共查询到20条相似文献,搜索用时 15 毫秒
1.
2.
The peroxiredoxins (Prxs) constitute a very large and highly conserved family of thiol-based peroxidases that has been discovered only very recently. We consider here these enzymes through the angle of their discovery, and of some features of their molecular and physiological functions, focusing on complex phenotypes of the gene mutations of the 2-Cys Prxs subtype in yeast. As scavengers of the low levels of H2O2 and as H2O2 receptors and transducers, 2-Cys Prxs have been highly instrumental to understand the biological impact of H2O2, and in particular its signaling function. 2-Cys Prxs can also become potent chaperone holdases, and unveiling the in vivo relevance of this function, which is still not established, should further increase our knowledge of the biological impact and toxicity of H2O2. The diverse molecular functions of 2-Cys Prx explain the often-hard task of relating them to peroxiredoxin genes phenotypes, which underscores the pleiotropic physiological role of these enzymes and complex biologic impact of H2O2. 相似文献
3.
Zul Kamal Farhat Ullah Muhammad Ayaz Abdul Sadiq Sajjad Ahmad Anwar Zeb Abid Hussain Muhammad Imran 《Biological research》2015,48(1)
Background
Atriplex laciniata L. was investigated for phenolic, flavonoid contents, antioxidant, anticholinesterase activities, in an attempt to explore its effectiveness in Alzheimer’s and other neurological disorders. Plant crude methanolic extract (Al.MeF), subsequent fractions; n-hexane (Al.HxF), chloroform (Al.CfF), ethyl acetate (Al.EaF), aqueous (Al.WtF), Saponins (Al.SPF) and Flavonoids (Al.FLVF) were investigated for DPPH, ABTS and H2O2 free radical scavenging activities. Further these extracts were subjected to acetylcholinesterase (AChE) & butyrylcholinesterase (BChE) inhibitory activities using Ellman’s assay. Phenolic and Flavonoid contents were determined and expressed in mg Gallic acid GAE/g and Rutin RTE/g of samples respectively.Results
In DPPH free radicals scavenging assay, Al.FLVF, Al.SPF and Al.MeF showed highest activity causing 89.41 ± 0.55, 83.37 ± 0.34 and 83.37 ± 0.34% inhibition of free radicals respectively at 1 mg/mL concentration. IC50 for these fractions were 33, 83 and 82 μg/mL respectively. Similarly, plant extracts showed high ABTS scavenging potential, i.e. Al.FLVF (90.34 ± 0.55), Al.CfF (83.42 ± 0.57), Al.MeF (81.49 ± 0.60) with IC50 of 30, 190 and 70 μg/ml respectively. further, H2O2 percent scavenging was highly appraised in Al.FLVF (91.29 ± 0.53, IC50 75), Al.SPF (85.35 ± 0.61, IC50 70) and Al.EaF (83.48 ± 0.67, IC50 270 μg/mL). All fractions exhibited concentration dependent AChE inhibitory activity as; Al.FLVF, 88.31 ± 0.57 (IC50 70 μg/mL), Al.SPF, 84.36 ± 0.64 (IC50 90 μg/mL), Al.MeF, 78.65 ± 0.70 (IC50 280 μg/mL), Al.EaF, 77.45 ± 0.46 (IC50 270 μg/mL) and Al.WtF 72.44 ± 0.58 (IC50 263 μg/mL) at 1 mg/mL. Likewise the percent BChE inhibitory activity was most obvious in Al.FLVF 85.46 ± 0.62 (IC50 100 μg/mL), Al.CfF 83.49 ± 0.46 (IC50 160 μg/mL), Al.MeF 82.68 ± 0.60 (IC50 220 μg/mL) and Al.SPF 80.37 ± 0.54 (IC50 120 μg/mL).Conclusions
These results stipulate that A. laciniata is enriched with phenolic and flavonoid contents that possess significant antioxidant and anticholinestrase effects. This provide pharmacological basis for the presence of compounds that may be effective in Alzheimer’s and other neurological disorders. 相似文献4.
