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Comparing new treatments for idiopathic pulmonary fibrosis--a network meta-analysis.
Loveman, E, Copley, VR, Scott, DA, Colquitt, JL, Clegg, AJ, O'Reilly, KM
BMC pulmonary medicine. 2015;:37
Abstract
BACKGROUND The treatment landscape for idiopathic pulmonary fibrosis, a devastating lung disease, is changing. To investigate the effectiveness of treatments for idiopathic pulmonary fibrosis we undertook a systematic review, network meta-analysis and indirect comparison. METHODS We searched MEDLINE, EMBASE and The Cochrane library for relevant studies. Randomised controlled trials of pirfenidone, nintedanib or N-acetylcysteine were eligible. Predefined processes for selecting references, extracting data and assessing study quality were applied. Our network meta-analysis of published data used a fixed effect model. For forced vital capacity measures a standardised mean difference approach was used and converted to odds ratios for interpretation. RESULTS Of 1076 references, 67 were retrieved and 11 studies included. Studies were of reasonable size, populations were similar, and the overall quality was good. Only two treatments, pirfenidone (odds ratio 0.62, 95% credible interval 0.52, 0.74) and nintedanib (0.41, 95% credible interval 0.34, 0.51) produced a statistically significant slowing in the rate of forced vital capacity decline compared with placebo. In an indirect comparison, results indicate that nintedanib is statistically significantly better than pirfenidone in slowing forced vital capacity decline (odds ratio 0.67, 95% credible interval 0.51, 0.88). Results were stable in scenario analysis and random effects models. Indirect comparisons of mortality were not statistically significant between nintedanib and pirfenidone. CONCLUSIONS Two treatments show beneficial effects and when compared indirectly nintedanib appears to have superior benefit on forced vital capacity. Limitations to indirect comparisons should be considered when interpreting these results, however, our findings can be useful to inform treatment decisions.
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Study and comparison of polydopamine and its derived carbon decorated nanoparticles in the magnetic solid-phase extraction of estrogens.
Huang, Z, Lee, HK
Journal of chromatography. A. 2015;:41-50
Abstract
Surface functionalization enabled by bioinspired polydopamine (PDA) is recognized as a convenient route for fabrication of multifunctional nanoparticles. In the present work, magnetic nanoparticles with polymer (Fe3O4@PDA) and carbon shell (Fe3O4@C) were prepared by self-oxidation of dopamine, and carbonization of the PDA coating. The performance of the two magnetic sorbents in the extraction and determination of four estrogens, estrone (E1), estradiol (E2), estriol (E3) and diethylstilbestrol (DES) from water samples in the form of magnetic solid-phase extraction was investigated. Orthogonal array design was utilized to facilitate the optimization of the proposed sample preparation approach. The highest extraction capabilities of the two sorbents were achieved under different experimental conditions. Fe3O4@PDA was shown to be superior to Fe3O4@C in the enrichment of estrogens, suggesting stronger interactions were established between the PDA coating and the target compounds. The extraction and desorption operations were enabled more conveniently by magnetic separation and the extracts were analyzed by high-performance liquid chromatography coupled with ultraviolet and fluorescence detection. The limits of detection achieved in the proposed method were in the range of 0.072-0.15ng/mL for E1 and DES, and 0.0017-0.0062ng/mL for E2 and E3. Good precision (>0.9995) was obtained with the linearity ranging from 0.2 to 100ng/mL, and from 0.01 to 5ng/mL. The method developed was assessed by analysis of the estrogens in tap water, drain water and bottled mineral water samples.
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Effect on push-out bond strength of glass-fiber posts functionalized with polydopamine using different adhesives.
Chen, Q, Cai, Q, Li, Y, Wei, XY, Huang, Z, Wang, XZ
The journal of adhesive dentistry. 2014;(2):177-84
Abstract
PURPOSE To evaluate the push-out bond strengths of prefabricated glass-fiber posts (Beijing Oya Biomaterials) with polydopamine functionalized to root dentin using two different resin cements (Paracore and RelyX Unicem) in different root regions (cervical, middle, and apical). MATERIALS AND METHODS Forty extracted human, single-rooted teeth were endodontically treated and a 9-mm post space was prepared in each tooth with post drills provided by the manufacturer. Specimens were then randomly assigned into four groups (n = 10 per group), depending on the adhesive system and post surface treatment used: group IA (Paracore + polydopamine); group IB (Paracore + control); group IIA (RelyX Unicem + polydopamine); group IIB (RelyX Unicem + control). Following post cementation, the specimens were stored in distilled water at 37°C for 7 days. The push-out test was performed using a universal testing machine (0.5 mm/ min), and the failure modes were examined with a stereomicroscope. Data were statistically analyzed using twoway ANOVA (p = 0.05). RESULTS Bond strengths (mean ± SD) were: 7.909 ± 3.166 MPa (group IA), 4.675 ± 2.170 MPa (group IB), 8.186 ± 2.766 MPa (group IIA), 4.723 ± 2.084 MPa (group IIB). The bond strength of polydopamine groups was significantly higher than one of the control groups (p < 0.0001). No significant difference was found in the micro push-out bond strengths between the two resin cement groups or the root regions (p > 0.05). Stereomicroscopic analysis showed a higher percentage of adhesive than cohesive failures in all groups. CONCLUSION Surface polydopamine functionalization was confirmed to be a reliable method for improving the bond strength of resin luting agents to fiber posts. The bond strength of Paracore to fiber posts was not significantly different from that of RelyX Unicem, and considering its convenient application, Paracore can be recommended.
