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PubMed1988

The inhibitory effects of the novel calcium antagonist Goe 5438 on calcium-dependent processes of excitation and contraction of single cardiomyocytes.

The calcium-antagonistic properties of the novel compound Goe 5438 have been studied in single cardiomyocytes from embryonic (chicken) and adult (guinea-pig) ventricles, in part in comparison with the inhibitory effects of the 1,4-dihydropyridine calcium antagonist nimodipine. Both substances block spontaneous action potentials and contractions of embryonic heart cells at about 0.1 mumol/l. In collagenase-dispersed ventricular cardiomyocytes of guinea-pigs, stereospecific inhibition of the slow calcium current (ICa) by Goe 5438 was observed at 10 mumol/l by means of voltage-clamp experiments. The (+)-enantiomer of Goe 5438 elicited a stronger inhibition of the slow inward current than the (-)-enantiomer. The frequency dependence of the inhibitory effect of Goe 5438 as well as that of nimodipine could be shown to be negligible in measurements of ICa and contractions, whereas the inhibitory influence of verapamil, verified in the same experimental arrangement, exhibited a distinct frequency dependence. With respect to a possible potential dependence of the inhibitory effect of Goe 5438 and nimodipine, it could be shown that a hyperpolarization during the course of application of either calcium antagonist produced recovery of the calcium-dependent excitation neither in adult nor in embryonic cells. In adult cardiomyocytes, the dependence of ICa on the membrane potential was not altered by Goe 5438. It is concluded that the mode of action of Goe 5438 resembles that of 1,4-dihydropyridine calcium antagonists.

Action Potentials↗
PubMed1994

The effect of cyclopyrrolones on GABAA receptor function is different from that of benzodiazepines.

The effects of the cyclopyrrolones zopiclone and suriclone on the function of the central gamma-amino-butyric acid type A (GABAA) receptor complex in mouse brain were evaluated both in vitro and in vivo. Added in vitro to mouse cerebral cortical membranes, these compounds potently inhibited [3H]flumazenil binding with IC50 (50% inhibitory concentration) values of 35.8 nM (zopiclone) and 1.1 nM (suriclone). Similar results were obtained with cerebellar membranes, indicating that these drugs do not discriminate between putative type I and type II benzodiazepine receptors. The interaction of cyclopyrrolones with recognition sites present at the level of the GABA receptor complex appears to be competitive, because zopiclone decreased the affinity of the receptors for [3H]flumazenil without affecting the maximal number of binding sites. Moreover, zopiclone and suriclone did not affect the rate of dissociation of [3H]flumazenil from benzodiazepine receptors. The in vitro efficacy of zopiclone appeared different from that of suriclone and the benzodiazepines diazepam and flunitrazepam. Thus, zopiclone failed to affect muscimol-stimulated 36Cl- uptake and only slightly inhibited t-[35S]butylbicyclophosphorothionate ([35S]TBPS) binding. In contrast, like diazepam and flunitrazepam, suriclone increased muscimol-stimulated 36Cl- uptake and markedly inhibited [35S]TBPS binding. In contrast, like diazepam and flunitrazepam, suriclone increased muscimol-stimulated 36Cl- uptake and markedly inhibited [35S]TBPS binding. On the other hand, suriclone, like zopiclone, did not modify [3H]muscimol binding to mouse cerebral cortical membranes. Moreover, zopiclone antagonized the reduction in [35S]TBPS binding elicited by the benzodiazepine receptor full of agonist diazepam. Consistent with its low efficacy in vitro, oral administration of zopiclone (2.5 to 100 mg/kg, p.o.) in mice failed to modify [35S]TBPS binding subsequently measured in cerebral cortical membranes "ex vitro".(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Hydrophobic properties of novel dihydronaphthyridine calcium antagonists and biological activity in porcine isolated cardiac and vascular smooth muscle.

