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Visceral obesity is linked to insulin resistance and cardiovascular disease. A recent genetic study indicated that the gene locus for the anti-oxidant defense enzyme methionine sulphoxide reductase A (MsrA) is positively associated with the development of visceral adiposity. This work tested the hypothesis that Msr activity is diminished in visceral fat as a result of obesity. It used two animal models of obesity, wild-type rats fed a high-fat (45% of calories from fat) diet and Zucker rats fed a 10% fat calorie diet. The data indicate that MsrA activity was selectively reduced by ~ 25% in the visceral adipose, but not subcutaneous adipose or liver, of both rat models as compared to control, wild type rats receiving a 10% fat calorie diet. MsrB activity was similarly reduced only in visceral fat. The data indicate that Msr activity is reduced by obesity and may alter oxidative stress signalling of obesity.  相似文献   

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This 24-week double-blind, randomized, multicenter, placebo-controlled, parallel-group study was performed in 632 drug-na?ve patients with type 2 diabetes to assess efficacy and tolerability of vildagliptin (50 mg qd, 50 mg bid, or 100 mg qd). HbA1c decreased modestly in patients receiving placebo (Delta=-0.3+/-0.1%) and to a significantly greater extent in patients receiving vildagliptin 50 mg qd (Delta=-0.8+/-0 .1%), 50 mg bid (Delta=-0.8+/-0.1%), or 100 mg qd (Delta=-0.9+/-0.1%, p<0.01 for all groups VS. placebo) from an average baseline of 8.4%. In patients diagnosed >or=3 months before enrollment, HbA1c increased with placebo (Delta=+0.2+/-0.2%) and between-treatment differences (vildagliptin-placebo) were -0.8+/-0.2% (p<0.001), -0.7+/-0.2% (p=0.003), and -0.9+/-0.2% (p<0.001) with vildagliptin 50 mg qd, 50 mg bid, and 100 mg qd, respectively. There was no apparent dose-response in the overall population; however, in patients with high baseline HbA1c, there were greater reductions with either 100 mg dose regimen (Delta=-1.3+/-0.2% and -1.4+/-0.2%) compared to 50 mg qd (Delta=-0.8+/-0.1%). Body weight decreased modestly in all groups (by 0.3 to 1.8 kg). The incidence of adverse events was similar across all groups and 相似文献   

5.

Background

Combining two long-acting bronchodilators with complementary mechanisms of action may provide treatment benefits to patients with chronic obstructive pulmonary disease (COPD) that are greater than those derived from either treatment alone. The efficacy and safety of a fixed-dose combination (FDC) of aclidinium bromide, a long-acting muscarinic antagonist, and formoterol fumarate, a long-acting β2-agonist, in patients with moderate to severe COPD are presented.

Methods

In this 24-week double-blind study, 1692 patients with stable COPD were equally randomized to twice-daily treatment with FDC aclidinium 400 μg/formoterol 12 μg (ACL400/FOR12 FDC), FDC aclidinium 400 μg/formoterol 6 μg (ACL400/FOR6 FDC), aclidinium 400 μg, formoterol 12 μg, or placebo administered by a multidose dry powder inhaler (Genuair®/Pressair®)*. Coprimary endpoints were change from baseline to week 24 in 1-hour morning postdose FEV1 (FDCs versus aclidinium) and change from baseline to week 24 in morning predose (trough) FEV1 (FDCs versus formoterol). Secondary endpoints were change from baseline in St. George’s Respiratory Questionnaire (SGRQ) total score and improvement in Transition Dyspnea Index (TDI) focal score at week 24. Safety and tolerability were also assessed.