Cervical cancer is the most common cancer amongst females in India and is associated with high risk HPVs, reactive oxygen species (ROS), and excessive inflammation in most cases. ROS in turn affects the expression of pro- and anti-apoptotic proteins. The objective of the present study was to elucidate the effect of hydrogen peroxide (H(2)O(2)) on apoptotic signaling molecules in vitro. HeLa cell line expresses the Human papilloma virus - 18, E6 oncoprotein which causes the ubiquitin mediated degradation of p53 protein and is thus p53 deficient. p53 is known to act as a cellular stress sensor and triggers apoptosis. p73, a member of the p53 family also induces apoptosis in response to DNA damaging agents but unlike p53, it is infrequently mutated in human tumors. We demonstrate here, that in HeLa cells, apoptosis is triggered by H(2)O(2) via the mitochondrial pathway involving upregulation of p73, and its downstream target Bax. This was accompanied by upregulation of ERK, JNK, c-Myc, Hsp-70 and down regulation of anti-apoptotic Bcl-XL, release of cytochrome c from mitochondria and activation of caspases-9 and -3. 相似文献
5.
Helen J Ambrose Rachael M Lawrance Carl J Cresswell Mitchell Goldman Deborah A Meyers Eugene R Bleecker 《Respiratory research》2012,13(1):37
Background
Evidence suggests that variation in the length of the poly-C repeat in the 3′ untranslated region (3′UTR) of the β2-adrenergic receptor gene (ADRB2) may contribute to interindividual variation in β-agonist response. However, methodology in previous studies limited the assessment of the effect of sequence variation in the context of poly-C repeat length. The objectives of this study were to design a novel genotyping method to fully characterize sequence variation in the ADRB2 3′UTR poly-C repeat in asthma patients treated with inhaled corticosteroid and long-acting β2-adrenergic agonist (ICS/LABA) combination therapy, and to analyze the effect of the poly-C repeat polymorphism on clinical response.Methods
In 2,250 asthma patients randomized to treatment with budesonide/formoterol or fluticasone/salmeterol in a six-month study (AstraZeneca study code: SD-039-0735), sequence diversity in the ADRB2 poly-C repeat region was determined using a novel sequencing-based genotyping method. The relationship between the poly-C repeat polymorphism and the incidence of severe asthma exacerbations, and changes in pulmonary function and asthma symptoms from baseline to the average during the treatment period, were analyzed.Results
Poly-C repeat genotypes were assigned in 97% (2,192/2,250) of patients. Of the 13 different poly-C repeat alleles identified, six alleles occurred at a frequency of >5% in one or more population in this study. The repeat length of these six common alleles ranged from 10 to 14 nucleotides. Twelve poly-C repeat genotypes were observed at a frequency of >1%. No evidence of an association between poly-C repeat genotype and the incidence of severe asthma exacerbations was observed. Patients’ pulmonary function measurements improved and asthma symptoms declined when treated with ICS/LABA combination therapy regardless of poly-C repeat genotype.Conclusions
The extensive sequence diversity present in the poly-C repeat region of the ADRB2 3′UTR did not predict therapeutic response to ICS/LABA therapy. 相似文献6.
Yakubenko VP Belevych N Mishchuk D Schurin A Lam SC Ugarova TP 《Experimental cell research》2008,314(14):2569-2578
Integrin αDβ2 (CD11d/CD18) is a multiligand macrophage receptor with recognition specificity identical to that of the major myeloid cell-specific integrin αMβ2 (CD11b/CD18, Mac-1). Despite its prominent upregulation on inflammatory macrophages, the role of αDβ2 in monocyte and macrophage migration is unknown. In this study, we have generated model and natural cell lines expressing different densities of αDβ2 and examined their migration to various extracellular matrix proteins. When expressed at a low density, αDβ2 on the surface of recombinant HEK293 cells and murine IC-21 macrophages cooperates with β1/β3 integrins to support cell migration. However, its increased expression on the αDβ2-expressing HEK293 cells and its upregulation by PMA on the IC-21 macrophages result in increased cell adhesiveness and inhibition of cell migration. Furthermore, ligation of αDβ2 with anti-αD blocking antibodies restores β1/β3-driven cell migration by removing the excess αDβ2-mediated adhesive bonds. Consistent with in vitro data, increased numbers of inflammatory macrophages were recovered from the inflamed peritoneum of mice after the administration of anti-αD antibody. These results demonstrate that the density of αDβ2 is critically involved in modulating macrophage adhesiveness and their migration, and suggest that low levels of αDβ2 contribute to monocyte migration while αDβ2 upregulation on differentiated macrophages may facilitate their retention at sites of inflammation. 相似文献
7.
