Saint-Grégoire, France
Saint-Grégoire, France

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Bassetti C.L.,Neurocenter EOC of Southern Switzerland | Baumann C.R.,Neurocenter EOC of Southern Switzerland | Dauvilliers Y.,French Institute of Health and Medical Research | Croyal M.,Bioprojet Biotech | And 2 more authors.
Journal of Sleep Research | Year: 2010

Histaminergic neurons of the hypothalamic tuberomammillary nucleus constitute a major wake-promoting system. In animals, cerebrospinal fluid (CSF) histamine levels are increased during wakefulness and after sleep deprivation and decreased during sleep. An involvement of the histamine system in human disorders has not, to our knowledge, been reported. We measured hypocretin-1 and histamine levels in the lumbar CSF of 28 patients with and without excessive daytime sleepiness (EDS) as assessed by the Epworth Sleepiness Scale (ESS). There were 10 patients with EDS (ESS > 10, mean ESS = 14). Diagnoses included narcolepsy (n = 4), idiopathic hypersomnia (n = 2), sleep apnoea (n = 2) and multiple sclerosis (n = 2). Three patients were treated with stimulants. Their mean CSF histamine was 258 ± 159 PM. There were 18 patients without EDS (ESS < 9, mean ESS = 5). No patients were treated with stimulants. Their mean CSF histamine was significantly higher (624 ± 481 PM, P = 0.007). There was a significant inverse correlation (r = -0.48, P = 0.02) between ESS and both CSF histamine and hypocretin-1 levels. These observations suggest that narcolepsy and EDS of other origin are associated in humans with lower CSF histamine levels and therefore with a reduced activity of the wake-promoting histaminergic neuronal system. © 2010 European Sleep Research Society.


Shah R.R.,8 Birchdale | Maison-Blanche P.,Hopital Bichat | Duvauchelle T.,Bioprojet Pharma | Robert P.,Bioprojet Biotech | Denis E.,Bioprojet Biotech
European Journal of Clinical Pharmacology | Year: 2015

Objective: To compare the effect of moxifloxacin as a positive control in a single ascending dose (SAD) study with that in a thorough QT (TQT) study. Methods: Moxifloxacin was used as a positive control in a SAD study and a TQT study during the evaluation of the QT liability of a new drug. The SAD study had enrolled 24 males and the TQT study 25 males. Both studies intensively monitored electrocardiograms (ECGs) and pharmacokinetic sampling. Effect of moxifloxacin on QTc interval was analysed in each study by intersection union test (IUT) and by exposure-response (ER) analysis and the results compared. Cost-effectiveness of this approach was computed. Results: Analysis by IUT revealed that the maximum mean (90 % confidence interval (CI)) placebo-corrected change from baseline (ΔΔQTcF) in the SAD study and the TQT study were remarkably similar (10.7 (6.5; 14.9) ms vs. 9.09 (6.20; 11.98) ms, respectively). In both studies, assay sensitivity was established by the 90 % lower bound exceeding 5 ms. ER analysis revealed the slopes in both studies to be significantly different from zero and comparable. Bootstrap-predicted effects of moxifloxacin at geometric mean concentrations of ~3000 ng/mL were 8.19 (90 % CI 5.86; 10.7) ms in the SAD study and 7.33 (90 % CI 5.69; 9.70) ms in the TQT study. Conclusion: Moxifloxacin can be integrated effectively in a SAD study to establish assay sensitivity, and a TQT study may be replaced by a SAD study which has the required assay sensitivity. Further experience is warranted to verify this conclusion. © 2015 Springer-Verlag Berlin Heidelberg.


Jacolot M.,University of Rennes 1 | Jean M.,University of Rennes 1 | Levoin N.,Bioprojet Biotech | Van De Weghe P.,University of Rennes 1
Organic Letters | Year: 2012

We report a TMSI-promoted Prins cyclization reaction with ketones as carbonyl partners to prepare polysubstituted chiral spirotetrahydropyrans. In the presence of racemic 2-methylcyclohexanone a dynamic kinetic resolution occurred affording one stereoisomer. The observed enantiospecificity has been rationalized by DFT calculation. © 2011 American Chemical Society.


Legouin B.,University of Rennes 1 | Gayral M.,University of Rennes 1 | Uriac P.,University of Rennes 1 | Cupif J.-F.,University of Rennes 1 | And 3 more authors.
European Journal of Organic Chemistry | Year: 2010

A chiral molecular tweezer obtained from (+)-usnic acid placed in solution in the presence of various aromatic compounds afforded complexes with low association constants. Thus, the X-ray structure of assembly 31 is presented, where the guest is sandwiched between the two pincers of the tweezer. The association constants for various guests were determined through different methods. Finally, other tweezers with electron-rich aromatic aldehydes and ketones were prepared from (1R,2R)-1,2-diaminocyclohexane. The most interesting complexes were also confirmed through structural analysis, and the best results were obtained with 10-hydroxyphenanthrene-9-carbaldehyde (51) as the aromatic moiety. © 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.


