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91.
I Sayers J Hawley CE Stewart CK Billington A Henry JR Leighton-Davies SJ Charlton IP Hall 《British journal of pharmacology》2009,158(1):277-286
Background and purpose:
Indacaterol is a novel β2-adrenoceptor agonist in development for the treatment of chronic obstructive pulmonary disease. The aim of this study was to investigate the comparative pharmacology of indacaterol in recombinant cells expressing the common polymorphic variants of the human β2-adrenoceptor and in human primary airway smooth muscle (ASM) cells.Experimental approach:
Chinese hamster ovarian-K1 cell lines expressing high and low levels of the common human β2-adrenoceptor variants were generated [Gly16-Glu27-Val34-Thr164(GEVT), RQVT, GQVT] and also the rare GQVI variant. Human primary ASM cells were isolated from explants of trachealis muscle. Adenosine-3′,5′-cyclic-monophosphate production was used as an outcome measure.Key results:
In both the low- and high-expression recombinant GEVT ‘wild type’ cell lines indacaterol is a high-efficacy agonist. Salmeterol and formoterol were identified as low- and high-efficacy agonists, respectively, and showed similar potencies to indacaterol irrespective of the β2-adrenoceptor genotype. The I164 variant cell line was associated with a reduced capacity to generate adenosine-3′,5′-cyclic-monophosphate in response to β2-adrenoceptor agonist. In the human primary ASM cells indacaterol gave a maximal response intermediate between that of salmeterol and formoterol.Conclusions and implications:
These data demonstrate that indacaterol is a high-efficacy agonist in recombinant cell systems but acts with lower efficacy in human primary ASM cells. No marked genotype-dependent effects were observed for common variants; however, changes in I164 receptor activity were identified, which were dependent on the level of expression of β2-adrenoceptors. 相似文献92.
Denise?W?Pallett Emily?Soh Mary-Lou?Edwards Kathleen?Bodey Laurie?CK?Lau J?Ian?Cooper Peter?H?Howarth Andrew?F?Walls Hui?Wang 《Environmental health : a global access science source》2009,8(Z1):S10
Background
Wild plants harbour a variety of viruses and these have the potential to alter the composition of pollen. The potential consequences of virus infection of grasses on pollen-induced allergic disease are not known.Methods
We have collected pollen from Dactylis glomerata (cocksfoot; a grass species implicated as a trigger of allergic rhino-conjunctivitis) from Wytham Wood, Oxfordshire UK. Extracts were prepared from pollen from uninfected grass, and from grass naturally infected by the Cocksfoot streak potyvirus (CSV). Preparations of pollen from virus-infected and non-infected grasses were employed in skin testing 15 grass pollen-allergic subjects with hayfever. Allergen profiles of extracts were investigated by Western blotting for IgE with sera from allergic subjects.Results
The prevalence of CSV infection in cocksfoot grasses sampled from the study site varied significantly over an eight-year period, but infection rates of up to 70% were detected. Virus infection was associated with small alterations in the quantities of pollen proteins detected by polyacrylamide gel electrophoresis, and in the patterns of allergens identified by Western blotting with IgE from grass pollen allergic subjects. For individual subjects there were differences in potencies of standardised extracts of pollen from virus-free and virus-infected plants as assessed by skin testing, though a consistent pattern was not established for the group of 15 subjects.Conclusion
Infection rates for CSV in cocksfoot grass can be high, though variable. Virus-induced alterations in components of grass pollen have the potential to alter the allergenic potency.93.
Menne S Butler SD George AL Tochkov IA Zhu Y Xiong S Gerin JL Cote PJ Tennant BC 《Antimicrobial agents and chemotherapy》2008,52(10):3617-3632
Adefovir dipivoxil (ADV) and tenofovir disoproxil fumarate (TDF) are nucleotide analogs that inhibit the replication of wild-type hepatitis B virus (HBV) and lamivudine (3TC)-resistant virus in HBV-infected patients, including those who are coinfected with human immunodeficiency virus. The combination of ADV or TDF with other nucleoside analogs is a proposed strategy for managing antiviral drug resistance during the treatment of chronic HBV infection. The antiviral effect of oral ADV or TDF, alone or in combination with 3TC or emtricitabine (FTC), against chronic woodchuck hepatitis virus (WHV) infection was evaluated in a placebo-controlled study in the woodchuck, an established and predictive model for antiviral therapy. Once-daily treatment for 48 weeks with ADV plus 3TC or TDF plus FTC significantly reduced serum WHV viremia levels from the pretreatment level by 6.2 log10 and 6.1 log10 genome equivalents/ml serum, respectively, followed by TDF plus 3TC (5.6 log10 genome equivalents/ml), ADV alone (4.8 log10 genome equivalents/ml), ADV plus FTC (one survivor) (4.4 log10 genome equivalents/ml), TDF alone (2.9 log10 genome equivalents/ml), 3TC alone (2.7 log10 genome equivalents/ml), and FTC alone (2.0 log10 genome equivalents/ml). Individual woodchucks across all treatment groups also demonstrated pronounced declines in serum WHV surface antigen, characteristically accompanied by declines in hepatic WHV replication and the hepatic expression of WHV antigens. Most woodchucks had prompt recrudescence of WHV replication after drug withdrawal, but individual woodchucks across treatment groups had sustained effects. No signs of toxicity were observed for any of the drugs or drug combinations administered. In conclusion, the oral administration of 3TC, FTC, ADV, and TDF alone and in combination was safe and effective in the woodchuck model of HBV infection. 相似文献
94.