Possibilities of the linear-polarized infrared (IR-LD) spectroscopy of oriented colloid suspensions in nematic liquid crystals, for structural and local structural elucidation for first time are demonstrated of inorganic compounds and glasses. The advantages of the method for tellurite and borate glasses are shown. The IR-band assignment of the typical local structural units in the glasses are proposed by a comparison with the IR-characteristics of appropriate crystalline analogues as α-TeO2, V2O5, MoO3 · H2O and its high temperature form. The IR-spectroscopic characteristics of BO3, BO4 and boroxol ring are elucidated, using crystalline β-BaB2O4, SrB4O7, H3BO3 and B2O3 as model systems, where the structural moieties have been refined by single crystal X-ray diffraction. 相似文献
8.
Background
Rumex species are traditionally used for the treatment of neurological disorders including headache, migraine, depression, paralysis etc. Several species have been scientifically validated for antioxidant and anticholinestrase potentials. This study aims to investigate Rumex hastatus D. Don crude methanolic extract, subsequent fractions, saponins and flavonoids for acetylcholinestrase, butyrylcholinestrase inhibition and diverse antioxidant activities to validate its folkloric uses in neurological disorders. Rumex hastatus crude methanolic extract (Rh. Cr), subsequent fractions; n-hexane (Rh. Hex), chloroform (Rh. Chf), ethyl acetate (Rh. EtAc), aqueous fraction (Rh. Aq), crude saponins (Rh. Sp) and flavonoids (Rh. Fl) were investigated against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) at various concentrations (125, 250, 500, 1000 μg/mL) using Ellman’s spectrophotometric analysis. Antioxidant potentials of Rh. Sp and Rh. Fl were evaluated using DPPH, H2O2 and ABTS free radical scavenging assays at 62.5, 125, 250, 500, 1000 μg/mL.Results
All the test samples showed concentration dependent cholinesterase inhibition and radicals scavenging activity. The AChE inhibition potential of Rh. Sp and Rh. Fl were most prominent i.e., 81.67 ± 0.88 and 91.62 ± 1.67 at highest concentration with IC50 135 and 20 μg/mL respectively. All the subsequent fractions exhibited moderate to high AChE inhibition i.e., Rh. Cr, Rh. Hex, Rh. Chf, Rh. EtAc and Rh. Aq showed IC50 218, 1420, 75, 115 and 1210 μg/mL respectively. Similarly, against BChE various plant extracts i.e., Rh. Sp, Rh. Fl, Rh. Cr, Rh. Hex, Rh. Chf, Rh. EtAc and Rh. Aq resulted IC50 165, 175, 265, 890, 92, 115 and 220 μg/mL respectively. In DPPH free radical scavenging assay, Rh. Sp and Rh. Fl showed comparable results with the positive control i.e., 63.34 ± 0.98 and 76.93 ± 1.13% scavenging at 1 mg/mL concentration (IC50 312 and 104 μg/mL) respectively. The percent ABTS radical scavenging potential exhibited by Rh. Sp and Rh. Fl (1000 μg/mL) were 82.58 ± 0.52 and 88.25 ± 0.67 with IC50 18 and 9 μg/mL respectively. Similarly in H2O2 scavenging assay, the Rh. Sp and Rh. Fl exhibited IC50 175 and 275 μg/mL respectively.Conclusion
The strong anticholinesterase and antioxidant activities of Rh. Sp, Rh. Fl and various fractions of R. hastatus support the purported ethnomedicinal uses and recommend R. hastatus as a possible remedy for the treatment of AD and neurodegenerative disorders. 相似文献9.