Dihydronaphthyridine calcium antagonists are structurally related to the well known dihydropyridines and act in a similar manner. In order to establish the vascular selectivity of these compounds contractile force was evaluated in porcine isolated ventricular trabeculae and right coronary arteries. The dihydropyridine derivatives nisoldipine and nitrendipine as well as the structurally different compounds gallopamil and flunarizine were included for comparison purpose. All compounds studied exhibited dose-dependent negative inotropic and vasodilator activities. The negative inotropic potency of all dihydronaphthyridines, especially of the highly lipophilic bulky ester-variated derivatives (Goe 5584-A, Goe 5806-A) was comparable to that of flunarizine but was considerably less pronounced than that of nisoldipine, nitrendipine or gallopamil. By contrast, half-maximal vasodilator responses of the dihydronaphthyridines studied in coronary arteries being in the nanomolar concentration range were comparable to the dihydropyridines nisoldipine and nitrendipine, whereas the activity of gallopamil and flunarizine was less marked. On the other side the dihydronaphthyridines, especially the more hydrophilic 3-ethylester-4-(2-cyanophenyl) derivative Goe 5606, exerted an obvious biphasic concentration-response behaviour in coronary arteries leading to a high affinity relaxant process in subnanomolar concentrations, whereas the low affinity response could be observed at rather high concentrations (mostly greater than 1 microM). Mainly due to their relative uneffectiveness in cardiac muscle, vascular selectivity of the dihydronaphthyridines was considerably higher than that of the structurally related dihydropyridines nisoldipine resp. nitrendipine increasing in the following order: nitrendipine less than nisoldipine less than Goe 5606 less than Goe 5438 less than Goe 5584-A less than Goe 5806-A. By contrast, gallopamil exerted a slight cardiac preference, whereas the vascular selectivity of flunarizine was also pronounced.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Suriclone and diazepam in the treatment of neurotic anxiety. A double-blind cross-over trial.

Suriclone is a new anxiolytic drug belonging to the family of cyclopyrrolones. Although chemically entirely different from the benzodiazepines, it acts as a benzodiazepine agonist with very high affinity for the benzodiazepine receptors. In the present cross-over study, 33 out-patients with a diagnosis of neurotic anxiety were treated with suriclone (mean dose 2 mg/day) and diazepam (25 mg/day) in two 6-week periods. Both drugs had a significant anxiolytic effect, but diazepam appeared to have a better effect within the first 2 weeks of treatment, while no significant difference was seen after treatment, while no significant difference was seen after treatment for 6 weeks. Suriclone and diazepam had a different side effect profile: suriclone produced mainly dizziness, while diazepam caused sedation. This may reflect the fact that suriclone and benzodiazepines bind to distinct sites or different allosteric conformations of the benzodiazepine receptors.

Adult↗
PubMed1995

Acute effects of the anxiolytics suriclone and alprazolam on cognitive information processing utilizing topographic mapping of event-related brain potentials (P300) in healthy subjects.

In a double-blind, placebo-controlled, cross-over study, acute effects of suriclone--a cyclopyrrolone derivative--were investigated by means of topographic mapping of event-related potentials (ERPs). Fifteen normal volunteers, aged 22-35 years, received randomized, oral single doses of placebo, 0.1 mg, 0.2 mg and 0.4 mg suriclone and 1 mg alprazolam as a reference compound. ERPs were investigated in an auditory oddball paradigm before and 3 h after intake of each drug. In addition to 17 EEG leads, vertical and horizontal electro-oculograms (EOGs) were recorded. After EOG minimization and artifact identification, the peak latencies of the spatial average were determined by an automatic procedure. Compared to placebo, no significant effects of the low and middle doses of suriclone on N1 amplitude were observed; the highest dosage reduced N1 amplitude, as did 1 mg alprazolam to an even greater extent. While no consistent effects on P2 amplitude were observed after suriclone, alprazolam reduced P2 amplitude. P300 amplitude was reduced only after the highest dosage of suriclone, but much more so after alprazolam. P300 latency was not affected significantly by suriclone, but a marked prolongation of P300 latency was observed after 1 mg alprazolam. Concerning N1 and P2 effects, alprazolam, but not suriclone, may have an inhibitory influence on stimulus-induced cortical arousal. Concerning P300 effects, the used doses of suriclone were superior to 1 mg alprazolam, which seemed to have reduced cognitive information processing capacity and prolonged stimulus evaluation time. Self-rated well-being (adjective checklist) showed subtle beneficial effects after 0.1 mg and 0.2 mg, but marked sedative effects after both 0.4 mg suriclone and 1 mg alprazolam.

