Neuroimaging of histamine H1-receptor occupancy in human brain by positron emission tomography (PET): a comparative study of ebastine, a second-generation antihistamine, and (+)-chlorpheniramine, a classical antihistamine.

AIMS: Sedation induced by antihistamines is widely recognized to be caused by their penetration through the blood-brain-barrier and the consequent occupation of brain histamine H1-receptors. We previously studied the mechanism of sedation caused by antihistamines using positron emission tomography (PET). Recently, we revealed the nonsedative characteristic of ebastine, a second-generation antihistamine, with cognitive performance tests. In the present study, H1-receptor occupation by ebastine was examined in the human brain using PET. METHODS: Ebastine 10 mg and (+)-chlorpheniramine 2 or 6 mg were orally given to healthy male volunteers. PET scans with [11C]-doxepin, a potent H1-receptor antagonist, were conducted near tmax of respective drugs. Other volunteers in the control group also received PET scans. The binding potential of doxepin (BP = Bmax/Kd) for available brain H1-receptors was imaged on a voxel-by-voxel basis through graphical analysis. By setting regions of interest, the H1-receptor occupancy of drugs was calculated in several H1-receptor rich regions. RESULTS: Brain distribution of radioactivity after ebastine treatment was similar to that without any drugs. However, after the oral administration of 2 mg (+)-chlorpheniramine, the level was lower than after ebastine and nondrug treatments. Graphical analysis followed by statistical parametric mapping (SPM96) revealed that H1-receptor rich regions such as cortices, cingulate gyrus and thalamus were regions where the BPs after ebastine were significantly higher than after (+)-chlorpheniramine (2 mg). H1-receptor occupancies in cortex were approximately 10% by ebastine and > or = 50% by either dose of (+)-chlorpheniramine (95% confidence interval for difference in the mean receptor occupancies: 27%, 54% for 2 mg and 35%, 62% for 6 mg vs ebastine, respectively). Receptor occupancies increased with increasing plasma concentration of (+)-chlorpheniramine, but not with concentration of carebastine, an active metabolite of ebastine. CONCLUSIONS: Ebastine (10 mg orally) causes brain histamine H1-receptor occupation of approximately 10%, consistent with its lower incidence of sedative effect, whereas (+)-chlorpheniramine occupied about 50% of brain H1-receptors even at a low but sedative dose of 2 mg; occupancy of (+)-chlorpheniramine was correlated with plasma (+)-chlorpheniramine concentration.

Effects of 5-HT(4) receptor agonists, cisapride and mosapride citrate on electrocardiogram in anaesthetized rats and guinea-pigs and conscious cats.

The purpose of this study was to examine the arrhythmogenic potential of 5-HT4 receptor agonists, cisapride and mosapride citrate (mosapride) in vivo. In anaesthetized rats, cisapride at intravenous infusion of 10 and 30 mg/kg/hr for 1 hr prolonged the electrocardiographic RR and QT intervals, whereas at 3 mg/kg/hr, it prolonged the RR interval without affecting the QT interval. Mosapride at 30 mg/kg/hr for 1 hr slightly, but not significantly, prolonged the QT interval. In anaesthetized guinea-pigs, cisapride at intravenous infusion of 0.3, 1 and 3 mg/kg over 15 min. prolonged the RR interval (18-44%), QT interval (18-42%) and the corrected QT interval (QTc; 8-19%). Mosapride at 3, 10 and 30 mg/kg over 15 min. little affected the QTc although at 30 mg/kg, it slightly prolonged the RR and QT intervals. With repeated oral administrations of 30 mg/kg twice a day for 7 days, cisapride prolonged the QT interval (11-35%) and QTc (11-32%) at the 3rd and 7th days in conscious cats. In addition, cisapride depressed the ST segment in two out of five cats. Mosapride at 60 mg/kg twice a day for 7 days did not affect the QT interval or QTc in cats. The maximal plasma concentrations of mosapride and its main metabolite (a des-4-fluorobenzyl-mosapride) at the 7th day in cats were 9.4+/-2.8 microM and 2.5+/-0.3 microM , respectively, being 100 and 30-60 times higher than those in man given therapeutic doses (Sakashita et al. 1993a&b). These results indicate that mosapride has little arrhythmogenic potential.

Simultaneous determination of the histamine H1-receptor antagonist ebastine and its two metabolites, carebastine and hydroxyebastine, in human plasma using high-performance liquid chromatography.

