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Biomedical subjects

B Nickel

Publications and source records attributed to B Nickel.

At least 19 recordsLinked to original sources
PubMed1995

5-HT3 receptor antagonism by anpirtoline, a mixed 5-HT1 receptor agonist/5-HT3 receptor antagonist.

1. The aim of this study was to provide evidence that anpirtoline, which is an agonist at 5-HT1B and 5-HT1D receptors and also displays submicromolar affinity for 5-HT1A recognition sites, in addition, acts as an antagonist at 5-HT3 receptors. 2. In radioligand binding studies on rat brain cortical membranes, anpirtoline inhibited specific binding of [3H]-(S)-zacopride to 5-HT3 receptor recognition sites (pKi: 7.53). 3. In N1E-115 neuroblastoma cells in which [14C]-guanidinium was used as a tool to measure cation influx through the 5-HT3 receptor channel, the 5-HT-induced influx was concentration-dependently inhibited by anpirtoline. In this respect, anpirtoline mimicked other 5-HT3 receptor antagonists; the rank order of potency was ondansetron > anpirtoline > metoclopramide. 4. The concentration-response curve for 5-HT as a stimulator of [14C]-guanidinium influx was shifted to the right by anpirtoline (apparent pA2: 7.78). 5. In urethane-anaesthetized rats, anpirtoline inhibited (at lower potency than zacopride and tropisetron) the 5-HT- or phenylbiguanide-induced bradycardia (Bezold-Jarisch reflex), but did not induce this reflex by itself. 6. Intravenous infusion of cisplatin in the domestic pig caused a consistent emetic response which was antagonized by anpirtoline. 7. It is concluded that anpirtoline, which was previously characterized as a 5-HT1 receptor agonist also proved to be a 5-HT3 receptor antagonist in several experimental models and, hence, exhibits a unique pattern of properties at different 5-HT receptors.

Animals↗
PubMed1994

Evaluation of physical dependence liability of l-deprenyl (selegiline) in animals.

l-Deprenyl is a useful drug that has been successful in the clinical treatment of parkinsonism. However, l-deprenyl is a phenylalkylamine derivative that undergoes metabolic transformation to l-methamphetamine and l-amphetamine. Therefore, the question arises whether l-deprenyl possesses amphetamine-like abuse liability. This article reviews a series of different preclinical studies in rats that used experimental procedures to provide preclinical information predictive of human abuse liability. In one series we investigated whether repeated administration of l-deprenyl to rats resulted in observable signs of physical dependence. In a second series of studies, the effects of l-deprenyl on the cortical electrical activity of freely moving rats were investigated. Finally, the influence of l-deprenyl on behavior of the animals was studied. In all studies, different stereospecific configurations of amphetamine and deprenyl were compared. During and after 6 weeks of oral administration of l-deprenyl, no signs of physical dependence were observed in rats after withdrawal of the drug. In contrast, with d-deprenyl, d-amphetamine, and racemic d,l-amphetamine, signs indicative of physical dependence were observed after withdrawal of the drug. For example, the body weight of the rats was increased. In addition, changes in electroencephalograms and behavior of rats induced by l-deprenyl and l-amphetamine were different from those produced by the d-enantiomers. Thus preclinical results confirm the clinical experience that therapeutically relevant doses of l-deprenyl are without physical dependence liability.

Amphetamine↗
PubMed1993

[New central analgesic-acting triaminopyridines].

New Triaminopyridines with a Central Analgesic Activity 2-Amino-3-((prop-1-en-3-yl)oxycarbonylamino)-6-(4-fluorobenzyla mino) pyridine hydrochloride (D-19050) is a centrally and peripherally acting analgesic with rapid onset, long duration of action and a good therapeutic range. D-19050 can be obtained in a 5-step-synthesis starting from 2,6-dichloropyridine.

Aminopyridines↗
PubMed1992

Influence of flupirtine, a novel nonopioid analgesic agent on somatosensory evoked potentials in rats.

The effect of flupirtine, a novel nonopioid analgesic, on somatosensory evoked potentials (SEP) was investigated in anesthetized rats. Primary somatosensory potentials were evoked in the cerebral cortex by stimulation of the skin of the whiskery part of the face. Flupirtine injected i.p. dose-dependently prolonged the latency and reduced the amplitude of SEP with ID50-values of 5.4 mg/kg (2.6-9.3 mg/kg) and 7.9 mg/kg (3.9-13.8 mg/kg), respectively. This effect of flupirtine (10 mg/kg, i.p.) on the latency and the amplitude of SEP, did not change when naloxone (1 mg/kg, i.p.) was given before flupirtine. The results indicate that the analgesic flupirtine decreases the primary somatosensory evoked potential by diminishing the excitability of cortical neurons. Opioid mechanisms are not involved.

