ABSTRACT
Background: This study evaluated the effects of exenatide, a GLP-1 receptor agonist, and sitagliptin, a DPP-4 inhibitor, on 2-h postprandial glucose (PPG), insulin and glucagon secretion, ...gastric emptying, and caloric intake in T2D patients.
Methods: This double-blind, randomized cross-over, multi-center study was conducted in metformin-treated T2D patients: 54% female; BMI: 33 ± 5 kg/m2; HbA1c: 8.5 ± 1.2%; 2-h PPG: 245 ± 65 mg/dL. Patients received exenatide (5 µg BID for 1 week, then 10 µg BID for 1 week) or sitagliptin (100 mg QAM) for 2 weeks. After 2 weeks, patients crossed-over to the alternate therapy. Postprandial glycemic measures were assessed via standard meal test; caloric intake assessed by ad libitum dinner (subset of patients). Gastric emptying was assessed by acetaminophen absorption (Clinicaltrials.gov Registry Number: NCT00477581).
Results: After 2 weeks of therapy, 2-h PPG was lower with exenatide versus sitagliptin: 133 ± 6 mg/dL versus 208 ± 6 mg/dL, p < 0.0001 (evaluable, N = 61). Switching from exenatide to sitagliptin increased 2-h PPG by +73 ± 11 mg/dL, while switching from sitagliptin to exenatide further reduced 2-h PPG by −76 ± 10 mg/dL. Postprandial glucose parameters (AUC, Cave, Cmax) were lower with exenatide than sitagliptin (p < 0.0001). Reduction in fasting glucose was similar with exenatide and sitagliptin (−15 ± 4 mg/dL vs. −19 ± 4 mg/dL, p = 0.3234). Compared to sitagliptin, exenatide improved the insulinogenic index of insulin secretion (ratio exenatide to sitagliptin: 1.50 ± 0.26, p = 0.0239), reduced postprandial glucagon (AUC ratio exenatide to sitagliptin: 0.88 ± 0.03, p = 0.0011), reduced postprandial triglycerides (AUC ratio exenatide to sitagliptin: 0.90 ± 0.04, p = 0.0118), and slowed gastric emptying (acetaminophen AUC ratio exenatide to sitagliptin: 0.56 ± 0.05, p < 0.0001). Exenatide reduced total caloric intake compared to sitagliptin (−134 ± 97 kcal vs. +130 ± 97 kcal, p = 0.0227, N = 25). Common adverse events with both treatments were mild to moderate in intensity and gastrointestinal in nature.
Conclusions: Although this study was limited by a 2-week duration of exposure, these data demonstrate that, exenatide had: (i) a greater effect than sitagliptin to lower postprandial glucose and (ii) a more potent effect to increase insulin secretion and reduce postprandial glucagon secretion in T2D patients. In contrast to sitagliptin, exenatide slowed gastric emptying and reduced caloric intake. These key findings differentiate the therapeutic actions of the two incretin-based approaches, and may have meaningful clinical implications.
Abstract Purpose The primary analysis of the ASPECCT study demonstrated that panitumumab was non-inferior to cetuximab for overall survival (OS) in patients with chemotherapy-refractory wild-type ...KRAS exon 2 metastatic colorectal cancer (mCRC). Here, we report the final analysis results of ASPECCT. Patients and methods Patients with wild-type KRAS exon 2 mCRC who progressed on or were intolerant to irinotecan- or oxaliplatin-based chemotherapy were randomised to receive panitumumab 6 mg/kg once every 2 weeks or cetuximab (400 mg/m2 ) followed by 250 mg/m2 weekly. The primary end-point was OS assessed for non-inferiority. Patients were followed for survival for 24 months after the last patient was randomised and a final analysis was conducted. No formal hypothesis testing was done. Post hoc analyses of outcomes by prior bevacizumab exposure, worst-grade skin toxicity (0–1 versus 2–4) and worst-grade hypomagnesaemia (0 versus 1–4) were conducted. Results Nine hundred ninety-nine patients were randomised and received ≥1 treatment dose (panitumumab, n = 499; cetuximab, n = 500). Median OS was 10.2 months with panitumumab versus 9.9 months with cetuximab (hazard ratio = 0.94; 95% confidence interval = 0.82–1.07). Median progression-free survival was 4.2 months with panitumumab and 4.4 months with cetuximab (hazard ratio = 0.98; 95% confidence interval = 0.87–1.12). Longer OS was observed for patients with increased skin toxicity and with hypomagnesaemia in both arms. Furthermore, OS was longer for patients with prior bevacizumab exposure treated with panitumumab than with cetuximab. The observed safety profiles were consistent with previous studies. Conclusion Consistent with the primary analysis, the final analysis of ASPECCT showed panitumumab was non-inferior to cetuximab for OS for patients with chemotherapy-refractory, wild-type KRAS exon 2 mCRC. Trial registration: ClinicalTrials.gov , NCT01001377.