Krishna R Bergman A Larson P Cote J Lasseter K Dilzer S Wang A Zeng W Chen L Wagner J Herman G 《Journal of clinical pharmacology》2007,47(2):165-174
Sitagliptin (MK-0431) is an orally active, potent, and selective dipeptidyl peptidase-4 inhibitor used for the treatment of patients with type 2 diabetes mellitus. Sitagliptin has been shown to be a substrate for P-glycoprotein in preclinical studies. Cyclosporine was used as a probe P-glycoprotein inhibitor at a high dose to evaluate the potential effect of potent P-glycoprotein inhibition on single-dose sitagliptin pharmacokinetics in healthy male subjects. Eight healthy young men received a single oral 600-mg dose of cyclosporine with a single 100-mg oral sitagliptin dose and a single oral 100-mg sitagliptin dose alone in an open-label, randomized, 2-period, crossover study. Single doses of sitagliptin with or without single doses of cyclosporine were generally well tolerated. The sitagliptin AUC(0-infinity) geometric mean ratio was 1.29 with a 90% confidence interval of (1.24, 1.34). The sitagliptin Cmax geometric mean ratio was 1.68 with a 90% confidence interval of (1.35, 2.08). Cyclosporine coadministration did not appear to affect apparent sitagliptin renal clearance, t(1/2), or C(24 h), suggesting that effects of these high doses of cyclosporine are more likely due to enhanced absorption of sitagliptin, potentially through inhibition of intestinal P-glycoprotein. These results rationalize the use of a single high-dose cyclosporine as a probe inhibitor of P-glycoprotein for compound candidates whose elimination is less dependent on CYP3A4-mediated metabolism. 相似文献
95.
A majority of the aggressive, invasive bladder carcinomas have alterations in the p53 and retinoblastoma genes and pathways.
Examination of the alterations in the molecules in these pathways that regulate the cell cycle and their effects on the prognosis
of bladder cancer are areas of active research. While defects in the p53-Mdm2-p14 axis have been implicated in urothelial
cancer, perturbations in the cyclin-dependent kinases and their inhibitors have also been extensively studied in this context.
Genetic alterations of the retinoblastoma gene and aberrant post-translational modifications of its protein have also been
incriminated in invasive bladder cancer. This article reviews the individual prognostic roles of alterations in these molecules
in the context of bladder cancer. Additionally, we review findings from recent studies that are attempting to analyze these
markers in combination in an effort to construct molecular panels that can serve as more robust outcome predictors. More importantly,
alterations in these molecules are now becoming enticing targets for novel therapeutics. We also review some of these agents
that can restore the tumor cells’ altered homeostatic mechanisms, thereby having potential in transitional cell carcinoma
therapy. Future management of bladder cancer will employ validated marker panels for outcome prediction, and novel genetic
and pharmacologic agents that will be able to target molecular alterations in individual tumors based on their respective
profiles.
A.P. Mitra and M. Birkhahn contributed equally to this paper. 相似文献
96.
97.
98.