Aminopyridines↗
PubMed1992

Anpirtoline, a novel, highly potent 5-HT1B receptor agonist with antinociceptive/antidepressant-like actions in rodents.

1. The purpose of the present study was to relate the effects of the novel drug, anpirtoline, on 5-hydroxytryptamine (5-HT) receptor subtypes to its antinociceptive and antidepressant-like actions in rodents. 2. Binding assays with rat brain membranes have shown that anpirtoline bound with a much higher affinity to 5-HT1B receptor (Ki = 28 nM) than to 5-HT1A (Ki = 150 nM) and 5-HT2 (Ki = 1.49 microM) receptors. 3. Like 5-HT, anpirtoline concentration-dependently inhibited forskolin-stimulated adenylate cyclase activity in homogenates from the rat substantia nigra. Both effects were not additive, and could be prevented by 5-HT1B receptor antagonists such as propranolol and penbutolol. 4. In superfused rat and pig brain cortex slices preincubated with [3H]-5-HT, the electrically evoked tritium overflow was inhibited by anpirtoline and 5-HT. Whereas 5-HT was equipotent in both tissues (EC50 = 69 nM), anpirtoline was markedly less potent in pig brain cortex slices (EC50 = 1190 nM) than in rat brain cortex slices (EC50 = 55 nM). The concentration-response curve for anpirtoline was shifted to the right by metitepine in both preparations. 5. In the social behaviour deficit test, anpirtoline and trifluoromethylphenyl-piperazine were effective in reversing the isolation-induced impairments in mice, an effect shown only by compounds with agonist properties at the 5-HT1B receptor. 6. In the electrostimulated pain test using mice, anpirtoline dose-dependently increased the pain threshold with an ED50 of 0.52 mg kg-1, i.p. The antinociceptive activity of anpirtoline was abolished by pretreatment with cyproheptadine or propranolol.7. In the forced swimming test in rats, anpirtoline induced a dose-related increase in swimming activity. With an ED50 value of 4.6mgkg-1, i.p., anpirtoline was 4 times more potent than the two standard compounds imipramine and desipramine. The decrease of immobility time or the increase of active periods in this model of behavioural despair is suggested to be characteristic of antidepressant drugs.8. Anpirtoline exhibits both antinociceptive and antidepressant-like activities in animals. It is probable that anpirtoline elicits these pharmacological effects via its agonist effect on 5-HT1B and 5-HT1A receptors.

Adenylyl Cyclase Inhibitors↗
PubMed1992

D-16949 (anpirtoline): a novel serotonergic (5-HT1B) psychotherapeutic agent assessed by its discriminative effects in the rat.

D-16949 [6-chlor-2-(piperidyl-4-thio)-pyridine; Anpirtoline] is a novel centrally acting compound with serotonergic effects. To assess its discriminative stimulus effects, rats were trained to discriminate D-16949 (2.0 mg/kg i.p., 30 min) from no drug. D-16949 induced dose-dependent discriminative stimulus effects (ED50, 0.31 mg/kg), and did not produce sedation. The opioid analgesics codeine, pentazocine and tramadol all failed to substitute for D-16949. The opioid antagonist naltrexone did not antagonize the discriminative stimulus effects of D-16949. Phencyclidine, d-amphetamine, lysergic acid diethylamide and quipazine produced between 0 and 35% responding on the D-16949 lever. 8-Hydroxy-2-(di-n-propylamino)-tetralin substituted partially (45%) for D-16949, whereas 1-(m-trifluoromethylphenyl)-piperazine and RU 24969 completely and dose-dependently substituted for D-16949. The discriminative stimulus effects of D-16949 were not reversed by either cyproheptadine, ketanserin, pirenperone, spiperone or methylsergide. The 5-hydroxytryptamine3 (5-HT3) active antagonists ICS 205-930 and MDL 72222 were also ineffective as D-16949 antagonists. It is concluded that the discriminative stimulus effects of D-16949 are not mediated through opioid or 5-HT2 mechanisms. The present data also do not suggest the involvement of 5-HT3 mechanisms, but that D-16949 produces its discriminative stimulus effects in the rat primarily via agonistic actions at 5-HT1B receptors.

Animals↗
PubMed1991

Determination of vesicle size distributions by freeze-fracture electron microscopy.

The most common electron microscopic technique for obtaining information on size distributions of uncollapsed membrane vesicles is based on the method of van Venetie (1980). This technique involves the sizing of only those vesicles that were freeze fractured at their equatorial planes. As a result, only a small number of images can be used to generate size distributions. Further, the technique is susceptible to systematic error. An alternate approach is to consider the complete distribution of image sizes and use this distribution to determine the average size and distribution of the vesicles. It is shown that the mean vesicle size is 4/pi times the mean image size. As well, a parameter, m, which can be determined from the image distribution, can be used to characterize the vesicle distribution. The advantage of this new approach is that images of all vesicles are used, leading to a statistically better determination of vesicle sizes.

