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41.
The efficacy, safety, and tolerability of Lu AA21004 versus placebo, using duloxetine as active reference, in patients with DSM-IV-TR diagnosed major depressive disorder (MDD) were evaluated in this 8-week, multi-site study. Patients (n = 766) had a baseline Montgomery–Åsberg Depression Rating Scale (MADRS) total score ≥ 26 and were randomly assigned (1:1:1:1:1) to 2.5, 5 or 10 mg Lu AA21004, placebo, or 60 mg duloxetine. The 5 mg and 10 mg doses of Lu AA21004 were tested separately versus placebo at p ≤ 0.025 in a pre-specified order. In the pre-defined primary efficacy analysis [mean change from baseline in MADRS total score at Week 8, full analysis set, ANCOVA, last observation carried forward (LOCF)], the differences to placebo (n = 145) of ? 1.7 (Lu AA21004 5 mg, n = 155) and ? 1.5 points (Lu AA21004 10 mg, n = 151) were not statistically significant; nor were those for Lu AA21004 2.5 mg (? 1.4 points, n = 155) or duloxetine (? 2.0 points, n = 149). Using mixed model, repeated measures (MMRM) analyses of the primary endpoint and most secondary endpoints were supportive of likely efficacy for Lu AA21004 5 mg and 10 mg and duloxetine. Treatment-emergent adverse events led to the withdrawal of 72 patients: 8% (placebo), 12% (duloxetine), and 6%, 11% and 9% in the Lu AA21004 groups (2.5 mg, 5 mg and 10 mg, respectively). The most common adverse events were nausea, headache, dizziness, and dry mouth. No clinically relevant changes were seen in vital signs, weight, ECG, or laboratory results. In summary, none of the active treatment groups, including duloxetine, separated from placebo in the primary analysis in this 'failed' study. Findings on secondary outcome measures, using MMRM instead of LOCF, were supportive of likely efficacy for Lu AA21004 5 mg and 10 mg and duloxetine. Lu AA21004 (2.5, 5 and 10 mg) was well tolerated. 相似文献
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INTRODUCTION: Behavioural disturbances are a common and distressing aspect of Alzheimer's disease (AD). This pooled analysis evaluated the specific benefits of memantine on behavioural disturbances in patients with moderate to severe AD. METHODS: Data were pooled from six 24/28-week, randomised, placebo-controlled, double-blind studies. Of the 2,311 patients included in these studies, 1,826 patients with moderate to severe AD (MMSE <20) were included in this analysis, corresponding to the extended indication for memantine in Europe. In this subgroup, 959 patients received memantine 20 mg/day and 867 received placebo. Behavioural symptoms were rated using the Neuropsychiatric Inventory (NPI) total and single-item scores at weeks 12 and 24/28. RESULTS: At weeks 12 and 24/28, ITT analysis demonstrated that memantine treatment produced statistically significant benefits over placebo treatment in NPI total score (p=0.001 and p=0.008), and in NPI single items: delusions (p=0.007 week 12, p=0.001 week 24/28), hallucinations (p=0.037 week 12), agitation/aggression (p=0.001 week 12, p=0.001 week 24/28), and irritability/lability (p=0.005 week 24/28), LOCF population. Analysis of the patients without symptoms at baseline indicated reduced emergence of agitation/aggression (p=0.002), delusions (p=0.047), and disinhibition (p=0.011), at week 12, and of agitation/aggression (p=0.002), irritability/lability (p=0.004), and night-time behaviour (p=0.050) at week 24/28 in those receiving memantine. OC analyses yielded similar results. CONCLUSIONS: The data suggest that memantine is effective in treating and preventing the behavioural symptoms of moderate to severe AD. Specific persistent benefits were observed on the symptoms of delusions and agitation/aggression, which are known to be associated with rapid disease progression, increased caregiver burden, early institutionalisation, and increased costs of care. 相似文献
44.
Hansen CS Sheykhzade M Møller P Folkmann JK Amtorp O Jonassen T Loft S 《Toxicology and applied pharmacology》2007,219(1):24-32
BACKGROUND: Particulate air pollution can aggravate cardiovascular disease by mechanisms suggested to involve translocation of particles to the bloodstream and impairment of endothelial function, possibly dependent on present atherosclerosis. AIM: We investigated the effects of exposure to diesel exhaust particles (DEP) in vivo and ex vivo on vasomotor functions in aorta from apoE(-/-) mice with slight atherosclerosis and from normal apoE(+/+) mice. METHODS: DEP 0, 0.5 or 5 mg/kg bodyweight in saline was administered i.p. The mice were sacrificed 1 h later and aorta ring segments were mounted on wire myographs. Segments from unexposed mice were also incubated ex vivo with 0, 10 and 100 microg DEP/ml before measurement of vasomotor functions. RESULTS: Exposure to 0.5 mg/kg DEP in vivo caused a decrease in the endothelium-dependent acetylcholine elicited vasorelaxation in apoE(-/-) mice, whereas the response was enhanced in apoE(+/+) mice. No significant change was observed after administration of 5 mg/kg DEP. In vivo DEP exposure did not affect constriction induced by K(+) or phenylephrine. In vitro exposure to 100 microg DEP/ml enhanced acetylcholine-induced relaxation and attenuated phenylephrine-induced constriction. Vasodilation induced by sodium nitroprusside was not affected by any DEP exposure. CONCLUSION: Exposure to DEP has acute effect on vascular functions. Endothelial dysfunction possibly due to decreased NO production as suggested by decreased acetylcholine-induced vasorelaxation and unchanged sodium nitroprusside response can be induced by DEP in vivo only in vessels of mice with some atherosclerosis. 相似文献
45.
