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81.
Z Kapui P Schaeffer E G Mikus E Boronkay J Gyürky J M Herbert M Pascal 《Arzneimittel-Forschung》1999,49(8):685-693
The effect of 1-cyclopentyl-3-ethyl-6-(3-ethoxypyrid-4-yl)- 1H-pyrazolo[3,4-d]pyrimidin-4-one (SR 265579), a potent inhibitor of guanosine 3',5'-cyclic monophosphate (cyclic GMP) phosphodiesterase (PDE5), was examined regarding its specificity toward the other cyclic nucleotide phosphodiesterases, the effect on cyclic nucleotide levels and the bronchodilatory activity, both in vitro and in vivo in guinea-pigs. The effects were compared to those obtained with zaprinast (CAS 37762-06-4), a known PDE5 inhibitor. Anion-exchange chromatography of the soluble fraction of guinea-pig homogenates revealed 5 peaks which corresponded to PDE1, PDE2, PDE3, PDE4 and PDE5. SR 265579 produced a potent and competitive inhibition, with respect to cyclic GMP, of PDE5 with a Ki of 6.4 nmol/l. The compound was 25 fold more potent than zaprinast and demonstrated selectivity toward PDE5. The selectivity index was 14 and 33 with respect to PDE4 and 3, respectively. PDE1 and 2 were only inhibited at considerably higher concentrations. SR 265579 specifically increased the intracellular cyclic GMP levels in guinea-pig tracheal epithelial cells (EC50 = 117 nmol/l). Moreover, in the guinea pig, plasma cyclic GMP levels were significantly increased after the intravenous or oral administration of doses as low as 1 mg/kg. Isolated guinea-pig trachea were relaxed by the addition of SR 265579 as evaluated by measuring either spontaneous tone or relaxation of histamine and acetylcholine-precontracted preparations. PD2 values were of 7.64, 6.52 and 5.25, respectively. In vivo, after i.v. administration, bronchodilatory activity was demonstrated in an artificially-ventilated guinea-pig histamine-induced bronchospasm model with an ED50 of 0.63 mg/kg. In all experiments, SR-265579 was proved to be more active than zaprinast. These results demonstrate that SR 265579 is an orally active, potent and specific inhibitor of PDE5. 相似文献
82.
Spray-dried redispersible oil-in-water emulsion to improve oral bioavailability of poorly soluble drugs. 总被引:5,自引:0,他引:5
Gilles Dollo Pascal Le Corre Alexis Guérin Fran?ois Chevanne Jean Louis Burgot Roger Leverge 《European journal of pharmaceutical sciences》2003,19(4):273-280
A physically stabilized dry emulsion dosage form reforming the original emulsion after rehydration was developed by spray-drying a liquid oil-in-water emulsion containing maltodextrin as carrier and sodium caseinate as emulsifying agent. Several oil:water as well as maltodextrin:water ratios were tested, the homogenization and spray-drying processes and the reconstitution properties were investigated and an optimum formulation was selected for poorly soluble drug incorporation, having an identical oil:water and carrier:water ratio of 10% (w/w) and a load of solid material of 20% (w/w). Lipophilic 5-phenyl-1,2-dithiole-3-thione (5-PDTT) was selected as a model drug. 5-PDTT release from the solid state emulsion was studied using an in vitro two-phase stirred model and the relative bioavailability of 5-PDTT in the dry emulsion was obtained in the rabbit after oral administration of the reconstituted emulsion, compared to a 5-PDTT-sulfobutyl ether 7 beta-cyclodextrin complex in solution. Incorporation of 5-PDTT in the oil phase neither affects the surface morphology of the powder nor the reconstitution, the droplet size or the drug releasing properties and, furthermore, allows a 3-fold improvement of 5-PDTT relative bioavailability in rabbit after oral administration. These results indicate that dry emulsions may be considered as relevant dosage forms to improve bioavailability of poorly absorbable lipophilic drugs. 相似文献
83.