Abstract Background: Exenatide, an incretin mimetic for adjunctive treatment of type 2 diabetes mellitus (T2DM), reduced glycosylated hemoglobin (HbA1c ) and weight in 30-week placebo-controlled ...trials. Some patients were followed up in open-label extensions to provide ‘real-world’ exenatide clinical experience. Objective: The purpose of this study was to examine the metabolic effects of 2 years of exenatide treatment in patients with T2DM. Methods: For this interim analysis, data were pooled from patients who completed 1 of three 30-week, multicenter, double-blind, placebo-controlled trials and their open-label extensions. In the initial trials, subjects were randomized to BID 5-pg exenatide, 10-pg exenatide, or placebo for 30 weeks. All subjects who enrolled in the extension phase then received 5-pg exenatide BID for 4 weeks, followed by open-label treatment with 10-pg exenatide BID. Subjects continued their existing metformin and/or sulfonylurea regimens. Analyses were conducted on data from all subjects who had the opportunity to achieve 2 years of exenatide exposure, irrespective of their treatment arm in the 30-week placebo-controlled trials. Results: A total of 974 patients entered the open-label, extension phase of the trial. Two hundred eighty-three subjects (mean SD age, 57 10 years; mean SD weight, 100 119 kg; sex, 63% male; mean SD body mass index, 34 6 kg/m2; mean SD HbA1c , 8.3% 1.0%1 completed 2 years of exenatide treatment. Reductions in mean (SE) HbA1c from baseline to week 30 (−0.9% 0.1%) were sustained through 2 years (−1.1% 0.1%; P < 0.05 vs baseline), with 50% of the population achieving HbA1c ≤ 7%. At week 30, exenatide was associated with a significant reduction in mean (SD) body weight from baseline (−2.1 0.2 kg), with progressive reductions after 2 years (−4.7 0.3 kg; P < 0.001 vs baseline). Patients with normal baseline alanine aminotransferase (ALT) (132/283 47%; normal: female ≤19 IU/L; male ≤30 IU/L) had no significant ALT change. However, patients with elevated ALT at baseline (151/283 53%) had a mean (SEM) reduction of ALT (−11 1 IU/L from baseline 38 1 IU/1,; P < 0.05) and 39% achieved normal ALT by week 104. Patients with elevated ALT at baseline lost significantly more weight than patients with normal ALT at baseline ( P = 0.04). However, weight change was minimally correlated with baseline ALT ( r = −0.09) or ALT change ( r = 0.31). Also, homeostasis model assessment of the β-cell function (HOMA-B), blood pressure, and aspartate aminotransferase (AST) all improved. The most frequently reported adverse event was mild-to-moderate nausea. Conclusions: In these patients with T2DM, adjunctive exenatide treatment for 2 years was generally well tolerated and resulted in a sustained reduction of HbA1c , progressive reduction in weight, and improvements in HOMA-B, blood pressure, and the hepatic injury biomarkers, AST and ALT.
Whether the helicopter or the aerotransport, NDT methods are used in the development phase, manufacture phase, use phase and maintenance phase. Especially penetrant testing is the efficient measure. ...We confirm the parts which do the penetrant testing according to the load in the development phase; Have penetrant testing after the working procedure which produce the defects in manufacture phase; Have penetrant testing for the area which use the big load in use phase. We must ensure the validity of penetrant testing in every phase. The arrangement of penetrant procedure, surface prepare of machine parts, protection of on-working parts, these are all the problems in the practice working. We analysis and innovate these problems, halve the experience with the other NDT technicians.
