References of "Geczy, J"
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See detailA pilot double-blind randomized placebo-controlled study of molsidomine 16 mg once-a-day in patients suffering from stable angina pectoris: correlation between efficacy and over time plasma concentrations
Messin, R.; Fenyvesi, T.; Carreer-Bruhwyler, F. et al

in European Journal of Clinical Pharmacology (2003), 59(3), 227-232

Objectives. A new once-a-day (o.a.d.) formulation of molsidomine (16 mg) was evaluated in patients with stable angina pectoris. The aims were to characterize its pharmacokinetics after a single dose, to ... [more ▼]

Objectives. A new once-a-day (o.a.d.) formulation of molsidomine (16 mg) was evaluated in patients with stable angina pectoris. The aims were to characterize its pharmacokinetics after a single dose, to demonstrate its clinical efficacy and safety versus placebo and to investigate correlations between pharmacokinetics and pharmacodynamics. Methods. Forty-two patients were recruited in a double-blind, crossover, randomized placebo-controlled trial. The pharmacokinetics of molsidomine and SIN-1, its active metabolite, were determined at specific time points (3, 6, 10, 14, 18, 22 and 24 h) after the administration of a single dose of molsidomine 16 mg o.a.d. in all patients distributed into seven groups. Twenty-eight of these 42 patients showed a positive baseline cycloergometric exercise test response during the run-in placebo period and were used to compare the efficacy of molsidomine to placebo. Relationships between plasma concentration in molsidomine or SIN-1 and ischemic threshold were assessed in 16 of the 28 patients with a positive exercise test at baseline. Indeed, the censored variable ischemia-limited tolerance to exercise could not be evaluated in those patients who did not show exercise-induced ischemia anymore under molsidomine 16 mg o.a.d. Pharmacokinetic-pharmacodynamic relationships were evaluated using regression models and correlation coefficients. Results. The highest average concentration in molsidomine and SIN-1 occurred after 6 h, then a plateau of 15-20 ng/ml molsidomine and 0.8-3.0 ng/ml SIN-1 was maintained for at least 8 h and the mean residual molsidomine concentration 24 h post-drug intake was around 8 ng/ml, still in the effective range of 5-10 ng/ml. A significant increase in total workload (+52 W min, P=0.009), total exercise time (+32 s, P=0.003) and time to angina (+25 s, P=0.016) was measured with molsidomine 16 mg o.a.d. relative to placebo. Using linear regression, significant correlation coefficients were determined between molsidomine plasma concentrations (but not SIN-1) and exercise test improvements (r=0.827, P<0.001 for the total workload; r=0.772, P<0.001 for the total exercise time; and r=0.566, P=0.028 for the time to 1 mm ST-segment depression). Conclusion. The pharmacokinetics of molsidomine 16 mg in patients with stable angina pectoris is compatible with a o.a.d. dosage regimen. This o.a.d. formulation is effective and well-tolerated, providing a 24-h therapeutic control of myocardial ischemia. A positive and significant linear relationship between molsidomine plasma concentration and the increase in exercise tolerance was observed. [less ▲]

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See detailNew pyridobenzodiazepine derivatives: Modifications of the basic side chain differentially modulate binding to dopamine (D-4.2, D-2L) and serotonin (5-HT2A) receptors
Liégeois, Jean-François ULg; Eyrolles, L.; Ellenbroek, B. A. et al

in Journal of Medicinal Chemistry (2002), 45(23), 5136-5149

A series of new pyridobenzodiazepines with variation of the basic side chain were synthesized and evaluated for their binding to D-4.2, D-2L, and 5-HT2A receptors in comparison with clozapine, haloperidol ... [more ▼]

A series of new pyridobenzodiazepines with variation of the basic side chain were synthesized and evaluated for their binding to D-4.2, D-2L, and 5-HT2A receptors in comparison with clozapine, haloperidol, and two parent compounds previously described, 8-chloro-6-(4-methyl-1-piperazinyl)-11H-pyrido[2,3-b][1,4]benzodiazepine (8) and 8-methyl-6-(4-methyl-1-piperazinyl)-11H-pyrido[2,3-b][1,4]benzodiazepine (9). In the piperazine series, replacing the N-methyl group by a N-phenyl moiety (15-17, 30-32) provided a dramatic decrease of affinity for all receptors (K-i > 1000 nM). A N-cyclohexyl group (20, 35) restored some affinity. Compounds with a N-benzyl (18, 33) or N-phenethyl side chain (19, 34) had significant affinities at D-4.2 and 5-HT2A receptors. Homologation of the piperazine nucleus (29, 44) led to a significant decrease of the affinity at all receptors investigated. In the 4-aminopiperidine series, N-methyl derivatives (21, 36) possessed less affinity in comparison with the N-metbylpiperazine analogues (8, 9) while the N-benzyl congeners (22, 37) showed similar affinities. The rigidification of piperidine nucleus as obtained in azabicyclo [3.2.1] octane derivatives (23, 38) involved a slight reduction of the affinity at D-4.2 and 5-HT2A receptors while the affinity at D-2L receptors was dramatically increased. The introduction of N-substituted aminoalkylamines to replace N-methylpiperazine generally led to a significant decrease in the affinity for D-4.2 receptors but some of these molecules (24, 25, 41) presented a significant 5-HT2A binding affinity. The presence of a more flexible side chain induced an increased conformational freedom. Consequently, the preferential position of the distal nitrogen or its basicity in piperazine derivatives was greatly modified. 19 with a high D-4.2 and 5-HT2A affinity (K-i = 40 and 103 nM, respectively) did not induce cataleptic phenomenon in the paw test in rats but significantly reduced the immobility time in Porsolt's test in mice suggesting antidepressant properties. [less ▲]