Levoin N.,Bioprojet Biotech | Labeeuw O.,Bioprojet Biotech | Calmels T.,Bioprojet Biotech | Poupardin-Olivier O.,Bioprojet Biotech | And 4 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2011

Pre-clinical investigation of some aryl-piperidinyl ether histamine H3 receptor antagonists revealed a strong hERG binding. To overcome this issue, we have developed a QSAR model specially dedicated to H3 receptor ligands. This model was designed to be directly applicable in medicinal chemistry with no need of molecular modeling. The resulting recursive partitioning trees are robust (80-85% accuracy), but also simple and comprehensible. A novel promising lead emerged from our work and the structure-activity relationships are presented. © 2011 Elsevier Ltd. All rights reserved.


Wicek M.,Jagiellonian University | Kottke T.,Goethe University Frankfurt | Ligneau X.,Bioprojet Biotech | Schunack W.,Free University of Berlin | And 4 more authors.
Bioorganic and Medicinal Chemistry | Year: 2011

Previous studies have shown that several imidazole derivatives posses affinity to histamine H3 and H4 receptors. Continuing our study on structural requirements responsible for affinity and selectivity for H3/H4 receptor subtypes, two series of 3-(1H-imidazol-4-yl)propyl carbamates were prepared: a series of unsaturated alkyl derivatives (1-9) and a series possessing a cycloalkyl group different distances to the carbamate moiety (10-13). The compounds were tested for their affinities at the human histamine H3 receptor, stably expressed in CHO-K1 cells. Compounds 1, 2, 5-7, 10-13 were investigated for their affinities at the human histamine H4 receptor co-expressed with Gαi2 and Gβ1γ2 subunits in Sf9 cells. To expand the pharmacological profile, compounds were further tested for their H3 receptor antagonist activity on guinea pig ileum and in vivo after oral administration to mice. All tested compounds exhibited good affinity for the human histamine H3 receptor with Ki values in the range from 14 to 194 nM. All compounds were active in vivo after peroral administration (p.o.) to Swiss mice, thus demonstrating their ability to cross the blood-brain barrier. The most potent H3 receptor ligand of these series was compound 5, 3-(1H-imidazol-4-yl)propyl pent-4-enylcarbamate with the highest affinity (Ki = 14 nM). Additionally, compound 3 showed remarkable central nervous system (CNS) H3R activity, increasing the Nτ-methylhistamine levels in mice with an ED 50 value of 0.55 mg/kg, p.o. evidencing therefore, a twofold increase of inverse agonist/antagonist potency compared to the reference inverse agonist/antagonist thioperamide. In this study, the imidazole propyloxy carbamate moiety was kept constant. The different lipophilic moieties connected to the carbamate functionality in the eastern part of the molecule had a range of influences on the human H4 receptor affinity (154-1326 nM). © 2011 Elsevier Ltd. All rights reserved.


Croyal M.,Bioprojet Biotech | Dauvilliers Y.,Montpellier University Hospital Center | Labeeuw O.,Bioprojet Biotech | Capet M.,Bioprojet Biotech | And 2 more authors.
Analytical Biochemistry | Year: 2011

An ultra-performance liquid chromatography tandem mass spectrometry (UPLC™-MS/MS) assay was developed for the simultaneous analysis of histamine, its major metabolite tele-methylhistamine, and an internal standard (N-tele-(R)-α-dimethylhistamine) from human cerebrospinal fluid (CSF) samples. The method involves derivatization of primary amines with 4-bromobenzenesulfonyl chloride and subsequent analysis by reversed phase liquid chromatography with mass spectrometry detection and positive electrospray ionization. The separation of derivatized biogenic amines was achieved within 3.5 min on an Acquity® BEH C18 column by elution with a linear gradient of acetonitrile/water/formic acid (0.1%). The assay was linear in the concentration range of 50-5000 pM for each amine (5.5-555 pg/ml for histamine and 6.25-625 pg/ml for tele-methylhistamine). For repeatability and precision determination, coefficients of variation (CVs) were less than 11.0% over the tested concentration ranges, within acceptance criteria. Thus, the developed method provides the rapid, easy, highly sensitive, and selective requirement to quantify these amines in human CSF. No significant difference was found in the mean ± standard error levels of these amines between a group of narcoleptic patients (histamine = 392 ± 64 pM, tele-methylhistamine = 2431 ± 461 pM, n = 7) and of neurological control subjects (histamine = 402 ± 72 pM, tele-methylhistamine = 2209 ± 463 pM, n = 32). © 2010 Elsevier Inc. All rights reserved.


