References of "Mouithys-Mickalad, Ange"
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See detailQuantification of lipid bilayer effective microviscosity and fluidity effect induced by propofol
Bahri, Mohamed Ali ULg; Heyne, B.; Hans, P. et al

Conference (2004)

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See detailInvestigation of singlet oxygen reactivity towards propofol
Heyne, Belinda; Kohnen, Stephan ULg; Brault, Daniel et al

in Photochemical & Photobiological Sciences (2003), 2(9), 939-945

The reaction between the anaesthetic agent 2,6-diisopropylphenol (propofol, PPF) and singlet oxygen (1O2) has been investigated in aqueous solution by means of HPLC, GC, absorption spectroscopy and laser ... [more ▼]

The reaction between the anaesthetic agent 2,6-diisopropylphenol (propofol, PPF) and singlet oxygen (1O2) has been investigated in aqueous solution by means of HPLC, GC, absorption spectroscopy and laser flash photolysis with infrared luminescence detection. The rate constants for the physical and chemical quenching of 1O2 by PPF (kPPF) are found to be 2.66 x 10(5) M(-1) s(-1) and approximately 3.2 x 10(6) M(-1) s(-1) in CD3OD and D2O-CD3OD (75:25 v/v), respectively. The reaction of propofol with singlet oxygen produced by light irradiation of Rose Bengal leads essentially to two reaction products, 2,6-diisopropyl-p-benzoquinone and 3,5,3',5'-tetraisopropyl-(4,4')-diphenoquinone that are unambiguously identified from comparison with authentic samples. [less ▲]

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See detailEFFECTS OF O2 TENSION AND GLUCOSE CONCENTRATION ON THE CELLULAR RESPIRATION OF EQUINE ARTICULAR CHONDROCYTES IN CULTURE.
Schneider, Nicole ULg; Lejeune, Jean-Philippe ULg; Duyckaerts, Claire ULg et al

Poster (2003)

In vivo, articular chondrocytes are exposed to 5 to 10% O2. Chondrocytes are also suspected to produce reactive oxygen species when submitted to anoxia/re-oxygenation. We were interested to study the ... [more ▼]

In vivo, articular chondrocytes are exposed to 5 to 10% O2. Chondrocytes are also suspected to produce reactive oxygen species when submitted to anoxia/re-oxygenation. We were interested to study the effects of O2 and glucose variations on cellular respiration, glucose consumption and lactate production. Equine articular chondrocytes were cultured in suspension for 2 days under 5 or 21 % O2 in the gaseous phase, and with 0, 1.0 or 4.5 g/L glucose. The viable cells were then counted and the respiration rate (O2 consumption) of 10.106 cells was monitored by oxymetry for 2 hours; after oxymetry, glucose and lactate were measured in the medium (enzymatic assays). After 2 days, the cell viability was the best at 5% O2 and 1g/L glucose; it decreased at 4.5 g/L glucose and was the worst at 0g/L glucose, for the two O2 tensions (n=3). There was no obvious difference of the respiration rate between cells cultured at 5 and 21% O2, but respiration of chondrocytes was surprisingly low. When cells were submitted to 20 min anoxia at 0% O2, the O2 consumption was doubled at re-oxygenation for cells previously cultured at 21% O2. Glucose and lactate values found in the medium after oxymetry: lactate release in medium was similar (36.23 and 34.57 mg/L respectively) for cells cultured with 1g glucose and 5 or 21% O2 conditions; lactate values were low (2.03 and 8,63 mg/L respectively) for 4.5 g glucose and 5 or 21% O2. Glucose uptake was not different whatever the culture conditions. These results indicate a low cellular respiration with a lactate production linked to the glucose concentrationin the medium, and raise the question of the capacity of chondrocytes to produce ROS in vivo starting from the mitochondrial chain. [less ▲]

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See detailEffects of O2 tension and glucose concentration on the cellular respiration of equine articular chondrocytes in culture.
Schneider, Nicole ULg; Lejeune, Jean-Philippe ULg; Mouithys-Mickalad, Ange ULg et al