Abstract Objective: This study assessed the pharmacokinetics, pharmacodynamics, and tolerability of single doses of exenatide in adolescent patients with type 2 diabetes mellitus (T2DM). Methods: ...This was a randomized, single-blind, dose-escalation, crossover study in adolescent (age 10–16 years) patients with T2DM who were being treated with diet and exercise or a stable dose of metformin, a sulfonylurea, or a combination of metformin and a sulfonylurea for at least 3 months before screening. Eligible patients were allocated to receive single subcutaneous doses of exenatide 2.5 μg, exenatide 5 μg, and placebo, each followed by a standardized meal, on 3 separate days (maximum interval between first and third doses, 5 weeks). Exenatide 2.5 μg always preceded exenatide 5 μg in each treatment sequence. The primary end points were the pharmacokinetics and safety profile of exenatide; secondary end points included postprandial plasma glucose, serum insulin, and plasma glucagon concentrations. Results: The study enrolled 13 adolescent patients with T2DM (7 females, 6 males; mean SD age, 15 1 years; body mass index, 32.5 5.0 kg/m2 ; glycosylated hemoglobin, 8.2% 1.5%). After administration of exenatide 5 μg, the geometric mean (SE) exenatide AUC0−∞ and Cmax were 339.5 (39.6) pg · h/mL and 85.1 (11.5) pg/mL, respectively (n = 12). The exenatide AUC appeared to be dose dependent, although exenatide was not quantifiable in all patients at the 2.5-μg dose; after administration of exenatide 2.5-μg, the geometric mean AUC0−∞ ) was 159.2 (23.1) pg · h/mL (n = 6) and the geometric mean Cmax was 56.3 (10.1) pg/mL (n = 9). Both exenatide doses were associated with significant reductions in postprandial plasma glucose excursions compared with placebo ( P < 0.01); the incremental mean (SE) AUC15–360min was −3465.6 (1587.3) mg · min/dL for exenatide 2.5 pg, −4422.2 (2434.4) mg · min/dL for exenatide 5 μg, and 3457.4 (1615.5) mg · min/dL for placebo. The 2 exenatide doses were also associated with significant reductions in postprandial plasma glucagon concentrations compared with placebo ( P < 0.01); the respective incremental mean values for AUC15–180min were 125.5 (658.4), −1403.8 (632.1), and 1843.1 (540.6) pg · min/mL. There were no significant differences in serum insulin concentrations between exenatide and placebo. Exenatide was generally well tolerated, with no hypoglycemic events recorded during the study. Conclusions: In these adolescent patients with T2DM, administration of single 2.5- and 5-μg doses of exenatide were associated with dose-dependent increases in plasma exenatide concentrations and improved postprandial glucose concentrations compared with placebo. Both doses appeared to be well tolerated. ClinicalTrials.gov Identifier: NCT00254254.
The dissertation introduced the development of the real-time imaging inspection technique, and contrast study of the techniques of the radiography on film and real-time imaging from the principle, ...technique parameter, system composing, post disposal manner and archive. Taking a verification test of inspected the main rotor blade and composite material insert part with the radiography on film and real-time imaging, the result is that the two kinds of inspection techniques are similar in two kinds of parts. If using the real-time imaging technique can improve the working efficiency, reduce the labor intensity and improve environmental protection. However, there are no evaluation criteria of imaging for the real-time imaging technique now, and still using the criteria films as the acceptance criteria. The radiography on film is the main inspection means, but the real-time imaging technique will be the development direction.
ABSTRACT
Background: Exenatide, an incretin mimetic for adjunctive treatment of type 2 diabetes (T2DM), reduced hemoglobin A1c (A1C) and weight in clinical trials. The objective of this study was to ...evaluate the effects of ≥ 3 years exenatide therapy on glycemic control, body weight, cardiometabolic markers, and safety.
Methods: Patients from three placebo-controlled trials and their open-label extensions were enrolled into one open-ended, open-label clinical trial. Patients were randomized to twice daily (BID) placebo, 5 µg exenatide, or 10 µg exenatide for 30 weeks, followed by 5 µg exenatide BID for 4 weeks, then 10 µg exenatide BID for ≥3 years of exenatide exposure. Patients continued metformin and/or sulfonylureas.
Results: 217 patients (64% male, age 58 ± 10 years, weight 99 ± 18 kg, BMI 34 ± 5 kg/m2, A1C 8.2 ± 1.0% mean ± SD) completed 3 years of exenatide exposure. Reductions in A1C from baseline to week 12 (−1.1 ± 0.1% mean ± SEM) were sustained to 3 years (−1.0 ± 0.1%; p < 0.0001), with 46% achieving A1C ≤ 7%. Exenatide progressively reduced body weight from baseline (−5.3 ± 0.4 kg at 3 years; p < 0.0001). Patients with elevated serum alanine aminotransferase (ALT) at baseline (n = 116) had reduced ALT (−10.4 ± 1.5 IU/L; p < 0.0001) and 41% achieved normal ALT. Patients with elevated ALT at baseline tended to lose more weight than patients with normal ALT at baseline (−6.1 ± 0.6 kg vs. −4.4 ± 0.5 kg; p = 0.03), however weight change was minimally correlated with baseline ALT (r = −0.01) or ALT change (r = 0.31). Homeostasis Model Assessment B (HOMA-B), blood pressure, and aspartate aminotransferase (AST) all improved. A subset achieved 3.5 years of exenatide exposure and had serum lipids available for analysis (n = 151). Triglycerides decreased 12% (p = 0.0003), total cholesterol decreased 5% (p = 0.0007), LDL-C decreased 6% (p < 0.0001), and HDL-C increased 24% (p < 0.0001). Exenatide was generally well tolerated. The most frequent adverse event was mild-to-moderate nausea. The main limitation of this study is the open-label, uncontrolled nature of the study design which does not provide a placebo group for comparison.