Epidemiological studies have shown that exposure to air pollution particles is associated with cardiovascular diseases, whereas the role in the initiation of atherosclerosis is unresolved. Atherosclerosis is considered to be an inflammatory disease that also involves oxidative stress. Here we investigated effects of oxidative stress elicited by diesel exhaust particles (DEP) in the aorta, liver, and lung of dyslipidemic ApoE(-/-) mice at the age when visual plaques appear in the aorta (11-13 weeks). DEP was administrated by intraperitoneal injection (0, 50, 500 and 5,000 microg DEP/kg bodyweight) in order to omit vascular effects secondary to pulmonary inflammation. The mice were killed either 6 or 24h after the administration. Inflammation was measured as the expression of inducible nitric oxide synthase (iNOS) and serum nitric oxide and DNA damage was measured by the comet assay. The expression of iNOS mRNA was increased in the liver 6h after the administration. The level of oxidized purine bases, determined as formamidopyrimidine DNA glycosylase sites was increased by 67% (95% CI: 11-124%) in the liver after 24h in the mice administrated with only 50 microg/kg bodyweight. However, there was no indication of systemic inflammation determined as the serum concentration of nitric oxide and iNOS expression, and DNA damage was not increased in the aorta. These observations indicate that intraperitoneal DEP injection does not induce inflammation or oxidatively damaged DNA in the lung and aorta, whereas a direct effect in terms of inflammation and oxidized DNA was observed in the liver of dyslipidemic ApoE(-/-) mice. 相似文献
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Interaction of smoking, uptake of polycyclic aromatic hydrocarbons, and cytochrome P450IA2 activity among foundry workers. 总被引:1,自引:0,他引:1
D Sherson T Sigsgaard E Overgaard S Loft H E Poulsen F J Jongeneelen 《British journal of industrial medicine》1992,49(3):197-202
An increased lung cancer risk has been described among foundry workers. Polycyclic aromatic hydrocarbons (PAHs) and silica are possible aetiological factors. This study describes a urinary PAH metabolite, 1-hydroxypyrene (hpU), as well as the degree of cytochrome P450IA2 activity/induction as reflected by the urinary caffeine ratio (IA2) in 45 foundry workers and 52 controls; IA2 was defined as the ratio of paraxanthine 7-demethylation products to a paraxanthine 8-hydroxylation product (1,7-dimethyluric acid). Mean exposure concentrations for foundry workers were defined by breathing zone hygienic samples (respirable dust 1.2 to 3.52 mg/m3 (93 samples)) and as total PAH (0.46 micrograms/m3) and pyrene concentrations (0.28 micrograms/m3) (six samples). Non-smoking controls and foundry workers had similar IA2 ratios (5.63, 95% confidence interval (95% CI) 4.56-6.70 and 4.40, 95% CI 3.56-5.24). The same was true for smoking controls and foundry workers (9.10, 95% CI 8.00-10.20 and 8.69, 95% CI 7.37-10.01). Both smoking groups had raised IA2 ratios compared with non-smokers (p less than 0.01). Non-smoking controls and foundry workers had similar hpU concentrations (0.16, 95% CI 0.10-0.22 and 0.11, 95% CI 0.09-0.13 mumol/mol creatinine). Smoking foundry workers had raised hpU concentrations (0.42, 95% CI 0.25-0.59) compared with smoking controls (0.26, 95% CI 0.18-0.34) (p less than 0.01). A small subgroup of smoking foundry workers with the highest exposures to both silica and PAH also had the highest hpU concentrations (0.70, 95% CI - 0.07-1.47 mumol/mol creatinine) (p less than 0.04). Increased hpU concentrations in smoking foundry workers suggest a more than additive effect from smoking and foundry exposures resulting in increased PAH uptake. Increased P450IA2 enzyme activity was only found in smokers and no additional effect of foundry exposures was seen. These data suggest that smoking as well as work related PAH exposure may be casually related to increased risk of lung cancer in foundry workers. 相似文献
48.
