Lorcaserin (APD356), a Selective 5‐HT2C Agonist,Reduces Body Weight in Obese Men and Women

Lorcaserin (APD356) is a potent, selective 5‐HT_2C agonist with ∼15‐fold and 100‐fold selectivity vs. 5‐HT_2A and 5‐HT_2B receptors, respectively. This study evaluated the safety and efficacy of lorcaserin for weight reduction in obese patients during a 12‐week period. The randomized, double‐blind, placebo‐controlled, parallel‐arm study enrolled 469 men and women between ages 18 and 65 and with BMI 30–45 kg/m². Patients received placebo, lorcaserin 10 mg q.d., lorcaserin 15 mg q.d., or lorcaserin 10 mg b.i.d. for 12 weeks, and were counseled to maintain their usual diet and activity. The primary end point was change in weight from baseline to day 85 by completer analysis. Safety analyses included echocardiograms at Screening and day 85/study exit. Lorcaserin was associated with progressive weight loss of 1.8 kg, 2.6 kg, and 3.6 kg at 10 mg q.d., 15 mg q.d., and 10 mg b.i.d., respectively, compared to placebo weight loss of 0.3 kg (P < 0.001 for each group). Similar results were seen by intent‐to‐treat last observation‐carried forward (ITT‐LOCF) analysis. The proportions of completers achieving ≥5% of initial body weight were 12.8, 19.5, 31.2, and 2.3% in the 10 mg q.d., 15 mg q.d., 10 mg b.i.d., and placebo groups, respectively. The most frequent adverse events (AEs) were transient headache, nausea, and dizziness. Echocardiograms showed no apparent drug‐related effects on heart valves or pulmonary artery pressure (PAP). Lorcaserin was well tolerated and efficacious for weight reduction in this 12‐week study. Longer‐term trials employing behavior modification will be needed to more fully assess its safety and efficacy.     

One-year treatment with mometasone furoate in chronic obstructive pulmonary disease

Many patients with chronic obstructive pulmonary disease (COPD) are treated with twice daily (BID) inhaled corticosteroids (ICS). This study evaluated whether daily PM mometasone furoate administered via a dry powder inhaler (MF-DPI) was equally effective compared to twice daily dosing.In a 52-week, randomized, double-blind, placebo-controlled study, 911 subjects with moderate-to-severe COPD managed without ICS received MF-DPI 800 μg QD PM, MF-DPI 400 μg BID, or placebo. The change from baseline in postbronchodilator forced expiratory volume in 1 second (FEV₁), total COPD symptom scores, and health status as well as the percentage of subjects with a COPD exacerbation were assessed. Adverse events were recorded.Mometasone furoate administered via a dry powder inhaler 800 μg QD PM and 400 μg BID significantly increased postbronchodilator FEV₁ from baseline (50 mL and 53 mL, respectively, versus a 19 mL decrease for placebo; P < 0.001). The percentage of subjects exacerbating was significantly lower in the pooled MF-DPI groups than in the placebo group (P = 0.043). Subjects receiving MF-DPI 400 μg BID reported a statistically significant (19%) reduction in COPD symptom scores compared with placebo (P < 0.001). Health status as measured with St. George''s Respiratory Questionnaire (SGRQ) improved significantly in all domains (Total, Activity, Impacts, and Symptoms) in the pooled MF-DPI groups versus placebo (P ≤ 0.031). MF-DPI treatment was well tolerated.Once-daily MF-DPI improved lung function and health status in subjects with moderate-to-severe COPD and was comparable to BID MF-DPI.     

Monotherapy with the once-weekly GLP-1 analogue dulaglutide for 12 weeks in patients with Type 2 diabetes: dose-dependent effects on glycaemic control in a randomized, double-blind, placebo-controlled study

Diabet. Med. 29, 1260-1267 (2012) ABSTRACT: Aims Evaluate dose-dependent effects of once-weekly dulaglutide, a glucagon-like peptide-1 analogue, on glycaemic control in patients with Type?2 diabetes treated with lifestyle measures with or without previous metformin. Methods This 12-week, double-blind, placebo-controlled, dose-response trial randomized 167 patients who were anti-hyperglycaemic medication-na?ve or had discontinued metformin monotherapy [mean baseline HbA(1c) 59?±?8 to 61?±?8?mmol/mol (7.6?±?0.7 to 7.8?±?0.8%)] to once-weekly injections of placebo or dulaglutide (0.1, 0.5, 1.0 or 1.5?mg). Results A significant dose-dependent reduction in HbA(1c) (least squares mean?±?se) was observed across doses (P?相似文献   

Effects of taspoglutide on glycemic control and body weight in obese patients with type 2 diabetes (T‐emerge 7 study)

Objective:

Therapies that lower blood glucose and provide weight loss may provide meaningful benefits for obese patients with type 2 diabetes mellitus (T2DM). This study assessed the efficacy of taspoglutide compared with placebo on glycemic control and weight in obese patients with T2DM inadequately controlled with metformin monotherapy.