Results

At study end, improvements from baseline in 1-hour postdose FEV1 were significantly greater in patients treated with ACL400/FOR12 FDC or ACL400/FOR6 FDC compared with aclidinium (108 mL and 87 mL, respectively; p < 0.0001). Improvements in trough FEV1 were significantly greater in patients treated with ACL400/FOR12 FDC versus formoterol (45 mL; p = 0.0102), a numerical improvement of 26 mL in trough FEV1 over formoterol was observed with ACL400/FOR6 FDC. Significant improvements in both SGRQ total and TDI focal scores were observed in the ACL400/FOR12 FDC group at study end (p < 0.0001), with differences over placebo exceeding the minimal clinically important difference of ≥4 points and ≥1 unit, respectively. All treatments were well tolerated, with safety profiles of the FDCs similar to those of the monotherapies.

Conclusions

Treatment with twice-daily aclidinium 400 μg/formoterol 12 μg FDC provided rapid and sustained bronchodilation that was greater than either monotherapy; clinically significant improvements in dyspnea and health status were evident compared with placebo. Aclidinium/formoterol FDC may be an effective and well tolerated new treatment option for patients with COPD.

Trial registration

Clinicaltrials.gov NCT01437397.*Registered trademarks of Almirall S.A., Barcelona, Spain; for use within the US as Pressair® and Genuair® within all other licensed territories.

Electronic supplementary material

The online version of this article (doi:10.1186/s12931-014-0123-0) contains supplementary material, which is available to authorized users.  相似文献   

6.
The efficacy and tolerability of clomipramine in the treatment of separation anxiety in dogs was tested in a prospective, randomized, double-blind, placebo-controlled, parallel-group, international multicenter clinical trial. For a diagnosis of separation anxiety, dogs had to exhibit at least one of the following signs in the absence of their owner: destruction, defecation, urination and/or vocalization, as well as the behaviour suggestive of "hyper-attachment" to their owner. A total of 95 dogs were randomized to receive one of the three treatments for 2-3 months: "standard-dose" clomipramine (1 to <2 mg/kg, PO, q. 12 h); "low-dose" clomipramine (0.5 to <1 mg/kg, PO, q. 12 h); and placebo (PO, q. 12 h). All dogs received behavioural therapy. Dogs were examined at four time points (days 0, 28, 56 and 84) after the initiation of therapy. Improvement in each dog's behaviour at days 28, 56 and 84 was evaluated in comparison to its behaviour at day 0.The results showed that, compared to placebo, dogs receiving standard-dose clomipramine were rated improved at least three times faster for the signs destruction, defecation and urination. At most time points, more dogs in the standard-dose clomipramine group were rated improved for the signs destruction, defecation and urination, and in an owner's global assessment of the dog's overall behaviour (p<0.05 at certain time points). However, there were no statistically significant differences at any time point between the standard dose and the placebo groups in the sign vocalization. The low-dose clomipramine group produced no statistically significant effect when compared with placebo. Mild and transient vomiting was noted as a side effect of clomipramine in a small number of dogs.It is concluded that addition of standard-dose (1 to <2 mg/kg, PO, q. 12 h) clomipramine to conventional behavioural therapy for 2-3 months ameliorated the signs of separation anxiety in dogs.  相似文献   

7.
N-3 polyunsaturated fatty acids (PUFA) have anti-inflammatory effects and may be useful for the treatment of inflammatory diseases such as rheumatoid arthritis (RA).We examined the efficacy of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) supplementation on RA on top of standard anti-inflammatory treatment. Patients with RA were randomized into two groups in a double-blind, placebo-controlled, parallel-design multicenter study. One hundred nine patients received five capsules of either n-3 PUFA (2.090 g of EPA and 1.165 g of DHA) or high-oleic-acid sunflower oil for 16 weeks. Eighty-one patients completed the study, and no adverse effects were reported. Dietary intake did not change significantly during the study. There were significant increases in n-3 PUFA and EPA levels in erythrocytes in the n-3 PUFA group versus the placebo group, but decreases in n-6 PUFA, 18:2n6, 20:4n6 and 18:1n9 levels in the n-3 PUFA group versus the placebo group. N-3 PUFA supplementation had no significant effects on nonsteroidal anti-inflammatory drug (NSAID) requirements, clinical symptoms of RA or the concentration of cytokines, eicosanoids and bone turnover markers. However, n-3 PUFA supplementation significantly decreased NSAID requirements and leukotriene B4 levels in patients who weighed more than 55 kg. Our results suggest that n-3 PUFA supplementation has no significant effect on RA but may decrease the requirement for NSAIDs in Korean patients with RA who weigh more than 55 kg.  相似文献   

8.

