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Biomedical subjects

K Bizière

Publications and source records attributed to K Bizière.

At least 19 recordsLinked to original sources
PubMed1990

Efficacy of a reversible monoamine oxidase-A inhibitor versus imipramine in subgroups of depressed patients.

Two multicentre studies comparing moclobemide with imipramine under similar conditions in patients undergoing a major depressive episode (DSM-III) were combined in the present analysis. A total of 353 patients received moclobemide (300-600 mg/day) and 356 imipramine (100-200 mg/day). In each study, the antidepressant efficacy of the 2 drugs was comparable, and subgroup analysis showed that moclobemide and imipramine were equally effective in endogenous depression. The response rate did not appear to be influenced by sex, but patients older than 60 years tended to respond less well to both drugs than did those under 60. The conclusion from the 2 studies is that, contrary to what is frequently stated for monoamine oxidase inhibitors, moclobemide appears as effective as a tricyclic in treating endogenous depression.

Antidepressive Agents↗
PubMed1989

Cerebral-activating (EEG) properties of two inverse agonists and of an antagonist at the benzodiazepine receptor in the rat.

In order to assess the effects of inverse benzodiazepine agonists and antagonists on brain function, computerized EEG (CEEG) analysis was performed in rats following the i.p. administration of SR 95195 (7-phenyl-3-methyl-1,2,4 triazolo-[4,3-b]pyridazine) and CGS 8216 (2-phenylpyrazolo-[4,3c]-quinoline-3-[5H]-one) two benzodiazepine receptor inverse agonists (BRIAGs) and of flumazepil (Ro 15-1788), a benzodiazepine receptor antagonist (BRANT). The EEG effects of SR 95195 (3, 10, 30 and 60 mg/kg), CGS 8216 (10 and 30 mg/kg) and flumazepil (3, 10, 30 and 60 mg/kg) were compared to those of the psychostimulant drugs DL-amphetamine (0.1, 0.3 and 1 mg/kg), and caffeine (10 and 30 mg/kg) and those of aniracetam (100 and 300 mg/kg), a nootropic pyrrolidone derivative. The CEEG profiles of SR 95195, CGS 8216 and flumazepil were mainly characterized by a power increase in the 20-32 Hz frequency range and by a power reduction in the 8-16 Hz range. These effects were quite similar to those of the psychostimulants DL-amphetamine and caffeine as well as to those of the nootropic aniracetam. Other psychotropic drugs with CNS-depressant properties, namely diazepam (10 mg/kg p.o.), pentobarbital (30 mg/kg p.o.), chlorpromazine (10 mg/kg i.p.) and imipramine (10 mg/kg i.p.) induced quite different EEG power modifications. These results show that BRIAGs and BRANTs possess a marked intrinsic activity at the central level and suggest that this activity is CNS-activating in nature.

Animals↗
PubMed1989

Sodium diethyldithiocarbamate protects against the MPTP-induced inhibition of immune responses in mice.

The effects of 1-methyl-4-phenyl - 1,2,3,6-tetrahydropyridine (MPTP) on immune parameters, and the restorative influence of sodium diethyldithiocarbamate (DTC) or deprenyl were evaluated in mice. The concentrations of dopamine (DA), 3-methoxytyramine (3-MT), 3-4-dihydroxyphenyl acetic acid (DOPAC), and homovanillic acid (HVA), were concomitantly measured in the striatum. MPTP depressed T-cell responses. DTC restored these responses as well as the concentration of striatal DA. Deprenyl had no effect on the concentrations of DA and its metabolites, yet it modified the immune responses alike MPTP. The findings suggest a dopamine pathway could be involved in the brain-controlled immunostimulation afforded by DTC.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1989

Efficacy and tolerability of moclobemide compared with imipramine in depressive disorder (DSM-III): an Austrian double-blind, multicentre study.

The antidepressant efficacy, tolerability, and safety of moclobemide, a reversible, monoamine oxidase-A inhibitor, were compared with those of imipramine in parallel groups of patients with a major depressive episode, in a 4-week, multicentre (17 centres), randomised study. A total of 381 patients were randomly allocated to either treatment; they were not required to avoid tyramine-rich foods. Drop-out rates were comparable in both groups at about 17%. Judged primarily on the HRSD, no significant differences in efficacy were observed between the groups, but the number of patients presenting with adverse events, as well as the total number of adverse events, was greater with imipramine. Cardiovascular tolerability was satisfactory and physical examination, body weight, and laboratory values were essentially unaffected in both groups.