Design and Methods:

In a 24‐week, randomized, double‐blind, placebo‐controlled, multicenter trial, obese adults with T2DM were randomized (1:1) to weekly subcutaneous taspoglutide 20 mg (10 mg for first 4 weeks) (n = 154) or placebo (n = 151) for 24 weeks. Efficacy measures included hemoglobin A1c (HbA1c) levels, body weight, percentage of patients achieving HbA1c ≤6.5 and ≤7.0%, and fasting plasma glucose (FPG). Adverse events (AEs) were assessed.

Results:

Mean baseline HbA1c was 7.55% and mean baseline BMI was 36.7 kg/m². HbA1c reductions from baseline were significantly greater with taspoglutide than placebo (least square mean [LSMean], ?0.81% vs. ?0.09%; P < 0.0001). Weight loss at week 24 was significantly greater with taspoglutide than placebo (LSMean, ?3.16 vs. ?1.85 kg; P < 0.01). In the taspoglutide and placebo groups, target HbA1c levels (≤6.5%) were achieved by 49 and 16% of patients, respectively, while 72 and 36% achieved HbA1c levels ≤7%. Decreases in FPG were significantly greater with taspoglutide than placebo (?23.59 vs. 0.09 mg/dl; P < 0.0001). Nausea and vomiting were the most common AEs associated with taspoglutide, but tended to be transient and generally mild or moderate.

Conclusions:

In obese patients with T2DM, once‐weekly taspoglutide provided the combined benefits of glycemic control and weight loss.

     

Diet-induced weight loss in overweight or obese women and changes in high-density lipoprotein levels and function

Diet-induced weight loss in women may be associated with decreases not only in plasma levels of low-density lipoprotein cholesterol (LDL-C), but also in high-density lipoprotein cholesterol (HDL-C). Whether a decrease in HDL-C is associated with altered HDL function is unknown. One hundred overweight or obese women (age 46 ± 11 years, 60 black; 12 diabetic) were enrolled in the 6-month program of reduced fat and total energy diet and low-intensity exercise. Serum cholesterol efflux capacity was measured in (3)H-cholesterol-labeled BHK cells expressing ABCA1, ABCG1, or SR-B1 transporters and incubated with 1% apolipoprotein B (apoB)-depleted serum. Antioxidant properties of HDL were estimated by paraoxonase-1 (PON1) activity and oxygen radical absorbance capacity (ORAC). Endothelial nitric oxide synthase (eNOS) activation was measured by conversion of L-arginine to L-citrulline in endothelial cells incubated with HDL from 49 subjects. Participants achieved an average weight loss of 2.2 ± 3.9 kg (P < 0.001), associated with reductions in both LDL-C (-6 ± 21 mg/dl, P = 0.004) and HDL-C (-3 ± 9 mg/dl, P = 0.016). Cholesterol efflux capacity by the ABCA1 transporter decreased by 10% (P = 0.006); efflux capacities by the ABCG1 and SR-B1 transporters were not significantly altered. ORAC decreased by 15% (P = 0.018); neither PON1 activity nor eNOS activation was significantly altered by reduction in HDL-C. Findings were similar for diabetic and nondiabetic subjects. Diet-induced weight loss in overweight or obese women is associated with a decrease in HDL-C levels, but overall HDL function is relatively spared, suggesting that decrease in HDL-C in this setting is not deleterious to cardiovascular risk.     