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Randomized phase III trial of temsirolimus versus sorafenib as second-line therapy after sunitinib in patients with metastatic renal cell carcinoma.
Hutson, TE, Escudier, B, Esteban, E, Bjarnason, GA, Lim, HY, Pittman, KB, Senico, P, Niethammer, A, Lu, DR, Hariharan, S, et al
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2014;(8):760-7
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Abstract
PURPOSE This international phase III trial (Investigating Torisel As Second-Line Therapy [INTORSECT]) compared the efficacy of temsirolimus (mammalian target of rapamycin inhibitor) and sorafenib (vascular endothelial growth factor receptor [VEGFR] tyrosine kinase inhibitor) as second-line therapy in patients with metastatic renal cell carcinoma (mRCC) after disease progression on sunitinib. PATIENTS AND METHODS In total, 512 patients were randomly assigned 1:1 to receive intravenous temsirolimus 25 mg once weekly (n = 259) or oral sorafenib 400 mg twice per day (n = 253), with stratification according to duration of prior sunitinib therapy (≤ or > 180 days), prognostic risk, histology (clear cell or non-clear cell), and nephrectomy status. The primary end point was progression-free survival (PFS) by independent review committee assessment. Safety, objective response rate (ORR), and overall survival (OS) were secondary end points. RESULTS Primary analysis revealed no significant difference between treatment arms for PFS (stratified hazard ratio [HR], 0.87; 95% CI, 0.71 to 1.07; two-sided P = .19) or ORR. Median PFS in the temsirolimus and sorafenib arms were 4.3 and 3.9 months, respectively. There was a significant OS difference in favor of sorafenib (stratified HR, 1.31; 95% CI, 1.05 to 1.63; two-sided P = .01). Median OS in the temsirolimus and sorafenib arms was 12.3 and 16.6 months, respectively. Safety profiles of both agents were consistent with previous studies. CONCLUSION In patients with mRCC and progression on sunitinib, second-line temsirolimus did not demonstrate a PFS advantage compared with sorafenib. The longer OS observed with sorafenib suggests sequenced VEGFR inhibition may benefit patients with mRCC.
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Effects of combination of statin and calcium channel blocker in patients with cardiac syndrome X.
Zhang, X, Li, Q, Zhao, J, Li, X, Sun, X, Yang, H, Wu, Z, Yang, J
Coronary artery disease. 2014;(1):40-4
Abstract
OBJECTIVES Statins and calcium channel blockers have been proven beneficial toward improvement of endothelial function. The aim of this study was to compare the effect of combination therapy of statin and calcium channel blocker with solo treatment in patients with cardiac syndrome X. METHODS AND RESULTS Sixty-eight patients with cardiac syndrome X were divided randomly into three groups: fluvastatin (40 mg/day, n=23), diltiazem (90 mg/day, n=22), and combination of fluvastatin (40 mg/day) and diltiazem (90 mg/day, n=23). At the end of 90 days, the coronary flow reserve was improved in the three groups (fluvastatin-treated group: 23.2%; diltiazem-treated group: 12.4%; fluvastatin+diltiazem-treated group: 29.1%, all P<0.05). The time to 1 mm ST segment depression increased significantly in the fluvastatin-treated group (from 241±97 to 410±140 s, P<0.05), the diltiazem-treated group (from 258±91 to 392±124 s, P<0.05), and the fluvastatin+diltiazem-treated group (from 250±104 to 446±164 s, P<0.05). The improvement in coronary flow reserve and prolonged time to 1 mm ST segment depression in the combination treatment group were more remarkable than in those who received monotherapy. Combination therapy also induced a significant increase (35.6%, P<0.05) in nitric oxide and an apparent reduction (48.7%, P<0.05) in endothelin-1. CONCLUSION Combination treatment with fluvastatin and diltiazem is more effective on endothelial function and exercise tolerance than solo treatment in patients with cardiac syndrome X. The benefits of these drugs may be related to the elevation of nitric oxide and reduction of endothelin-1.
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Skin cancer associated with the use of sorafenib and sunitinib for renal cell carcinoma.