Summary In sepsis tissue O2 uptake may be abnormally limited because of a depressed O2 consumption/O2 transport relationship. This study has been performed to assess patterns of O2 consumption, CO2 production and O2 transport in septic patients undergoing total parenteral nutrition; more in particular, this study has investigated the interdependence between the patterns of blood O2 uptake and simultaneous CO2 release, and the availability of substrates (amino acids, glucose and fat). It has been shown that the O2 consumption/O2 transport relationship is significantly influenced by the exogenous amino acid load, which tends to increase O2 uptake and O2 consumption at any given O2 transport, thus suggesting a favourable effect of amino acid administration on energy metabolism. The data on CO2 production and CO2 release, in addition to reconfirming the results of previous studies, have shown that the changes in O2 uptake and in CO2 production mediated by substrate doses have a quantifiable impact on blood O2-CO2 exchange interactions. 相似文献
10.
The severity of the incidence of the fungal disease, potato scab, varies with different soil groups at the same soil pH. At a soil pH of 5.3, potato scab is easily controlled in soils of western Hokkaido (soil group A) by simply decreasing soil pH, but in soils from eastern Hokkaido (soil group B) it is not so easily controlled. The difference appears to be due to higher levels and exchangeable aluminium in Group A.Addition of sufficient aluminium or ferrous sulfate to a group B soil decreased the incidence of potato scab in a field experiment. Higher levels of aluminium sulfate depressed crop production. It is concluded that aluminium ions control the incidence of potato scab in acid soils. It is suggested that, in soils with low exchange acidity Y1, potato scab can be controlled by adding sufficient aluminium to increase their exchange acidity Y1 to above 7–8. 相似文献
11.
Xibao Wang Shengyang Zhou Xiaoyang Wu Qinguo Wei Yongquan Shang Guolei Sun Xuesong Mei Yuehuan Dong Weilai Sha Honghai Zhang 《Ecology and evolution》2021,11(21):15077
The high‐altitude environment may drive vertebrate evolution in a certain way, and vertebrates living in different altitude environments might have different energy requirements. We hypothesized that the high‐altitude environment might impose different influences on vertebrate mitochondrial genomes (mtDNA). We used selection pressure analyses and PIC (phylogenetic independent contrasts) analysis to detect the evolutionary rate of vertebrate mtDNA protein‐coding genes (PCGs) from different altitudes. The results showed that the ratio of nonsynonymous/synonymous substitutions (dN/dS) in the mtDNA PCGs was significantly higher in high‐altitude vertebrates than in low‐altitude vertebrates. The seven rapidly evolving genes were shared by the high‐altitude vertebrates, and only one positive selection gene (ND5 gene) was detected in the high‐altitude vertebrates. Our results suggest the mtDNA evolutionary rate in high‐altitude vertebrates was higher than in low‐altitude vertebrates as their evolution requires more energy in a high‐altitude environment. Our study demonstrates the high‐altitude environment (low atmospheric O2 levels) drives vertebrate evolution in mtDNA PCGs. 相似文献
12.