Acute exercise and training alter blood lipid and lipoprotein profiles differently in overweight and obese men and women

Our purpose was to elucidate effects of acute exercise and training on blood lipids-lipoproteins, and high-sensitivity C-reactive protein (hsCRP) in overweight/obese men (n = 10) and women (n = 8); age, BMI, body fat percentage, and VO(2)max were (mean ± SEM): 45 ± 2.5 years, 31.9 ± 1.4 kg·m(-2), 41.1 ± 1.5%, and 25.2 ± 1.3 mlO(2)·kg(-1)·min(-1). Before exercise training subjects performed an acute exercise session on a treadmill (70% VO(2)max, 400 kcal energy expenditure), followed by 12 weeks of endurance exercise training (land-based or aquatic-based treadmill): 3 sessions·week(-1), progressing to 500 kcal·session(-1) during which subjects maintained accustomed dietary habits. After training, the acute exercise session was repeated. Blood samples, obtained immediately before and 24 h after acute exercise sessions, were analyzed for serum lipids, lipoproteins, and hsCRP adjusted for plasma volume shifts. Exercise training increased VO(2)max (+3.67 mlO(2)·kg(-1)·min(-1), P < 0.001) and reduced body weight (-2.7 kg, P < 0.01). Training increased high-density lipoprotein (HDL) and HDL(2b)-cholesterol (HDL-C) concentrations (+3.7 and +2.4 mg·dl(-1), P < 0.05) and particle numbers (+588 and +206 nmol·l(-1), P < 0.05) in men. In women despite no change in total HDL-C, subfractions shifted from HDL(3)-C (-3.2, P < 0.01) to HDL(2b)-C (+3.5, P < 0.05) and HDL(2a)-C (+2.2 mg·dl(-1), P < 0.05), with increased HDL(2b) particle number (+313 nmol·l(-1), P < 0.05). Training reduced LDL(3) concentration and particle number in women (-1.6 mg·dl(-1) and -16 nmol·l(-1), P < 0.05). Acute exercise reduced the total cholesterol (TC): HDL-C ratio in men (-0.16, P < 0.01) and increased hsCRP in all subjects (+0.05 mg·dl(-1), P < 0.05), regardless of training. Training did not affect acute exercise responses. Our data support the efficacy of endurance training, without dietary intervention, to elicit beneficial changes in blood lipids-lipoproteins in obese men and women.     

Reduced plasma lipoprotein lipase activity in patients with malignancy-associated weight loss

Post-heparin plasma lipoprotein lipase activity was measured in 28 cancer patients with varying degrees of weight loss, and in 16 normal volunteers. Total lipoprotein lipase activity was decreased by 35.4% (P less than 0.001) in the cancer group. The component lipase activities, hepatic (HLPL), and peripheral (PLPL), were decreased by 40% (P less than 0.001) and 38% (P less than 0.005) respectively. In addition, the level of total peripheral lipoprotein lipase correlated well with the percent body weight lost by these patients (r = 0.6, P less than 0.01). Regardless of extent of disease, patients with lung cancer showed the lowest enzyme activity (mean 191 mU/ml +/- 30 SEM, P less than 0.001) and the greatest percent of weight loss (mean 16%), while patients with breast cancer had nearly normal lipase activity (mean 315 mU/ml +/- 50 SEM, normal 340 mU/ml +/- 22 SEM, P less than 0.10) and minimal weight loss (mean 8.4%). Fasting serum triglycerides were significantly elevated in the patient group (mean 120 mg/dl +/- 9.7 SEM) as compared to normal (mean 71 mg/dl +/- 7 SEM, P less than 0.001). The mean fasting insulin level was elevated in the patient group (13 mU/ml +/- 3.0 SEM), although in the majority of the patients it was found within the normal range (4-24 mU/ml). We conclude that the significant decrease in the total LPL activity may be responsible in part for the characteristic hypertriglyceridemia present in cancer patients.     

Weight Loss,Weight Maintenance,and Improved Cardiovascular Risk Factors after 2 Years Treatment with Orlistat for Obesity

Objective: To determine the effect of orlistat, a new lipase inhibitor, on long‐term weight loss, to determine the extent to which orlistat treatment minimizes weight regain in a second year of treatment, and to assess the effects of orlistat on obesity‐related risk factors. Research Methods and Procedures: This was a 2‐year, multicenter, randomized, double‐blind, placebo‐controlled study. Obese patients (body mass index 28 to 43 kg/m²) were randomized to placebo or orlistat (60 or 120 mg) three times a day, combined with a hypocaloric diet during the first year and a weight maintenance diet in the second year of treatment to prevent weight regain. Changes in body weight, lipid profile, glycemic control, blood pressure, quality of life, safety, and tolerability were measured. Results: Orlistat‐treated patients lost significantly more weight (p < 0.001) than placebo‐treated patients after Year 1 (6.6%, 8.6%, and 9.7% for the placebo, and orlistat 60 mg and 120 mg groups, respectively). During the second year, orlistat therapy produced less weight regain than placebo (p = 0.005 for orlistat 60 mg; p < 0.001 for orlistat 120 mg). Several obesity‐related risk factors improved significantly more with orlistat treatment than with placebo. Orlistat was generally well tolerated and only 6% of orlistat‐treated patients withdrew because of adverse events. Orlistat leads to predictable gastrointestinal effects related to its mode of action, which were generally mild, transient, and self‐limiting and usually occurred early during treatment. Discussion: Orlistat administered for 2 years promotes weight loss and minimizes weight regain. Additionally, orlistat therapy improves lipid profile, blood pressure, and quality of life.     