Dauvilliers Y.,Montpellier University Hospital Center | Dauvilliers Y.,French Institute of Health and Medical Research | Dauvilliers Y.,Montpellier University | Delallee N.,Bioprojet Biotech | And 9 more authors.
Sleep | Year: 2012

Study Objectives: To determine the activity of cerebral histaminergic system evaluated by CSF levels of histamine (HA) and tele-methylhistamine (t-MHA), its major metabolite, and their relationships with hypocretin-1 levels in a large population of patients with hypersomnia and neurological conditions. Design: A sensitive liquid chromatographic-electrospray/tandem mass spectrometric assay was developed for the simultaneous quantification of CSF HA and t-MHA. Setting: Data were collected and CSF hypocretin-1 levels were measured using radioimmunoassay at the Sleep Disorders Center, Montpellier, France. CSF HA and t-MHA were measured in Bioprojet-Biotech, France Participants: One hundred fourteen unrelated patients with a suspicion of central hypersomnia underwent one night of polysomnography followed by the multiple sleep latency test. Sleep disorders were diagnosed clinically and using sleep studies: narcolepsy-cataplexy NC (n = 56), narcolepsy without cataplexy NwC (n = 27), idiopathic hypersomnia IH (n = 11), secondary narcolepsy (n = 3), and unspecified hypersomnia Uns EDS (n = 17). Fifty neurological patients without daytime sleepiness were included as controls. Measurements and Results: No between-hypersomnia group differences were found for CSF HA levels (median 708.62 pM extreme range [55.92-3335.50] in NC; 781.34 [174.08-4391.50] in NwC; 489.42 [177.45-906.70] in IH, and 1155.40 [134.80-2736.59] in Uns EDS) or for t-MHA levels. No association was found between CSF HA, t-MHA, or HA + t-MHA, sleepiness, treatment intake, and frequency of cataplexy. A slight negative correlation was found between age and HA levels. Further adjustment for the age revealed no significant HA levels difference between hypersomnia patients and controls. Conclusion: CSF histamine and tele-methylhistamine did not significantly differ between patients with narcolepsy-cataplexy and other etiologies of non-hypocretin-1 deficient central hypersomnias; these measurements, therefore, are not useful in assessing the etiology or severity of centrally mediated hypersomnia.


Gros D.,Institut Universitaire de France | Theveniau-Ruissy M.,Institut Universitaire de France | Bernard M.,Aix - Marseille University | Calmels T.,Bioprojet Biotech | And 6 more authors.
Cardiovascular Research | Year: 2010

AimsThis study aimed at characterizing expression and the functional role of the Gjb6 gene, encoding for connexin 30 (Cx30) protein, in the adult mouse heart.Methods and resultsThe expression of the Gjb6 gene in the mouse heart was investigated by RT-PCR and sequencing of amplified cDNA fragments. The sites of Gjb6 expression were identified in the adult heart using transgenic mice with reporter genes (Cx30LacZ/LacZ and Cx30LacZ/LacZ/Cx40 EGFP/EGFP mice), as well as anti-HCN4 (hyperpolarization activated cyclic nucleotide-gated potassium channel 4) or anti-connexin antibodies. Cine-magnetic resonance imaging and telemetric ECG recordings were used to evaluate the impact of Cx30 deficiency on cardiac physiology. Gjb6 was shown to be expressed in the sinoatrial (SA) node of the adult mouse heart. Eighty from 100 nuclei on average were LacZ-positive in the SA node of Cx30 LacZ/LacZ mice. No significant LacZ expression was seen in other cardiac tissues. Cx30 protein was identified in low abundance in the SA node of wild-type mice, as indicated by immunofluorescence experiments. Telemetric ECG recordings indicated that Cx30-deficient mice displayed a mean daily heart rate (HR) that was 9 faster than that measured in control mice (572 ± 38 b.p.m. vs. 524 ± 23, P < 0.05). This moderate tachycardia was still observed after inhibition of the autonomic nervous system, demonstrating that Cx30 deficiency resulted in changes in the intrinsic electrical properties of the SA node. Consistent with this hypothesis, Cx30LacZ/LacZ displayed a significant reduction of SDNN (standard deviation of the interbeat interval) compared with control mice. Increase of both the cardiac index (20) and the end-diastolic volume to body weight ratio (16) with no deficiency in ejection fraction or stroke volume were observed in mutant mice. An increase in cardiac index was interpreted as being a direct consequence of high HR, whereas large end-diastolic volume may be an indirect consequence of prolonged high HR.ConclusionCx30 is functionally expressed, in low abundance, in the SA node of the adult mouse heart where it participates in HR regulation.


PubMed | Bioprojet Biotech
Type: | Journal: Methods in molecular biology (Clifton, N.J.) | Year: 2017

This work aimed at building a 3D model of trimeric apo CD95. By combining different molecular modeling approaches and experimental information, we have been able to obtain a consensual organization of the complex. Our strategy permitted the construction of a plausible trimer, and to sketch the interface between protomers. The final model will guide further experimental investigations and understanding of CD95 structure and functions.

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