Poster (2003)

In vivo, articular chondrocytes are exposed to 5 to 10% O21,2. Chondrocytes are also suspected to produce reactive oxygen species when submitted to anoxia/re-oxygenation3,4. We were interested to study ... [more ▼]

In vivo, articular chondrocytes are exposed to 5 to 10% O21,2. Chondrocytes are also suspected to produce reactive oxygen species when submitted to anoxia/re-oxygenation3,4. We were interested to study the effects of O2 and glucose variations on cellular respiration, glucose consumption and lactate production. Equine articular chondrocytes were cultured in suspension for 2 days under 5 or 21 % O2 in the gaseous phase, and with 0, 1.0 or 4.5 g/L glucose. The viable cells were then counted and the respiration rate (O2 consumption) of 10.106 cells was monitored by oxymetry for 2 hours; after oxymetry, glucose and lactate were measured in the medium (enzymatic assays). After 2 days, the cell viability was the best at 5% O2 and 1g/L glucose; it decreased at 4.5 g/L glucose and was the worst at 0g/L glucose, for the two O2 tensions (n=3). There was no obvious difference of the respiration rate between cells cultured at 5 and 21% O2, but respiration of chondrocytes was surprisingly low. When cells were submitted to 20 min anoxia at 0% O2, the O2 consumption was doubled at re-oxygenation for cells previously cultured at 21% O2. Glucose and lactate values found in the medium after oxymetry : lactate release in medium was similar (36.23 and 34.57 mg/L respectively) for cells cultured with 1g glucose and 5 or 21% O2 conditions; lactate values were low (2.03 and 8,63 mg/L respectively) for 4.5 g glucose and 5 or 21% O2. Glucose uptake was not different whatever the culture conditions. These results indicate a low cellular respiration with a lactate production linked to the glucose concentration in the medium, and raise the question of the capacity of chondrocytes to produce ROS in vivo starting from the mitochondrial chain. [less ▲]

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See detailOxidant activity of rabbit synoviocytes (HIG-82) demonstrated by oxymetry and ethylene production.
Schneider, Nicole ULg; Lejeune, Jean-Philippe ULg; Mouithys-Mickalad, Ange ULg et al

Poster (2003)

We are interested in a possible role of synoviocytes in the ROS production implicated in osteoarthritis, therefore we studied the response of a rabbit synoviocyte cell line (HIG-82) to variable oxygen ... [more ▼]

We are interested in a possible role of synoviocytes in the ROS production implicated in osteoarthritis, therefore we studied the response of a rabbit synoviocyte cell line (HIG-82) to variable oxygen tensions and the oxidant activity of these cells in response to stimuli. Synoviocytes were cultured at 5 and 21 % O2, their O2 consumption (cellular respiration, monitored with Clark electrode) was measured at 21% O2 and after anoxia, before and after stimulation with phorbol myristate acetate (PMA), and their oxidant response to PMA stimulation was quantified by measuring ethylene (gas chromatography) released when the substrate, alpha-keto-gamma-methylbutyric acid, is oxidised by the ROS produced by the cells. Cell growth was faster at 21 % O2 than at 5% O2, and microscopic observation revealed 2 cell populations: a few small round cells in suspension and many adherent cells. By oxymetry, we observed that a 106 synoviocytes suspension in 2 ml completely consumed O2 within 15 min, that anoxia (7 min) slightly slowed the respiration rate down and that PMA stimulation increased O2 consumption (150 % increase). The oxidant activity (ethylene production) of the cells was stimulated by PMA in a dose-dependent manner (10-9 to 10-7M) but the cell response was highly variable (from 150 to 1500 % increase) and was largely reduced by diphenyliodonium, an inhibitor of NADPH-oxidase and NO-synthase. The capacity to produce free radical species was confirmed for the small round cells by detection of an electron paramagnetic resonance (EPR) signal after stimulation. These results thus demonstrate a sensibility to O2 and an oxidant activity of synoviocytes at least related to ROS production by NADPH-oxidase activity. [less ▲]