Yves Claustre Danielle De Peretti Philippe Brun Christiane Gueudet Nathalie Allouard Richard Alonso Jo?lle Lourdelet André Oblin Gabrielle Damoiseau Dominique Fran?on Marie-Fran?oise Suaud-Chagny Régis Steinberg Mireille Sevrin Hans Schoemaker Pascal George Philippe Soubrié Bernard Scatton 《Neuropsychopharmacology》2003,28(12):2064-2076
SSR181507 ((3-exo)-8-benzoyl-N-[[(2S)7-chloro-2,3-dihydro-1,4-benzodioxin-1-yl]methyl]-8-azabicyclo[3.2.1]octane-3-methanamine monohydrochloride) is a novel tropanemethanamine benzodioxane derivative that possesses high and selective affinities for D2-like and 5-HT(1A) receptors (K(I)=0.8, 0.2, and 0.2 nM for human D(2), D(3), and 5-HT(1A), respectively). In vivo, SSR181507 inhibited [(3)H]raclopride binding to D(2) receptors in the rat (ID(50)=0.9 and 1 mg/kg, i.p. in limbic system and striatum, respectively). It displayed D(2) antagonist and 5-HT(1A) agonist properties in the same concentration range in vitro (IC(50)=5.3 nM and EC(50)=2.3 nM, respectively, in the GTPgammaS model) and in the same dose range in vivo (ED(50)=1.6 and 0.7 mg/kg, i.p. on striatal DA and 5-HT synthesis, respectively, and 0.03-0.3 mg/kg, i.v. on dorsal raphe nucleus firing rate). It selectively enhanced Fos immunoreactivity in mesocorticolimbic areas as compared to the striatum. This regional selectivity was confirmed in electrophysiological studies where SSR181507, given acutely (0.1-3 mg/kg, i.p.) or chronically (3 mg/kg, i.p., o.d., 22 days), increased or decreased, respectively, the number of spontaneous active DA cells in the ventral tegmental area, but not in the substantia nigra. Moreover, SSR181507 increased both basal and phasic DA efflux (as assessed by microdialysis and electrochemistry) in the medial prefrontal cortex and nucleus accumbens, but not in the striatum. This study shows that the combination of D(2) receptor antagonism and 5-HT(1A) agonism, in the same dose range, confers on SSR181507 a unique neurochemical and electrophysiological profile and suggests the potential of this compound for the treatment of the main dimensions of schizophrenia. 相似文献
84.
Thierry Andre Philippe Colin Christophe Louvet Erik Gamelin Olivier Bouche Emmanuel Achille Nicolas Colbert Catherine Boaziz Pascal Piedbois Nicole Tubiana-Mathieu Arnaud Boutan-Laroze Michel Flesch Marc Buyse Aimery de Gramont 《Journal of clinical oncology》2003,21(15):2896-2903
PURPOSE: This randomized, 2 x 2 factorial study compared a semimonthly (LVFU2) with a monthly (FULV) regimen of fluorouracil and leucovorin and 24 versus 36 weeks of each regimen as adjuvant treatment of patients with stage II (Dukes' B2) and III (Dukes' C) colon cancer. PATIENTS AND METHODS: LVFU2 was administered semi-monthly for 2 consecutive days as dl- or l-leucovorin (200 or 100 mg/m2, respectively) as a 2-hour infusion, followed by a 400 mg/m2 FU bolus and 600 mg/m2 of FU as a 22-hour continuous infusion. FULV was administered monthly for 5 consecutive days as a 15-minute infusion of dl- or l-leucovorin, followed by 400 mg/m2 of FU as a 15-minute infusion. RESULTS: A total of 905 patients were randomly assigned. The median follow-up was 41 months. Disease-free survival was similar between the LVFU2 and FULV groups (127 v 124 events; hazard ratio [HR] = 1.04; P =.74) and between 24 and 36 weeks of therapy (128 v 123 events; HR = 0.94; P =.63). Analysis of overall survival showed a slight excess in the number of deaths in LVFU2 compared with FULV (73 v 59), but this difference was not statistically significant (HR = 1.26; 95% confidence interval, 0.90 to 1.78; P =.18). The most commonly observed grade 3 to 4 toxicities were neutropenia, diarrhea, and mucositis. Toxicities were significantly lower in the LVFU2 group (all toxicities, P <.001). CONCLUSION: Our data confirm that LVFU2 is less toxic than FULV. At a median follow-up of 41 months, no statistically significant difference could be detected in disease-free or overall survival between the treatment groups or treatment durations. 相似文献
85.
