References of "Dogné, Jean-Michel"
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See detailLe bm-573, un antagoniste original du récepteur au thromboxane a2, réduit le développement des lésions athéromateuses chez des souris déficientes en apolipoprotéine e (apo e-/-) contrairement a l’aspirine.
Cherdon, Céline ULg; Rolin, Stéphanie; Ooms, Annie ULg et al

(2009, May 28)

Afin d’examiner l'efficacité de l’aspirine et du BM-573 dans l'athérogenèse, des souris apo E-/- femelles ont été traitées durant 10 et 20 semaines avec le BM-573 (10mg/kg/j), l’aspirine (30mg/kg/j) ou un ... [more ▼]

Afin d’examiner l'efficacité de l’aspirine et du BM-573 dans l'athérogenèse, des souris apo E-/- femelles ont été traitées durant 10 et 20 semaines avec le BM-573 (10mg/kg/j), l’aspirine (30mg/kg/j) ou un placébo. Au cours de cette expérience, aucune modification du poids corporel ou de la cholestérolémie n’a été observée. Par contre, le traitement des animaux par le BM-573, a eu pour effet de diminuer les lésions athéromateuses de manière significative tandis que l’aspirine a été sans effet sur ce paramètre. Ces données ont été confirmées par des analyses histopathologiques et biochimiques. Ces résultats confirment que l'antagonisme sélectif des récepteurs TP associé à une inhibition de la thromboxane synthétase réduit significativement les lésions athéromateuses chez les souris apo E-/-. Le BM-573 est, par conséquent, un agent thérapeutique potentiel pour la prévention de l'athérosclérose. [less ▲]

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See detailIs thrombin generation the new rapid, reliable and relevant pharmacological tool for the development of anticoagulant drugs ?
Robert, S.; Ghiotto, J.; Pirotte, Bernard ULg et al

in Pharmacological Research (2009), 59

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See detailStudy of thromboxane modulators in a murine model of atherosclerosis
Cherdon, Céline ULg; Rolin, Stéphanie; de Leval, Laurence ULg et al

(2008, July 04)

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See detailBm-573, an original thromboxane receptor antagonist, reduces development of atherosclerosis in apoe–deficient (apo e-/-) mice
Cherdon, Céline ULg; Rolin, Stéphanie; Hanson, Julien ULg et al

Poster (2007, October 11)

To test the efficacy of BM-573 in atherogenesis, the effect of 10 weeks of treatment with BM573 (10 mg/l) on early aortic atherosclerotic lesions of apo E deficient mice was assessed. These mice were fed ... [more ▼]

To test the efficacy of BM-573 in atherogenesis, the effect of 10 weeks of treatment with BM573 (10 mg/l) on early aortic atherosclerotic lesions of apo E deficient mice was assessed. These mice were fed with chow diet, with spontaneous increase of total plasma cholesterol and triglycerides. In this experiment, while BM-573 did not affect body weight, it significantly decreases early atherogenesis lesions confirmed by macroscopic, microscopic and biochemical analysis. These results confirm that selective antagonism of TP receptor is effective in reducing atherosclerotic lesion in apo E deficient mice. Consequently, BM-573 could be a potential drug for prevention of atherosclerosis [less ▲]

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See detailBm-573, a thromboxane receptor antagonist, reduces development of atherosclerosis in apoe–deficient mice
Cherdon, Céline ULg; Rolin, Stéphanie; Hanson, Julien ULg et al

Poster (2007, June 22)

Atherosclerotic cardiovascular disease, according to World Health Organization, is the primary cause of heart disease and stroke. Atherosclerosis is a chronic vascular disease whose development is ... [more ▼]