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See detailInfluence of copper(II) salt on the reaction of peroxynitrite with propofol
Kohnen, Stephan ULg; Mouithys-Mickalad, Ange ULg; Deby-Dupont, G. et al

in Free Radical Research (2003), 37(Suppl. 1), 106

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See detailSodium nitrite and ascorbic acid: a metal-free combination that controls the free-radical polymerization of tert-butyl methacrylate in water
Detrembleur, Christophe ULg; Mouithys-Mickalad, Ange ULg; Teyssié, Philippe et al

in e-Polymers (2002), (4), 1-16

A mixture of sodium nitrite and ascorbic acid is able to control the radical polymerization of tert-butyl methacrylate (tBMA) in water at 80°C. Indeed, sodium nitrite is reduced by the ascorbic acid, and ... [more ▼]

A mixture of sodium nitrite and ascorbic acid is able to control the radical polymerization of tert-butyl methacrylate (tBMA) in water at 80°C. Indeed, sodium nitrite is reduced by the ascorbic acid, and the nitric oxide (NO) which is formed in situ is nothing but a promoter of nitroxyl radicals. The radical polymerization of tBMA is thus basically controlled by a nitroxide-mediated process. [less ▲]

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See detailOxidative Processes in Human Promonocytic Cells (Thp-1) after Differentiation into Macrophages by Incubation with Chlamydia Pneumoniae Extracts
Mouithys-Mickalad, Ange ULg; Deby-Dupont, Ginette; Nys, Monique ULg et al

in Biochemical and Biophysical Research Communications (2001), 287(3), 781-8

Human monocytes differentiated into macrophages by Chlamydia pneumoniae were able to oxidize blood lipoproteins, as discovered by Kalayoglu et al. (1998). Using a model of human promonocytic cells (THP-1 ... [more ▼]

Human monocytes differentiated into macrophages by Chlamydia pneumoniae were able to oxidize blood lipoproteins, as discovered by Kalayoglu et al. (1998). Using a model of human promonocytic cells (THP-1), the cells were differentiated into macrophages by preincubation with C. pneumoniae extract, and further stimulated by phorbol myristate acetate. In these conditions, the differentiated cells oxidized a thiol compound and released superoxide anion as demonstrated respectively by gas liquid chromatography and electron spin resonance. The thiol oxidation and superoxide anion release were inhibited by diphenyliodonium, a NADPH oxidase and NOsynthase inhibitor, proving that the respiratory burst and the NOsynthase were involved in the oxidation processes occurring in the differentiated THP-1. The role of H(2)O(2) (derived from superoxide anion) was indicated by the enhancing effect of a peroxidase on the thiol oxidation. The presence of alpha-tocopherol in the surrounding medium strongly diminished the oxidation of the thiol target. [less ▲]

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See detailPotential Antioxidant properties of Aceclofenac and its Metabolites: Investigation on an in vitro model
Mouithys-Mickalad, Ange ULg; Mathy, Marianne ULg; Deby, Carol et al

Poster (2001, June 22)

Introduction: Recent studies have shown that some steroidal anti-inflammatory drugs (NSAIDs) could exert their actions by multifactorial processes. Among them, the potential antioxidant activity of ... [more ▼]