Ebastine (CAS 90729-43-4) is an antiallergic agent which selectively and potently blocks histamine H1-receptors in vivo. A simple and sensitive high-performance liquid chromatography (HPLC) method is described for the simultaneous determination of ebastine and its two oxidized metabolites, carebastine (CAS 90729-42-3) and hydroxyebastine (M-OH), in human plasma. After a pretreatment of plasma sample by solid-phase extraction, ebastine and its metabolites were analyzed on an HPLC system with ultraviolet detection at 254 nm. Chromatography was performed on a cyano column (250x4.0 mm I.D.) at 40 degrees C with the mobile phase of acetonitrile-methanol-0.012 M ammonium acetate buffer (20:30:48, v/v/v) at a flow rate of 1.2 ml/min. Accurate determinations were possible over the concentration range of 3-1000 ng/ml for the three compounds using 1 ml plasma samples. The intra- and inter-day assay accuracy of this method were within 100+/-15% of nominal values and the precision did not exceed 12.4% of relative standard deviation. The lower limits of quantitation were 3 ng/ml for ebastine and its metabolites in human plasma. This method was satisfactorily applied to the determination of ebastine and its two oxidized metabolites in human plasma after oral administration of ebastine.

The effects of diazepam on sleep spindles: a qualitative and quantitative analysis.

The effects of 2.5 or 5 mg diazepam (DIZ) on the sleep spindles were studied in 12 healthy male subjects. Polygraphic recordings and the state anxiety scale of the State Trait Anxiety Inventory (STAI) were made for 6 consecutive nights. An inert placebo was given on the first 3 nights and on the sixth night, and DIZ was administered on the fourth and fifth nights. DIZ produced increases in the amount of the slow and fast spindles in a dose-dependent manner. DIZ dose-dependently lowered the frequency of the fast spindles and elevated that of the slow spindles. Furthermore, the influence of DIZ on fast spindles was greater than that on slow spindles. DIZ decreased the state anxiety of the subjects in a dose-dependent manner. These results suggest that measuring the amount and the frequency of fast spindles could be a useful tool in predicting the anxiolytic effects of benzodiazepines.

Effects of pertussis toxin on behavioral responses during different withdrawal periods from chronic cocaine treatment.

1. The role of Gi-proteins on cataleptic responses induced by SCH23390 and haloperidol in chronic cocaine-treated mice was examined by intracerebroventricullor (i.c. v.) and intravenous (i. v.) injections of pertussis toxin (PTX), which catalyzes adenosine diphosphate (ADP)-ribosylation of Gi-proteins. 2. In animals pretreated chronically with cocaine (10 mg/kg, s.c. on alternating days for 21 days), haloperidol (0.1 mg/kg i.p.) exerted an enhanced cataleptic response, but SCH23390 (0.1 mg/kg i.p.) produced an attenuated response at day 1, which converted to a supernormal response, when it was administered 20 days after the last cocaine injection. 3. The attenuated SCH23390 cataleptic response (D1 receptor supersensitivity induced one day after chronic cocaine treatment), was reversed one day after a single dose of PTX, which by itself had no effect, whereas the enhanced haloperidol catalepsy was further enhanced with same dose of toxin. 4. On the other hand, the enhanced SCH23390- and haloperidol-induced cataleptic responses seen during longer withdrawal period (20 days) were potentiated 20 days after a single coadministration of PTX. The stimulatory effects of PTX on the enhanced SCH23390-induced cataleptic response (D1 receptor subsensitivity induced during long-term withdrawal periods from chronic cocaine treatment), may be due to an indirect inhibition of D1 receptors (a synergistic effect) via blockade of postsynaptic dopamine D2 receptors. 5. The postsynaptic D1 receptor supersensitivity and D2 receptor subsensitivity induced one day after chronic cocaine treatment may involve greater Gi-protein ADP-ribosylation in the presynaptic cell body (VTA) than that in the postsynaptic cell body. On the other hand, the subsensitivity of postsynaptic dopamine D1 and D2 receptors (the enhanced SCH23390- and haloperidol-induced cataleptic responses) seen during longer withdrawal periods may mainly involve Gi-protein ADP ribosylation in the postsynaptic cell body, and which may be mediated by a PTX-sensitive muscarinic M2 and/orGABAB receptor activation.

Appearance of frontal midline theta activity in patients with generalized anxiety disorder.