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See detailAutomated determination of pirlindole enantiomers in plasma by on-line coupling of a pre-column packed with restricted access material to a chiral liquid chromatographic column
Chiap, Patrice ULg; Ceccato, Attilio ULg; Gora, R. et al

in Journal of Pharmaceutical & Biomedical Analysis (2002), 27(3-4), 447-455

A fully automated liquid chromatographic method has been developed for the determination of the enantiomers of pirlindole, an antidepressant drug, in human plasma. The method is based on the use of a pre ... [more ▼]

A fully automated liquid chromatographic method has been developed for the determination of the enantiomers of pirlindole, an antidepressant drug, in human plasma. The method is based on the use of a pre-column packed with restricted access material (RAM) (LiChrospher ADS RP-4) for sample clean-up coupled to a column containing a cellulose tris-(3,5-dimethylphenylcarbamate) based chiral stationary phase (Chiralcel OD-R) for the separation and quantitative analysis of pirlindole enantiomers. A 50-microl plasma volume was injected directly onto the pre-column using a mixture of phosphate buffer (pH 5.0) and methanol (97:3; v/v) as washing liquid. By rotation of a switching valve, the analytes were then eluted in the back-flush mode with the LC mobile phase. A complete separation of pirlindole enantiomers was obtained in 22 min on the Chiralcel OD-R column, using a mobile phase made of a mixture of phosphate buffer (pH 5.0) containing 50 mM sodium perchlorate and acetonitrile (65:35; v/v). The flow-rate was 0.6 ml/min and the analytes were detected fluorometrically using 295 and 340 nm as excitation and emission wavelengths, respectively. The method was then validated and was found to be linear in the 2.5-200 ng/ml range. The limit of detection was lower than 1 ng/ml. Repeatability and intermediate precision at a concentration of 50 ng/ml were about 1.5 and 3.5%, respectively. [less ▲]

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See detailElectrooxidation Potential as a Tool in the Early Screening for New Safer Clozapine-Like Analogues
Mouithys-Mickalad, Ange ULg; Kauffmann, J. M.; Petit, C. et al

in Journal of Medicinal Chemistry (2001), 44(5), 769-76

The chemical modification of clozapine (1) has permitted the finding of new analogues, e.g., olanzapine (2), quetiapine (3), 5-(4-methylpiperazin-1-yl)-8-chloropyrido[2,3-b][1,5]benzoxazepine fumarate (9 ... [more ▼]

The chemical modification of clozapine (1) has permitted the finding of new analogues, e.g., olanzapine (2), quetiapine (3), 5-(4-methylpiperazin-1-yl)-8-chloropyrido[2,3-b][1,5]benzoxazepine fumarate (9), with a clinical or psychopharmacological profile similar to that of clozapine. However, when developing new derivatives, the designers are discouraged by the development of clozapine-induced agranulocytosis. Different researchers have raised the role played by the oxidizability of the molecule in such a deleterious effect. In the present paper, we examined the oxidation profile (direct scavenging abilities, efficacy in inhibiting lipid peroxidation, and electrooxidation potential) of newly developed methoxy and trifluoromethylsulfonyloxy analogues related to clozapine, some of them being described as putative antipsychotic. The oxazepine derivative 7, unlike the other diazepine derivatives (6, 10--12), was not readily oxidized. Using a statistical predictive model for hematotoxicity previously described, 7 was found in the cluster of potentially nontoxic compounds while diazepine derivatives 6 and 10-12 were classified as potentially toxic compounds. Among these original compounds, 7, which presents a preclinical clozapine-like profile and a low sensitivity to oxidation, could be a promising antipsychotic candidate with low side effects. Considering the tricyclic derivatives examined so far, some elements of structure-oxidation relationship (SOR) might be pointed out. Regarding the nature of the tricyclic ring substituent, from the most to the least sensitive to oxidation, the sequence was as follows: HO > Cl > CH(3)O > CF(3)SO(2)O. The nature of the tricyclic ring influenced also the sensitivity to oxidation; the diazepine moiety appeared to be the most reactive ring compared to oxa- and thiazepine congeners. These parameters could be advantageously integrated in the early design of new safer clozapine-like analogues. [less ▲]