Freeze Fracturing↗
PubMed1991

Pharmacological profile of flupirtine, a novel centrally acting, non-opioid analgesic drug.

Flupirtine is a new non-opioid, non-addicting centrally acting analgesic. In animals, antinociceptive activity of flupirtine was attenuated after reserpine pretreatment or in the presence of alpha-adrenergic antagonists suggesting the possible involvement of the noradrenergic system in its analgesic mode of action. Additionally, flupirtine possesses skeletal muscle relaxing activity in rats.

Adrenergic alpha-Antagonists↗
PubMed1991

[The concept of amnesia and quantitative assessment of amnesic disorders].

This article presents first a short historical overview of the different viewpoints concerning psychiatric approaches to define the concept "amnesia" (Ribot, Korsakow, K. Schneider, Bleuler, Bonhoeffer et al.). A generally accepted result is the differentiation between retrograde and anterograde amnesia. Research work of the last two decades has focussed on the experimental investigation of anterograde amnesia, the so-called amnesic syndrome. In this context four main factors responsible for memory performance are distinguished: encoding, retrieval, forgetting and interference. One of the main results of neuropsychological research in amnesia consists in having discovered a set of symptoms or features common to most if not all forms of amnesia. These features appear regardless of etiology and locus of lesion. This set or features is described in detail in the paper. On the basis of these amnesic features a clinical test was developed, the Berliner Amnesie Test (BAT). This standardized test can be used for the assessment from mild up to severe memory disorders.

Alzheimer Disease↗
PubMed1990

Kinetic evaluation of MAO-B-activity following oral administration of selegiline and desmethyl-selegiline in the rat.

The monoamine oxidase (MAO) B activity of rat brain was inhibited by selegiline and its desmethyl-metabolite in vitro with IC50-values of 11.25 nmol/l and 625.00 nmol/l, respectively. When measured in an ex vivo experiment following oral treatment of rats, the large difference in potency was distinctly reduced, from factor 60 in vitro to factor 3 ex vivo. Restoration experiments of MAO-B-activity after cessation of treatment revealed a nearly identical time course for both compounds. It is concluded that desmethyl-selegiline is an irreversible blocker of MAO-B, nearly equipotent to selegiline after multiple oral administration. No pharmacologically relevant inhibition of MAO-A was found with both compounds.

Administration, Oral↗
PubMed1990

Effect of selegiline and desmethyl-selegiline on cortical electric activity in rats.

The pharmaco-EEG changes caused by the monoamine oxidase (MAO) B inhibitor selegiline were compared with the frequency band alterations aroused by its desmethyl metabolite after oral administration in rats. After single administration (5 mg/kg) the EEG changes caused by selegiline or desmethyl-selegiline differed significantly. Distinct decreases in delta and clear increases in theta EEG frequency bands were obvious after administration of selegiline. The single oral dose of desmethyl-selegiline (5 mg/kg) caused only trendly the same EEG changes observed after giving the mother compound. Following repeated administration on four consecutive days no significant differences in the frequency band changes could be seen after selegiline or desmethyl-selegiline. Based on present results it is likely that the mode of action of desmethyl-selegiline appears to be similar or identical with the mode of action of the parent compound, selegiline.

Amphetamines↗
PubMed1990

Effect of enantiomers of deprenyl (selegiline) and amphetamine on physical abuse liability and cortical electrical activity in rats.

In the present study, whether the repeated administration of (-)deprenyl to rats resulted in physical dependency was investigated. In a second experiment, the effect of (-)-deprenyl was investigated on the cortical electrical activity of freely moving rats and last, the influence of (-)-deprenyl on the behaviour of the animals was studied. In all experiments, different stereospecific configurations of amphetamine and deprenyl were also employed in order to establish differences and similarities. During and after the chronic oral administration of (-)-deprenyl (4 mg/kg) over 6 weeks, no signs of physical dependency were observed in rats after withdrawal of the drug. By contrast, (+)-deprenyl (5 mg/kg, p.o.) and (+)-amphetamine (5 mg/kg, p.o.) induced typical symptoms of amphetamine-dependency: during withdrawal of drug, the body weight of the rats was increased. A similar phenomenon was observed after oral administration of (+/-)-amphetamine (6 mg/kg, p.o.). After a single oral administration of (-)-deprenyl (1 and 5 mg/kg) and (-)-amphetamine (10 mg/kg, p.o.), decreases in delta and increases in theta frequency bands in the EEG were observed. In contrast, (+)-amphetamine (1 mg/kg, p.o.), (+/-)-amphetamine (5 mg/kg, p.o.) and (+)-deprenyl (1 and 5 mg/kg, p.o.) evoked increases in the mean power values in delta and decreases in theta frequency bands. In agreement with the EEG studies, the (-) and (+)-isomers of amphetamine and deprenyl caused differences in the behaviour of the animals. Based on these findings, it can be concluded that (-)-deprenyl undergoes a stereospecific metabolism in the organism and the amounts of its metabolites with (+) configuration might be negligible, even at the larger doses which are necessary to inhibit monoamine oxidase-B (MAOB) in brain.