Emma L. Woods Irina V. Grigorieva Adam C. Midgley Charlotte V.M. Brown Yueh-an Lu Aled O. Phillips Timothy Bowen Soma Meran Robert Steadman 《The Journal of biological chemistry》2021,297(3)
Progressive fibrosis leads to loss of organ function and affects many organs as a result of excessive extracellular matrix production. The ubiquitous matrix polysaccharide hyaluronan (HA) is central to this through association with its primary receptor, CD44, which exists as standard CD44 (CD44s) or multiple splice variants. Mediators such as profibrotic transforming growth factor (TGF)-β1 and proinflammatory interleukin (IL)-1β are widely associated with fibrotic progression. TGF-β1 induces myofibroblast differentiation, while IL-1β induces a proinflammatory fibroblast phenotype that promotes fibroblast binding to monocyte/macrophages. CD44 expression is essential for both responses. Potential CD44 splice variants involved, however, are unidentified. The TGF-β1-activated CD44/epidermal growth factor receptor complex induces differentiation of metastatic cells through interactions with the matrix metalloproteinase inducer, CD147. This study aimed to determine the CD44 variants involved in TGF-β1- and IL-1β-mediated responses and to investigate the potential profibrotic role of CD147. Using immunocytochemistry and quantitative PCR, standard CD44s were shown to be essential for both TGF-β1-induced fibroblast/myofibroblast differentiation and IL-1β-induced monocyte binding. Co-immunoprecipitation identified that CD147 associated with CD44s. Using CD147-siRNA and confocal microscopy, we also determined that incorporation of the myofibroblast marker, αSMA, into F-actin stress fibers was prevented in the absence of CD147 and myofibroblast-dependent collagen gel contraction was inhibited. CD147 did not associate with HA, but removal of HA prevented the association of CD44s with CD147 at points of cell–cell contact. Taken together, our data suggest that CD44s/CD147 colocalization is essential in regulating the mechanical tension required for the αSMA incorporation into F-actin stress fibers that regulates myofibroblast phenotype. 相似文献
13.
Paul M. O’Byrne Tony D’Urzo Ekkehard Beck Matja? Fle?ar Martina Gahlemann Lorna Hart Zuzana Blahova Robert Toorawa Kai-Michael Beeh 《Respiratory research》2015,16(1)
Background
Olodaterol is a novel, inhaled long-acting β2-agonist (LABA) with >24-hour duration of action investigated in asthma and chronic obstructive pulmonary disease.Methods
Two multicentre studies examined the efficacy and safety of 4 weeks’ once-daily (QD) olodaterol (2, 5, 10 and 20 μg, with background inhaled corticosteroids) in patients with asthma. One randomised, double-blind, parallel-group study (1222.6; 296 patients) administered treatment in the morning. Pulmonary function tests (PFTs) were performed pre-dose (trough) and ≤3 hours post-dose (weeks 1 and 2), and ≤6 hours post-dose after 4 weeks; primary end point was trough forced expiratory volume in 1 second (FEV1) response (change from baseline mean FEV1) after 4 weeks. A second randomised, double-blind, placebo- and active-controlled (formoterol 12 μg twice-daily) incomplete-block crossover study (1222.27; 198 patients) administered QD treatments in the evening. PFTs were performed over a 24-hour dosing interval after 4 weeks; primary end point was FEV1 area under the curve from 0–24 hours (AUC0–24) response (change from study baseline [mean FEV1] after 4 weeks).Results
Study 1222.6 showed a statistically significant increase in trough FEV1 response with olodaterol 20 μg (0.147 L; 95 % confidence interval [CI]: 0.059, 0.234; p = 0.001) versus placebo, with more limited efficacy and no evidence of dose response compared to placebo across the other olodaterol doses (2, 5 and 10 μg). Study 1222.27 demonstrated increases in FEV1 AUC0–24 responses at 4 weeks with all active treatments (p < 0.0001); adjusted mean (95 % CI) differences from placebo were 0.140 (0.097, 0.182), 0.182 (0.140, 0.224), 0.205 (0.163, 0.248) and 0.229 (0.186, 0.272) L for olodaterol 2, 5, 10 and 20 μg, respectively, and 0.169 (0.126, 0.211) for formoterol, providing evidence of increased efficacy with higher olodaterol dose. Olodaterol was generally well tolerated, with a few events associated with known sympathomimetic effects, mainly with 20 μg.Conclusions
The LABA olodaterol has >24-hour duration of action. In patients with asthma, evidence of bronchodilator efficacy was demonstrated with statistically and clinically significant improvements in the primary end point of trough FEV1 response measured in clinics over placebo for the highest administered dose of 20 μg in Study 1222.6, and statistically and clinically significant improvements versus placebo in FEV1 AUC0–24 responses at 4 weeks for all doses tested in Study 1222.27, which also exhibited a dose response. Bronchodilator efficacy was seen over placebo for all olodaterol doses for morning and evening peak expiratory flow in both studies. All doses were well tolerated.Trial registrations
(1222.6) and NCT00467740 (1222.27). NCT01013753Electronic supplementary material
The online version of this article (doi:10.1186/s12931-015-0249-8) contains supplementary material, which is available to authorized users. 相似文献14.