Randomised,double-blind,placebo-controlled crossover study to investigate different dosing regimens of olodaterol delivered via Respimat? in patients with moderate to severe persistent asthma

Background

A Phase II, multicentre, randomised, double-blind, placebo-controlled, crossover trial comparing the 24-h forced expiratory volume in 1 s (FEV₁) time profile after 3 weeks’ treatment with once-daily (QD) or twice-daily (BID) olodaterol (at the same total daily dose) versus placebo delivered via Respimat® in patients with moderate to severe asthma.

Methods

Patients were randomised to different sequences of olodaterol with 2-week washout, either as a total daily dose of 5 μg (5 μg QD [AM] or 2.5 μg BID) or placebo, or 10 μg (10 μg QD [AM] or 5 μg BID) or placebo. Primary end point was FEV₁ area under the curve from 0 to 24 h (AUC_0–24) response (defined as change from study baseline FEV₁) after 3 weeks. Key secondary end points were FEV₁ AUC_0–12 and AUC_12–24 responses.

Results

Two hundred and six patients received treatment. All olodaterol treatments demonstrated statistically significant improvements in FEV₁ AUC_0–24 response at 3 weeks versus placebo (p < 0.0001); adjusted mean treatment difference versus placebo was 0.191 L for olodaterol 2.5 μg BID (95 % confidence interval [CI] 0.152, 0.229), 0.150 L for 5 μg QD (95 % CI 0.111, 0.189), 0.228 L for 5 μg BID (95 % CI 0.190, 0.266) and 0.209 L for 10 μg QD (95 % CI 0.170, 0.247). These results were supported by the key secondary end points. Olodaterol 5 μg QD provided numerically lower mean values for 24-h bronchodilation than olodaterol 2.5 μg BID (p = 0.0465), with no statistically significant difference between treatment with olodaterol 10 μg QD and 5 μg BID. No relevant differences in morning and evening peak expiratory flow or Asthma Control Questionnaire scores at 3 weeks were observed between different doses and regimens. Adverse events were generally mild to moderate and comparable between groups.

Conclusions

All doses and dose frequencies provided adequate 24-h bronchodilation superior to placebo. Based on the results of this study, it would be reasonable to include both posologies of 5 μg olodaterol daily (5 μg QD or 2.5 μg BID, both delivered in two puffs per dose from the Respimat® inhaler) in subsequent studies. Further studies are necessary to confirm the optimum dosing regimen in asthma. No safety concerns were identified.

Trial registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01311661","term_id":"NCT01311661"}}NCT01311661

Electronic supplementary material

The online version of this article (doi:10.1186/s12931-015-0243-1) contains supplementary material, which is available to authorized users.     

Moderate effect of duodenal-jejunal bypass surgery on glucose homeostasis in patients with type 2 diabetes

Gastric bypass surgery causes resolution of type 2 diabetes (T2DM), which has led to the hypothesis that upper gastrointestinal (UGI) tract diversion, itself, improves glycemic control. The purpose of this study was to determine whether UGI tract bypass without gastric exclusion has therapeutic effects in patients with T2DM. We performed a prospective trial to assess glucose and β-cell response to an oral glucose load before and at 6, 9, and 12 months after duodenal-jejunal bypass (DJB) surgery. Thirty-five overweight or obese adults (BMI: 27.0 ± 4.0 kg/m(2)) with T2DM and 35 sex-, age-, race-, and BMI-matched subjects with normal glucose tolerance (NGT) were studied. Subjects lost weight after surgery, which was greatest at 3 months (6.9 ± 4.9%) with subsequent regain to 4.2 ± 5.3% weight loss at 12 months after surgery. Glycated hemoglobin (HbA(1c)) decreased from 9.3 ± 1.6% before to 7.7 ± 2.0% at 12 months after surgery (P < 0.001), in conjunction with a 20% decrease in the use of diabetes medications (P < 0.05); 7 (20%) subjects achieved remission of diabetes (no medications and HbA(1c) <6.5%). The area under the curve after glucose ingestion was ~20% lower for glucose but doubled for insulin and C-peptide at 12 months, compared with pre-surgery values (all P < 0.01). However, the β-cell response was still 70% lower than subjects with NGT (P < 0.001). DJB surgery improves glycemic control and increases, but does not normalize the β-cell response to glucose ingestion. These findings suggest that altering the intestinal site of delivery of ingested nutrients has moderate therapeutic effects by improving β-cell function and glycemic control.     

