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Thierry Durand

Publications and source records attributed to Thierry Durand.

At least 19 recordsLinked to original sources
PubMed2006

Pharmacological actions of isoprostane metabolites and phytoprostanes in human and bovine pulmonary smooth muscles.

We examined the responses to various isoprostane derivatives in bovine/human airway and pulmonary arteries. All biological activity of 15-F(2t)-IsoP was lost in its two major metabolites (15-keto-15-F(2t)-IsoP and 13,14-dihydro-15-keto-15-F(2t)-IsoP). We also examined the effects of several metabolites of 15-F(2t)-IsoP synthesized within our own laboratory-both epimers of 2,3-dinor-15-F(2t)-IsoP and of 2,3-dinor-5,6-dihydro-15-F(2t)-IsoP, as well as 20-carboxy-2,3,4,5-tetranor-15 oxo-5,6,13,14-tetrahydro-15-F(2t)-isoP)-finding none of these to have any substantial excitatory effect. Finally, several plant-derived isoprostanes ("phytoprostanes") synthesized within our laboratory elicited little or no excitatory response in these three pulmonary smooth muscle preparations. We conclude that, although isoprostane exhibit powerful constrictor effects on airway and pulmonary vascular smooth muscles, metabolic processing of those isoprostanes essentially abolishes those biological actions; also, the phytoprostanes lack any appreciable pharmacological activity on those smooth muscle preparations.

Animals↗
PubMed2006

Development of the first potential covalent inhibitors of anandamide cellular uptake.

On the basis of the chemical structures of two previously developed metabolically stable and relatively potent inhibitors of anandamide uptake, OMDM-1,2, two series of potential covalent inhibitors of anandamide cellular reuptake, which might be used for the molecular characterization of the protein(s) involved in the membrane transport of endocannabinoids, have been designed and synthesized. Most of the compounds inhibited uptake to a varied extent and in a generally enantio-sensitive manner when co-incubated with [(14)C]anandamide, but only three of them, the photoactivatable 1a (OMDM-37), 1b (OMDM-39), and 8(Lo395), also produced a significant inhibition of uptake following the preincubation only of the cells, and this effect was significantly enhanced following UV exposure only in the case of 8. None of the new compounds inhibited [(14)C]anandamide hydrolysis with IC(50) < 50 microM, except for 1b.

Amidohydrolases↗
PubMed2006

Impact of diabetic polyneuropathy and cardiovascular autonomic neuropathy on the excretion of urinary 8-epi-PGF2alpha and its metabolites (2, 3-dinor and 2, 3-dinor-5, 6-dihydro).

The objective of this study was to establish if diabetes in the presence of polyneuropathy (PN) and/or cardiovascular autonomic neuropathy (CAN) is associated with alterations in the amounts of 8-epi-PGF2alpha (IP) and its metabolites including 2, 3-dinor-8-epi-PGF2alpha (dinor-IP) and 2, 3-dinor-5, 6 dihydro-8-epi-PGF2alpha (dinor-dihydro-IP) in urine. Mass spectrometric separation showed that excretion of IP was similar in the PN + /CAN- and PN+/CAN+ groups but higher than in the PN-/CAN- group (n = 103, 22 and 60, respectively; P < 0.05). By contrast, excretion of dinor-IP or dinor-dihydro-IP were similar in the PN-/CAN- and PN+/CAN- groups but higher than in PN+/CAN+ group. Correlations were obtained between IP and dinor-IP or dinor-dihydro-IP (r = 0.30; P < 0.001 and r = 0.31; P < 0.001, respectively). A significant association was also observed between dinor-IP and dinor-dihydro-IP (r = 0.48; P < 0.001). In conclusion, these biomarkers should prove useful in studies evaluating the impact of therapeutic drugs or antioxidant interventions aimed at delaying the onset of diabetic complications.

Adult↗
PubMed2006

Cardiovascular pharmacology and physiology of the isoprostanes.

F(2)-isoprostanes are a complex family of compounds produced from arachidonic acid via a free radical-catalyzed mechanism. Their quantification as a pathophysiological biomarker provides a unique opportunity to investigate lipid peroxidation in vascular diseases. Their measurement also provides an interesting biomarker for the rational dose selection of antioxidants in vascular diseases where oxidative stress might be involved. In addition to their use as biomarkers, some isoprostanes possess a biological activity. The 15-series F(2)- and E(2)-isoprostanes mediate vasoconstriction in different vascular beds and species. In addition, 15-F(2t)-IsoP induces smooth muscle cells mitogenesis and monocyte adhesion to endothelial cells. The data available supports but does not prove the hypothesis that isoprostanes are involved in vascular physiology and pathogenesis.

Animals↗
PubMed2006

[An interactive and evolutive software program to personalize treatment schedule : implication on daily life: the Centre Léon Bérard experience].