Background:

Spasticity is a common and poorly controlled symptom of multiple sclerosis. Our objective was to determine the short-term effect of smoked cannabis on this symptom.

Methods:

We conducted a placebo-controlled, crossover trial involving adult patients with multiple sclerosis and spasticity. We recruited participants from a regional clinic or by referral from specialists. We randomly assigned participants to either the intervention (smoked cannabis, once daily for three days) or control (identical placebo cigarettes, once daily for three days). Each participant was assessed daily before and after treatment. After a washout interval of 11 days, participants crossed over to the opposite group. Our primary outcome was change in spasticity as measured by patient score on the modified Ashworth scale. Our secondary outcomes included patients’ perception of pain (as measured using a visual analogue scale), a timed walk and changes in cognitive function (as measured by patient performance on the Paced Auditory Serial Addition Test), in addition to ratings of fatigue.

Results:

Thirty-seven participants were randomized at the start of the study, 30 of whom completed the trial. Treatment with smoked cannabis resulted in a reduction in patient scores on the modified Ashworth scale by an average of 2.74 points more than placebo (p < 0.0001). In addition, treatment reduced pain scores on a visual analogue scale by an average of 5.28 points more than placebo (p = 0.008). Scores for the timed walk did not differ significantly between treatment and placebo (p = 0.2). Scores on the Paced Auditory Serial Addition Test decreased by 8.67 points more with treatment than with placebo (p = 0.003). No serious adverse events occurred during the trial.

Interpretation:

Smoked cannabis was superior to placebo in symptom and pain reduction in participants with treatment-resistant spasticity. Future studies should examine whether different doses can result in similar beneficial effects with less cognitive impact.Spasticity is a common and disabling symptom that remains a substantial problem for many patients with multiple sclerosis. Some patients have adverse effects from conventional antispasticity medications; for others, spasticity persists despite treatment. A report from the Institute of Medicine in the United States concluded that the active compounds of cannabis (marijuana) are potentially effective in treating neurologic conditions and “should be tested rigorously in clinical trials.”1 There is evidence that the cannabinoid receptors CB1 and CB2 may be involved in the control of spasticity in multiple sclerosis2 and that the endogenous ligand of CB1, anandamide, is itself an effective antispasticity agent.3 CB1 receptors are primarily presynaptic; their activation inhibits calcium influx and glutamate release, and reduces neuronal excitability by activating somatic and dendritic potassium channels.4Although many patients with multiple sclerosis endorse smoking cannabis as therapy, evidence that it relieves spasticity is largely anecdotal, as most trials focus on orally administered cannabinoids. We sought to assess the safety and efficacy of smoked cannabis versus placebo in patients with multiple sclerosis who have treatment-resistant spasticity.  相似文献   

9.
Conjugation of bile acids (BAs) to the amino acids taurine or glycine increases their solubility and promotes liver BA secretion. Supplementing diets with taurine or glycine modulates BA metabolism and enhances fecal BA excretion in rats. However, it is still unclear whether dietary proteins varying in taurine and glycine contents alter BA metabolism, and thereby modulate the recently discovered systemic effects of BAs. Here we show that rats fed a diet containing saithe fish protein hydrolysate (saithe FPH), rich in taurine and glycine, for 26 days had markedly elevated fasting plasma BA levels relative to rats fed soy protein or casein. Concomitantly, the saithe FPH fed rats had reduced liver lipids and fasting plasma TAG levels. Furthermore, visceral adipose tissue mass was reduced and expression of genes involved in fatty acid oxidation and energy expenditure was induced in perirenal/retroperitoneal adipose tissues of rats fed saithe FPH. Our results provide the first evidence that dietary protein sources with different amino acid compositions can modulate the level of plasma bile acids and our data suggest potential novel mechanisms by which dietary protein sources can affect energy metabolism.  相似文献   