Atherosclerotic cardiovascular disease, according to World Health Organization, is the primary cause of heart disease and stroke. Atherosclerosis is a chronic vascular disease whose development is influenced by several mediators. Among them, the action of eicosanoïds such as thromboxane A2 and 8-iso-PGF2a have recently received a lot of attention. The aim of our study was the evaluation of benefits of original molecules, synthesised in our lab, targeting the thromboxane receptor (TP) in an apo E deficient mouse. We previously demonstrated in several in vitro and in vivo pharmacological experiments that our original sulfonylurea derivate, BM-573 was a potent combined inhibitor of the thromboxane synthase and antagonist of TP. Since TP is implied in atherosclerosis development, such antagonist could have a great therapeutic impact in atherogenesis.To test the efficacy of BM-573 in atherogenesis, the effect of 10 weeks of treatment with BM573 (10 mg/kg) on early aortic atherosclerotic lesions of apo E deficient mice was assessed. These mice were fed with chow diet, with spontaneous increase of total plasma cholesterol and triglycerides. In this experiment, while BM-573 did not affect body weight, it significantly decreased early atherogenesis lesions confirmed by macroscopic, microscopic and biochemical analysis. These results confirm that selective antagonism of TP receptor is effective in reducing atherosclerotic lesion in apo E deficient mice. Consequently, BM-573 could be a potential drug for prevention of atherosclerosis. [less ▲]

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See detailLe bm-573, un antagoniste original de récepteur au thromboxane a2, réduit le développement des lesions atheromateuses chez des souris deficientes en apolipoproteine e (apo e-/-)
Cherdon, Céline ULg; Rolin, Stéphanie; Hanson, Julien ULg et al

Poster (2007, May 10)

Afin d’examiner l'efficacité du BM-573 dans l'athérogenèse, des souris apo E-/- ont été traitées durant 10 semaines avec le BM573 (10mg/kg). Au cours de cette expérience, le traitement des animaux par le ... [more ▼]

Afin d’examiner l'efficacité du BM-573 dans l'athérogenèse, des souris apo E-/- ont été traitées durant 10 semaines avec le BM573 (10mg/kg). Au cours de cette expérience, le traitement des animaux par le BM-573, a eu pour effet de diminuer les lésions athéromateuses précoces de manière significative. Ces données ont été confirmées par des analyses histopathologiques et biochimiques. Ces résultats confirment que l'antagonisme sélectif des récepteurs TP associé à une inhibition de la thromboxane synthase réduit significativement les lésions athéromateuses chez les souris apoE-/-.. Le BM-573 est, par conséquent, un agent thérapeutique potentiel pour la prévention de l'athérosclérose [less ▲]

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See detailCardiovascular haemodynamics and ventriculo-arterial coupling in an acute pig model of coronary ischaemia-reperfusion
Lanoye, Lieve; Segers, Patrick; Tchana-Sato, Vincent ULg et al

in Experimental Physiology (2007), 92(1), 127-137

Although reperfusion after coronary occlusion is mandatory for myocardial salvage, reperfusion may trigger a cascade of harmful events (reperfusion injury) adding to myocardial injury. We investigated ... [more ▼]

Although reperfusion after coronary occlusion is mandatory for myocardial salvage, reperfusion may trigger a cascade of harmful events (reperfusion injury) adding to myocardial injury. We investigated effects of reperfusion on left ventricular (LV) haemodynamics and ventriculo-arterial (VA) coupling in pigs following acute myocardial ischaemia induced by coronary artery occlusion. Experiments were performed in six animals, with measurements of cardiac and arterial function at baseline, after 60 min of ischaemia (T60) and after 2 (T180) and 4 h of reperfusion (T300). Ventriculo-arterial coupling was assessed using the ventriculo-arterial elastance ratio of paper, as well as using a 'stiffness coupling' and 'temporal coupling' index. Reperfusion following ischaemia (T180 versus T60) induced a progressive decline in cardiovascular function, evidenced by a decrease in mean arterial blood pressure, cardiac output and ejection fraction which was not restored at T300. Although reperfusion also induced an increase in slope of the end-systolic pressure-volume relationship (ESPVR), the ESPVR curve shifted to the right, associated with a depression of contractile function. Histology demonstrated irreversible myocardial damage at T300. The ventriculo-arterial elastance ratio and the 'stiffness coupling' index were unaffected throughout the protocol, but the 'temporal coupling' parameter indicated a relative shift between heart period and the time constant of the arterial system. It is unlikely that these alterations are attributable to ischaemic injury alone. The combination of both the stiffness and temporal coupling index may provide more information when studying ventriculo-arterial coupling than the more commonly used ventricular end-systolic stiffness/effection arterial elastance (E-es/E-a) ratio. [less ▲]