The appearance of frontal midline theta activity (Fmθ), recognized as distinct EEG theta rhythm in the frontal midline area during performance of a mental task, reflects feelings of relief from anxiety in humans. In the present study, EEGs were recorded, and the Hamilton Rating Scale for Anxiety and the state anxiety scale of Spielberger's State-Trait Anxiety Inventory were evaluated once a week in 28 patients with generalized anxiety disorder. The Taylor Manifest Anxiety Scale and the trait anxiety scale of Spielberger's State-Trait Anxiety Inventory were used to assess anxiety before and after the tests. The present results suggest that the appearance of Fmθ might be closely related to an improvement in the anxiety symptoms associated with generalized anxiety disorder.

Modification of cataleptic responses to dopamine receptor antagonists after withdrawal from chronic cocaine or cocaine plus dopamine antagonist administration.

1. In mice pretreated chronically with cocaine (indirect dopamine agonist: 10 mg/kg, s.c. on alternating days for 15 days), haloperidol (dopamine D2 antagonist: 0.3 mg/kg i.p.) exerted an enhanced cataleptic response, but SCH23390 (dopamine D1 antagonist: 0.3 mg/kg i.p.) produced an attenuated response at 24 h, which converted to a supernormal response, when it was administered 15-60 days after withdrawal from cocaine. 2. A challenge dose of SCH23390 exhibited enhanced catalepsy when given 15 days, but not at 24 h, after the last pretreatment dose of SCH23390 (0.1-1.0 mg/kg s.c.). In contrast, haloperidol catalepsy was not affected by the SCH23390 pretreatment. 3. However, in animals chronically pretreated with haloperidol (0.1-1.0 mg/kg s.c.), a challenge dose of SCH23390 as well as haloperidol exhibited attenuated cataleptic effects at 24 h and normal cataleptic responses at 15 days after the last dose of the pretreatment regimen. 4. Challenge doses of haloperidol or SCH23390 given to mice 24 h after chronic cocaine pretreatment produced enhanced and attenuated cataleptic responses, respectively; however, these responses were no longer produced when haloperidol or SCH23390 was given to mice pretreated chronically with a combination of cocaine and either haloperidol or SCH23390. 5. The enhanced catalepsy produced by a challenge dose of SCH23390 (15-60 days after chronic cocaine) was further potentiated when it was administered to animals that had been pretreated chronically with a combination of SCH23390 and cocaine, but was antagonized in animals pretreated chronically with haloperidol and cocaine. In contrast, the degree of enhanced cataleptic responses produced by a challenge dose of haloperidol 30-60 days after pretreatment chronically with a combination of cocaine + SCH23390 was similar to that seen after chronic cocaine alone. However, this enhanced response was antagonized in animals that had been pretreated chronically with the combination of cocaine + haloperidol. 6. The results suggest that the coadministration of SCH23390 with cocaine was able to block indirectly dopamine D2 receptor inhibition (subsensitivity) induced during the early withdrawal period from chronic cocaine, despite the fact that by itself SCH23390 did not have an effect on haloperidol catalepsy. Accordingly, the stimulatory effects of dopamine D2 receptors by a single administration of cocaine may be mediated mainly by an indirect stimulation of dopamine D2 receptor function via its D1 receptor stimulating action. 7. The coadministration of SCH23390 with cocaine rather aggravate the subsensitive effect of dopamine D1 receptors (increased SCH23390 catalepsy) produced during long-term withdrawal period from chronic cocaine, but did not affect that of the dopamine D2 receptor. On the other hand, the coadministration of haloperidol with cocaine normalized both D1 and D2 receptor subsensitive effect. 8. These result suggest that a single administration of SCH23390 or haloperidol after long-term withdrawal periods from chronic cocaine may not be effective as antipsychotic drugs because of further aggravation of suppressive behaviors. These results also provide evidence that D2 receptor antagonists may be more effective as antipsychotic drugs than dopamine D1 receptor antagonist, since the coadministration of haloperidol with cocaine normalized the abnormal behaviors seen during early and long-term withdrawal periods from chronic cocaine.

A polysomnographic study of sleep patterns in normal humans with low- or high-anxiety personality traits.