10.
《Cell reports》2023,42(3):112166
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  相似文献   

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Objective: We tested sex, race, and age differences in the patterning of visceral adipose tissue (VAT) and subcutaneous adipose tissue. Research Methods and Procedures: Contiguous 1‐cm‐thick magnetic resonance (MR) images of the abdomen were collected from 820 African‐American and white adults. Repeated‐measures ANOVA was used to examine the effects of image location, sex, race, and age (≥50 vs. <50 years) on adipose tissue areas. Maximum VAT area was identified for each subject from the raw data. Results: Compared to women, men had greater total VAT volume (p < 0.0001), and their maximum VAT area occurred higher in the abdomen (p < 0.0001). Among white men, maximim VAT area most frequently occurred 5 to 10 cm above L4‐L5, whereas in the other groups, maximim VAT area most frequently occurred 1 to 4 cm above L4‐L5 (p < 0.0001). African‐American men had greater total VAT volume than African‐American women (p < 0.01), but this sex difference was only significant using single images cranial to L4‐L5 + 2 cm. Age‐related increases in VAT tended to be greatest 5 to 10 cm above L4‐L5 in men and near L4‐L5 in women. Discussion: A single MR image 5 to 10 cm above L4‐L5 may allow more accurate conclusions than the L4‐L5 image regarding group differences in visceral adiposity.  相似文献   

13.

Background

Despite the high prevalence of insomnia in patients with advanced cancer, there are no randomized controlled trials on pharmacological interventions for insomnia in this group of patients. A variety of pharmacological agents is recommended to manage sleep disturbance for insomnia in the general population, but their efficacy and safety in adults with advanced cancer are not established. Thus, there is a need to evaluate the effectiveness of medications for insomnia in order to improve the evidence in patients with advanced cancer. One of the most used sleep medications at present in patients with cancer is zopiclone.

Methods

This is a randomized, double-blind, placebo-controlled, parallel-group, multicenter trial. A total of 100 patients with metastatic cancer who report insomnia will be randomly allocated to zopiclone or placebo. The treatment duration with zopiclone/placebo is 6 consecutive nights. The primary endpoint is patient-reported sleep quality during the final study night (night 6) assessed on a numerical rating scale of 0–10, where 0?=?Best sleep and 10?=?Worst possible sleep. Secondary endpoints include the mean patient-reported total sleep time and sleep onset latency during the final study night (night 6).

Discussion

Results from this study on treatment of insomnia in advanced cancer will contribute to clinical decision-making and improve the treatment of sleep disturbance in this patient cohort.

Trial registration

ClinicalTrials.gov, NCT02807922. Registered on 21 June 2016.
  相似文献   

14.

Background

Fluticasone furoate (FF) is a novel long-acting inhaled corticosteroid (ICS). This double-blind, placebo-controlled randomized study evaluated the efficacy and safety of FF 200 mcg or 400 mcg once daily, either in the morning or in the evening, and FF 200 mcg twice daily (morning and evening), for 8 weeks in patients with persistent asthma.

Methods

Asthma patients maintained on ICS for ≥ 3 months with baseline morning forced expiratory volume in one second (FEV1) 50-80% of predicted normal value and FEV1 reversibility of ≥ 12% and ≥ 200 ml were eligible. The primary endpoint was mean change from baseline FEV1 at week 8 in pre-dose (morning or evening [depending on regimen], pre-rescue bronchodilator) FEV1.

Results

A total of 545 patients received one of five FF treatment groups and 101 patients received placebo (intent-to-treat population). Each of the five FF treatment groups produced a statistically significant improvement in pre-dose FEV1 compared with placebo (p < 0.05). FF 400 mcg once daily in the evening and FF 200 mcg twice daily produced similar placebo-adjusted improvements in evening pre-dose FEV1 at week 8 (240 ml vs. 235 ml). FF 400 mcg once daily in the morning, although effective, resulted in a smaller improvement in morning pre-dose FEV1 than FF 200 mcg twice daily at week 8 (315 ml vs. 202 ml). The incidence of oral candidiasis was low (0-4%) and UC excretion was comparable with placebo for all FF groups.