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See detailSolid lipid microparticles as a sustained release system for pulmonary drug delivery
Jaspart, Séverine ULg; Bertholet, Pascal; Piel, Géraldine ULg et al

in European Journal of Pharmaceutics & Biopharmaceutics (2007), 65(1), 47-56

The controlled release of drugs for pulmonary, delivery is a research field which has been so far rather unexploited but is currently becoming increasingly attractive. The introduction part of this ... [more ▼]

The controlled release of drugs for pulmonary, delivery is a research field which has been so far rather unexploited but is currently becoming increasingly attractive. The introduction part of this research article first details the potential advantages of solid lipid microparticles (SLMs) as drug carrier compared to liposomes and polymeric microspheres. The aim of this work is to use SLMs to impart a sustained release profile to a model drug, salbutamol acetonide (SA). SA was synthesized from salbutamol in order to increase the lipophilicity of this molecule and thereby to increase its incorporation efficiency into SLMs. SA-loaded SLMs were then produced by a hot emulsion technique followed by high-shear homogenisation and the manufacturing parameters were optimized using the experimental design methodology in order to reach a suitable particle size for pulmonary administration. Scanning electron micrographs showed that SLMs are spherical, have a smooth surface and that SA crystallises outside of the particles when the drug loading is higher than 20%. This was confirmed by X-ray diffraction. SA in vitro release study from SLMs showed that the release rate increased with SA loading but remained in every case lower than the dissolution rate of pure SA. (c) 2006 Elsevier B.V. All rights reserved. [less ▲]

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See detailBM-573, a thromboxane receptor antagonist, reduces development of atherosclerosis in apoE–deficient mice
Cherdon, Céline ULg; Rolin, Stéphanie; Hanson, Julien ULg et al

in Journal of Molecular and Cellular Cardiology (2007), 42(suppl 1.), 33-34

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See detailBM-520, an original TXA(2) modulator, inhibits the action of thromboxane A(2) and 8-iso-prostaglandin F-2 alpha in vitro and in vivo on human and rodent platelets, and aortic vascular smooth muscles from rodents
Rolin, S.; Hanson, Julien ULg; Vastersaegher, C. et al

in Prostaglandins & Other Lipid Mediators (2007), 84(1-2), 14-23

Thromboxane A(2) (TXA(2)) and 8-iso-PGF(2 alpha). are two prostanoid agonists of the thromboxane A(2) receptor (TP), whose activation has been involved in platelet aggregation and atherosclerosis. Agents ... [more ▼]

Thromboxane A(2) (TXA(2)) and 8-iso-PGF(2 alpha). are two prostanoid agonists of the thromboxane A(2) receptor (TP), whose activation has been involved in platelet aggregation and atherosclerosis. Agents able to counteract the actions of these agonists are of great interest in the treatment and prevention of cardiovascular events. Here, we investigated in vitro and in vivo the pharmacological profile of BM-520, a new TP antagonist. In our experiments, this compound showed a great binding affinity for human washed platelets TP receptors, and prevented human platelet activation and aggregation induced by U-46619, arachidonic acid and 8-iso-PGF(2 alpha). The TP receptor antagonist property of BM-520 was confirmed by its relaxing effect on rat aorta smooth muscle preparations precontracted with U-46619 and 8-iso-PGF(2 alpha). Further, its TP antagonism was also demonstrated in vivo in guinea pig after a single intravenous injection (10 mg kg(-1)). We conclude that this novel TP antagonist could be a promising therapeutic tool in pathologies such as atherosclerosis where an increased production of TXA(2) and 8-iso-PGF2., as well as TP activation are well-established pathogenic events. (c) 2007 Elsevier Inc. All rights reserved. [less ▲]