Peidong Han Xiao-Hai Zhou Nannan Chang Cheng-Lu Xiao Shouyu Yan He Ren Xin-Zhuang Yang Mei-Ling Zhang Qing Wu Boyang Tang Ju-Peng Diao Xiaojun Zhu Chuanmao Zhang Chuan-Yun Li Heping Cheng Jing-Wei Xiong 《Cell research》2014,24(9):1091-1107
While the adult human heart has very limited regenerative potential, the adult zebrafish heart can fully regenerate after 20% ventricular resection. Although previous reports suggest that developmental signaling pathways such as FGF and PDGF are reused in adult heart regeneration, the underlying intracellular mechanisms remain largely unknown. Here we show that H2O2 acts as a novel epicardial and myocardial signal to prime the heart for regeneration in adult zebrafish. Live imaging of intact hearts revealed highly localized H2O2 (∼30 μM) production in the epicardium and adjacent compact myocardium at the resection site. Decreasing H2O2 formation with the Duox inhibitors diphenyleneiodonium (DPI) or apocynin, or scavenging H2O2 by catalase overexpression markedly impaired cardiac regeneration while exogenous H2O2 rescued the inhibitory effects of DPI on cardiac regeneration, indicating that H2O2 is an essential and sufficient signal in this process. Mechanistically, elevated H2O2 destabilized the redox-sensitive phosphatase Dusp6 and hence increased the phosphorylation of Erk1/2. The Dusp6 inhibitor BCI achieved similar pro-regenerative effects while transgenic overexpression of dusp6 impaired cardiac regeneration. H2O2 plays a dual role in recruiting immune cells and promoting heart regeneration through two relatively independent pathways. We conclude that H2O2 potentially generated from Duox/Nox2 promotes heart regeneration in zebrafish by unleashing MAP kinase signaling through a derepression mechanism involving Dusp6. 相似文献
15.
16.
The effectiveness of the metal oxide nanoparticles viz. CuO and Fe2O3 as antibacterial agents against multidrug resistant biofilm forming bacteria was evaluated. CuO nanoparticles were also experimented for antibiofilm and time kill assay. The CuO displayed maximum antibacterial activity with zone of inhibition of (22 ± 1) mm against methicillin resistant Staphylococcus aureus (MRSA) followed by Escherichia coli (18 ± 1) mm. The Fe2O3 showed the zone of inhibition against MRSA of (14 ± 1) mm followed by E. coli (12 ± 1) mm. CuO proved to be more toxic than Fe2O3 nanoparticles showing significantly high antibacterial activity and found to possess dose dependent antibiofilm properties. 相似文献
17.