Breaker, K, Naam, M, La Rosa, FG, Flaig, IP, Flaig, TW
Dermatologic surgery : official publication for American Society for Dermatologic Surgery [et al.]. 2013;(7):981-7
Abstract
BACKGROUND Several case series have reported an association between sorafenib and the development of skin cancer, but they differ in the reported rapidity of skin cancer onset and the frequency of recurrence with ongoing multikinase inhibitor (MKI) treatment. OBJECTIVE To compare the presentation and incidence of skin cancer in patients with renal cell carcinoma (RCC) treated with sorafenib and sunitinib. MATERIALS AND METHODS This retrospective study reviewed the records of 69 patients with RCC treated with sorafenib or sunitinib at the University of Colorado Hospital between January 2005 and July 2009. RESULTS Seven patients treated with MKI developed skin cancer (5 (13.5%) with sorafenib, 2 (6.3%) with sunitinib; 5 squamous cell carcinomas (SCC), 3 basal cell carcinomas (BCC)); all developed in sun-exposed areas during first-line MKI therapy. The median time from the start of MKI therapy until observation of a skin cancer lesion was 13.5 months. CONCLUSION We observed more cases of skin cancer during sorafenib treatment than during sunitinib treatment for advanced RCC; median MKI treatment duration before the identification of skin cancer was longer than 1 year.
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Pharmacogenomic association of nonsynonymous SNPs in SIGLEC12, A1BG, and the selectin region and cardiovascular outcomes.
McDonough, CW, Gong, Y, Padmanabhan, S, Burkley, B, Langaee, TY, Melander, O, Pepine, CJ, Dominiczak, AF, Cooper-Dehoff, RM, Johnson, JA
Hypertension (Dallas, Tex. : 1979). 2013;(1):48-54
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Abstract
We sought to identify novel pharmacogenetic markers associated with cardiovascular outcomes in patients with hypertension on antihypertensive therapy. We genotyped a 1:4 case:control cohort (n=1345) on the Illumina HumanCVD Beadchip from the INternational VErapamil SR-Trandolapril STudy (INVEST), where participants were randomized to a β-blocker strategy or a calcium channel blocker strategy. Genome-spanning single nucleotide polymorphism (SNP)×treatment interaction analyses of nonsynonymous SNPs were conducted in white and Hispanic race/ethnic groups. Top hits from whites were tested in Hispanics for consistency. A genetic risk score was constructed from the top 3 signals and tested in the Nordic Diltiazem study. SIGLEC12 rs16982743 and A1BG rs893184 had a significant interaction with treatment strategy for adverse cardiovascular outcomes (INVEST whites and Hispanics combined interaction P=0.0038 and 0.0036, respectively). A genetic risk score, including rs16982743, rs893184, and rs4525 in F5, was significantly associated with treatment-related adverse cardiovascular outcomes in whites and Hispanics from the INVEST study and in the Nordic Diltiazem study (meta-analysis interaction P=2.39×10(-5)). In patients with a genetic risk score of 0 or 1, calcium channel blocker treatment was associated with lower risk (odds ratio [95% confidence interval]=0.60 [0.42-0.86]), and in those with a genetic risk score of 2 to 3, calcium channel blocker treatment was associated with higher risk (odds ratio [95% confidence interval]=1.31 [1.08-1.59]). These results suggest that cardiovascular outcomes may differ based on SIGLEC12, A1BG, F5 genotypes, and antihypertensive treatment strategy. These specific genetic associations and our risk score provide insight into a potential approach to personalized antihypertensive treatment selection.
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Determinants of lipid goal achievement in patients on extended-release nicotinic acid/laropiprant in primary care clinical practice.
Dänschel, W, Steinhagen-Thiessen, E, Buffleben, C, Pittrow, D, Hildemann, SK
Current medical research and opinion. 2013;(1):33-40
Abstract
OBJECTIVES To establish determinants of lipid goal attainment in primary care patients, with particular focus on participation in a disease management programme (DMP) on diabetes mellitus (DM) and/or coronary heart disease (CHD), with real-world practical relevance. METHODS The present analysis was based on an observational study in 2359 patients with dyslipidaemia or hypercholesterolaemia that were treated with nicotinic acid 1000 mg/laropiprant 20 mg (Tredaptive) one or two tablets daily. Subgroups were formed by DMP participation (DMP vs. no DMP). A stepwise logistic regression model with backward selection of variables was applied to investigate factors influencing the probability of reaching lipid goals. Follow-up was 23 ± 7 weeks. RESULTS Low density lipoprotein cholesterol (LDL-C) <100 mg/dl was achieved by 30.8% in DMP versus 26.8% (no DMP), high density lipoprotein (HDL-C) >40/50 mg/dl in 61.3% versus 66.1%, and triglycerides (TG) <150 mg/dl in 28.9% versus 31.7%. On multivariate analysis, age, sex, concomitant high-risk cardiovascular disease, or participation in a DMP appeared to have inconsistent effects on reaching LDL-C, HDL-C and TG goals. Likelihood to reach the LDL-C goal tended to be higher in males, in patients outside DMP, and in patients with DM or CHD, and those treated with 1 tablet (versus 2 tablets) extended release nicotinic acid 1000 mg/laropiprant 20 mg. The likelihood of reaching the HDL-C goal was higher in males and in patients without DM or DM+CHD (no effect of DMP). The likelihood of reaching the TG goals was higher in females, in patients outside DMP, and in patients with DM and/or CHD. Limitations include potential bias due to study design, physician and patient selection, and missing values at follow-up. CONCLUSION DMP participation was not associated with overall improved lipid goal attainment. Physicians cannot predict the magnitude of effects of newly initiated lipid modifying therapy based on baseline characteristics of their patients.