NXX-066 in patients with Alzheimer's disease: a bridging study

Reduced cholinergic transmission is a key neurotransmitter dysfunction in Alzheimer's Disease (AD). NXX-066, a physostigmine analog and acetylcholinesterase (AChE) inhibitor, has demonstrated activity in animal models of memory function, and was well tolerated in healthy subjects up to a single dose of 64 mg and multiple doses of 60 mg QD for seven days. Since AChE inhibitors are often tolerated differently in AD patients than in healthy volunteers, a randomized, placebo-controlled, double-blind, single-center, inpatient bridging study was conducted to determine the maximum tolerated dose (MTD) of NXX-066 in the target patient population. Seven consecutive panels of eight AD patients each (6 active, 2 placebo) received fixed oral doses of NXX-066 (20, 30, 40, 50, 60, 70, or 80 mg BID) for seven days. Initiation of each subsequent panel (dose group) was contingent upon the tolerability of lower dose levels. The MTD was determined to be 70 mg BID when four of six patients receiving 80 mg BID were prematurely discontinued from the study due to nausea and/or vomiting, accompanied in some patients by mild to moderate dizziness, headache, asthenia, and gastric symptoms. Wide variability in plasma levels of NXX-066 was observed in all dose panels. AChE inhibition in whole blood correlated with both maximum plasma concentration and dose; however, AChE inhibition was not predictive of adverse events. In this study, AD patients tolerated larger daily doses of NXX-066 on a BID regimen than healthy normal subjects had tolerated with QD dosing. Further studies are warranted to examine whether differing tolerability between patients and healthy subjects or the reduced dosing interval explains these findings.     

Association of low plasma high density lipoprotein (HDL)-cholesterol concentration with documented coronary artery disease in males with non-insulin dependent diabetes mellitus

Plasma lipid and lipoprotein concentrations were determined in 30 males without diabetes or symptomatic coronary artery disease (CAD), and compared to the values in age-matched and weight-matched males (n = 55) with non-insulin-dependent diabetes mellitus (NIDDM). Patients with NIDDM were further subdivided into those with (n = 30) and without (n =25) CAD. Mean (+/- SEM) plasma triglyceride concentrations were significantly increased (P less than 0.001) over control values (96 +/- 5 mg/dl) in patients with NIDDM, whether with (172 +/- 14 mg/dl) or without documented CAD (164 +/- 25 mg/dl). Plasma cholesterol concentrations were also higher (P less than 0.001) than normal (168 +/- 5 mg/dl) in both groups of patients with NIDDM (201 +/- 11 and 199 +/- 7 mg/dl, respectively, in patients with and without evidence of CAD). Plasma LDL-cholesterol concentrations were also greater (P less than 0.001) than normal (104 +/- 4 mg/dl) in patients with NIDDM, but were again similar in the group of diabetics (120 +/- 9 vs 128 +/- 6 mg/dl). However, plasma HDL-cholesterol concentrations were only reduced below control values in diabetes patients with CAD (30 +/- 1 mg/dl), whereas patients with NIDDM and no subjective evidence of CAD had HDL-cholesterol concentrations (37 +/- 3 mg/dl) which were similar to normal values (38 +/- 2 mg/dl). As a result, the ratio of LDL-cholesterol to HDL-cholesterol was highest in patients with NIDDM and CAD (4.2 +/- 0.3), lowest in the control population (2.8 +/- 0.2), and intermediate in those patients with NIDDM without subjective or objective evidence of CAD (3.6 +/- 0.3).(ABSTRACT TRUNCATED AT 250 WORDS)     

