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Titolo:
Oxidation sensitivity may be a useful tool for the detection of the hematotoxic potential of newly developed molecules: Application to antipsychotic drugs
Autore:
Liegeois, JF; Bruhwyler, J; Petit, C; Damas, J; Delarge, J; Geczy, J; Kauffmann, JM; Lamy, M; Meltzer, H; Mouithys-Mickalad, A;
Indirizzi:
Univ Liege, Med Chem Lab, B-4000 Liege, Belgium Univ Liege Liege BelgiumB-4000 ege, Med Chem Lab, B-4000 Liege, Belgium Univ Liege, Physiol Lab, B-4020 Liege, Belgium Univ Liege Liege Belgium B-4020 iege, Physiol Lab, B-4020 Liege, Belgium Therabel Res, B-1180 Brussels, Belgium Therabel Res Brussels Belgium B-1180 rabel Res, B-1180 Brussels, Belgium Free Univ Brussels, Lab Instrumental Anal & Bioelectrochem, B-1050 Brussels, Belgium Free Univ Brussels Brussels Belgium B-1050 hem, B-1050 Brussels, Belgium Univ Liege, Ctr Oxygen Res & Dev, B-4000 Liege, Belgium Univ Liege LiegeBelgium B-4000 Oxygen Res & Dev, B-4000 Liege, Belgium Vanderbilt Univ, Sch Med, Dept Psychiat, Nashville, TN 37212 USA Vanderbilt Univ Nashville TN USA 37212 Psychiat, Nashville, TN 37212 USA
Titolo Testata:
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
fascicolo: 1, volume: 370, anno: 1999,
pagine: 126 - 137
SICI:
0003-9861(19991001)370:1<126:OSMBAU>2.0.ZU;2-2
Fonte:
ISI
Lingua:
ENG
Soggetto:
PERFORMANCE LIQUID-CHROMATOGRAPHY; PEROXIDASE-CATALYZED OXIDATION; CLOZAPINE-INDUCED AGRANULOCYTOSIS; SIDE-EFFECT PROFILES; HUMAN-NEUTROPHILS; APLASTIC-ANEMIA; ULTRAVIOLET DETECTION; 2-ELECTRON OXIDATION; REACTIVE METABOLITES; IN-VITRO;
Keywords:
oxidation; clozapine; antipsychotic; agranulocytosis; pyridobenzazepine; predictive model;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
77
Recensione:
Indirizzi per estratti:
Indirizzo: Liegeois, JF Univ Liege, Med Chem Lab, 1 Ave Hop B36, B-4000 Liege, Belgium Univ Liege 1 Ave Hop B36 Liege Belgium B-4000 Liege, Belgium
Citazione:
J.F. Liegeois et al., "Oxidation sensitivity may be a useful tool for the detection of the hematotoxic potential of newly developed molecules: Application to antipsychotic drugs", ARCH BIOCH, 370(1), 1999, pp. 126-137

Abstract

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 freeradical 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 4.7and 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. (C) 1999 Academic Press.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 20/01/20 alle ore 22:13:01