Adjustment Disorders↗
PubMed1988

Brain neocortex and imuthiol regulate the expression of MHC antigens on mouse T lymphocytes.

The induction of T-cell responses involves the recognition of extrinsic antigens in association with antigens of the major histocompatibility complex (MHC). The present results demonstrate that the lateralized control exerted by the brain neocortex on T-cell activities extends to the expression of MHC antigens, yet differently on spleen or lymph node T cells. This study also shows that the neocortex influences the changes induced by an immunopotentiator, sodium diethyldithiocarbamate (imuthiol), on the MHC antigen content on mouse T cell-surface.

Animals↗
PubMed1987

Asymmetrical involvement of the cerebral neocortex on the response to an immunopotentiator, sodium diethyldithiocarbamate.

We have previously shown that the neocortex in mice has a lateralized influence on the immune system. A partial left or bilateral neocortical lesion selectively decreases spleen T-cell numbers and function, natural killer and (NK) activity, but a right neocortical lesion do not affect NK activity, and increases T-cell numbers and T-cell-mediated events. Here we report that the immunopotentiating activity of sodium diethyldithiocarbamate (Imuthiol), a compound that selectively increases T-cell numbers and activities, is dependent on an intact neocortex. The effects of Imuthiol were examined in female C3H/HeJ mice 10 weeks after partial neocortical lesions. In animals with right or bilateral neocortical lesions, Imuthiol failed to increase the percentage of spleen T cells, did not influence the expression of class I MHC antigen on these cells, no longer induced the release in serum of specific T-cell-inducing factors, and failed to enhance T-cell-mediated events. In contrast, in animals with a left neocortical lesion, Imuthiol increased T-cell numbers and activities in a fashion that was comparable to that observed in unlesioned controls, but did not enhance NK activity. It is concluded that Imuthiol may affect immune responsiveness by acting directly on the neocortex and/or by interacting at subcortical levels with signals emitted by the neocortex. Moreover, this study reveals a major hemispheric asymmetry in the response to a drug.

Adjuvants, Immunologic↗
PubMed1987

SR 95191, a selective inhibitor of type A monoamine oxidase with dopaminergic properties. I. Psychopharmacological profile in rodents.

SR 95191 [3-(2-morpholino-ethyl-amino)-4-cyano-6-phenyl-pyridazine], a novel compound, has been shown in preliminary experiments to inhibit type A monoamine oxidase (MAO). This report describes the activities of SR 95191 in behavioral experiments in mice and rats and shows that SR 95191 has the profile of a selective type A MAO inhibitor (MAOI). Moreover, SR 95191 also possesses dopamine (DA) stimulant properties. The activities of SR 95191 were compared to those of the MAOIs moclobemide, clorgyline, pargyline and l-deprenyl, as well as to those of the antidepressant drugs imipramine, nomifensine and indalpine and to those of the DAergic drugs (+)-amphetamine and apomorphine. SR 95191 p.o. antagonized the effects of reserpine in mice and rats, decreased immobility in the mouse despair test, antagonized haloperidol-induced catalepsy in rats and potentiated 5-hydroxytryptophan in mice and rats with an overall potency which was half that of imipramine. SR 95191, like moclobemide, did not potentiate yohimbine-induced lethality and did not antagonize oxotremorine-induced tremor. Like selective type A MAOIs, SR 95191 potentiated 5-hydroxytryptophan-induced tremor without affecting beta-phenethylamine-induced stereotypies in mice. SR 95191 did not antagonize 3-hydroxy-4-methyl-alpha-phenylethylamine-induced hyperthermia. Like all DA stimulant drugs, SR 95191 induced stereotypies in rats, which were blocked by haloperidol and alpha-methylparatyrosine, and induced contralateral turning in mice with a unilateral striatal 6-hydroxydopamine lesion. Based on these results, it is postulated that SR 95191 has a unique profile of activity combining the properties of a selective type A MAO inhibitor and those of an atypical DAergic drug.

5-Hydroxytryptophan↗
PubMed1987

SR 95191, a selective inhibitor of type A monoamine oxidase with dopaminergic properties. II. Biochemical characterization of monoamine oxidase inhibition.