Darius Razavi Isabelle Merckaert Serge Marchal Yves Libert Sandrine Conradt Jacques Boniver Anne-Marie Etienne Ovide Fontaine Pascal Janne Jean Klastersky Christine Reynaert Pierre Scalliet Jean-Louis Slachmuylder Nicole Delvaux 《Journal of clinical oncology》2003,21(16):3141-3149
PURPOSE: Although there is wide recognition of the usefulness of improving physicians' communication skills, no studies have yet assessed the efficacy of post-training consolidation workshops. This study aims to assess the efficacy of six 3-hour consolidation workshops conducted after a 2.5-day basic training program. METHODS: Physicians, after attending the basic training program, were randomly assigned to consolidation workshops or to a waiting list. Training efficacy was assessed through simulated and actual patient interviews that were audiotaped at baseline and after consolidation workshops for the consolidation-workshop group, and approximately 5 months after the end of basic training for the waiting-list group. Communication skills were assessed according to the Cancer Research Campaign Workshop Evaluation Manual. Patients' perceptions of communication skills improvement were assessed using a 14-item questionnaire. RESULTS: Sixty-three physicians completed the training program. Communication skills improved significantly more in the consolidation-workshop group compared with the waiting-list group. In simulated interviews, group-by-time repeated measures analysis of variance showed a significant increase in open and open directive questions (P =.014) and utterances alerting patients to reality (P =.049), as well as a significant decrease in premature reassurance (P =.042). In actual patient interviews, results revealed a significant increase in acknowledgements (P =.022) and empathic statements (P =.009), in educated guesses (P =.041), and in negotiations (P =.008). Patients interacting with physicians who benefited from consolidation workshops reported higher scores concerning their physicians' understanding of their disease (P =.004). CONCLUSION: Consolidation workshops further improve a communication skills training program's efficacy and facilitate the transfer of acquired skills to clinical practice. 相似文献
86.
We report on a 7 year-old-girl with mandibulo-acral dysplasia. When she was 3 years of age it mimicked scleroderma because
of skin atrophy and later on a Hutchinson-Gilford progeria syndrome (HGP). Acro-mandibular dysplasia was diagnosed because
of facial hypoplasia and mandibular hypoplasia. The bilateral proximal mid-humeral notch seen in this case is unusual.
Received: 22 June 2000 Revision requested: 10 July 2000 Revision received: 7 August 2000 Accepted: 10 August 2000 相似文献
87.
Automated selection of beam orientations and segmented intensity-modulated radiotherapy (IMRT) for treatment of oesophagus tumors. 总被引:1,自引:0,他引:1
BACKGROUND AND PURPOSE: For some treatment sites, there is evidence in the literature that five to nine equi-angular input beam directions are enough for generating IMRT plans. For oesophagus cancer, there is a report showing that going from four to nine beams may even result in lower quality plans. In this paper, our previously published algorithm for automated beam angle selection (Cycle) has been extended to include segmented IMRT. For oesophagus cancer patients, we have investigated whether automated orientation selection from a large number of equi-angular input beam directions (up to thirty-six) for IMRT optimisation can result in improved lung sparing. MATERIALS AND METHODS: CT-data from five oesophagus patients treated recently in our institute were used for this study. For a prescribed mean PTV dose of 55 Gy, Cycle was used in an iterative procedure to minimise the mean lung dose under the following hard constraints: standard deviation for PTV dose inhomogeneity 2% (1,1 Gy), maximum spinal cord dose 45 Gy. Conformal radiotherapy (CFRT) and IMRT plans for a standard four field oesophagus beam configuration were compared with IMRT plans generated by automated selection from nine or thirty-six equi-angular input beam orientations. Comparisons were also made with dose distributions generated with our commercial treatment planning system (TPS), and with observations in the literature. RESULTS: Using Cycle, automated orientation selection from nine or thirty-six input beam directions resulted in improved lung sparing compared to the four field set-ups. Compared to selection from nine input orientations, selection from thirty-six directions did always result in lower mean lung doses, sometimes with even fewer non-zero weight beams. On average only seven beams with a non-zero weight were enough for obtaining the lowest mean lung dose, yielding clinically feasible plans even in case of thirty-six input directions for the optimisation process. With our commercial TPS we observed the same contra-intuitive, unfavourable results as reported in the literature; nine field equi-angular IMRT plans had substantially higher mean lung doses than plans for the conventional four field set-ups. For all cases, the Cycle plans generated from nine equi-angular input directions were superior compared to similar plans generated with our commercial TPS. CONCLUSIONS: For the studied oesophagus cancer patients the best plans for IMRT were obtained with Cycle, using automated beam orientation selection from thirty-six input beam directions. The lowest mean lung doses could be obtained with, on average, a selection of only seven beams with non-zero weight. 相似文献
88.