Adult↗
PubMed1994

Suriclone enhances the actions of chlorpromazine on human psychomotor performance but not on memory or plasma prolactin in healthy subjects.

Twelve healthy subjects received single oral doses of 0.4 mg suriclone (SU), 7.5 mg zopiclone (ZO) and placebo, alone and together with 50 mg chlorpromazine (CP), double blind and crossover, in Latin square order, at one-week intervals. Performance tests administered before and 1.5, 3.5 and 6 h after drug intake included digit symbol substitution and simulated driving combined in a "Global test", flicker fusion frequency, body balance and memory and subjective assessments. Changes from baseline were examined statistically. Performance and memory data were analysed from only 11 subjects. Compared to placebo, SU minimally affected "global" performance, although it slowed reactions and tended to impair digit substitution. ZO impaired "global" performance at 1.5 h, affected performance in several separate tests, and produced subjective muzziness. CP did not impair "global" performance, although it did impair digit substitution and render the subjects drowsy, weak and dreamy. The combinations SU + CP and ZO + CP definitely impaired "global" performance more than CP alone. This difference was also found in most objective tests but less so in the subjective tests. CP and its combinations produced similar increases in plasma prolactin. Active drugs and their combinations variably lowered blood pressure and increased heart rate, and one subject collapsed after CP. The treatments irregularly impaired spatial memory and learning acquisition. No pharmacokinetic interactions were seen in the plasma levels of suriclone, zopiclone and chlorpromazine. The impairment of performance after these combinations resembles that previously encountered after 2.5 mg lorazepam, or 15 mg diazepam + 100 mg remoxipride.

Adult↗
PubMed1994

Reduction of vitamin D induced stone formation by calcium.

Investigations were carried out as to whether cytoprotective agents such as calcium antagonists can influence vitamin D induced nephrolithiasis. Increased vitamin D levels are found in 10-30% of all calcium oxalate stone formers. Male rats were assigned to one of the following groups: (1) 1,25-dihydroxycholecalciferol (DHCC) (n = 8), (2) 1,25-DHCC + calcium antagonist Goe 6070 (a new 1,4-dihydronaphthyridine, Goedecke, Berlin) (n = 8), or (3) control (n = 8). 1,25-DHCC was administered for 6 days (120 pmol/24 h s.c.), Goe 6070 (1 mg/kg/24 h) by gavage. Clearance studies were performed on day 6. Kidneys were taken for histological examination and determination of calcium tissue content. 1,25-DHCC induced substantial concrement formation, which could be significantly limited by Goe 6070. The calcium tissue content was also reduced (0.17 vs. 0.04 mg/100 mg dry weight). 1,25-DHCC induced a dramatic fall in the glomerular filtration rate (GFR) (3.84 ml/min per kilogram). This reduction could be almost completely inhibited by the concomitant application of Goe 6070 (9.4 ml/min per kilogram; control 10.7 ml/min per kilogram). Goe 6070 did not influence the calcium handling. The results demonstrate a protective effect of Goe 6070 on vitamin D induced nephrolithias. The histological pattern (intracellular and membrane-bound concretions) and the fact that biochemical parameters were not influenced significantly by Goe 6070 indicate that cellular proceses are important for 1,25-DHCC-induced nephrolithiasis.

Animals↗
PubMed1992

The interactions of ethanol with single and repeated doses of suriclone and diazepam on physiological and psychomotor functions in normal subjects.

