. In the presence of ENX or BPAA, there was a small shift to the right of the concentration-response curve for GABA without any effect on the maximum response. However, the co-administration of these drugs suppressed the maximum of the GABA concentration-response curve, indicating a non-competitive inhibition, for which no voltage-dependency was observed.(ABSTRACT TRUNCATED AT 250 WORDS)     

Inhibition of cell differentiation by quinolones in micromass cultures of rat embryonic limb bud and midbrain cells.

Micromass cultures (MMC) of rat embryonic limb bud (LB) and midbrain (CNS) cells were applied to compare the developmental toxicity of three quinolone antimicrobials: norfloxacin (Nor), enrofloxacin (Enr) and ciprofloxacin (Cip). Cultures were exposed for 5 days to seven concentrations of drugs. Cytotoxicity was assessed by quantifying neutral red uptake; differentiation-by quantifying alcian blue uptake (LB) or by image analysis of Gill's haematoxylin stained foci (CNS). Both, LB and CNS cultures showed dose-dependent reduction in total cell number and differentiation. To distinguish specific effect on differentiation, IC(50) for proliferation (P) and differentiation (D) were calculated and P/D ratios were compared. In LB cultures all three drugs were cytotoxic (P/D ratios were 1). In CNS cultures P/D ratios were 1 (up to 2.7 for Nor, up to 4.4 for Enr and up to 16 for Cip) what can suggest specific action on differentiation. Ciprofloxacin was the most toxic and CNS cells were more sensitive than LB. The ranges of IC(50)-D values (microg/ml) were as follows: Nor (79-14), Enr (127-179), Cip (91-101) in LB cultures; Nor (22-52), Enr (38-91), Cip (3-17) in CNS cultures. With one exception (Cip in CNS culture) all drugs were classified as weak embryotoxic.