Pascal Sève Sylvie Isaac Olivier Trédan Pierre-Jean Souquet Yves Pachéco Maurice Pérol Laurence Lafanéchère Aurélie Penet Eva-Laure Peiller Charles Dumontet 《Clinical cancer research》2005,11(15):5481-5486
PURPOSE: To determine the prevalence and the prognostic value of microtubule component expression in tumors of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC). EXPERIMENTAL DESIGN: Expression of microtubular components was immunohistochemically examined in 93 tumor samples from untreated patients with stage III and IV NSCLC. All patients received vinorelbine-based chemotherapy. Response to chemotherapy, progression-free survival, and overall survival were correlated with the expression of microtubule proteins. RESULTS: The response rate was 27.3% (21 partial responses among 77 valuable patients). Although expression of microtubule components was not associated with the response rate, high class III beta-tubulin expression was correlated with resistance to vinorelbine, defined as disease progression under treatment. Patients whose tumors expressed high levels of class III beta-tubulin isotype had shorter progression-free survival and overall survival (P = 0.002 and 0.001, respectively). High Delta2 alpha-tubulin expression was associated with a shorter overall survival (P = 0.018). Tubulin II levels were not found to be correlated with patient outcome. A multivariate analysis, taking into account sex, age, histology, stage, weight loss, and class II beta-tubulin, class III beta-tubulin, and Delta2 alpha-tubulin levels, confirmed that class III beta-tubulin expression was independently correlated with progression-free survival (P = 0.04) and overall survival (P = 0.012). CONCLUSIONS: These findings suggest that a high level of expression of class III beta-tubulin in tumor cells is associated with resistance to vinorelbine and a poor prognosis in patients with NSCLC receiving vinorelbine-based chemotherapy. 相似文献
89.
Simon P. Jochems Karin de Ruiter Carla Solrzano Astrid Voskamp Elena Mitsi Elissavet Nikolaou Beatriz F. Carniel Sherin Pojar Esther L. German Jesús Rein Alessandra Soares-Schanoski Helen Hill Rachel Robinson Angela D. Hyder-Wright Caroline M. Weight Pascal F. Durrenberger Robert S. Heyderman Stephen B. Gordon Hermelijn H. Smits Britta C. Urban Jamie Rylance Andrea M. Collins Mark D. Wilkie Lepa Lazarova Samuel C. Leong Maria Yazdanbakhsh Daniela M. Ferreira 《The Journal of clinical investigation》2022,132(11)
90.
Ulrich Hegerl Roland Mergl Christian Sander Jens Dietzel Istvan Bitter Koen Demyttenaere Ricardo Gusmão Ana González-Pinto Iñaki Zorrilla Adriana García Alocén Victor Perez Sola Eduard Vieta Georg Juckel Ulrich S. Zimmermann Michael Bauer Pascal Sienaert Sónia Quintão Marc-Andreas Edel Michael Kluge 《European neuropsychopharmacology》2018,28(1):185-194
Based on many clinical and preclinical findings the ‘vigilance regulation model of mania’ postulates that an unstable regulation of wakefulness is a pathogenetic factor in both mania and Attention Deficit Hyperactivity Disorder (ADHD) and induces hyperactivity and sensation seeking as an autoregulatory attempt to stabilize wakefulness. Accordingly, stimulant medications with their vigilance stabilizing properties could have rapid antimanic effects similar to their beneficial effects in ADHD. The MEMAP study – a multi-center, double-blind, placebo-controlled and randomized clinical trial (RCT) – assessed the antimanic efficacy and safety of a 2.5-day treatment with methylphenidate (20–40 mg/day). Of 157 screened patients with acute mania, 42 were randomly assigned to receive 20–40 mg per day of methylphenidate in one or two applications, or placebo. The primary outcome was the change in Young Mania Rating Scale (YMRS) sum scores from baseline to day 2.5 in the methylphenidate group compared to the placebo group. A group sequential design was chosen to justify early RCT termination based on efficacy or futility at an interim analysis after inclusion of 40 patients. In the interim analysis, the change from baseline in the YMRS total score at day 2.5 was not significantly different between both groups (F(1,37)=0.23; p=0.64). Thus, futility was declared for methylphenidate and the RCT was stopped. In summary, although methylphenidate was well tolerated and safe in the full analysis set, it failed to show efficacy in the treatment of acute mania. Trial registration: clinicaltrials.gov (URL: http://www.clinicaltrials.gov; registration number: NCT01541605). 相似文献