To clarify the effects of anxiety-related personality traits on sleep patterns, polysomnographic examinations (PSG) were performed over 4 consecutive nights on normal humans who tested within the low- or high-anxiety ranges. The subjects consisted of two groups of six male university students who scored either less than 45 points (low-anxiety group) or more than 55 points (high-anxiety group) on the Spielberger's State Trait Anxiety Inventory. Compared to the levels of sleep change in the high-anxiety group, the low-anxiety group exhibited a greater change in REM sleep and stage 2 sleep. The REM sleep in the low-anxiety group was shorter on the first and second nights compared to the third and fourth nights, and the stage 2 sleep was longer on the first night than on the remaining three nights. Thus, the low-anxiety group showed a first-night effect followed by partial recovery on the second night, while the high-anxiety group exhibited no obvious first-night effect. These results suggest that there is a difference in sleep patterns, assessed by consecutive PSG, between those with low- and high-anxiety traits, and that anxiety-related personality traits attenuate the occurrence of the first-night effect, reflecting a lower adaptability to a novel environment.

Anxiolytic effects of low-dose clomipramine in highly anxious healthy volunteers assessed by frontal midline theta activity.

1. The appearance of Fm theta, the distinct EEG theta rhythm in the frontal midline area during performance of a mental task, reflects relief from anxiety in humans. 2. In the present study, the anxiolytic effects of low-dose clomipramine were examined by monitoring the Fm theta amount, the STAI scores and the plasma 5-HIAA concentration in 24 male university students with (Fm theta group, n = 12) and without (non-Fm theta group, n = 12) Fm theta. 3. Subjects were given placebo, 10 mg and 30 mg clomipramine in a double-blind crossover design. Blood samples were obtained, STAI scores were determined, and EEGs were recorded before and during the performance of an arithmetic addition task. The test was repeated twice: before and 3 hrs after drug administration. 4. In the non-Fm theta group, 10 mg clomipramine decreased the 5-HIAA concentration and state anxiety scores but increased the Fm theta amount, while 30 mg clomipramine slightly increased only the Fm theta amount. However, there were no differences in these items before and after clomipramine administration in the Fm theta group. 5. These results suggest that low doses of clomipramine such as 10 mg may exert anxiolytic effects during the acute phase of treatment in highly anxious humans.

Vitamin B12 treatment for delayed sleep phase syndrome: a multi-center double-blind study.

The active form of vitamin B12 (methylcobalamin) has been reported to be effective on sleep-wake rhythm disorders. Previous studies, however, were performed under open trial, and the effect of vitamin B12 has not been properly evaluated. The aim of this double-blind study was to investigate the efficacy of methylcobalamin on delayed sleep phase syndrome (DSPS). Methylcobalamin (3 mg/day) or placebo was administered for 4 weeks. The subjects were 50 patients with DSPS aged 13-55 years (26.8 +/- 1.3), 27 of whom received the active drug while 23 received the placebo. No significant differences were observed between the 2 groups in subjective evaluations of mood or drowsiness during the daytime or in night sleep by sleep-log evaluation. These results indicate that 3 mg methylcobalamin administered over 4 weeks is not an effective treatment for DSPS.

Dopaminergic and cholinergic interaction in cataleptic responses in mice.

The cataleptogenic effects of haloperidol, a dopamine D2 receptor antagonist; SCH23390, a D1 receptor antagonist; physostigmine, a cholinesterase inhibitor; and pilocarpine, a muscarinic M1 receptor agonist, were challenged by pretreatment of mice with SKF38393, a dopamine D1 receptor agonist; apomorphine, a dopamine D1/D2 receptor agonist (mainly D2 receptor); pirenzepine, a muscarinic M1 receptor antagonist; and scopolamine, a muscarinic M1/M2 receptor antagonist. The effect of physostigmine and pilocarpine on haloperidol and SCH23390 cataleptic responses was also examined. Each of the challenging agents blocked one or more of the cataleptogenic agents, but only scopolamine blocked all four. Pirenzepine blocked cataleptic responses induced by SCH23390 and pilocarpine, but not those by haloperidol and physostigmine. The results of this study suggest that the action of physostigmine (endogenous acetylcholine) on M2 receptors might be more potent than that on muscarinic M1 receptors. A further interesting observation was that the haloperidol-induced catalepsy was enhanced by physostigmine pretreatment, but not by pilocarpine pretreatment, whereas the SCH23390-induced catalepsy showed the opposite spectrum of enhancement by the two cholinergic agonists. We conclude that, although the four cataleptogenic agents act via the dopaminergic-cholinergic systems, their pharmacological differences may be due largely to the different receptor subtypes that are involved in the mediation of catalepsy produced by each agent. Thus, dopamine receptors not only influence the cholinergic muscarinic receptors, but muscarinic M1 and M2 receptors also might mediate dopamine D1 and D2 receptor responses, respectively. The results suggest that there are, at the least, relationships between muscarinic M1 receptors and dopaminergic D1 receptors, and between muscarinic M2 receptors and dopaminergic D2 receptors. Dopamine D1 and D2 receptors may interact in a synergistic fashion on dopaminergic systems, but act independently of each other in influencing other system such as cholinergic neurons.