SR 95191 [3-(2-morpholino-ethyl-amino)-4-cyano-6-phenylpyridazine] is a novel psychotropic drug which possesses the pharmacological properties of a selective, reversible type A monoamine oxidase inhibitor (MAOI). The MAOI activity of SR 95191 was examined in the rat brain, liver and duodenum and compared to that of clorgyline, harmaline, l-deprenyl, moclobemide and cimoxatone. In vitro, SR 95191 selectively inhibited MAO-A and was less potent than cimoxatone, clorgyline and harmaline, but was more potent than moclobemide. Ex vivo, SR 95191 also preferentially inhibited MAO-A in the brain and was 6 and 13 times less potent than cimoxatone and moclobemide, respectively. Like all MAO-A inhibitors, SR 95191 in vivo caused a dose-dependent increase in striatal 3-methoxytyramine, dopamine, serotonin and in hypothalamic norepinephrine contents. A concomitant decrease in deaminated metabolites was observed. SR 95191 inhibited peripheral MAO activity in liver and duodenum. In brain, liver and duodenum, MAO inhibition induced by SR 95191 was short-lasting. Repeated dosing for 14 days did not enhance MAO-A inhibition. Like all reversible MAOIs, SR 95191 antagonized the long-lasting MAO-A inhibition induced by clorgyline. Finally, SR 95191 did not affect monoamine uptake either in vitro or in vivo and did not interact in vitro with a variety of neurotransmitter or drug receptor sites. Based on these results it is postulated that SR 95191 is a selective and reversible type A MAOI of medium potency, which may be of therapeutic benefit in depressed patients.

Animals↗
PubMed1987

[Animal models of epilepsy and experimental seizures].

Animal models of epilepsy are essential for the search of new effective antiepileptic drugs. Moreover they may lead to the discovery of the basic neuronal dysfunction(s) which underlies human epilepsies. Animal epilepsies as well as experimental seizures are usually considered as valid models of human epilepsies when, and only when, the drugs which are effective in human epilepsies prevent seizures in animals. This, however, precludes finding new drugs for resistant epilepsies. Animal models of epilepsy can be classified as follows: (i) experimental seizures induced by convulsant drugs or by an electrical stimulation; (ii) reflex epilepsies; (iii) idiopathic epilepsies. Examples of animal models of epilepsy taken from each of these three classes are briefly reviewed. Seizures induced by convulsant drugs or by an electroshock are widely used as simple and rapid screening systems for new anticonvulsant compounds. Moreover, the use of chemical convulsants can lead to new hypotheses concerning the mechanisms underlying human epilepsies. Thus, one of the main arguments in favor of the GABAergic hypothesis of epilepsy is that GABA antagonists induce seizures which are readily counteracted by most antiepileptic drugs. Among the other models of experimentally induced seizures, the kindling model is usually considered, on the basis of its pharmacological characteristics, as a Grand Mal type epilepsy model. Thirty years after this model was first described, the exact modifications induced in the brain by the kindling procedure remain unknown. Various animal species exhibit reflex epilepsies. Myoclonic seizures can be induced by photic stimulation in Papio-papio baboons; tonic-clonic seizures can be induced by various auditory stimuli in certain strains of mice and rats; myoclonic and tonic-clonic seizures can be induced by a variety of environmental stimuli in the mongolian gerbil; photosensitive and febrile seizures have been described in fowl. Most antiepileptic drugs are effective in these reflex epilepsies. Alterations in several neurotransmitter systems have been reported in susceptible strains as compared to resistant strains, such as modifications in noradrenergic, serotoninergic, GABAergic or glutamatergic transmissions, but no single abnormal parameter can unequivocally be correlated to seizure susceptibility. Idiopathic epilepsy is not uncommon in dogs and the prevalence of the disease appears to be comparable to that observed in man. Grand Mal type epilepsy appears to be the most frequent type of epilepsy in dogs; little work has been devoted to the study of the neurochemical alterations which may underly the disease.

Acoustic Stimulation↗
PubMed1987

Minaprine and imipramine in the treatment of major depressive disorders. A comparative double-blind study.