Introduction: Recent studies have shown that some steroidal anti-inflammatory drugs (NSAIDs) could exert their actions by multifactorial processes. Among them, the potential antioxidant activity of certain NSAIDs towards various reactive oxygen species (ROS) is often suggested and could have pharmacological relevance. Objective: This study was designed to assess the potential antioxidant properties (IC50 values) of aceclofenac and its metabolites (4’OH-aceclofenanc and diclofenac) on three different systems of ROS production, using chemiluminescence (CL) technique with luminal and electron spin resonance (ESR) spin trapping. Material and Methods: Isolated human PMNs (1x106 cells) were activated with 5x10-7 M PMA in the presence of luminal (CL assays) with or without drug addition. For spin trapping experiments, 100 mM DMPO, a radical trapping agent, was added to the reaction milieu containing 6x106 cells/ml. For free-cell experiments, the Fenton’s reagent was used for generation of ·OH and xanthine/xanthine-oxidase system for O2-radicals. The NaOCl-induced CL, amplified by luminal, was used to test the drug effects on HOCl. Results: On the model of PMA-activated PMNs, 4’OH-aceclofenac exhibited the best antioxidant profile (IC50 = 10 µM) while the effect of the parent drug was less pronounced (IC50 = 100 µM). Diclofenac did not inhibit CL response even at the high dose of 1 mM. Quite similar results were obtained on the NaOCl-induced chemiluminescence, where the efficacy of the drug was as follows: 4’HO-ACE (25 µM) > ACE (1 mM) > DICLO (no effect at 1 mM). By ESR technique, 4’HO-ACE also showed an inhibitory effect (501 µM) on the ROS production by PMA-activated PMN as well as on the ·OH production, while ACE (IC50 = 100 µM) was less efficient and DICLO (IC50 = 1 mM) without significant effect. These findings indicate that beside its anti-inflammatory effects, aceclofenac acts as an antioxidant, at least in part, by the way of its metabolite especially 4’HO-ACE. [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 detailIn vitro effects of aceclofenac and its metabolites on the production by chondrocytes of inflammatory mediators.
Henrotin, Yves ULg; de Leval, X.; Mathy, Marianne ULg et al

in Inflammation Research (2001), 50(8), 391-9

OBJECTIVES: To investigate the mechanisms of action underlying the anti-inflammatory action of aceclofenac in vivo, we studied in vitro the effect of aceclofenac and its main metabolite, 4 ... [more ▼]

OBJECTIVES: To investigate the mechanisms of action underlying the anti-inflammatory action of aceclofenac in vivo, we studied in vitro the effect of aceclofenac and its main metabolite, 4'-hydroxyaceclofenac, in comparison with diclofenac, another metabolite, on cyclooxygenases activity as well as interleukin-1beta, -6 and -8, nitric oxide, and prostaglandin E2 production by human osteoarthritic and normal articular chondrocytes. METHODS: Enzymatically isolated human chondrocytes were cultured for 72 h in the absence or presence of interleukin-1beta (IL-1beta) or lipopolysacharride (LPS) and with or without increased amounts (1 to 30 microM) of aceclofenac or metabolites. The production of different cytokines was measured by Enzyme Amplified Sensitivity Immunoassays (EASIA). Prostaglandin E2 was quantified by a specific radioimmunoassay. Nitrite and nitrate concentrations in the culture supernatants were determined by spectrophotometric method based upon the Griess reaction. Cyclooxygenase-2, inducible NO synthase and IL-1beta gene expression were quantified by reverse transcription of mRNA followed by real time and quantitative polymerase chain reaction. Finally, cyclooxygenase inhibitory potency of the drugs was also tested in both a cell-free system using purified ovine cyclooxygenase-1 and -2 (COX-1 and COX-2) and at a cellular level using human whole blood assay. RESULTS: We have demonstrated that aceclofenac, 4'-hydroxyaceclofenac and diclofenac significantly decreased interleukin-6 production at concentrations ranged among 1 to 30 microM and fully blocked prostaglandin E2 synthesis by IL-1beta- or LPS-stimulated human chondrocytes. Aceclofenac and diclofenac had no effect on interleukin-8 production while 4'-hydroxyaceclofenac slightly decreased this parameter at the highest dose (30 microM). Aceclofenac was without effect on IL-1beta- or LPS-stimulated nitric oxide production. At 30 microM, 4'-hydroxyaceclofenac inhibited both IL-1beta or LPS-stimulated nitric oxide production while diclofenac inhibited only the LPS-stimulated production. Finally, at 30 microM, the three drugs significantly decreased IL-1beta mRNA. In the whole blood test, aceclofenac and 4'-hydroxyaceclofenac weakly inhibited COX-1 with IC50 values superior to 100 microM, but decreased by 50% COX-2 activity at the concentration of 0.77 and 36 microM, respectively. Diclofenac strongly inhibited both COX-1 and COX-2 with IC50 values of 0.6 and 0.04 microM, respectively. On the other hand, aceclofenac and diclofenac weakly inhibited purified ovine cyclooxygenases with IC50 values superior to 100 microM, whereas 4'-hydroxyaceclofenac was without effect. CONCLUSIONS: These results suggest that aceclofenac actions are multifactorial and that metabolites could contribute to its anti-inflammatory actions. [less ▲]