Amphetamine↗
PubMed1990

Cortisol and beta-endorphin response in alcoholics and alcohol abusers following a high naloxone dosage.

The course of plasma cortisol and beta-endorphin-like immunoreactivity (beta-EP-IR) was determined following a single i.v. administration of 20 mg naloxone. The test subjects included 20 male alcoholics (medication-free), investigated one to three days and four weeks after the onset of abstinence, as well as 10 short-time abstinent alcohol abusers and 10 healthy control subjects. The mean baseline values of cortisol and beta-EP-IR remained within normal limits in all groups. The significant decrease in the plasma cortisol baseline values in the alcoholics after 4 weeks abstinence may indicate a lower level of the regulation of the hypothalamic-pituitary-adrenal axis (HPA) under conditions of abstinence. After naloxone administration an increase in plasma cortisol and beta-EP-IR was observed in all groups. The multivariate trend analysis showed significant differences in the time course of plasma cortisol between the three groups, however not in the course of beta-EP-IR. The changes in the dynamic regulation of the HPA axis, resulting from chronic alcohol consumption, appears to be irrespective of whether the drinking pattern is dependent or abusive. In alcoholics these changes could still be identified following a 4-week abstinence period.

Adaptation, Physiological↗
PubMed1990

Chemistry and pharmacology of the non-benzodiazepine anxiolytic enciprazine and related compounds.

In the course of studies on tranquilizers, new non-benzodiazepine-like compounds were synthesized. These are 1-(3,4,5-trimethoxyphenoxy)-3-[4-(2-methoxyphenyl)piperazinyl]prop an-2-ol (INN: enciprazine) and derivatives thereof which were screened pharmacologically in order to evaluate their central nervous system activity. Compounds with marked antiaggressive and anxiolytic properties but without dependence potential could be detected. Enciprazine was selected for clinical investigations.

Aggression↗
PubMed1990

Investigations with the novel non-opioid analgesic flupirtine in regard to possible benzodiazepine-like abuse inducing potential.

Flupirtine (D-9998, Katadolon, CAS 56995-20-1); CAS 56995-20-1), a novel non-opioid analgesic was investigated for possible benzodiazepine-like activities. In receptor binding studies flupirtine and its metabolite were found to reveal no affinity for specific 3H-flunitrazepam binding up to a concentration of 10 mumol/l. In drug discrimination studies, rats were trained to discriminate the novel analgesic flupirtine (10 mg/kg i.p.) from no drug (NaCl 0.9%) under a two-choice fixed-ratio 5 shock-termination schedule. Flupirtine yielded a dose-response curve with an ED50 of 3.9 mg/kg i.p. In generalization tests with a benzodiazepine-type compound lorazepam (0.3 mg/kg, i.p.) did not generalize to the flupirtine training dose. In physical dependence studies using rats, during and after chronic oral administration of flupirtine (2 x 80 mg/kg p.o.) over 45 days no signs of benzodiazepine- and opiate-like physical dependence were observed in rats after withdrawal of the drug. In contrast diazepam (2 x 5 bzw. 2 x 10 mg/kg p.o.) induced typical symptoms of physical dependence. A significant weight loss of the codeine treated animals (2 x 60 mg/kg p.o.) and other typical side effects were also observed after withdrawal of codeine. These results clearly demonstrate that flupirtine has no affinity for benzodiazepine receptors and is free of benzodiazepine or opiate/opioid-like abuse potential.

Aminopyridines↗
PubMed1990

[The Korsakoff concept of Karl Bonhoeffer and its relation to the psychometrics of amnestic disorders].

Karl Bonhoeffer set great value on the precise description of psychopathological findings, and was the first to stress the very close relationship between Wernicke's encephalopathy and Korsakoff's psychosis. Proof of mnestic deficiency is still today very important in the exact analysis of chronic symptomatic psychoses. Knowledge acquired in neuropsychology must be incorporated into psychopathometry to enable a more exact analysis of chronic cerebral psychosyndromes. The paper presents a new test to measure mnestic deficiency, suitable for the examination of patients with pseudoneurasthenic syndromes, organic change of personality, or mild early forms of dementia.

Alcohol Amnestic Disorder↗