The effects of diazepam (5 mg t.i.d.), suriclone (0.2 and 0.4 mg t.i.d.) and placebo (t.i.d.) were assessed in 12 normal, healthy volunteer subjects after a single dose and after treatment for a period of 8 days. A battery of physiological, psychomotor and subjective tests was administered on days 1 and 8 both before and after drug and after a measured dose of ethanol. The effects of diazepam on the EEG were characteristic of benzodiazepines-a decrease in the slow frequency wave-bands, an increase in fast frequency wave-band and diminished evoked response amplitude. Suriclone had similar effects on fast frequency activity and evoked response amplitude but, in contrast to diazepam, also increased the slow frequency wave-bands after 7 days treatment. Some improvements in performance were seen with suriclone on critical flicker fusion, tapping speed, spiral maze and digit cancellation. In contrast, suriclone impaired performance to a greater extent than diazepam on digit symbol substitution and symbol copying. Body sway was also enhanced by suriclone to a greater extent than diazepam. Subjective ratings for mood and adverse-effects showed few differences between suriclone or diazepam. However, suriclone caused greater gastro-intestinal disturbances than diazepam, especially after ethanol, and subjects rated themselves as more antagonistic and more irritable on suriclone. Ratings for calmness suggested that in contrast to diazepam, suriclone had no anxiolytic effect. Several of the parameters tested showed a build up of effect with diazepam over the treatment period which was not seen with suriclone. It is suggested that this difference may be due to differences in elimination rate.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Stereoselective analysis of the disposition of tosufloxacin enantiomers in man.

The pharmacokinetics of tosufloxacin enantiomers after oral administration of racemic tosufloxacin were examined in healthy volunteers. Only small differences were observed in time to peak concentration (2.6 +/- 0.3 [mean +/- SEM] h for (+)-tosulfoxacin vs 2.4 +/- 0.2 h for (-)-tosufloxacin), elimination half-life (3.61 +/- 0.24 h vs 3.49 +/- 0.23 h), and area under the curve (2.78 +/- 0.19 h.micrograms/ml vs 2.87 +/- 0.19 h.micrograms/ml); however, peak concentration (0.40 +/- 0.03 microgram/ml vs 0.44 +/- 0.03 microgram/ml), renal clearance (226 +/- 10 ml/min vs 202 +/- 10 ml/min), and urinary recovery (35.4 +/- 2.2% vs 32.4 +/- 1.9%) differed significantly between enantiomers.

Administration, Oral↗
PubMed1983

Differential effects of dopaminergic agonists on food-reinforced operant behavior in the long-tailed macaque (Macaca fascicularis).

Dopaminergic involvement in the regulation of operant behavior was examined by monitoring responding after administration of different dopaminergic agonists. A chain schedule of reinforcement was used to classify the effects of these agonists in long-tailed macaques (Macaca fascicularis). The schedule included the following: (1) a 30-s time-out period; (2) a clock-cued 30-s period of differential reinforcement of zero-response rate; (3) a time-in period whose duration depended on response latency; (4) a 2-s reinforcement period in which applesauce was delivered. This cycling schedule maintained a low operant rate and was sensitive to both inhibition (decreases) and excitation (increases) of responding. IV injection of the dopaminergic agonists resulted in the following two basic effects: (1) d-amphetamine and amfonelic acid disrupted performance by response inhibition, which was shown not to be attributable to anorexia; (2) apomorphine and bromocriptine disrupted performance by response excitation. Both effects were reduced by pretreatment with trifluperidol, a dopaminergic antagonist. The results, indicating that dopaminergic systems mediate disruption of food-reinforced operant behavior by altering the frequency of responding, are interpreted in terms of the known neuropharmacological actions of the agonists.

Animals↗
PubMed1984

Role of cAMP for regulation of impulse-evoked noradrenaline release from the rabbit pulmonary artery and its possible relationship to presynaptic ACTH receptors.