The second plan against cancer, initiated by the French President in 2003, has introduced a two-step procedure to announce cancer to the patient. During initial visit, the doctor tells the patient about his disease. On the second visit, the doctor elaborates the treatment strategy and proposes an individualized treatment plan for each patient. The objective of this plan is to offer to patients and caregivers an accurate, precise and personalized treatment schedule. The Centre Léon Bérard (Regional Cancer Center) has implemented a computerized model to manage all different treatment schedules. We developed a software program based on two different steps. Firstly, standard treatment schedules are programmed for each type of disease. To offer a better view of the influence of treatment on daily life, we added information such as place of treatment (ambulatory, inpatient, outpatient) impact on well being (side effects, risk of aplasia...), future evaluations and medical acts (CT scan, MRI, lumbar puncture...) as well as actions the patient should take (blood cell count, to have eaten nothing...). Secondly, it tailors these standard treatments as well as all complementary information's to the specific needs of each patient, based on the medical information available in their computerized records. This personalized plan may be modified and adjusted at any time including therefore more and more real details and insights for each patient (delay of chemotherapy, dates of CT scan....). This would help patients and caregivers to better understand the different phases of the treatment and, thus, improve patient follow-up and information at every step of patient management. This tool is currently being tested at the Centre Léon Bérard.

Case Management↗
PubMed2005

Different pharmacological profile of two closely related endocannabinoid ester analogs.

The pharmacological and neuroprotective properties of two ester analogs of the endocannabinoids, arachidonoylethyleneglycol (AA-EG) and alpha,alpha,-dimethyl arachidonoylethyleneglycol (DMA-EG), were investigated. We examined the interaction of both compounds with cannabinoid receptors (CB1 and CB2) and their efficacy in functional assays. In competition binding assays, AA-EG and DMA-EG had low potency to displace the CB1/CB2 agonist [3H]CP-55,940 in membrane preparations expressing rodent or human receptors. Binding data correlate with low efficacy of both compounds as regards to inhibition of adenylyl cyclase activity. It was also shown that DMA-EG resists hydrolysis by rat brain membranes while AA-EG undergo complete splitting under these conditions. In the cannabinoid tetrad, AA-EG induced hypomotility, analgesia, catalepsy and decreased rectal temperature indicating cannabimimetic activity. By contrast, DMA-EG was completely inactive in the same models. DMA-EG and AA-EG potently protected rat cortical neurons in culture against oxygen deprivation at nanomolar concentrations. In glutamate-induced damage, the compounds were less active protecting neurons at micromolar concentrations. The data obtained indicate that the ester endocannabinoid template can be used for the development of new compounds with potent biological activity lacking some of the undesirable behavioral side effects.

Animals↗
PubMed2005

A flexible synthesis of the phytoprostanes B1 type I and II.

Syntheses of the enantiomerically pure phytoprostanes B(1) type I and II are described starting from furfural and n-propylfuran. Key steps include the preparation of the Freimanis (+/-)-hydroxycyclopentenone and Wittig coupling using chiral phosphonium salts.

Alkenes↗
PubMed2005

Synthesis of a photoactivatable probe of the anandamide re-uptake.

To date, despite extensive investigations, full understanding of the endocannabinoid system remains elusive; in particular, anandamide cellular uptake is a current controversial topic. An iodo-arylazido probe was synthesized from commercially available azelaic acid monomethyl ester, in order to shed light on the anandamide transport process.

Arachidonic Acids↗
PubMed2004

B1-phytoprostanes trigger plant defense and detoxification responses.

Phytoprostanes are prostaglandin/jasmonate-like products of nonenzymatic lipid peroxidation that not only occur ubiquitously in healthy plants but also increase in response to oxidative stress. In this work, we show that the two naturally occurring B(1)-phytoprostanes (PPB(1)) regioisomers I and II (each comprising two enantiomers) are short-lived stress metabolites that display a broad spectrum of biological activities. Gene expression analysis of Arabidopsis (Arabidopsis thaliana) cell cultures treated with PPB(1)-I or -II revealed that both regioisomers triggered a massive detoxification and defense response. Interestingly, expression of several glutathione S-transferases, glycosyl transferases, and putative ATP-binding cassette transporters was found to be increased by one or both PPB(1) regioisomers, and hence, may enhance the plant's capacity to inactivate and sequester reactive products of lipid peroxidation. Moreover, pretreatment of tobacco (Nicotiana tabacum) suspension cells with PPB(1) considerably prevented cell death caused by severe CuSO(4) poisoning. Several Arabidopsis genes induced by PPB(1), such as those coding for adenylylsulfate reductase, tryptophan synthase beta-chain, and PAD3 pointed to an activation of the camalexin biosynthesis pathway that indeed led to the accumulation of camalexin in PPB(1) treated leaves of Arabidopsis. Stimulation of secondary metabolism appears to be a common plant reaction in response to PPB(1). In three different plant species, PPB(1)-II induced a concentration dependent accumulation of phytoalexins that was comparable to that induced by methyl jasmonate. PPB(1)-I was much weaker active or almost inactive. No differences were found between the enantiomers of each regioisomer. Thus, results suggest that PPB(1) represent stress signals that improve plants capacity to cope better with a variety of stresses.