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See detailConfirmation of high cytokine clearance by hemofiltration with a cellulose triacetate membrane with large pores: an in vivo study
Delanaye, Pierre ULg; Lambermont, Bernard ULg; Dogné, Jean-Michel ULg et al

in International Journal of Artificial Organs (2006), 29(10), 944-948

Objective: To confirm in vivo the hypothesis that hemofiltration with a large pore membrane can achieve significant cytokine clearance. Method: We used a well-known animal model of endotoxinic shock (0.5 ... [more ▼]

Objective: To confirm in vivo the hypothesis that hemofiltration with a large pore membrane can achieve significant cytokine clearance. Method: We used a well-known animal model of endotoxinic shock (0.5 mg/kg of lipopolysaccharide from Escherichia Coli over a period of 30 mins). Six pigs were hemofiltrated for 3 hours with a large pore membrane (78 angstrom pore, 80 kDa cut off) (Sureflux FH 70, Nipro, Osaka, Japan). The ultrafiltration rate was 45 ml/kg/min. Samples were taken from arterial, venous line and in the ultrafiltrate at T120 and T240. We measured concentrations of interleukin 6, interleukin 10 and albumin. Results: At T120 and T240, the IL-6 clearances were 22 +/- 7 and 15 +/- 3 ml/min, respectively. The IL-6 sieving coefficients were 0.97 and 0.7 at T120 and T240, respectively. At T120 and T240, the IL-10 clearances were 14 +/- 4 and 10 +/- 7 ml/min, respectively. The sieving coefficients were 0.63 and 0.45 at T120 and T240, respectively. The concentrations of IL-6 and IL-10 were the same at T0 and T240. At T60 and T240, the plasmatic albumin concentrations were 24 +/- 4 g/L and 23 +/- 4 g/L, respectively ( p = 0.13). Conclusions: In this animal model of endotoxinic shock, we confirm the high cytokine clearance observed when hemofiltration is applied to a large pore membrane. The loss of albumin seems negligible. The impact of such clearances on hemodynamic stability and survival remains to be proved. [less ▲]

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See detailEvaluation of original dual thromboxane A2 modulators as antiangiogenic agents
de Leval, Xavier; Dassesse, Thibaut; Dogné, Jean-Michel ULg et al

in Journal of Pharmacology and Experimental Therapeutics (The) (2006), 318(3), 1057-1067

Angiogenesis is a promising target for the therapy of several diseases including cancer. This study was undertaken to characterize the antiangiogenic properties of a series of original dual thromboxane A ... [more ▼]

Angiogenesis is a promising target for the therapy of several diseases including cancer. This study was undertaken to characterize the antiangiogenic properties of a series of original dual thromboxane A(2) (TXA(2)) inhibitors derived from torasemide, a marketed loop diuretic with TXA(2) antagonistic properties, by evaluating their effects on human endothelial cell migration, adhesion, and viability in vitro, as well as in the ex vivo rat aortic ring assay. All drugs tested exhibited a marked affinity toward human platelet TXA(2) receptor, significantly prevented platelet aggregation induced by U-46,619, a stable TXA(2) receptor agonist, and inhibited platelet TXA(2) synthase without affecting cyclooxygenase (COX)-1 or COX-2 enzymatic activities. These dual TXA(2) inhibitors dose dependently inhibited endothelial cell migration in chemotaxis assays using vascular endothelial growth factor ( VEGF) as a chemoattractant but failed to affect cell adhesion and viability. The highest rates of cell migration inhibition were obtained with original compounds BM-567 and BM-573 (50.3 and 59.4% inhibition, respectively) when used at the final concentration of 10 mu M. In addition, pretreatment of endothelial cells with these two drugs significantly prevented U-46,619-induced intracellular Ca2+ pool mobilization, thus suggesting a mechanistic link between inhibition of the TXA(2) pathway and reduced endothelial cell migration. Treatment of rat aortic explants with U-46,619 (9,11- dideoxy- 9,11- methanoepoxyprostaglandin F 2) significantly enhanced vessel sprouting whereas aortic rings treated with some of the compounds, including BM-567 (N-n-pentyl-N'-[2-(cyclohexylamino)-5-nitrobenzenesulfonyl] urea) and BM-573 (N-tert-butyl-N'-[5-nitro-2p- toluylaminobenzenesulfonyl]urea), showed a significant decrease in vessel sprouting, which was not reversed by the addition of VEGF. These data suggest that our original dual TXA(2) inhibitors bear antiangiogenic properties, mainly by inhibiting endothelial cell migration. [less ▲]