Renal resistance to vasopressin in poorly controlled type 1 diabetes mellitus

To investigate the hypothesis that diabetes induces nephrogenic diabetes insipidus, we studied the urine-concentrating ability in response to vasopressin (AVP) in 12 patients with insulin-dependent diabetes mellitus (IDDM) and 12 nondiabetic controls. Subjects were euglycemic-clamped, and after oral water loading, AVP was infused intravenously for 150 min. AVP induced a greater (P<0.001) rise in urine osmolality in controls (67.6+/-10.7 to 720+/-31.1 mosmol/kg, P<0.001) than in IDDM patients (64.3+/-21.6 to 516.7+/-89.3 mosmol/kg, P<0.001). Urinary aquaporin-2 concentrations after AVP infusion were higher in controls (611.8+/-105.6 fmol/mg creatinine) than in IDDM (462.0+/-94.9 fmol/mg creatinine, P = 0. 003). Maximum urine osmolality in IDDM was inversely related to chronic blood glucose control, as indicated by Hb A(Ic) (r = -0.87, P = 0.002). To test the hypothesis that improved glycemic control could reverse resistance to AVP, 10 IDDM subjects with poor glycemic control (Hb A(Ic) >9%) were studied before (B) and after (A) intensified glycemic control. Maximum urine osmolality in response to AVP increased with improved glycemic control (B, 443.8+/-49.0; A, 640.0+/-137.2 mosmol/kg, P<0.001), and urinary aquaporin-2 concentrations after AVP increased from 112.7 +/-69 to 375+/-280 fmol/mg creatinine (P = 0.006), with improved glycemic control. Poorly controlled IDDM is associated with reversible renal resistance to AVP.     

Effects of an oral androgen on muscle and metabolism in older,community-dwelling men

To determine whether oxymetholone increases lean body mass (LBM) and skeletal muscle strength in older persons, 31 men 65-80 yr of age were randomized to placebo (group 1) or 50 mg (group 2) or 100 mg (group 3) daily for 12 wk. For the three groups, total LBM increased by 0.0 +/- 0.6, 3.3 +/- 1.2 (P < 0.001), and 4.2 +/- 2.4 kg (P < 0.001), respectively. Trunk fat decreased by 0.2 +/- 0.4, 1.7 +/- 1.0 (P = 0.018), and 2.2 +/- 0.9 kg (P = 0.005) in groups 1, 2, and 3, respectively. Relative increases in 1-repetition maximum (1-RM) strength for biaxial chest press of 8.2 +/- 9.2 and 13.9 +/- 8.1% in the two active treatment groups were significantly different from the change (-0.8 +/- 4.3%) for the placebo group (P < 0.03). For lat pull-down, 1-RM changed by -0.6 +/- 8.3, 8.8 +/- 15.1, and 18.4 +/- 21.0% for the groups, respectively (1-way ANOVA, P = 0.019). The pattern of changes among the groups for LBM and upper-body strength suggested that changes might be related to dose. Alanine aminotransferase increased by 72 +/- 67 U/l in group 3 (P < 0.001), and HDL-cholesterol decreased by -19 +/- 9 and -23 +/- 18 mg/dl in groups 2 and 3, respectively (P = 0.04 and P = 0.008). Thus oxymetholone improved LBM and maximal voluntary muscle strength and decreased fat mass in older men.     

Vildagliptin in drug-na?ve patients with type 2 diabetes: a 24-week, double-blind, randomized, placebo-controlled, multiple-dose study.

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   

Effects of oral and intravenous fat load on blood pressure, endothelial function, sympathetic activity, and oxidative stress in obese healthy subjects

We compared the effects of high and low oral and intravenous (iv) fat load on blood pressure (BP), endothelial function, autonomic nervous system, and oxidative stress in obese healthy subjects. Thirteen obese subjects randomly received five 8-h infusions of iv saline, 20 (32 g, low iv fat) or 40 ml/h intralipid (64 g, high iv fat), and oral fat load at 32 (low oral) or 64 g (high oral). Systolic BP increased by 14 ± 10 (P = 0.007) and 12 ± 9 mmHg (P = 0.007) after low and high iv lipid infusions and by 13 ± 17 (P = 0.045) and 11 ± 11 mmHg (P = 0.040) after low and high oral fat loads, respectively. The baseline flow-mediated dilation was 9.4%, and it decreased by 3.8 ± 2.1 (P = 0.002) and 4.1 ± 3.1% (P < 0.001) after low and high iv lipid infusion and by 3.8 ± 1.8 (P = 0.002) and 5.0 ± 2.5% (P < 0.001) after low and high oral fat load, respectively. Oral and iv fat load stimulated oxidative stress, increased heart rate, and decreased R-R interval variability. Acute iv fat load decreased blood glucose by 6-10 mg/dl (P < 0.05) without changes in insulin concentration, whereas oral fat increased plasma insulin by 3.7-4.0 μU/ml (P < 0.01) without glycemic variations. Intravenous saline and both oral and iv fat load reduced leptin concentration from baseline (P < 0.01). In conclusion, acute fat load administered orally or intravenously significantly increased blood pressure, altered endothelial function, and activated sympathetic nervous system by mechanisms not likely depending on changes in leptin, glucose, and insulin levels in obese healthy subjects. Thus, fat load, independent of its source, has deleterious hemodynamic effects in obese subjects.     