Simultaneous enantiomeric determination of a gastroprokinetic agent mosapride citrate and its metabolite in plasma using alpha 1-acid glycoprotein HPLC column.

Mosapride citrate, a novel benzamide-type gastroprokinetic agent, is clinically prescribed as a racemate and is metabolized to its des-4-fluorobenzyl structure (M-1). In order to analyze simultaneously the enantiomers of mosapride and M-1 in plasma, a simple and reproducible high-performance liquid chromatographic (HPLC) method has been developed. The enantiomeric separation and determination were successfully achieved using an alpha 1-acid glycoprotein column and gradient elution with a fluorimetric detection (excitation 314 nm/emission 352 nm). Both enantiomers of mosapride and M-1 were well separated between 20 and 22 min at pH 4.4 and between 4 and 7 min at pH 5.0, respectively. Accurate determinations are possible in the concentration ranges of 10-5000 ng ml-1 for mosapride enantiomers and 50-5000 ng ml-1 for M-1 enantiomers. The intra- and inter-day coefficients of variation are satisfactory for the pharmacokinetic study of mosapride.

Differential effects of dopaminergic drugs on anxiety and arousal in healthy volunteers with high and low anxiety.

1. The appearance of frontal midline theta activity (Fm theta), the distinct EEG theta rhythm in the frontal midline area during performance of a mental task, indicates relief from anxiety in humans. 2. The authors examined the effects of bromocriptine and sulpiride on anxiety and arousal in 24 male university students with (Fm theta group, n = 12) and without (non-Fm theta group, n = 12) Fm theta. Subjects were given placebo, 2.5 mg bromocriptine and 100 mg sulpiride in a double-blind crossover design. 3. Blood samples were obtained, STAI scores were determined, and EEGs were recorded before and during the performance of an arithmetic addition task. The test was repeated twice: before and 1 hr after drug administration. 4. Bromocriptine reduced the HVA concentration in both groups; sulpiride caused an increase in both groups. In the Fm theta group, bromocriptine did not alter the appearance time of Fm theta, the state anxiety score or the task performance; sulpiride increased the Fm theta amount and reduced the state anxiety but did not affect the task performance. In the non-Fm theta group, bromocriptine increased the Fm theta duration and reduced the state anxiety score but did not influence the task performance, while sulpiride reduced Fm theta and increased the state anxiety but had no effect on the task performance. 5. These results suggest that the sensitivity of presynaptic D2 receptors is higher in high-anxiety subjects compared with low-anxiety subjects, and that anxiolytic effects in high-anxiety humans and those in low-anxiety humans may be caused by decreased and increased DA activity, respectively. In addition, the stimulation of DA function may cause anxiogenic effects in high-anxiety individuals.

Effects of dopamine antagonists on changes in spontaneous EEG and locomotor activity in ketamine-treated rats.

We investigated the effects of dopamine antagonists on spontaneous cortical and hippocampal electroencephalographic (EEG) changes, and on hyperlocomotion in ketamine-treated rats. Ketamine (20-60 mg/kg IP) synchronized cortical EEG and desynchronized hippocampal EEG in a dose-dependent manner indicating that the drug induced a dissociation between the cortical and hippocampal EEG. These EEG changes were accompanied by an increase in spontaneous locomotor activity, which involved lack of focused direction, stereotypy, irritability and other abnormalities. Dopamine antagonists, such as haloperidol (0.3-1 mg/kg IP), and nemonapride (0.3-1 mg/kg IP), reversed the dissociation between the cortical and hippocampal EEG in ketamine (60 mg/kg IP)-treated rats. Ketamine-induced hyperlocomotion was also decreased by administration of haloperidol (0.3 and 1 mg/kg IP) or nemonapride (0.1-1 mg/kg IP). Thus, it was found that dopamine antagonists reversed the EEG alterations and behavioural changes in ketamine-treated rats.