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See detailNovel inhibitors of the sodium-calcium exchanger: benzene ring analogues of N-guanidino substituted amiloride derivatives
Rogister, F.; Laeckmann, D.; Plasman, P.-O. et al

in European Journal of Medicinal Chemistry (2001), 36

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See detailOxidation Sensitivity May Be a Useful Tool for the Detection of the Hematotoxic Potential of Newly Developed Molecules: Application to Antipsychotic Drugs
Liégeois, Jean-François ULg; Bruhwyler, J.; Petit, C. et al

in Archives of Biochemistry & Biophysics (1999), 370(1), 126-37

Some antipsychotic agents have been found to produce agranulocytosis and aplastic anemia. The oxidation phenomena and/or the formation of free radicals has been suggested to be causally related to various ... [more ▼]

Some antipsychotic agents have been found to produce agranulocytosis and aplastic anemia. The oxidation phenomena and/or the formation of free radicals has been suggested to be causally related to various hematological disorders, e.g., agranulocytosis. Using five experimental conditions, we tested the oxidative potential of compounds with and without a history of hematological side effects, e.g., agranulocytosis and aplastic anemia. A statistical analysis was undertaken for each experimental condition and a multivariate analysis combining all results was performed. Two peroxidase-induced free radical models did not successfully discriminate between drugs with and without a history of causing hematologic problems (<70%). The lipid peroxidation system provided even less satisfactory discrimination, with only 56.25% correct classification. However, an 87.5% correct classification was obtained when using the oxidation potentials of these drugs determined at pH 4.7 and at pH 7.4. A multivariate analysis taking into account the five variables provided 87.5% success in classification. The two clusters were better discriminated in terms of a "distance coefficient." In a second analysis, the putative antipsychotic pyridobenzodiazepine analogues (JL5, JL8, JL18, and JL25) were classified in the cluster of toxic compounds, while the oxa- and thiazepine analogues (JL2, JL3, and JL13) were classified as nontoxic compounds. On the other hand, a few metabolites of clozapine and fluperlapine were classified in the toxic compound group. The procedure described herein is, to our knowledge, the first which classifies molecules of different structures as well as different pharmacological profiles according to their hematotoxic potential. Such a procedure could be used to predict drug-induced hematological side effects. [less ▲]

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See detailEffective resolution of racemic pirlindole at the preparative scale
De Tullio, Pascal ULg; Ceccato, A.; Liégeois, Jean-François ULg et al

in Chirality (1999), 11

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See detailEnantiomeric Separation of Pirlindole by Liquid Chromatography Using Different Types of Chiral Stationary Phases
Ceccato, Attilio ULg; Hubert, Philippe ULg; De Tullio, Pascal ULg et al

in Journal of Pharmaceutical & Biomedical Analysis (1998), 18(4-5), 605-14

The enantioseparation of pirlindole by liquid chromatography (LC) was investigated using three different chiral stationary phases (CSPs) containing either cellulose tris-(3,5-dimethylphenylcarbamate ... [more ▼]

The enantioseparation of pirlindole by liquid chromatography (LC) was investigated using three different chiral stationary phases (CSPs) containing either cellulose tris-(3,5-dimethylphenylcarbamate) (Chiralcel OD-R), ovomucoid (OVM) or beta-cyclodextrin (beta-CD). The effects of the mobile phase pH on retention, enantioselectivity and resolution were studied. Methanol and acetonitrile were tested as organic modifiers while the influence of the addition to the mobile phase of sodium alkanesulfonates or sodium perchlorate was also investigated. Sodium perchlorate was only used on the Chiralcel OD-R column while sodium alkanesulfonates were tested as mobile phase additives on the three kinds of CSPs. The enantioseparation of pirlindole could be obtained on all CSPs tested, the best results with respect to chiral resolution being achieved on the Chiralcel OD-R and the OVM columns. The use of sodium octanesulfonate (NaOS) was found to improve the enantioseparation of pirlindole on the OVM column while enantioselectivity was considerably enhanced by addition of sodium perchlorate on the Chiralcel OD-R column. [less ▲]

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See detailSimultaneous Determination of Pirlindole Enantiomers and Dehydropirlindole by Chiral Liquid Chromatography
Ceccato, Attilio ULg; Hubert, Philippe ULg; De Tullio, Pascal ULg et al

in Journal of Pharmaceutical & Biomedical Analysis (1998), 17(6-7), 1071-9

Liquid chromatography was employed for the determination of pirlindole enantiomers and its oxidation product dehydropirlindole (DHP). The direct separation of pirlindole enantiomers and DHP was achieved ... [more ▼]