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See detailIn Vitro Study of the Antioxidant Properties of Nimesulide and 4-Oh Nimesulide: Effects on Hrp- and Luminol-Dependent Chemiluminescence Produced by Human Chondrocytes
Zheng, S. X.; Mouithys-Mickalad, Ange ULg; Deby-Dupont, G. P. et al

in Osteoarthritis and Cartilage (2000), 8(6), 419-25

OBJECTIVES: Reactive oxygen species (ROS) are now recognized to play an important role in the pathogenesis of rheumatic diseases and constitute an interesting therapeutic target for drugs. This in vitro ... [more ▼]

OBJECTIVES: Reactive oxygen species (ROS) are now recognized to play an important role in the pathogenesis of rheumatic diseases and constitute an interesting therapeutic target for drugs. This in vitro study was designed to evaluate the antioxidant properties of nimesulide (NIM), a nonsteroidal antiinflammatory drug of the sulfonanilide class, and its main metabolite 4-OH nimesulide (4-OHNIM). METHODS: The scavenging effects of NIM and 4-OH NIM on hydroxyl radical ((.)OH) and superoxide anions (O(minusd)(2)) were investigated by electron spin resonance (ESR), using 5, 5-dimethylpyrroline-N-oxide (DMPO) as the spin trap agent. The quenching properties of these drugs on hypochlorite anion was studied by luminol enhanced chemiluminescence. Finally, the effects of NIM and 4-OHNIM on the reactive oxygen species production by human articular chondrocytes were recorded by HRP and luminol-enhanced chemiluminescence. RESULTS: By this method it has been demonstrated that NIM and 4-OHNIM, at concentrations ranging from 10 to 100 microM, are potent scavengers of(.)OH whereas only 4-OHNIM was capable to scavenge O(minusd)(2). Chemiluminescence generated by HOCl was also significantly and dose-dependently inhibited by both NIM and 4-OHNIM. Nevertheless, at each concentration tested, the inhibitory effect of 4-OHNIM was significantly more marked, even at the highest concentration (100 microM). Furthermore, when chondrocytes were pre-incubated for 48-96 h with NIM or 4-OHNIM, the luminol- and HRP-dependent CL produced by the cells was significantly inhibited in a dose-dependent manner. CONCLUSIONS: NIM and 4-OHNIM may protect cartilage against oxidative stress, not only by scavenging ROS but also by inhibiting their production by chondrocytes. [less ▲]

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See detailThe antioxidant properties of non stroidal anti-inflammatory drugs
Henrotin, Yves ULg; Mouithys-Mickalad, Ange ULg; Mathy-Hartert, M et al

in Osteoarthritis and Cartilage (2000), 8

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See detailIn vitro study of the antioxidant properties of non steroidal anti-inflammatory drugs by chemiluminescence and electron spin resonance (ESR).
Mouithys-Mickalad, Ange ULg; Zheng, S. X.; Deby-Dupont, G. P. et al

in Free Radical Research (2000), 33(5), 607-21

OBJECTIVES: To determine the antioxidant activities of nonsteroidal anti-inflammatory drugs (NSAIDS), we examined by chemiluminescence (CL) and electron spin resonance (ESR) their scavenging properties ... [more ▼]