Differential effects of noradrenergic drugs on anxiety and arousal in healthy volunteers with high and low anxiety.

1. The appearance of frontal midline theta activity (Fm theta), the distinct EEG theta rhythm in the frontal midline area during performance of a mental task, indicates relief from anxiety in humans. 2. The authors investigated the effects of clonidine and yohimbine on anxiety and arousal in 24 male university students with (Fm theta group, n = 12) and without (non-Fm theta group, n = 12) Fm theta. Subjects received placebo, 0.15 mg clonidine and 15 mg yohimbine in a double-blind crossover design. 3. Blood samples were obtained, state-trait anxiety inventory (STAI) scores were determined, and EEGs were recorded before and during the performance of an arithmetic addition task. The test was repeated twice: before and 1 hr after drug administration. 4. Clonidine reduced the 3-methoxy-4-hydroxyphenylglycol (MHPG) concentration in both groups; yohimbine caused an increase in both groups. In the Fm theta group, clonidine reduced the appearance time of Fm theta and the number of task performance but did not alter the state anxiety scores; yohimbine had no effects on Fm theta or the state anxiety but increased the task performance. In the non-Fm theta group, clonidine increased the Fm theta amount and reduced the state anxiety score but did not affect task performance, while yohimbine reduced Fm theta but increased the state anxiety, the task performance and the number of errors. 5. These results suggest that changes in noradrenaline (NA) activity affect both anxiety and arousal levels in high-anxiety humans, but predominantly affect only the arousal level in low-anxiety humans.

Intermolecular interactions of antimicrobial fluoroquinolones with purified rat liver CYP1A2 studied by proton nuclear magnetic resonance spectroscopy.

1. Binding and inhibition of antimicrobial fluoroquinolones towards liver CYP1A2 purified from 3-methylcholanthrene-treated rats were investigated using proton nuclear magnetic resonance (nmr) and phenacetin metabolism. 2. The proton nmr longitudinal relaxation rate study indicated that the paramagnetic effects of the haem iron of CYP1A2 were observed in protons of enoxacin with a 1,8-naphthyridine skeleton and its 4'-nitrogen atom on the 7-piperazine ring probably participated in specific binding to the haem iron. These data suggest a facile accessibility and strong binding of enoxacin to the active site of the enzyme. On the contrary, the binding region of norfloxacin with a quinoline skeleton could not be specified, and an 8-fluorinated derivative (AT-3970) had much lower paramagnetic effects and no specific binding region. 3. In a reconstituted CYP1A2 system, enoxacin exhibited the most potent inhibition of phenacetin O-deethylation. The metabolism was less inhibited by norfloxacin, and AT-3970 had a weak inhibitory activity. 4. The binding ability of the fluoroquinolones to the CYP1A2 active site is likely to determine their inhibitory activity against phenacetin metabolism.

Structure-related inhibitory effect of antimicrobial enoxacin and derivatives on theophylline metabolism by rat liver microsomes.

Enoxacin, an antimicrobial fluoroquinolone with a 7-piperazinyl-1, 8-naphthyridine skeleton, is a potent inhibitor of cytochrome P-450-mediated theophylline metabolism. The present study was designed to clarify, using seven enoxacin derivatives, the molecular characteristics of the fluoroquinolone responsible for the inhibition. Three derivatives with methyl-substituted 7-piperazine rings inhibited rat liver microsomal theophylline metabolism to 1,3-dimethyluric acid to an extent similar to that of enoxacin (50% inhibitory concentrations [IC50s] = 0.39 to 0.48 mM). 7-Piperazinyl-quinoline derivatives, 8-hydroenoxacin (8-Hy) and 1-cyclopropyl-8-fluoroenoxacin (8-F1), which have a hydrogen and a fluorine at position 8, respectively, more weakly inhibited metabolite formation (IC50s = 0.88 and 1.29 mM, respectively). Little inhibition (IC50 > 2 mM) was observed in those with 3'-carbonyl and 4'-N-acetyl groups on the piperazine rings. The substrate-induced difference spectra demonstrated that the affinities of enoxacin, 8-Hy, and 8-F1 to cytochrome P-450 were parallel with their inhibitory activities. The substituent at position 8 was found to determine the molecular conformations of the fluoroquinolones, and the planarity in molecular shape decreased in the same order as the inhibitory activity (enoxacin > 8-Hy > 8-F1). Moreover, the 3'-carbonyl and 4'-N-acetyl groups decreased the basicity of their vicinal 4'-nitrogen atoms when judged from their electrostatic potentials, which showed a remarkably broadened negative charge around the nitrogens. As a result, the planarity of the whole molecule and the basicity of the 4'-nitrogen atom of enoxacin are likely to be dominant factors in the inhibition of theophylline metabolism by cytochrome P-450.