Arabidopsis↗
PubMed2004

Total syntheses of iso-, neuro- and phytoprostanes: new insight in lipid chemistry.

Isoprostanes (IsoPs) are a complex family of compounds produced, in vivo, from peroxidation of polyunsaturated fatty acids (AA, DHA, EPA, alpha-linolenic) via a free-radical-catalyzed mechanism. Carbocyclic annulations are extremely important reactions and the stereocontrolled intramolecular free-radical cyclization has emerged as a powerful tool for carbon-carbon bond formation in synthetic chemistry. The hex-5-enyl radical cyclization is the most well-known for the synthesis of cyclopentane rings. After a short review of the literature, concerning the total synthesis of isoprostanes and intermediates, we will present our own contributions on the preparation of chiral cyclopentane rings from glucose leading to new isoprostanes. This study allowed us to control the cyclization outcome to yield the all-syn and/or syn-anti-syn precursors which permit us to the total synthesis of a large set of iso-, neuro-, and phytoprostanes.

Arachidonic Acids↗
PubMed2003

The metabolic effects of inhibitors of 5-lipoxygenase and of cyclooxygenase 1 and 2 are an advancement in the efficacy and safety of anti-inflammatory therapy.

Chronic treatment of inflammatory diseases with non-steroidal anti-inflammatory drugs is effective but not always devoid of serious side effects. In particular, the use of traditional non-steroidal aspirin-like drugs has been associated with a high incidence of gastrointestinal bleedings. The development of a new class of drugs, the selective cyclooxygenase type 2 (COX-2) inhibitors, has generated much expectation on the possibility to have safer compounds. After the initial enthusiasm of the scientific community, a re-evaluation of some large, randomized double-blind clinical studies performed with two of these compounds, has disclosed that the late serious gastrointestinal complications are not significantly reduced in comparison with non-selective inhibitors and that cardiovascular concerns might arise particularly if theses drugs are utilized in patients with underlying heart diseases. A new promising class of drugs to control inflammatory diseases is in advanced clinical development. The balanced inhibitors of 5-lipoxygenase (5-LOX) and of cyclooxygenase (both types 1 and 2) block the formation of all the enzymatically arachidonic acid-derived metabolites, both prostaglandins (like COX inhibitors) and leukotrienes (LT); these drugs have been shown to possess a very good anti-inflammatory efficacy without serious side effects. Licofelone, previously known as ML3000, is the molecule in the most advanced phase of clinical development (phase III) among this class of compounds; it is a potent, competitive, and well balanced inhibitor of 5-LOX and COX pathways. The drug has been shown to possess analgesic, anti-inflammatory, antipyretic antibronchocostrictory and antiplatelet properties at doses which are safe for the gastrointestinal tract. Moreover, the newly performed preclinical studies, here briefly reviewed, appear to indicate that the compound seems particularly suitable to protect the articular cartilage and the synovial space in degenerative joint disease and to exert a relevant antithrombotic activity. Preliminary results of clinical studies of licofelone in osteoarthritis indicate that the drug has a comparable or slightly better efficacy than that of naproxen but possesses a much better gastrointestinal safety. This latter important aspect has been also evaluated by an endoscopic study in normal volunteers randomly assigned to a 4-week treatment with licofelone, placebo or naproxen. The results indicate that no ulcers occurred in either licofelone group or the placebo group, while ulcers with unequivocal depth were present in 20% of the naproxen-treated subjects.

Acetates↗
PubMed2002

Total synthesis of (15R)- and (15S)-F(2t)-isoprostanes by a biomimetic process using the cyclization of acyclic dihydroxylated octa-5,7-dienyl radicals.

We report a new route to F(2t)-IsoP (formerly named 8-epi-PGF(2alpha)) using a biomimetic radical cyclization of a highly functionalized C20 precursor. The strategy employed gives a beta-hydroxy free radical followed by molecular oxygen trapping, which is an unusual method for quenching carbon free radicals. We observed the formation of unique diastereoisomers (15R)- and (15S)-F(2t)-IsoP. This result is consistent with a strong stereoelectronic control associated with a steric effect initiated by the side chains alpha and omega on the cyclopentane ring.

Cyclization↗
PubMed2002

Isoprostanes as a biomarker of lipid peroxidation in humans: physiology, pharmacology and clinical implications.