OBJECTIVES: To determine the antioxidant activities of nonsteroidal anti-inflammatory drugs (NSAIDS), we examined by chemiluminescence (CL) and electron spin resonance (ESR) their scavenging properties towards lipid peroxides, hypochlorous acid and peroxynitrite. METHODS: The antioxidant properties of nimesulide (NIM), 4-hydroxynimesulide (4-HONIM), aceclofenac (ACLO), 4-hydroxyaceclofenac (4-HOA-CLO), diclofenac (DICLO) and indomethacin (INDO) were tested on four different reactive oxygen species (ROS) generating systems: (I) phorbol-myristate acetate (PMA)-activated neutrophils, (II) Fe2+/ascorbate-induced lipid peroxidation, (III) HOCl-induced light emission, (IV) the kinetics of ONOO- decomposition followed by spectrophotometry. ROS production was monitored by luminol-enhanced CL or by ESR using two different spin traps. RESULTS: At 10 microM, ACLO, NIM, 4-HONIM, 4-HOA-CLO, and DICLO decreased luminol-enhanced CL generated by PMA-activated neutrophils. Inversely, INDO increased the luminol enhanced CL. Interestingly, hydroxylated metabolites were more potent antioxidants than the parent drugs. Furthermore, all drugs tested, excepted ACLO, lowered lipid peroxidation induced by Fe2+/ascorbate system. ACLO and DICLO, even at the highest concentration tested (100 microM), did not significantly lower HOCl induced CL, whereas the other drugs were potent scavengers. Finally, all the NSAIDS accelerated decomposition of ONOO-, suggesting a potential capacity of the molecules to scavenge peroxynitrite. CONCLUSION: The NSAIDs possess variable degrees of antioxidant activities, linked to their ability to react with HOCl, lipid peroxides or ONOO-. These antioxidant activities could offer interesting targeted side-effects in the treatment of joint inflammatory diseases. [less ▲]

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See detailEffects of propofol on endothelial cells subjected to a peroxynitrite donor (SIN-1).
Mathy, Marianne ULg; Mouithys-Mickalad, Ange ULg; Kohnen, S. et al

in Anaesthesia (2000), 55(11), 1066-71

We investigated the effect of propofol on endothelial cells subjected to the peroxynitrite (ONOO-) donor 3-morpholino sydnonimine (SIN-1). Cells were incubated overnight with 0.5, 1.0 or 2.0 mM SIN-1 ... [more ▼]

We investigated the effect of propofol on endothelial cells subjected to the peroxynitrite (ONOO-) donor 3-morpholino sydnonimine (SIN-1). Cells were incubated overnight with 0.5, 1.0 or 2.0 mM SIN-1, with or without 10-3 M propofol (Diprivan). Cytotoxicity, assessed by measuring the release of pre-incorporated 51Cr, increased when the concentration of SIN-1 increased, and was significantly decreased by 10-3 M propofol (90%, 78% and 28% of protection against 0.5, 1.0 and 2.0 mM SIN-1, respectively). Cell protection against 1 mM SIN-1 was tested with 0.03-1.0 mM propofol and this was compared to tyrosine, a target molecule for peroxynitrite. Propofol protected cells in a dose-dependent manner (r = 0.98; p < 0.001) and was as effective as tyrosine. Finally, using high-performance liquid chromatography, we demonstrated that propofol reacted with ONOO- more rapidly than did tyrosine, inhibiting nitrotyrosine formation. In the absence of propofol, 3.5 mM ONOO- with 1 mM tyrosine yielded 39.6% nitrotyrosine, but nitrotyrosine was not produced when 5 mM propofol was added. We conclude that propofol protects endothelial cells against the toxicity of ONOO-. The anti-oxidant properties of propofol can be partially attributed to its scavenging effect on peroxynitrite, a property that might be relevant in pathological situations involving a significant contribution of peroxynitrite to tissue damage. [less ▲]

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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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