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3,3'-Diindolylmethane, but not indole-3-carbinol, inhibits histone deacetylase activity in prostate cancer cells.
Beaver, LM, Yu, TW, Sokolowski, EI, Williams, DE, Dashwood, RH, Ho, E
Toxicology and applied pharmacology. 2012;(3):345-51
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Abstract
Increased consumption of cruciferous vegetables is associated with a reduced risk of developing prostate cancer. Indole-3-carbinol (I3C) and 3,3'-diindolylmethane (DIM) are phytochemicals derived from cruciferous vegetables that have shown promise in inhibiting prostate cancer in experimental models. Histone deacetylase (HDAC) inhibition is an emerging target for cancer prevention and therapy. We sought to examine the effects of I3C and DIM on HDACs in human prostate cancer cell lines: androgen insensitive PC-3 cells and androgen sensitive LNCaP cells. I3C modestly inhibited HDAC activity in LNCaP cells by 25% but no inhibition of HDAC activity was detected in PC-3 cells. In contrast, DIM significantly inhibited HDAC activity in both cell lines by as much as 66%. Decreases in HDAC activity correlated with increased expression of p21, a known target of HDAC inhibitors. DIM treatment caused a significant decrease in the expression of HDAC2 protein in both cancer cell lines but no significant change in the protein levels of HDAC1, HDAC3, HDAC4, HDAC6 or HDAC8 was detected. Taken together, these results show that inhibition of HDAC activity by DIM may contribute to the phytochemicals' anti-proliferative effects in the prostate. The ability of DIM to target aberrant epigenetic patterns, in addition to its effects on detoxification of carcinogens, may make it an effective chemopreventive agent by targeting multiple stages of prostate carcinogenesis.
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STATIN-D study: comparison of the influences of rosuvastatin and fluvastatin treatment on the levels of 25 hydroxyvitamin D.
Ertugrul, DT, Yavuz, B, Cil, H, Ata, N, Akin, KO, Kucukazman, M, Yalcin, AA, Dal, K, Yavuz, BB, Tutal, E
Cardiovascular therapeutics. 2011;(2):146-52
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Several studies have shown that low 25-hydroxyvitamin D levels are associated with higher risk of cardiovascular disease and an increase in 25-hydroxyvitamin D levels protects against cardiovascular disease. In this study, we aimed to compare the effects of rosuvastatin and fluvastatin on vitamin D metabolism. The study population consisted of 134 hyperlipidemic patients who had not previously been treated with lipid lowering medications. Patients were randomized in a 1:1 ratio to rosuvastatin 10 mg or fluvastatin 80 mg XL during the study. Lipid parameters, 25 hydroxyvitamin-D, and bone alkaline phosphatase (BALP) were obtained at baseline and after 8 weeks of rosuvastatin and fluvastatin treatment. Sixty-nine patients were administered rosuvastatin, and 65 patients fluvastatin. Total Cholesterol and LDL cholesterol decreased after 8 weeks of both rosuvastatin and fluvastatin treatments. Rosuvastatin was significantly more effective than fluvastatin on lowering total (P < 0.001) and LDL cholesterol (P < 0.001). There was a significant increase in 25-hydroxyvitamin D with rosuvastatin treatment (P < 0.001), whereas no significant change in 25-hydroxyvitamin D was observed with fluvastatin treatment. Mean BALP fell from 18.5 to 9.6 u/I (P < 0.001) with rosuvastatin and from 17.0 to 12.8 with fluvastatin (P= 0.004). There was no significant difference in BALP levels between rosuvastatin and fluvastatin treatment (P= 0.368). The present study demonstrated that 25-hydroxyvitamin D levels increased with rosuvastatin treatment; whereas fluvastatin treatment had no effect on 25-hydroxyvitamin D. This disparity could be related to the potency or the bioavailability of these two statins. Further studies are needed to clarify the relationship between statins and the vitamin D physiology.