Liquid chromatography was employed for the determination of pirlindole enantiomers and its oxidation product dehydropirlindole (DHP). The direct separation of pirlindole enantiomers and DHP was achieved on a cellulose tris-(3,5-dimethylphenylcarbamate) chiral stationary phase (Chiralcel OD-R). Acetonitrile was used as the organic modifier and sodium perchlorate was used as an ionic additive in the mobile phase. The influence of acetonitrile and sodium perchlorate concentrations on enantioselectivity and achiral selectivity towards DHP was investigated in order to find suitable conditions for the determination of low amounts of each analyte. The mobile phase selected consisted of a mixture of acetonitrile and phosphate buffer (pH 5.0) containing sodium perchlorate (0.05 M) (35:65, v/v) and the UV detector was set at 220 nm. The method developed was validated and was found to be linear in the 0.1-5 microg ml(-1) range (r2 = 0.999 for the three compounds). Repeatability and the intermediate precision for the three analytes at a concentration of 0.1 microg ml(-1) were about 3 and 4%, respectively. This concentration corresponds to the quantification of 0.1% for the minor enantiomer. Actual determinations of enantiomeric purity for single enantiomers of pirlindole were performed. [less ▲]

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See detailSéparation énantiomérique du pirlindole à l’échelle préparative
De Tullio, Pascal ULg; Ceccato, A.; Felekidis, Apostolos ULg et al

Poster (1998, January 16)

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See detailComparative study of pirlindole, a selective RIMA, and its two enantiomers using biochemical and behavioural techniques.
Bruhwyler, J.; Liégeois, Jean-François ULg; Gerardy, J. et al

in Behavioural Pharmacology (1998), 9(8), 731-7

The interaction with monoamine oxidase A (MAO-A) and B has been shown to be sensitive to the absolute configuration of molecules. Therefore, the aim of this study was to compare the effects of the racemic ... [more ▼]

The interaction with monoamine oxidase A (MAO-A) and B has been shown to be sensitive to the absolute configuration of molecules. Therefore, the aim of this study was to compare the effects of the racemic pirlindole (a selective and reversible MAO-A inhibitor) and its two enantiomers using biochemical techniques (in vitro and ex vivo determination of rat brain MAO-A and MAO-B activity) and behavioural models (forced swimming test and reserpine-induced hypothermia and palpebral ptosis test). In vitro, the MAO-A IC50 of (+/-)-pirlindole, R-(-)-pirlindole and S-(+)-pirlindole were 0.24, 0.43 and 0.18 microM, respectively. Ex vivo, their ID50 were 24.4, 37.8 and 18.7 mg/kg i.p. The differences between the three compounds were not significant, with a ratio between the two enantiomers [R-(-)/S-(+)] of 2.2 in vitro and 2.0 ex vivo. MAO-B was only slightly inhibited. In the forced swimming test and the reserpine-induced hypothermia and ptosis model, the three compounds had an antidepressant profile. In the forced swimming test, the minimal effective dose ratio between the R-(-) and the S-(+) was again around 2.0. The behavioural observations were thus clearly in accordance with the biochemical data. [less ▲]

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See detailFacilitatory effects of chronically administered citicoline on learning and memory processes in the dog.
Bruhwyler, J.; Liégeois, Jean-François ULg; Geczy, J.

in Progress in Neuro-Psychopharmacology & Biological Psychiatry (1998), 22(1), 115-28

1. Citicoline (cytidine (5') diphosphocholine) has been shown to reverse aging-induced memory deficits, scopolamine-induced amnesia and nucleus basalis magnocellularis lesion-induced learning impairment ... [more ▼]

1. Citicoline (cytidine (5') diphosphocholine) has been shown to reverse aging-induced memory deficits, scopolamine-induced amnesia and nucleus basalis magnocellularis lesion-induced learning impairment. 2. This study aimed to evaluate the effects of citicoline on learning and retrieval processes in a complex differential reinforcement of response duration schedule in normal dogs. 3. The effects of citicoline on a stabilized performance were also measured in order to be able to differentiate specific memory effects from non specific influences on the motor, neuro-vegetative and motivational systems. 4. The results demonstrate that citicoline can exert facilitatory effects on learning and memory but also on retrieval processes. The complete absence of effects on the stabilized performance and on the motor, neuro-vegetative and motivational systems constitutes arguments in favour of a selectivity of action on the memory processes. [less ▲]

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See detailTentatives de synthèse énantiosélective des isomères R et S du pirlindol
Pirotte, Bernard ULg; De Tullio, Pascal ULg; Stachow, M. et al

in Journal de Pharmacie de Belgique (1998), 53

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