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See detailLarge-pore membrane hemofiltration increases cytokine clearance and improves right ventricular-vascular coupling during endotoxic shock in pigs
Lambermont, Bernard ULg; Delanaye, Pierre ULg; Dogné, Jean-Michel ULg et al

in Artificial Organs (2006), 30(7), 560-564

Hemodynamic improvement in patients suffering from both septic shock and renal failure who received hemofiltration suggested that an extrarenal epuration technique could be of interest in patients with ... [more ▼]

Hemodynamic improvement in patients suffering from both septic shock and renal failure who received hemofiltration suggested that an extrarenal epuration technique could be of interest in patients with septic shock alone. However, most of the studies using continuous venovenous hemofiltration (CVVH) in this setting evidenced neither cytokine clearance nor significant reduction in their plasma level. Lack of significant clearance was explained in part by the small size of the membrane pores. Therefore, we investigated the effects of large-pore membrane hemofiltration (LPHF) during endotoxic shock in pigs on interleukin 6 (IL-6) and interleukin 10 (IL-10) clearances, and on right ventricular (RV)-vascular coupling. Thirteen anesthetized healthy pigs weighing 20-30 kg were divided into two groups. In the Endo group (n = 6), the pigs received a 0.5-mg/kg endotoxin infusion over a period of 30 mins from T0 to T30. In the EndoHF group (n = 7), LPHF (cutoff = 80 kDa) and an ultrafiltration rate of 45 mL/kg/h were started 30 mins after the end of the endotoxin infusion, from T60 to T240. In this model of porcine endotoxic shock, LPHF was responsible for a significant clearance of IL-6 (20 mL/min) and Il-10 (14 mL/min), and for an improvement in RV-vascular coupling. [less ▲]

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See detailSynthesis and pharmacological evaluation of novel thromboxane modulators as antiplatelet agents acting on both the alpha and beta isoforms of the human thromboxane receptor
Hanson, Julien ULg; Reynaud, Denis; Qiao, Na et al

in Journal of Medicinal Chemistry (2006), 49(12), 3701-3709

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See detailThe use of an apoE–deficient (apoE-/-) mice model to characterize the therapeutic benefits of original thromboxane modulators
Cherdon, Céline ULg; Rolin, stephanie; Hanson, Julien ULg et al

Poster (2006, May 17)

The aim of our study was to use an apoE–deficient mouse model to test drugs acting as thromboxane A2 antagonist. Presented here is the “en face” method 6 which allows the evaluation of atherosclerosis ... [more ▼]

The aim of our study was to use an apoE–deficient mouse model to test drugs acting as thromboxane A2 antagonist. Presented here is the “en face” method 6 which allows the evaluation of atherosclerosis lesions development in wild type and APO E-/- mice. This method involves pinning out the aorta and quantifying lesion area as a percentage of total surface area. The use of this mice model offers a unique opportunity to characterize the therapeutic benefits of pharmacologicals agents designed in our laboratory of which antioxidants and thromboxane modulators. The pharmacological characterization of BM-573 as potential antiatherosclerotic agent will also be discussed [less ▲]

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See detailEvaluation of BM-573, a novel TXA(2) synthase inhibitor and receptor antagonist, in a porcine model of myocardial ischemia-reperfusion
Kolh, Philippe ULg; Rolin, S.; Tchana-Sato, Vincent ULg et al

in Prostaglandins & Other Lipid Mediators (2006), 79(1-2), 53-73

Aims: To investigate whether BM-573 (N-tert-butyl-N'-[2-(4'-methylphenylam\ino)-5-nitro-benzenesulfonyl]urea), an original combined thromboxane A(2) synthase inhibitor and receptor antagonist, prevents ... [more ▼]