Strips of the rabbit pulmonary artery preincubated with 3H-noradrenaline were superfused with physiological salt solution containing cocaine, corticosterone and propranolol. Basal tritium efflux and electrically evoked tritium overflow were determined. The basal efflux of tritium was not affected by forskolin 0.01-10 mumol/l, 8-Br-cAMP and dibutyryl-cAMP 10-330 mumol/l, or the phosphodiesterase inhibitors rolipram 1-10 mumol/l and AH 21-132 l mumol/l; it was increased by AH 21-132 10-100 mumol/l. Forskolin concentration-dependently increased the evoked 3H overflow, and this effect was not attenuated by omission of cocaine. The facilitatory effect of forskolin was more pronounced at 0.66 Hz than at 2 Hz. Rolipram, AH 21-132, 8-Br-cAMP or dibutyryl-cAMP also produced a concentration-dependent increase in evoked 3H overflow (8-Br-cAMP was more effective than dibutyryl-cAMP in this respect). Except for the highest concentration investigated, AH 21-132 was more effective in facilitating evoked overflow than in increasing basal efflux. Forskolin, AH 21-132 or 8-Br-cAMP did not alter the percentages of 3H-noradrenaline and 3H-metabolites contained in basal tritium efflux or in stimulation-evoked tritium overflow. When a combination of AH 21-132 plus 8-Br-cAMP or AH 21-132 plus forskolin was administered, the facilitatory effect on evoked tritium overflow was more pronounced than with the single compounds alone. ACTH1-24 also facilitated the evoked tritium overflow. Combined exposure to ACTH1-24 plus forskolin, ACTH1-24 plus AH 21-132 or ACTH1-24 plus forskolin plus AH 21-132 resulted in a clearly more pronounced increase in evoked tritium overflow than exposure to the single compounds alone.(ABSTRACT TRUNCATED AT 250 WORDS)

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1985

Involvement of cAMP in modulation of noradrenaline release in the human pulmonary artery.

After incubation with 3H-noradrenaline, strips of human pulmonary arteries from patients undergoing surgery for lung tumour were superfused with physiological salt solution containing cocaine and corticosterone. Forskolin, AH 21-132 (a cAMP phosphodiesterase inhibitor), 8-Br-cAMP and isoprenaline did not affect the basal tritium efflux from the strips, but produced a concentration-dependent facilitation of the tritium overflow evoked by transmural electrical stimulation (2 Hz). The facilitatory effect of isoprenaline was potentiated by forskolin which produced a shift to the left of the concentration-response curve of isoprenaline. It is concluded that cAMP plays a role in the modulation of noradrenaline release in the human pulmonary artery and that presynaptic beta-adrenoceptors appear to be coupled to an adenylate cyclase in the sympathetic nerve terminals.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1987

The effect of age on the pharmacokinetics of enoxacin.

We have studied the pharmacokinetics of enoxacin in two groups of subjects, 10 young (18-45 years) and 10 elderly adults (greater than 65 years) after a single oral dose of enoxacin (600 mg). Enoxacin was absorbed rapidly, peak plasma concentrations being reached within two hours in both groups. However, the peak plasma concentration of enoxacin was significantly higher in the elderly than in the young adults. The area under the concentration-time curve extrapolated to infinity was also significantly greater in the elderly compared with the young subjects, and the apparent renal clearance was significantly less in the elderly than in the young adults. Consequently, the urinary elimination of unchanged enoxacin was significantly reduced in the elderly. The apparent volume of distribution in the elderly was significantly less than in the young adults. The elimination half-time of enoxacin was similar in the two groups.

Adult↗
PubMed1987

Enoxacin--a potent inhibitor of theophylline metabolism.

The mechanism of the theophylline-enoxacin interaction has been studied in six healthy subjects. Theophylline 250 mg was administered p.o., twice daily for 11 days in a sustained release dosage form. On the 4th day of treatment, blood samples were taken every 2 h and urine was collected over 1 dose interval. From Days 5 to 11 coated tablets of enoxacin 400 mg b.i.d. were coadministered. On Day 11 blood and urine were collected as on Day 4. The mean plasma theophylline concentration rose from 4.4 to 15.1 mg/l, corresponding to a 73.6% reduction in total clearance. The urinary excretion of unchanged theophylline increased from 12.7 to 35.3%, whereas the production of metabolites was reduced (1-demethylation 81.4%; 3-demethylation 83.1%, 8-hydroxylation 74.6%). The results indicate that the theophylline-enoxacin interaction may be due to inhibition of the cytochrome P-450 isozymes responsible for theophylline metabolism. Unexpectedly, the renal clearance of theophylline metabolites was found to be drastically reduced when enoxacin was coadministered. This led to unchanged or even to elevated plasma levels of the metabolites. The mechanism of this interaction is still to be elucidated, but it may be due to competition for renal tubular secretion.