Differential gender responses to hypoglycemia are due to alterations in CNS drive and not glycemic thresholds

The aims of this study were 1) to determine whether differential glycemic thresholds are the mechanism responsible for the sexual dimorphism present in neuroendocrine responses during hypoglycemia and 2) to define the differences in counterregulatory physiological responses that occur over a range of mild to moderate hypoglycemia in healthy men and women. Fifteen (8 male, 7 female) lean healthy adults underwent four separate randomized 2-h hyperinsulinemic (1.5 mU. kg(-1).min(-1)) glucose clamp studies at euglycemia (90 mg/dl) or hypoglycemia of 70, 60, or 50 mg/dl. Plasma insulin levels were similar during euglycemic and hypoglycemic studies (91-96 +/- 8 microU/ml) in men and women. Hypoglycemia of 70, 60, and 50 mg/dl all resulted in significant increases (P < 0.05, P < 0.01) in epinephrine, glucagon, growth hormone, cortisol, and pancreatic polypeptide levels compared with euglycemic studies in men and women. Plasma norepinephrine levels were increased (P < 0.05) only relative to euglycemic studies at a hypoglycemia of 50 mg/dl. Muscle sympathetic nerve activity (MSNA) increased significantly during hyperinsulinemic-euglycemic control studies. Further elevations of MSNA did not occur until hypoglycemia of 60 mg/dl in both men and women. Plasma epinephrine, glucagon, growth hormone, and pancreatic polypeptide were significantly increased in men compared with women during hypoglycemia of 70, 60, and 50 mg/dl. MSNA, heart rate, and systolic blood pressure responses were also significantly increased in men at hypoglycemia of 60 and 50 mg/dl. In summary, these studies have demonstrated that, in healthy men and women, the glycemic thresholds for activation of epinephrine, glucagon, growth hormone, cortisol, and pancreatic polypeptide occur between 70 and 79 mg/dl. Thresholds for activation of MSNA occur between 60 and 69 mg/dl, whereas norepinephrine is not activated until glycemia is between 50 and 59 mg/dl. We conclude that 1) differential glycemic thresholds are not the cause of the sexual dimorphism present in counterregulatory responses to hypoglycemia; 2) reduced central nervous system efferent input appears to be the mechanism responsible for lowered neuroendocrine responses to hypoglycemia in women; and 3) physiological counterregulatory responses (neuroendocrine, cardiovascular, and autonomic nervous system) are reduced across a broad range of hypoglycemia in healthy women compared with healthy men.     

Maraviroc, a chemokine receptor-5 antagonist, fails to demonstrate efficacy in the treatment of patients with rheumatoid arthritis in a randomized, double-blind placebo-controlled trial

Introduction

The purpose of this study was to determine whether maraviroc, a human CC chemokine receptor 5 (CCR5) antagonist, is safe and effective in the treatment of active rheumatoid arthritis (RA) in patients on background methotrexate (MTX).

Methods

This phase IIa study comprised two distinct components: an open-label safety study of the pharmacokinetics (PK) of MTX in the presence of maraviroc, and a randomized, double-blind, placebo-controlled, proof-of-concept (POC) component. In the PK component, patients were randomized 1:1 to receive maraviroc 150 or 300 mg twice daily (BID) for four weeks. In the POC component, patients were randomized 2:1 to receive maraviroc 300 mg BID or placebo for 12 weeks. Patients were not eligible for inclusion in both components.