Minaprine dihydrochloride is an aminopyridazine derivative which is chemically unrelated to other known psychotropic drugs. In rodents minaprine is active in most models of depression and is thought to exert this activity by enhancing serotonergic and dopaminergic transmission. In humans minaprine has been shown to be more effective than placebo in the treatment of major depressive episodes as defined by the DSM-III. In the present study, the efficacy and safety of minaprine (100 mg b.i.d.) in the treatment of major depressive disorders (DSM-III) were compared with those of imipramine (50 b.i.d.) in 104 patients, in a 4-week randomized, double-blind, multicentre trial. The two drugs were comparable in efficacy as judged by the Hamilton Depression Rating Scale, a Clinical Global impression and a Zung Self-Rating Scale. The onset of activity appeared to be significantly more rapid with minaprine. The incidence and intensity of unwanted effects was significantly higher in the imipramine treatment group.

Adult↗
PubMed1986

Quantitative electroencephalographic profile of 3-(4-hydroxy-1-piperidinyl)-6-(2,4-dichlorophenyl)-pyridazine (SR 41378) in the rat.

Quantitative electroencephalographic (QEEG) analysis was performed in rats following the oral administration of SR 41378 [3-(4-hydroxy-1-piperidinyl)-6-(2,4-dichlorophenyl)-pyridazine], a novel aminopyridazine derivative, which has been shown to possess anticonvulsant, antianxiety and hypnotic activities in mice and rats. The EEG effects of SR 41378 (10, 30 and 100 mg/kg) were compared to those of secobarbital (30 and 60 mg/kg) and diazepam (1, 3 and 10 mg/kg). SR 41378 and secobarbital increased the power of the middle-frequencies (8-16 Hz) of the EEG, reduced that of 4-8 Hz (theta) activities and did not affect 1-4 Hz (delta) activities. Diazepam also increased the power of middle-frequency activities and decreased that of both delta and theta activities. Quantitative EEG profiles were calculated from the mean integrated power (MIP) of selected frequency bands. The QEEG profile of SR 41378 was found to share common characteristics with those of secobarbital and diazepam: dose-dependent decrease of theta band MIP and increase of 8-20 Hz (middle beta bands) MIP. However, both SR 41378 and secobarbital induced a reduction of the 28-32 Hz (fast beta bands) MIP, whereas diazepam diminished the delta band. These results suggest that SR 41378, a novel chemical structure, shares common psychotropic properties with barbiturates and benzodiazepines.

Alpha Rhythm↗
PubMed1986

Interactions between three pyridazinyl-GABA derivatives and central GABA and glycine receptors in the rat, an in vivo microiontophoretic study.

Three pyridazinyl-gamma-aminobutyric acid (GABA) derivatives, SR 95103, SR 42641 and SR 95531, have previously been shown to be specific, competitive and reversible GABAA antagonists. For all three compounds selectivity was claimed mainly on the basis of biochemical results. However the absence of an interaction with the binding site for strychnine does not preclude an interaction with the glycine receptor. Therefore the interaction between these compounds and GABA- and glycine-elicited responses in the rat cuneate nucleus was examined in vivo by microiontophoretic techniques using extracellular recordings. Preliminary experiments in the somesthetic cortex of the rat (18 cells) confirmed that SR 95103 (100 mM; 0-100 nA) blocked GABA-evoked responses. In the cuneate nucleus SR 95103 (100 mM), SR 42641 (5 mM), SR 95531 (5 mM) and bicuculline methochloride (BMC; 5 mM) blocked GABA-elicited responses in a dose-dependent, competitive and reversible fashion for ejection currents up to 100 nA. The compound SR 95103 appeared to be less potent than bicuculline and also antagonized glycine-induced responses. Both SR 42641 and SR 95531 appeared to be equipotent to bicuculline and selective for the GABA receptor. Based on these results, it is postulated that SR 42641 and SR 95531 are potent and reversible GABAA antagonists and could be useful tools to further characterize the GABA receptor.

Afferent Pathways↗
PubMed1985

Ethyl loflazepate: a prodrug from the benzodiazepine series designed to dissociate anxiolytic and sedative activities.