Conclusions

FF at total daily doses of 200 mcg or 400 mcg was significantly more effective than placebo. FF 400 mcg once daily in the evening had similar efficacy to FF 200 mcg twice daily and all FF regimens had a safety tolerability profile generally similar to placebo. This indicates that inhaled FF is an effective and well tolerated once-daily treatment for mild-to-moderate asthma.

Trial registration

NCT00398645  相似文献   

15.
Zhang L  Ma J  Pan K  Go VL  Chen J  You WC 《Helicobacter》2005,10(2):139-145
BACKGROUND: Helicobacter pylori infection is a major cause of peptic ulcer disease and gastric cancer. This study postulated that cranberry juice would be effective in the suppression of H. pylori in an endemically infected population at high risk for gastric cancer. MATERIALS AND METHODS: A prospective, randomized, double-blind, placebo-controlled trial was conducted in Linqu County of Shandong Province, China, where 189 adults aged 48.9 +/- 11.2 years (mean +/- SD) with H. pylori infection were randomly divided into two groups: cranberry juice (n = 97) and placebo (n = 92). Participants were assigned to orally receive two 250-ml juice boxes of cranberry juice or matching placebo beverage daily for 90 days. The degree of H. pylori infection was determined using the 13C-urea breath test before randomization at 35 and 90 days of intervention to assess the efficacy of cranberry juice in alleviating infection. RESULTS: A total of 189 subjects with positive 13C-urea breath test results prior to randomization completed the study. At day 35 of intervention, 14 of the 97 (14.43%) from the the cranberry juice treatment group and 5 of the 92 (5.44%) of the placebo recipients had negative 13C-urea breath test results. After 90 days, the study concluded that 14 of the 97 subjects in the cranberry juice treatment group versus 5 of the 92 in the placebo group yielded negative test results. Eleven individuals from the cranberry juice treatment group and only two from the placebo group were negative at 35 and 90 days of experiment. These results are significant (p < .05). CONCLUSIONS: Regular consumption of cranberry juice can suppress H. pylori infection in endemically afflicted populations.  相似文献   

16.
Glutathione (GSH) dysregulation at the gene, protein, and functional levels has been observed in schizophrenia patients. Together with disease-like anomalies in GSH deficit experimental models, it suggests that such redox dysregulation can play a critical role in altering neural connectivity and synchronization, and thus possibly causing schizophrenia symptoms. To determine whether increased GSH levels would modulate EEG synchronization, N-acetyl-cysteine (NAC), a glutathione precursor, was administered to patients in a randomized, double-blind, crossover protocol for 60 days, followed by placebo for another 60 days (or vice versa). We analyzed whole-head topography of the multivariate phase synchronization (MPS) for 128-channel resting-state EEGs that were recorded at the onset, at the point of crossover, and at the end of the protocol. In this proof of concept study, the treatment with NAC significantly increased MPS compared to placebo over the left parieto-temporal, the right temporal, and the bilateral prefrontal regions. These changes were robust both at the group and at the individual level. Although MPS increase was observed in the absence of clinical improvement at a group level, it correlated with individual change estimated by Liddle's disorganization scale. Therefore, significant changes in EEG synchronization induced by NAC administration may precede clinically detectable improvement, highlighting its possible utility as a biomarker of treatment efficacy. TRIAL REGISTRATION: ClinicalTrials.gov NCT01506765.  相似文献   

17.

Background

The treatment of Herpes-simplex-virus-encephalitis (HSVE) remains a major unsolved problem in Neurology. Current gold standard for therapy is acyclovir, a drug that inhibits viral replication. Despite antiviral treatment, mortality remains up to 15%, less than 20% of patients are able to go back to work, and the majority of patients suffer from severe disability. This is a discouraging, unsatisfactory situation for treating physicians, the disabled patients and their families, and constitutes an enormous burden to the public health services. The information obtained from experimental animal research and from recent retrospective clinical observations, indicates that a substantial benefit in outcome can be expected in patients with HSVE who are treated with adjuvant dexamethasone. But currently there is no available evidence to support the routine use of adjuvant corticosteroid treatment in HSVE. A randomized multicenter trial is the only useful instrument to address this question.