Adult↗
PubMed1991

Effects of subchronic amphetamine or amfonelic acid on rat brain dopaminergic and serotonergic function.

Repeated doses of direct or indirect CNS stimulants are known to cause behavioral hypersensitivity. The biochemical basis for hypersensitization remains unclear. Since the dopaminergic system uses a large storage pool that is only slowly mobilized to releasable sites, a change in this relationship may underlie the biochemical changes leading to increased responsiveness to stimulants. To test this hypothesis, rats were first tested with low doses of 2.5 mg/kg amphetamine or 1.0 mg/kg amfonelic acid (AFA) for their locomotor response, then 5.0 mg/kg amphetamine or 2.5 mg/kg AFA were injected daily for 7 days and the rats retested with the lower doses of amphetamine or AFA, respectively. Both drugs produced hypersensitivity, but the cataleptic response to acute dopamine (DA) receptor blockade by haloperidol was unaltered. The ability of haloperidol to increase DA metabolism was unaltered and the ability of acute AFA to synergize with haloperidol was similar in the striatum of stimulant and saline treated rats, but reduced in the medial prefrontal cortex of both AFA and d-amphetamine treated rats. Additional rats had DA2 receptor sensitivity measured in the striatum and frontal cortex, but no significant differences were found. Only amphetamine caused a significant decrease in frontal cortex serotonin type 2 receptors. Since there was no alteration in the ability of AFA to increase neurogenic release of DA in the striatum and a decrease occurred in prefrontal cortex, an increase in the storage to functional pool exchange in the nigrostriatal and mesocortical DA containing neurons seems unlikely. In contrast, both the amphetamine and AFA treatment groups had their brain 5HT and 5HIAA levels reduced by about 50%. This suggests that changes in other transmitter systems may have a permissive effect allowing exaggerated responses to excessive DA release.

Amphetamine↗
PubMed1983

The effects of amfonelic acid on 5-HT metabolism in rat brain.

The non-amphetamine stimulant amfonelic acid (AFA), an inhibitor of dopamine (DA) uptake, has been found to increase the levels of tryptophan (TRYP) and 5-hydroxyindoleacetic acid (5-HIAA) in the rat c. striatum, cerebral cortex, and brain stem. Pretreatment with the DA antagonist haloperidol did not affect this action of AFA in the c. striatum, suggesting that it is independent of the effects of this compound on DA neurons. The duration of action of the effect of AFA on TRYP and 5-HIAA appeared to be longer than that of the increase of the striatal DA metabolites homovanillic acid and 3,4-dihydroxyphenylacetic acid. The increased 5-HIAA concentrations seemed only in part be due to a probenecid-like effect of AFA; evidence for an increased 5-HT synthesis, probably related to the increased TRYP concentrations, was also obtained. This biochemical effect of AFA seems to differ from those reported in the literature on amphetamine and other, related stimulating agents. It might be of interest to see whether corresponding behavioural differences between AFA and these agents can be found.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1979

Effect of mazindol on brain dopamine turnover in spiperone-treated rats.

Mazindol, an anorexic drug, caused a large increase in brain 3, 4-dihydroxyphenylacetic acid (DOPAC) concentration in spiperone-pretreated rats. The increase was dose-related over a 1--10 mg/kg dose range of mazindol and was maximum within 1 hour after maxzindol injection into rats pretreated 1 hour previously with spiperone. In spiperone-pretreated rats, mazindol accelerated the disappearance of dopamine after the inhibition of dopamine synthesis by alpha-methyltyrosine. Mazindol apparently resembles amfonelic acid, methylphenidate, and cocaine in facilitating the impulse-mediated release of dopamine.

3,4-Dihydroxyphenylacetic Acid↗