Conclusion: Adjunctive exenatide treatment for ≥3 years in T2DM patients resulted in sustained improvements in glycemic control, cardiovascular risk factors, and hepatic biomarkers, coupled with progressive weight reduction.
Purpose
To report planned final overall (OS) and progression-free survival (PFS) analyses from the phase II PEAK trial (NCT00819780).
Methods
Patients with previously untreated,
KRAS
exon 2 wild-type ...(WT) metastatic colorectal cancer (mCRC) were randomised to mFOLFOX6 plus panitumumab or bevacizumab. The primary endpoint was PFS; secondary endpoints included OS, objective response rate, duration of response (DoR), time to response, resection and safety. Treatment effect by tumour
RAS
status was a prespecified objective. Exploratory analyses included early tumour shrinkage (ETS) and depth of response (DpR).
Results
One hundred seventy patients had
RAS
WT and 156 had
RAS
WT/
BRAF
WT mCRC. Median PFS was longer for panitumumab versus bevacizumab in the
RAS
WT (12.8 vs 10.1 months; hazard ratio (HR) = 0.68 95% confidence intervals (CI) = 0.48–0.96;
p =
0.029) and
RAS
WT/
BRAF
WT (13.1 vs 10.1 months; HR = 0.61 95% CI = 0.42–0.88;
p =
0.0075) populations. Median OS (68% OS events) for panitumumab versus bevacizumab was 36.9 versus 28.9 months (HR = 0.76 95% CI = 0.53–1.11;
p =
0.15) and 41.3 versus 28.9 months (HR = 0.70 95% CI = 0.48–1.04;
p =
0.08), in the
RAS
WT and
RAS
WT/
BRAF
WT populations, respectively. Median DoR (11.4 vs 9.0 months; HR = 0.59 95% CI = 0.39–0.88;
p =
0.011) and DpR (65.0 vs 46.3%;
p =
0.0018) were improved in the panitumumab group. More panitumumab patients experienced ≥30% ETS at week 8 (64 vs 45%;
p =
0.052); ETS was associated with improved PFS/OS. No new safety signals occurred.
Conclusions
First-line panitumumab + mFOLFOX6 increases PFS versus bevacizumab + mFOLFOX6 in patients with
RAS
WT mCRC.
Exenatide, an incretin mimetic for adjunctive treatment of type 2 diabetes (T2DM), reduced hemoglobin A(1c) (A1C) and weight in clinical trials. The objective of this study was to evaluate the ...effects of > or = 3 years exenatide therapy on glycemic control, body weight, cardiometabolic markers, and safety.
Patients from three placebo-controlled trials and their open-label extensions were enrolled into one open-ended, open-label clinical trial. Patients were randomized to twice daily (BID) placebo, 5 mug exenatide, or 10 mug exenatide for 30 weeks, followed by 5 mug exenatide BID for 4 weeks, then 10 mug exenatide BID for > or = 3 years of exenatide exposure. Patients continued metformin and/or sulfonylureas.
217 patients (64% male, age 58 +/- 10 years, weight 99 +/- 18 kg, BMI 34 +/- 5 kg/m(2), A1C 8.2 +/- 1.0% mean +/- SD) completed 3 years of exenatide exposure. Reductions in A1C from baseline to week 12 (-1.1 +/- 0.1% mean +/- SEM) were sustained to 3 years (-1.0 +/- 0.1%; p < 0.0001), with 46% achieving A1C < or = 7%. Exenatide progressively reduced body weight from baseline (-5.3 +/- 0.4 kg at 3 years; p < 0.0001). Patients with elevated serum alanine aminotransferase (ALT) at baseline (n = 116) had reduced ALT (-10.4 +/- 1.5 IU/L; p < 0.0001) and 41% achieved normal ALT. Patients with elevated ALT at baseline tended to lose more weight than patients with normal ALT at baseline (-6.1 +/- 0.6 kg vs. -4.4 +/- 0.5 kg; p = 0.03), however weight change was minimally correlated with baseline ALT (r = -0.01) or ALT change (r = 0.31). Homeostasis Model Assessment B (HOMA-B), blood pressure, and aspartate aminotransferase (AST) all improved. A subset achieved 3.5 years of exenatide exposure and had serum lipids available for analysis (n = 151). Triglycerides decreased 12% (p = 0.0003), total cholesterol decreased 5% (p = 0.0007), LDL-C decreased 6% (p < 0.0001), and HDL-C increased 24% (p < 0.0001). Exenatide was generally well tolerated. The most frequent adverse event was mild-to-moderate nausea. The main limitation of this study is the open-label, uncontrolled nature of the study design which does not provide a placebo group for comparison.
Adjunctive exenatide treatment for > or = 3 years in T2DM patients resulted in sustained improvements in glycemic control, cardiovascular risk factors, and hepatic biomarkers, coupled with progressive weight reduction.
PDF
