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101.
Ba2+ differentially inhibits the Rb+ efflux promoting and the vasorelaxant effects of levcromakalim and minoxidil sulfate in rat isolated aorta 总被引:1,自引:0,他引:1
Ulrich Quast Yves Baumlin Cornelia Löffler 《Naunyn-Schmiedeberg's archives of pharmacology》1995,353(1):86-93
The K+ channel openers activate ATP-sensitive K+ channels (KATP) in vascular smooth muscle and induce relaxation. In this study, the relationship between these two effects was examined in rings of rat aorta using levcromakalim and minoxidil sulfate as the openers and Ba2+ as the K+ channel blocker; K+ channel opening was assessed by determining the rate constant of 86Rb+ efflux from the preparation.Ba2+ inhibited the 86Rb+ efflux stimulated by levcromakalim in a noncompetitive manner with an IC50 value of 29 M and a Hill-coefficient of 1.2. At concentrations > 300 M, Ba2+ increased the tension of rat aortic rings concentration-dependently. Levcromakalim relaxed contractions to Ba2+ (0.5 and 1 mM) with potencies similar to those determined against KCl (25 mM) or noradrenaline as spasmogens (EC50 values 15–40 nM). The vasorelaxant effect against Ba2+ was inhibited by the KATP channel blockers, glibenclamide and tedisamil, and abolished in depolarizing medium (55 mM KCl). At 3 mM Ba2+, levcromakalim was still able to transiently induce complete relaxation; however, within 1 h oscillations in tension developed, leading to a stable level of only 15% relaxation. A similar level of relaxation was achieved against 10 mM Ba2+ whereas the combination of 0.5 mM Ba2+ and 3 M tedisamil blocked the relaxant effect of levcromakalim completely. With minoxidil sulfate as the KATP channel opener the results of the 86Rb+ efflux and tension experiments were similar to those obtained with levcromakalim.It is concluded that Ba2+ is more potent in inhibiting the K+ channel opening than the vasorelaxant effects of the openers. On the basis of the 86Rb+ efflux experiments it is estimated that at least 97% of the channels opened by the activators can be blocked without major effects on vasorelaxation suggesting a dissociation between the two effects. However, if the block is pushed to extremes ( 99.95%) the vasorelaxant effect of the openers is also abolished suggesting a link between both effects. This paradoxon remains to be solved. 相似文献
102.
Buolamwini John K. Raghavan Krishnamchari Fesen Mark R. Pommier Yves Kohn Kurt W. Weinstein John N. 《Pharmaceutical research》1996,13(12):1892-1895
Purpose. A QSAR study based on electrotopological state (E-state) indices was conducted for a series of flavone HIV-1 integrase inhibitors to guide drug design.
Methods. E-state indices formulated to encode electronic and topological information for each skeletal atom in a molecule (Kier and Hall Pharm. Res. 7:801–807 (1990)) were calculated using the Molconn-X program, and partial least squares (PLS) multivariate regression was used to derive QSAR models.
Results. Predictive models with correlation coefficients (r2) of 0.98 (3 PLS components) and 0.99 (5 PLS components) and corresponding cross-validated correlation coefficients (c.v. r2) of 0.51 and 0.73, were obtained for inhibition of cleavage and integration, respectively, with one molecule omitted from the analysis.
Conclusions. E-state indices at C6, C3, C5, C5, and O4 were found to be more important for prediction of activity than those for any of the other 12 flavone skeletal atoms that are common to the molecules in the data set. 相似文献
103.
Bernard Tetu Yves Fradet Pierre Allard Chantal Veilleux Nancy Roberge Pascale Bernard 《The Journal of urology》1996,155(5):1784-1788
Purpose
The usefulness of the expression of HER2/neu oncoprotein and of p53 and Rb suppressor gene product as predictors of tumor recurrence was evaluated by using a bank of prospectively collected primary papillary bladder tumors treated initially only by transurethral resection.Materials and Methods
The expression of HER-2/neu oncoprotein and of p53 and Rb suppressor genes was evaluated by immunohistochemistry in 256, 265 and 74 specimens of primary Ta/T1 superficial bladder tumors obtained from patients enrolled in a prospective study from 1990 to 1992. Survival analysis was used to evaluate the association between time to first recurrence and expression of each marker, the follow-up period extending to March 1994. Immunostaining for p53 and HER-2/neu was performed on paraffin-embedded tissue and, for Rb, on frozen tissue only.Results
Her-2/neu was expressed in 21 (8.2 percent) cases and p53 in 39 cases (14.7 percent); Rb expression was altered in 12 (16.2 percent). In this study, p53 expression was only related to earlier recurrence in a univariate analysis. Multivariate analysis, however, failed to recognize p53 expression as an independent predictor of recurrence.Conclusions
Our study demonstrate the low prevalence of HER2/neu, p53 and altered Rb expression in superficial TCC at initial resection. Only p53 expression was significantly associated with an earlier first tumor recurrence, but this association was not independent of other prognostic factors. 相似文献104.