Isoprostanes are a complex family of compounds produced from arachidonic acid via a free-radical-catalyzed mechanism. They can be quantified as reliable markers of lipid peroxidation. Among the isoprostanes, 15-F(2t)-IsoP and 15-E(2t)-IsoP are biologically active and mediate vasoconstriction and bronchoconstriction and augment nociception. These effects are thought to be mediated via the activation of prostanoid TP receptors, with isoprostanes acting as full or partial agonists. A strong link between lipid peroxidation and diseases associated with ischaemia-reperfusion, atherosclerosis and inflammation has been suggested by elevated levels of F(2)-isoprostanes observed in such diseases. Thus, quantification of F(2)-isoprostanes as a pathophysiological marker provides a unique opportunity to investigate lipid peroxidation in human diseases and provides an interesting biomarker for rational dose selection of antioxidants in diseases where oxidative stress might be involved.

Animals↗
PubMed2002

The 5-series F(2)-isoprostanes possess no vasomotor effects in the rat thoracic aorta, the human internal mammary artery and the human saphenous vein.

1. Among the F(2)-isoprostanes, the 15- and the 5-series are currently used as markers of lipid peroxidation in vascular diseases. 15-F(2t)-IsoP (also named iPF(2 alpha)-III) exerts a vasoconstriction in most vessels, whereas no data is available concerning 5-F(2t)-IsoP (also named iPF(2 alpha)-VI), which is more abundant in plasma. 2. The aim of this study was to determine whether 5-F(2t)-IsoP possess any vascular effects on various vessels including the isolated rat thoracic aorta, the human internal mammary artery and the saphenous vein. 3. In organ baths, 5-F(2t)-IsoP and its 5-epimer did not affect the basal tone of any vessel, unlike 15-F(2t)-IsoP. These compounds possessed no antagonist effects on 15-F(2t)-IsoP-induced contractions, No dilator effect was observed in comparison with sodium nitroprusside and acetylcholine on the rat aorta. 4. In conclusion, we show that unlike 15-F(2t)-IsoP, 5-F(2t)-IsoP and its 5-epimer possess no vasomotor effects and as such are unlikely to be involved in the pathogenesis of vascular diseases. Further studies are required to test whether these mediators may have effects on systems not being measured in the current study.

Animals↗
PubMed2002

Response of rat thoracic aorta to F(2)-isoprostane metabolites.

SUMMARY: This study was undertaken to investigate the vascular actions (contraction and relaxation) of the F(2)-isoprostane metabolites 15-keto-15-F(2t)-IsoP, 2,3-dinor-15-F(2t)-IsoP, and 2,3-dinor-5,6-dihydro -15-F(2t)-IsoP in comparison with 15-F(2t)-IsoP on the rat thoracic aorta. 15-keto-15-F(2t)-IsoP induced a vasoconstriction in a concentration-dependent manner with a pD(2) value of 5.80 +/- 0.05, whereas 2,3-dinor-15-F(2t)-IsoP and 2,3-dinor-5,6-dihydro-15-F(2t)-IsoP had no effect. The parent compound 15-F(2t)-IsoP was more potent (pD(2) value: 6.46 +/- 0.1). Endothelium removal had no influence on the contraction to 15-keto-15-F(2t)-IsoP. GR32191 (a TP-receptor antagonist) concentration-dependently inhibited the contraction induced by 15-keto-15-F(2t)-IsoP, with a significant decrease in the E(max) values for GR32191 10(-7) M. Pretreatment with 2,3-dinor-15-F(2t)-IsoP and 2,3-dinor-5,6-dihydro-15-F(2t)-IsoP induced no alteration of 15-F(2t)-IsoP concentration-response curves. In contrast, 15-keto-15-F(2t)-IsoP pretreatment competitively inhibited the response to 15-F(2t)-IsoP. When concentration ratios of EC(50) values were used, a Schild regression of this data was linear with a slope of 0.974 and a pA(2) value of 6.13. 15-keto-15-F(2t)-IsoP at high concentrations caused a weak concentration-dependent relaxation of rat aorta rings contracted with U46619 (3.10(-8) M) that was not modified in the absence of endothelium. In contrast, 2,3-dinor-15-F(2t)-IsoP and 2,3-dinor-5,6-dihydro-15-F(2t)-IsoP induced no vasodilation. In conclusion, among the F(2)-isoprostane metabolites, 2,3-dinor-15-F(2t)-IsoP and 2,3-dinor-5,6-dihydro-15-F(2t)-IsoP did not cause vasorelaxation or vasoconstriction on the rat thoracic aorta. In contrast, 15-keto-15-F(2t)-IsoP mediates contraction through activation of TP-receptors, probably as a partial agonist, and induces a weak endothelium-independent relaxation at high concentrations.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