Design

GACHE is a multicenter, randomized, double-blind, placebo-controlled, parallel group clinical trial of treatment with acyclovir and adjuvant dexamethasone, as compared with acyclovir and placebo in adults with HSVE. The statistical design will be that of a 3-stage-group sequential trial with potential sample size adaptation in the last stage.

Conclusion

372 patients with proven HSVE (positive HSV-DNA-PCR), aged 18 up to 85 years; with focal neurological signs no longer than 5 days prior to admission, and who give informed consent will be recruited from Departments of Neurology of academic medical centers in Germany, Austria and The Netherlands. Sample size will potentially be extended after the second interim analysis up to a maximum of 450 patients.

Trial Registration

Current Controlled Trials ISRCTN45122933  相似文献   

18.
We tested the hypothesis that leptin, in addition to reducing body fat by restraining food intake, reduces body fat through a peripheral mechanism requiring uncoupling protein 1 (UCP1). Leptin was administered to wild-type (WT) mice and mice with a targeted disruption of the UCP1 gene (UCP1 deficient), while vehicle-injected control animals of each genotype were pair-fed to each leptin-treated group. Leptin reduced the size of white adipose tissue (WAT) depots in WT mice but not in UCP1-deficient animals. This was accompanied by a threefold increase in the amount of UCP1 protein and mRNA in the brown adipose tissue (BAT) of WT mice. Leptin also increased UCP2 mRNA in WAT of both WT and UCP1-deficient mice but increased UCP2 and UCP3 mRNA only in BAT from UCP1-deficient mice. These results indicate that leptin reduces WAT through a peripheral mechanism requiring the presence of UCP1, with little or no involvement of UCP2 or UCP3.  相似文献   

19.
BACKGROUND: Activation of inflammatory pathways plays an important contributory role in coronary plaque instability and subsequent rupture, which can lead to the development of acute coronary syndrome (ACS). Elevated levels of serum inflammatory markers such as C-reactive protein (CRP) represent independent risk factors for further cardiovascular events. Recent evidence indicates that in addition to lowering cholesterol levels, statins also decrease levels of inflammatory markers. Previous controlled clinical trials reporting the positive effects of statins in participants with ACS were designed for very early secondary prevention. To our knowledge, no controlled trials have evaluated the potential benefits of statin therapy, beginning immediately at the time of hospital admission. A previous pilot study performed by our group focused on early initiation of cerivastatin therapy. We demonstrated a highly significant reduction in levels of inflammatory markers (CRP and interleukin-6). Based on these preliminary findings, we are conducting a clinical trial to evaluate the efficacy of another statin, fluvastatin, as an early intervention in patients with ACS. METHODS: The FACS-trial (Fluvastatin in the therapy of Acute Coronary Syndrome) is a multicenter, randomized, double-blind, placebo-controlled study evaluating the effects of fluvastatin therapy initiated at the time of hospital admission. The study will enroll 1,000 participants admitted to hospital for ACS (both with and without ST elevation). The primary endpoint for the study is the influence of fluvastatin therapy on levels of inflammatory markers (CRP and interleukin-6) and on pregnancy associated plasma protein A (PAPP-A). A combined secondary endpoint is 30-day and one-year occurrence of death, nonfatal myocardial infarction, recurrent symptomatic ischemia, urgent revascularization, and cardiac arrest. CONCLUSION: The primary objective of the FACS trial is to demonstrate that statin therapy, when started immediately after hospital admission for ACS, results in reduction of inflammation and improvement of prognosis. This study may contribute to new knowledge regarding therapeutic strategies for patients suffering from ACS and may offer additional clinical indications for the use of statins.  相似文献   

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