Kim Francis Andersen Hanna Maria Fuglo Sine Hvid Rasmussen Michael Mork Petersen Annika Loft 《Medicine》2015,94(28)
To assess the prognostic value of primary tumor metabolic activity in patients with high-grade bone sarcomas (BS) or soft tissue sarcomas (STS) using F-18 FDG PET/CT.A single-site, retrospective study including 92 patients with high-grade BS or STS. Pretreatment F-18 FDG PET/CT scan was performed. Clinical data were registered. Accuracy of maximum standardized uptake value of primary tumor (SUVmax) and tumor-to-background (T/B) uptake ratio as prognostic variables and identification of cut-off values to group patients were determined. Kaplan–Meier survival estimates and log-rank test were used to compare survival distributions. Prognostic variables were assessed using Cox proportional hazards regression analysis.Forty-one of 92 patients died during follow-up (45%). Average survival was 6.5 years (95% CI 5.8–7.3 years) and probability of 5-year survival was 52%. Accuracy of SUVmax and T/B uptake ratio as prognostic variables in all patients and during subgroup analysis of patients with STS was significant. No significant results for AUCs were registered in patients with BS. Surgery was independently prognostic for survival throughout multivariate regression analysis of all patients (P = 0.001, HR 3.84) and subgroup analysis (BS: P = 0.02, HR 11.62; STS: P = 0.005, HR 4.13). SUVmax was significant as prognostic variable in all patients (P = 0.02, HR 3.66) and in patients with STS (P = 0.007, HR 3.75). No significant results were demonstrated for T/B uptake ratio.Estimation of primary tumor metabolic activity with pretherapeutic SUVmax using F-18 FDG PET/CT demonstrates independent properties beyond histologic grading for prediction of survival in patients with high-grade STS, but not with high-grade BS. 相似文献
49.
O Raaschou-Nielsen ZJ Andersen SS Jensen M Ketzel M Sørensen J Hansen S Loft A Tjønneland K Overvad 《Environmental health : a global access science source》2012,11(1):60
ABSTRACT: BACKGROUND: Traffic air pollution has been linked to cardiovascular mortality, which might be due to co-exposure to road traffic noise. Further, personal and lifestyle characteristics might modify any association. METHODS: We followed up 52 061 participants in a Danish cohort for mortality in the nationwide Register of Causes of Death, from enrollment in 1993-1997 through 2009, and traced their residential addresses from 1971 onwards in the Central Population Registry. We used dispersion-modelled concentration of nitrogen dioxide (NO2) since 1971 as indicator of traffic air pollution and used Cox regression models to estimate mortality rate ratios (MRRs) with adjustment for potential confounders. RESULTS: Mean levels of NO2 at the residence since 1971 were significantly associated with mortality from cardiovascular disease (MRR, 1.26; 95% confidence interval [CI], 1.06-1.51, per doubling of NO2 concentration) and all causes (MRR, 1.13; 95% CI, 1.04-1.23, per doubling of NO2 concentration) after adjustment for potential confounders. For participants who ate < 200 g of fruit and vegetables per day, the MRR was 1.45 (95% CI, 1.13-1.87) for mortality from cardiovascular disease and 1.25 (95% CI, 1.11-1.42) for mortality from all causes. CONCLUSIONS: Traffic air pollution is associated with mortality from cardiovascular diseases and all causes, after adjustment for traffic noise. The association was strongest for people with a low fruit and vegetable intake. 相似文献
50.
Increased susceptibility to liver disease in relation to alcohol consumption in women 总被引:3,自引:0,他引:3
Sex-related differences were prospectively studied in patients with the first presentation of alcoholic liver disease. Among 42 patients the diagnosis was cirrhosis in 8 women and 15 men, alcoholic hepatitis in 4 women and 1 man, steatosis in 6 women and 6 men, and no histologic changes were found in the liver biopsy specimens from 2 men (p greater than 0.1). The median (range) antipyrine clearance was 14.6 (1.0-64) versus 17.2 (3.0-83) ml/min and the clinical score in accordance with the Pugh modification of the Child-Turcotte classification was 8 (5-13) versus 8 (5-11) in the women and men, respectively (p greater than 0.05). In 5 women and only 1 man the antipyrine clearance was less than 5 ml/min, indicating an almost total loss of functional liver mass (p less than 0.05), whereas the Pugh score was above 11 in 6 women, but not in any of the men (p less than 0.05). On an average, the men estimated their total lifetime consumption of alcohol to be 2.1 times greater and the number of days they had consumed more than 5 drinks 2.9 times higher than the women (p less than 0.05). These ratios are reduced to 1.4 and 1.7, respectively (p greater than 0.05), if the female alcohol intake is adjusted to the average male volume of distribution. The results support the concept that women may develop similar, and sometimes even more severe, liver disease after consumption of less alcohol than men. The apparent difference in susceptibility to alcohol may be partly explained by differences in volume of distribution. 相似文献