Results

Sixteen patients were treated in the safety/PK component. Maraviroc was well tolerated and there was no evidence of drug-drug interaction with MTX. One hundred ten patients were treated in the POC component. The study was terminated after the planned interim futility analysis due to lack of efficacy, at which time 59 patients (38 maraviroc; 21 placebo) had completed their week 12 visit. There was no significant difference in the number of ACR20 responders between the maraviroc (23.7%) and placebo (23.8%) groups (treatment difference -0.13%; 90% CI -20.45, 17.70; P = 0.504). The most common all-causality treatment-emergent adverse events in the maraviroc group were constipation (7.8%), nausea (5.2%), and fatigue (3.9%).

Conclusions

Maraviroc was generally well tolerated over 12 weeks; however, selective antagonism of CCR5 with maraviroc 300 mg BID failed to improve signs and symptoms in patients with active RA on background MTX.

Trial Registration

ClinicalTrials.gov: NCT00427934     

Loss of the preconditioning effect of rosuvastatin during sustained therapy: a human in vivo study

Studies have demonstrated that the acute administration of 3-hydroxy-3 methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors has protective effects in the setting of ischemia-reperfusion (IR). Previously, we demonstrated that a single dose of rosuvastatin prevented IR-induced endothelial dysfunction in humans through a cyclooxygenase-2-dependent mechanism. Whether the chronic administration of HMG-CoA reductase inhibitors provides similar protection remains controversial and is unknown in humans. Eighteen male volunteers were randomized to receive a single dose of rosuvastatin (20 mg) or placebo. Twenty-four hours later, endothelium-dependent, radial artery flow-mediated dilation (FMD) was measured before and after IR (15 min of upper arm ischemia followed by 15 min of reperfusion). In a separate protocol, 30 healthy volunteers were randomized in a double-blind fashion to receive oral rosuvastatin (20 mg/day) and placebo, rosuvastatin, and celecoxib (100 mg bid) or placebo alone, all for 21 days. Twenty-four hours after the final administration of study medication, FMD was measured before and after IR. Pre-IR FMD was similar between groups in both protocols. In the acute administration protocol, rosuvastatin significantly prevented the blunting of FMD associated with IR (FMD pre-IR: 8.4 ± 1.3%; post-IR: 6.2 ± 1.3%; P = 0.01 ANOVA, treatment group interaction). In the daily administration protocol, IR significantly blunted FMD in the placebo group (FMD pre-IR: 7.5 ± 0.9%; post-IR: 3.3 ± 0.7%; P < 0.001). Chronic treatment with rosuvastatin did not modify this ischemic injury (FMD pre-IR: 6.9 ± 0.4%; post-IR: 1.6 ± 1.0%; P < 0.001; P = NS ANOVA, treatment group interaction). Similarly, FMD responses post-IR in volunteers receiving rosuvastatin and celecoxib did not significantly differ from placebo (FMD pre-IR: 8.3 ± 0.9%; post-IR: 2.1 ± 0.8%; P < 0.001; P = NS ANOVA, treatment group interaction). In contrast to acute administration, chronic rosuvastatin does not prevent the development of IR-induced endothelial dysfunction in normal humans.     

Long-term outcome comparison for standard fractionation (&gt;59 Gy) versus hyperfractionated (&gt;45 Gy) radiotherapy plus concurrent chemotherapy for limited-stage small-cell lung cancer

BackgroundConcurrent chemoradiotherapy (CCRT) is commonly employed in limited-stage small-cell lung cancer (LS-SCLC); however, the optimal radiotherapy regimen is still unknown. This 3-institution analysis compares long-term disease control and survival outcomes for once- (QD) versus twice-daily (BID) radiotherapy at contemporary doses.Methods and MaterialsData were collected for LS-SCLC patients treated with platinum-based CCRT and planned RT doses of >5940 cGy at >180 cGy QD or >4500 cGy at 150 cGy BID. Comparative outcome analyses were performed for treatment groups.ResultsFrom 2005 through 2014, 132 patients met inclusion criteria for analysis (80 QD, 52 BID). Treatment groups were well-balanced, excepting higher rate of advanced mediastinal staging, longer interval from biopsy to treatment initiation, and lower rate of prophylactic cranial irradiation for the QD group, as well as institutional practice variation. At median survivor follow-up of 33.5 months (range, 4.6–105.8), 80 patients experienced disease failure (44 QD, 36 BID), and 106 died (62 QD, 44 BID). No differences in disease control or survival were demonstrated between treatment groups.ConclusionThe present analysis did not detect a difference in disease control or survival outcomes for contemporary dose QD versus BID CCRT in LS-SCLC.