全破壁灵芝孢子治疗男性更年期综合征 总被引:3,自引:0,他引:3
目的 :探讨全破壁灵芝孢子治疗法对男性更年期综合征的疗效。方法 :通过对 138例诊断为男性更年期综合征病人分组 ,其中 80例作全破壁灵芝孢子胶囊治疗并对其临床症状 ,血睾酮、SOD、MDA水平及主观抑郁症状评分作观察 ,并与 5 8例病情相同的病人予安慰剂对照。结果 :治疗组的病人症状改善率为 74 .3% ,血睾酮水平 3周前后分别为 (131.5 1± 19.12 )mg/L与 (2 5 3.78± 2 1.4 5 )mg/L ,SOD水平 3周前后分别为 (10 6 8.3± 12 1.4 )U/ g·Hb与 (1178.1± 132 .6 )U/ g .Hb ,MDA水平 3周前后分别为 (7.6± 0 .8) μmol/L与 (5 .8± 0 .6 )μmol/L。抑郁症状评分各指标均有较大改善。 结论 :全破壁灵芝孢子胶囊是治疗男性更年期综合征的一种有效、安全的方法。 相似文献
99.
B C Tennant N Mrosovsky K McLean P J Cote B E Korba R E Engle J L Gerin J Wright G R Michener E Uhl 《Hepatology (Baltimore, Md.)》1991,13(6):1215-1221
During studies of seasonal obesity, a high frequency of hepatic neoplasms was observed in Richardson's ground squirrels. Of 12 Richardson's ground squirrels examined thoroughly, 7 had mild or moderate degrees of chronic portal hepatitis and 6 (50%) had hepatocellular carcinoma. Serological tests for hepadnavirus surface antigen, anti-core antibody and virion DNA that recognize the ground squirrel hepatitis virus of California ground squirrels (Spermophilus beecheyi) were uniformly negative. Southern blot analyses of EcoRI digests of liver cell DNA demonstrated 3.2 kb fragments that hybridized with a ground squirrel hepatitis virus-specific probe in nontumorous liver tissue from 6 of 10 ground squirrels and in hepatocellular carcinoma specimens from 2 of 5 squirrels indicating infection with a hepadnavirus related to ground squirrel hepatitis virus. Failure, however, to detect serum antibody to ground squirrel hepatitis core antigen suggested probable antigenic differences between the ground squirrel hepatitis virus of California ground squirrels and the putative Richardson's ground squirrel agent. Further studies are required to fully characterize the hepadnavirus of Richardson's ground squirrels and to determine its relationship to hepatocarcinogenesis in this species. 相似文献
100.
Claudia Cote James L. Pearle Amir Sharafkhaneh Selwyn Spangenthal 《Pulmonary pharmacology & therapeutics》2009,22(1):44-49
BackgroundChronic obstructive pulmonary disease (COPD) is a growing public health problem that has increased in recent years. It similarly affects men and women, especially those who smoke. The goals of COPD pharmacotherapy are to improve lung function, reduce symptoms, prevent exacerbations, and improve patients' health status. Bronchodilators are the foundation of treatment for COPD, and the long-acting β2-agonists formoterol and salmeterol are both indicated for regular use by patients with stable COPD.ObjectiveA clinical study was conducted to compare the onset of bronchodilator effects following treatment with formoterol 12 μg administered twice-daily (BID) or salmeterol 50 μg BID. The trial also assessed whether the bronchodilator effects of treatment resulted in significant differences in clinical response.MethodsThis was a randomized, multicenter, open-label, parallel-group study of formoterol 12 μg BID versus salmeterol 50 μg BID, both administered for 28 days. Patients were current or previous smokers aged ≥40 years, with a diagnosis of stable COPD. The primary efficacy variable was change from baseline in forced expiratory volume in 1 s (FEV1) 5 min after drug administration on day 28. Secondary efficacy variables included changes from baseline in the 6-min walk test (6MWT) and rescue medication use. The primary variable was assessed by analysis of covariance, with baseline FEV1 as the covariate.ResultsA total of 270 patients were randomized to formoterol 12 μg BID (n = 137) or salmeterol 50 μg BID (n = 133). In the intent-to-treat population the least square (LS) mean change from baseline in FEV1 at 5 min postdose on day 28 was 0.13 L in the formoterol group compared with 0.07 L in the salmeterol group (P = 0.022). At 30 min postdose on day 28, the LS mean change from baseline in FEV1 was 0.17 L in the formoterol group compared with 0.07 L in the salmeterol group (P < 0.001). Similar changes were reported at 60 min postdose (0.19 L for the formoterol group versus 0.13 L for the salmeterol group, P = 0.069). Patients in the formoterol group walked longer distances in the 6MWT and used less rescue medication compared with patients in the salmeterol group, although the differences were not statistically significant.ConclusionsSignificantly greater improvements from baseline in FEV1 were observed at 5 and 30 min postdose with formoterol 12 μg compared with salmeterol 50 μg after 28 days of treatment. Numeric improvements in the 6MWT and rescue medication use were also observed with formoterol. 相似文献