Ethyl loflazepate (Victan) is an original 1,4-benzodiazepine (BZD) being used as a potent, nonsedative, minor tranquillizer. Ethyl loflazepate was designed to be a prodrug that would gradually release within the organism an active 1,4-BZD. It was hypothesized that this type of pharmacokinetic profile would dissociate anxiolytic from sedative activities. Previously published pharmacokinetic studies performed in rats, baboons and humans have confirmed that ethyl loflazepate gradually releases in the plasma an active 1,4-BZD, descarboxyloflazepate. In the present study, the activity of ethyl loflazepate and its main plasmatic metabolites were examined in rodent models predictive of anxiolytic, anticonvulsant, myorelaxant and sedative properties. The activities of ethyl loflazepate and its metabolites were compared to those of reference BZDs: diazepam, bromazepam, nitrazepam, flunitrazepam, lorazepam, clorazepate. Ethyl loflazepate and its metabolites revealed the typical profile of activity of minor tranquillizers. The activity of ethyl loflazepate was long-lasting. The overall anxiolytic potency of ethyl loflazepate was similar to that of diazepam but ethyl loflazepate appeared to be less sedative than diazepam. Thus in the approach-avoidance conflict procedure in rats the threshold anxiolytic doses were 1 and 2 mg/kg i.p. for ethyl loflazepate and diazepam, respectively, whereas the threshold sedative doses were 16 and 8 mg/kg i.p., respectively. In vitro ethyl loflazepate exhibited a weak affinity for the BZD receptor site. In vivo ethyl loflazepate displaced [3H]-flunitrazepam from mice brain membranes with a potency comparable to that of lorazepam. In vitro, descarboxyloflazepate, the main plasmatic metabolites of ethyl loflazepate, revealed a 4-fold greater affinity for the BZD receptor than diazepam.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Minaprine, a new drug with antidepressant properties.

Minaprine is a new psychotropic drug which has recently proved to be effective in the treatment of various depressive states. In rodents, minaprine exhibits an atypical spectrum of antidepressant and dopaminomimetic activities. Thus in mice minaprine antagonizes the effects of reserpine, decreases immobility time in the behavioural despair test and potentiates the effects of 5-HTP; in rats it antagonizes muricidal behaviour (blocked by PCPA or raphectomy). However, minaprine does not affect yohimbine lethality and does not induce anticholinergic effects in mice. Minaprine also activates central dopaminergic transmission. Thus at low doses the drug antagonizes neuroleptic-induced catalepsy and induces stereotypies in rats. These stereotypies are blocked by neuroleptics. In addition, minaprine (like apomorphine) induces contralateral turning in mice with a unilateral lesion of the striatum, whereas d-amphetamine induces ipsilateral rotations. Unlike classical dopaminomimetic drugs, minaprine does not stimulate locomotor activity in rats. The mechanisms by which minaprine exerts its effects are still unclear, since in vitro minaprine does not affect monoamine uptake or release and does not interact with monoamine receptors. In vivo, minaprine (acute doses) increases 5-HT, decreases 5-HIAA levels in various brain areas and weakly and reversibly inhibits type A MAO; subacute treatments lead to a decrease in the number of 5-HT1 and 5-HT2 receptors. In addition, in the striatum the drug decreases HVA and DOPAC, and increases 3-MT levels, without affecting DA levels. Minaprine also weakly displaces (3H)-spiperone from striatal D2 receptors and increases striatal ACh levels. Finally, minaprine fails to affect brain NA or MHPG levels in acute doses and does not modify beta receptor density in subacute treatment. Thus minaprine appears to be a chemically and pharmacologically original antidepressant drug which activates both 5-HT- and DA-mediated transmission but which is devoid of NAergic and anticholinergic effects. This latter statement is confirmed by the good cardiovascular tolerance of minaprine in dog, monkey and humans, and by the lack of "tricyclic-like" anticholinergic side-effects in man.

Acetylcholine↗
PubMed1984

Involvement of brain neocortex and liver in the regulation of T cells: the mode of action of sodium diethyldithiocarbamate (imuthiol).

Sodium diethyldithiocarbamate ( imuthiol ), a non-antigenic and non-carcinogenic compound, devoid of toxic effects at immunostimulant doses, shows distinctive properties in recruitment and activation of T cells. Studies on its mode of action disclosed unsuspected links between the immune system, the endocrine liver and the central nervous system. Evidence was obtained indicating that the brain neocortex modulates T-cell mediated events, most likely via control of specific hormonal synthesis by the liver. The influence of imuthiol is determined at the level of the brain neocortex.

Animals↗