Pharmacokinetic interactions related to the chemical structures of fluoroquinolones.

Fluoroquinolone derivatives interact with methylxanthines (theophylline, caffeine) and metallic ion-containing drugs to different degrees. The rat appears to be a suitable model for predicting such interactions in man. It has been possible to determine the relationship between the chemical structure of the fluoroquinolone and the magnitude of the interaction. Fluoroquinolones with a bulky substituent at the position 8, such as sparfloxacin, lomefloxacin and fieroxacin, are less prone to interact with theophylline than those without an 8-substituent, such as enoxacin. This substituent determines the planarity of the whole fluoroquinolone molecule and the interaction tends to be more significant for planar fluoroquinolones. Furthermore, a 4'-nitrogen atom in the 7-piperazinyl group is essential for the interaction to occur. The nitrogen atom is possibly the site that binds cytochrome P-450, which catalyses theophylline metabolism. The reduction in bioavailability of fluoroquinolones by concurrent administration of aluminium hydroxide is more striking for derivatives with fewer substituents on the essential structure and on the piperazinyl group, such as norfloxacin, ciprofloxacin and enoxacin. Substitution at the 5-position diminishes the interaction, which suggests that the 5-substituent may affect the formation and/or stability of unabsorbable chelate complex which is the probable cause of the interaction. These findings are potentially useful in designing fluoroquinolones less prone to drug interactions.

Effects of chronic methamphetamine on SCH23390- or haloperidol-induced catalepsy, and effects of coadministration of SCH23390 or haloperidol in mice.

The influence of chronic treatment of mice with methamphetamine, an indirect dopamine agonist, on the cataleptic effects of R-(+)-chloro-2,3,4,5,-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin -7ol hydrochloride (SCH23390), a D1 receptor agonist, or haloperidol, a mainly D2 antagonist, was investigated. Once every other day treatment with 3 mg/kg SC methamphetamine for 15 days resulted in an increase in the catalepsy produced by haloperidol (0.3 mg/kg IP) (haloperidol catalepsy), but in a decrease in the catalepsy produced by SCH23390 (0.3 mg/kg IP) (SCH23390 catalepsy), 24 h and 7 days after withdrawal of methamphetamine. These effects of chronic methamphetamine were antagonized by coadministration of either SCH23390 (0.5 mg/kg SC) or haloperidol (1.0 mg/kg SC). These results suggest that the decreased responsiveness to SCH23390 in chronic methamphetamine-pretreated mice results from a supersensitivity of D1 receptors, and that the increased responsiveness to haloperidol catalepsy results from a subsensitivity of D2 receptors. The attenuated response to SCH23390 may be interpreted as an example of sensitization to methamphetamine, and the enhanced haloperidol response as an example of tolerance to methamphetamine, based on the development of supersensitivity and subsensitivity of D1 and D2 receptors, respectively, after chronic methamphetamine administration. Furthermore, it is suggested that coadministration of either SCH23390 or haloperidol could prevent the development of D1 receptor supersensitivity and D2 receptor subsensitivity induced by chronic methamphetamine.

An automatic sleep-stage analysis system with off-line high-speed processing using a super mini-computer.

An automatic sleep analysis system using a super mini-computer was developed. The system improved and expanded the data processed by the mini-computer. It had the following features: 1) wave-forms were collected and analyzed at a high speed (reproduced at 10 or 20 times the speed of a data recorder) by an off-line procedure to utilize the computer resources more efficiently; 2) all information and the original wave-forms were output to a laser printer because of the lower cost and more efficient arrangement of the data; 3) various wave-form parameters were measured by wave-form analysis; 4) the application program was based on general-purpose language; and 5) wave-form reanalysis and reconstruction of the logic was easily implemented for automatic evaluation of the sleep stages. Automatic analysis of the sleep stages was impossible for 15 of 1484 periods (20 sec per period) with one of the cases analyzed, and 142 of 1484 periods had to be corrected because of erroneous identification.