Effects of specific versus cross-training on running performance 总被引:1,自引:0,他引:1
Carl Foster Lisa L. Hector Ralph Welsh Mathew Schrager Megan A. Green Ann C. Snyder 《European journal of applied physiology and occupational physiology》1995,70(4):367-372
The cross-training (XT) hypothesis suggests that despite the principle of specificity of training, athletes may improve performance in one mode of exercise by training using another mode. To test this hypothesis we studied 30 well-trained individuals (10 men, 20 women) in a randomized longitudinal trail. Subjects were evaluated before and after 8 weeks of enhanced training (+10%/week), accomplished by adding either running (R) or swimming (XT) to baseline running, versus continued baseline running (C). Both R ( – 26.4s) and XT (– 13.2s) improved time trial (3.2 km) performance, whereas C did not (– 5.4s). There were no significant changes during treadmill running in maximum oxygen uptake (O2peak; – 0.2, – 6.0, and + 2.7%), steady state submaximal O2 at 2.68 m · s–1 ( – 1.2, – 3.3 and + 0.2 ml · kg–1 · min–1), velocity at O2peak (+0.05, +0.25 and +0.09 m · s–1) or accumulated O2 deficit (+ 11.2, – 6.1 and + 9.4%) in the R, XT or C groups, respectively. There was a significant increase in velocity associated with a blood lactate concentration of 4 mmol · l–1 in R but not in XT or C ( + 0.32, + 0.07 and + 0.08 m · s–1). There were significant changes in arm crank O2peak ( + 5%) and arm crank O2 at 4 mmol · l–1 ( + 6.4%) in XT. There was no significant changes in arm crank O2peak ( + 1.3 and – 7.7%) or arm crank O2 at 4 mmol · l–1 ( + 0.8 and + 0.4%) in R or C, respectively. The data suggest that muscularly non-similar XT may contribute to improved running performance but not to the same degree as increased specific tranining. 相似文献
18.
Piotr Kuna Yavor Ivanov Vasily Ivanovich Trofimov Takefumi Saito Ola Beckman Thomas Bengtsson Carin Jorup Fran?ois Maltais 《Respiratory research》2013,14(1):64
Background
We investigated the efficacy and safety of AZD3199, a novel inhaled ultra-LABA, with the main aim of establishing a dose that would maintain 24-hour bronchodilation in patients with COPD.Methods
Patients (n = 329) were randomized to AZD3199 (200, 400 or 800 μg o.d.), formoterol (9 μg b.i.d.) or placebo via Turbuhaler® in a parallel group study. The primary objective of the study was to compare the clinical efficacy of three doses of AZD3199 inhaled once daily with 9 μg formoterol twice daily and placebo, over a 4-week treatment period in adults with moderate-to-severe COPD. After 4 weeks, peak (0–4 h) and trough (24–26 h) forced expiratory volume in 1 second (FEV1) were assessed as the primary efficacy outcome variables.Results
All AZD3199 doses significantly increased mean peak and trough FEV1 versus placebo (106–171 ml and 97–110 ml increases, respectively), but with no clear dose–response; the level of bronchodilation was comparable to or greater than that achieved with formoterol. Forced vital capacity (FVC) at peak bronchodilation also significantly increased with AZD3199 versus placebo (153–204 ml). COPD symptom scores and reliever use were reduced with AZD3199, while FEV1 reversibility was unaltered. Adverse events were mild-to-moderate, with no safety concerns identified. Drug exposure was dose-proportional, but lower than predicted from healthy volunteers.Conclusions
All three doses of AZD3199 produced 24-hour bronchodilation, but with no clear dose–response, suggesting that doses of 200 μg or less may be sufficient to maintain bronchodilation over 24 hours in patients with COPD. No safety concerns were identified. Further studies are required to determine the once-daily AZD3199 dose for COPD.Trial registration
Clinicaltrials.gov, NCT00929708相似文献19.
The 24 h O2 uptake and release together with the CO2 balance have been measured in two CAM plants, one a non-succulent Sempervivum grandifolium, the other a succulent Prenia sladeniana. The O2 uptake was estimated by the use of 18O2. It was found that the mean hourly O2 uptake in the light was 7 times that in the dark for Sempervivum and 5 times that for Prenia, after correction for the lightdark temperature difference. It was estimated that oxygen uptake in the light was 2.4 times greater than oxygen release (=net photosynthesis) in Sempervivum and 1.4 times greater in Prenia. In both plants there was a positive carbon balance over the 24 h period under the experimental conditions. It was estimated that malate formed during the night could, if completely oxidized to CO2 and water, account for 74% of the light phase O2 uptake in Sempervivum. In Prenia the O2 uptake was more than sufficient to account for a full oxidation of malate.Abbreviations CAM
Crassulacean acid metabolism
- PAR
photosynthetically active radiation
- PEP
phosphoenolpyruvate
- RrBP
ribulose-1,5-bisphosphate
- TCA
tricarboxylic acid cycle 相似文献