S. Larry Goldenberg Laurence H. Klotz John Srigley Michael A.S. Jewett David Mador Yves Fradet Jack Barkin Joseph Chin Jean-Marie Paquin Martin J. Bullock Suzanne Laplante 《The Journal of urology》1996,156(3):873-877
Purpose
A prospective, multicenter, randomized study was done to test the hypothesis that neoadjuvant androgen withdrawal decreases the incidence of positive margins following radical prostatectomy for localized prostate cancer.Materials and Methods
Observations were made of 213 patients randomized to undergo radical prostatectomy alone (101) or to receive a 12-week course of 300 mg. cyproterone acetate daily followed by surgery (112). Groups were similar at baseline in terms of clinical stage, serum prostate specific antigen and Gleason score. Of 192 patients available for efficacy analysis 9 had stage T1b, 8 stage T1c, 63 stage T2a, 36 stage T2b and 76 stage T2c disease.Results
One or more positive surgical margins were found in 59 of 91 patients (64.8 percent) in the surgery only group compared to 28 of 101 (27.7 percent) in the cyproterone acetate group (p = 0.001). Patients who received preoperative therapy had a statistically significantly lower rate of apical margin involvement than those who did not (17.8 versus 47.8 percent, respectively, p less than 0.0001). There was no statistically significant difference in surgical (p = 0.8645) or postoperative (p = 0.173) complications between the 2 groups.Conclusions
Neoadjuvant androgen withdrawal with a 12-week course of 300 mg. cyproterone acetate daily results in a lower rate of positive margins without adversely affecting postoperative recovery. The impact on patient survival will be determined by long-term followup. 相似文献105.
Yves Bécouarn Binh Nguyen Bui René Brunet Alain Ravaud 《Cancer chemotherapy and pharmacology》1991,29(2):159-163
Summary A total of 2,238 new cancer patients were treated in our institution in 1988; among the 423 (18.9%) who were>70 years old, 51 underwent chemotherapy. The median age was 75.8 years, and the Karnofsky performance status (KPS) was 70% for 40 patients. Malignancies were hematopoietic in 24 cases (47%) and digestive in 15 patients (29%), and 12 subjects (24%) had other types of cancers. The first chemotherapy course was given at the full dose to 23/51 (45.1%) patients. The drug dose was reduced for 28/51 (54.9%) patients, due in 25 cases to the subjects being>70 years old. Neither age, KPS, pretreatment assessment, nor cancer extent was correlated with the modifications made to the first cycle. An overall toxicity of grade 3+4 (WHO grading scale) was noted in 10 subjects (19.6%). Although these elderly patients were probably selected, analysis of their charts did not evidence an increase in chemotherapy toxicity, regardless of the dose they received.Presented at the EORTC Pharmacokinetics and Metabolism Group Meeting, Bordeaux, November 1990 相似文献
106.
107.
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
108.
Daniela S Pontes Fernanda A Dorella Luciana A Ribeiro Anderson Miyoshi Yves Le Loir Alexandra Gruss Sérgio C Oliveira Philippe Langella Vasco Azevedo 《Journal of drug targeting》2003,11(8-10):489-493
The Brucella abortus ribosomal protein L7/L12 is an immunodominant antigen and an interesting candidate for the development of oral live vaccines against brucellosis. Here, a recombinant Lactococcus lactis strain producing L7/L12 under the control of nisin inducible promoter was orally administered to BALB/c mice. Significant levels of anti-L7/L12 specific IgA detected in feces revealed an induced local humoral immune response. However, serum analysis did not reveal any anti-L7/L12 antibodies suggesting the absence of a systemic response. Nevertheless, the vaccinated mice showed a partial protective immunity against B. abortus virulent strain (S2308) challenged by intraperitoneal inoculation. 相似文献
109.
Marc-David Leclair Olivier Hartmann Yves Heloury Laurent Fourcade Anne Laprie Fran?oise Mechinaud Caroline Munzer Herve Rubie 《Journal of clinical oncology》2004,22(9):1689-1695
PURPOSE: To assess the results and morbidity of treatment of children with localized pelvic neuroblastoma (NB). PATIENTS AND METHODS: All consecutive cases of localized pelvic NB registered in the French multicenter prospective studies NBL90 and NBL94 between 1990 and 1999 were reviewed. Resectability was decided on the basis of clinical and radiologic evaluation. In unresectable tumors, primary chemotherapy (combinations of carboplatin-etoposide and vincristine-cyclophosphamide-doxorubicine) was administered before surgery. RESULTS: Forty-seven children (with 26 resectable tumors and 21 unresectable) were included in this study. At the end of treatment, 31 children were in complete remission (66%). Long-term neurologic sequelae were observed in seven patients (15%), directly attributable to surgery in three cases. After a median follow-up of 48 months (range, 13 to 129 months), 44 patients are alive. Six children experienced local relapse; four of these children achieved subsequent remission. The projected overall survival and event-free survival (EFS) rates at 5 years are, respectively, 93% +/- 4% and 84% +/- 5%. Survival of children treated with preoperative chemotherapy are similar to those treated by primary surgery (80% and 88% respectively). The extent of surgical resection seemed to have no influence on the outcome (EFS rates 76% and 89% in case of gross residue and complete resection or microscopic residue, respectively). CONCLUSION: Our data confirm the excellent survival of localized pelvic NBs. Considering the efficacy of preoperative chemotherapy, patients with pelvic NB should be carefully screened for primary surgery. The risk of neurologic impairment during radical excision should be balanced with the good survival of children with minimal residual disease. 相似文献
110.
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