Aims: To investigate whether BM-573 (N-tert-butyl-N'-[2-(4'-methylphenylam\ino)-5-nitro-benzenesulfonyl]urea), an original combined thromboxane A(2) synthase inhibitor and receptor antagonist, prevents reperfusion injury in acutely ischemic pigs. Methods: Twelve animals were randomly divided in two groups: a control group (n = 6) intravenously infused with vehicle, and a BM-573-treated group (n = 6) infused with BM-573 (10 mg kg(-1) h(-1)). In both groups, the left anterior descending (LAD) coronary artery was Occluded for 60 min and reperfused for 240 min. Either vehicle or BM-573 was infused 30 min before LAD occlusion and throughout the experiment. Platelet aggregation induced by arachidonic acid ex vivo measured was prevented by BM-573. Results: In both groups, LAD occlusion decreased cardiac output, ejection fraction, slope of stroke work-end-diastolic volume relationship, and induced end-systolic pressure-volume relationship (ESPVR) rightward shift, while left ventricular afterload increased. Ventriculo-arterial coupling and mechanical efficiency decreased. In both groups, reperfusion further decreased cardiac output and ejection fraction, while ESPVR displayed a further rightward shift. Ventriculo-arterial coupling and mechanical efficiency remained impaired. Area at risk, evidenced with Evans blue, was 33.2 +/- 3.4% of the LV mass (LVM) in both groups, and mean infarct size, revealed by triphenyltetrazolium chloride (TTC), was 27.3 +/- 2.6% of the LVM in the BM-573-treated group (NS). Histological examination and immunohistochemical identification of desmin revealed necrosis in the anteroseptal region similar in both groups, while myocardial ATP dosages and electron microscopy also showed that BM-573 had no cardioprotective effect. Conclusions: These data suggest that BM-573 failed to prevent reperfusion injury in acutely ischemic pigs. (C) 2005 Elsevier Inc. All rights reserved. [less ▲]

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See detailFrom the design to the clinical application of thromboxane modulators
Dogné, Jean-Michel ULg; Hanson, Julien ULg; de Leval, Xavier et al

in Current Pharmaceutical Design (2006), 12(8), 903-923

Arachidonic acid (AA) metabolites are key mediators involved in the pathogenesis of numerous cardiovascular, pulmonary, inflammatory, and thromboembolic diseases. One of these bioactive metabolites of ... [more ▼]

Arachidonic acid (AA) metabolites are key mediators involved in the pathogenesis of numerous cardiovascular, pulmonary, inflammatory, and thromboembolic diseases. One of these bioactive metabolites of particular importance is thromboxane A(2) (TXA(2)). It is produced by the action of thromboxane synthase on the prostaglandin endoperoxide H-2 (PGH(2)) which results from the enzymatic transformation of AA by the cyclooxygenases. It is a potent inducer of platelet aggregation, vasoconstriction and bronchoconstriction, and has been involved in a series of major pathophysiological conditions. Therefore, TXA(2) receptor antagonists, thromboxane synthase inhibitors and drugs combining both properties have been developed by different laboratories since the early 1980s. Several Compounds have been launched on the market and others are tinder clinical evaluation. In the first part of this review. we will describe the physiological properties of TXA(2), thromboxane synthase and thromboxane receptors. The second part is dedicated to a description of each class of thromboxane modulators with the advantages and disadvantages they offer. In the third part. we aim to describe recent studies performed with the most interesting thromboxane modulators in major pathologies: myocardial infarction and thrombosis, atherosclerosis, diabetes, pulmonary embolism, septic shock.. preeclampsia, and asthma. Each pathology will be systematically reviewed. Finally, in the last part we will highlight the latest perspectives in drug design of thromboxane modulators and in their future therapeutic applications such as cancer, metastasis and angiogenesis. [less ▲]

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