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241.
Xin-gang Li Liang Li Xuan Zhou Ye Chen Yu-peng Ren Tian-yan Zhou Wei Lu 《Acta pharmacologica Sinica》2012,33(11):1379-1386
Aim:
To quantitatively evaluate the blood glucose-lowering effect of exenatide in diabetic rats.Methods:
Male Harlan-Sprague-Dawley rats were treated with high-fat diet/streptozotocin to induce type 2 diabetes. After subcutaneous administration of a single dose of exenatide (4.2, 42, or 210 μg/kg), serum exenatide, insulin concentration and blood glucose were measured. The pharmacokinetics of exenatide was characterized by a two-compartment model with first-order absorption. Insulin turnover was characterized by an effect compartment and indirect response combined model. Glucose turnover was described using an indirect response model with insulin (in effect compartment) stimulating glucose disposition and insulin (in insulin compartment) inhibiting glucose production simultaneously. The model parameters were estimated using nonlinear mixed-effects model program. Visual predictive check and model evaluation were used to make assessments.Results:
Exenatide exhibited rapid absorption with ka=4.45 h-1, and the two-compartment model well described its pharmacokinetic profile. For the pharmacodynamic model, exenatide increased insulin release with the estimated Sm1 of 0.822 and SC50 of 4.02 μg/L. It was demonstrated that insulin stimulated glucose dissipation (Sm2=0.0513) and inhibited the production of glucose (Im=0.0381). Visual predictive check and model evaluation study indicated that a credible model was developed.Conclusion:
The glucose-lowering effect of exenatide in diabetic rats is reliably described and predicted by the combined effect compartment/indirect response model. 相似文献242.
Kevin Niswender 《Diabetes, obesity & metabolism》2010,12(4):267-287
Obesity is a major risk factor for the development of diabetes and predisposes individuals to hypertension and dyslipidaemia. Together these pathologies increase the risk for cardiovascular disease (CVD), the major cause of morbidity and mortality in type 2 diabetes mellitus (T2DM). Worsening trends in obesity and T2DM raise a serious conundrum, namely, how to control blood glucose, blood pressure, and lipids when many antidiabetic agents cause weight gain and thereby exacerbate other cardiovascular risk factors associated with T2DM. Further, evidence suggests that some established antihypertensive agents may worsen glucose intolerance. Many patients who are obese, hypertensive, and/or hyperlipidaemic fail to achieve blood pressure, lipid and glycaemic goals, and this failure may in part be explained by physician reluctance to utilize complex combination regimens for fear of off‐target effects. Thus, a clear need exists for clinicians to understand the risks and benefits of different pharmacologic, and indeed non‐pharmacologic, options in order to maximize treatment outcomes. While intensive lifestyle modification remains an elusive gold standard, newer diabetes targets, including the incretin axis, may offer greater cardiovascular risk reduction than other antidiabetes therapies, although definitive clinical trial data are needed. The glucagon‐like peptide‐1 (GLP‐1) receptor agonists exenatide and liraglutide and the dipeptidyl peptidase‐4 (DPP‐4) inhibitors sitagliptin and vildagliptin effectively lower HbA1c; exenatide and liraglutide reduce weight and blood pressure and improve lipid profiles. Sitagliptin and vildagliptin are weight neutral but also appear to improve lipid profiles. Integration of incretin therapies into the therapeutic armamentarium is a promising approach to improving outcomes in T2DM, and perhaps even in reducing complications of T2DM, such as co‐morbid hypertension and dyslipidaemia. Additional long‐term studies, including CVD end‐point studies, will be necessary to determine the appropriate places for incretin‐based therapies in treatment algorithms. 相似文献
243.
目的 评价艾塞那肽治疗2型糖尿病的疗效.方法 糖尿病住院患者20例(治疗组)给予二甲双胍联合艾塞那肽治疗.随机选择与治疗组同期住院,病程、年龄、空腹血糖(FBG)及餐后2 h血糖(PG2 h)、糖化血红蛋白(HbA1c)、体重指数(BMI)无显著差异的患者作为对照组,给予二甲双胍联合格列美脲治疗.比较治疗前后两组患者FBG,PG2 h,HbA1c,BMI,低血糖发生次数.结果 两组治疗16周后FBG、PG2 h、HbA1c均较治疗前明显下降(P<0.05),但两组之间差异无统计学意义(P>0.05).对照组治疗前后BMI差异无统计学意义,而治疗组治疗16周后BMI明显低于治疗前(P>0.05).治疗组发生症状性低血糖及夜间低血糖次数均明显少于对照组(P<0.01).结论 艾塞那肽可有效控制血糖,并且能明显降低BMI和低血糖发生次数. 相似文献
244.
Linnebjerg H Kothare PA Park S Mace K Reddy S Mitchell M Lins R 《British journal of clinical pharmacology》2007,64(3):317-327
AIMS: To evaluate the pharmacokinetics (PK), safety and tolerability of a single exenatide dose in patients with renal impairment (RI). METHODS: Exenatide (5 or 10 microg) was injected subcutaneously in 31 subjects (one with Type 2 diabetes) stratified by renal function [Cockcroft-Gault creatinine clearance (CrCL), number of subjects]: normal (>80 ml min(-1), n = 8), mild RI (51-80 ml min(-1), n = 8), moderate RI (31-50 ml min(-1), n = 7) or end-stage renal disease (ESRD) requiring haemodialysis (n = 8). PK data were combined with four previous single-dose studies in patients with Type 2 diabetes to explore the relationship of exenatide clearance (CLp/F) and CrCL. RESULTS: Mean half-life for healthy, mild RI, moderate RI and ESRD groups were 1.5, 2.1, 3.2 and 6.0 h, respectively. After combining data from multiple studies, least squares geometric means for CLp/F in subjects with normal renal function, mild RI, moderate RI and ESRD were 8.14, 5.19, 7.11 and 1.3 l h(-1), respectively. Exenatide was generally well tolerated in the mild and moderate RI groups, but not in subjects with ESRD due to nausea and vomiting. Simulations of exenatide plasma concentrations also suggest patients with ESRD should have a propensity for poor tolerability at the lowest available therapeutic dosage (5 microg q.d.). CONCLUSIONS: Since tolerability and PK changes were considered clinically acceptable in patients with mild to moderate RI, it would be appropriate to administer exenatide to these patients without dosage adjustment. However, poor tolerability and significant changes in PK make the currently available therapeutic doses (5 and 10 microg) unsuitable in severe RI or ESRD. 相似文献
245.
目的 探讨艾塞那肽对2型糖尿病(T2DM)患者的血糖、体质量、胰岛功能等的影响.方法 将50例T2DM患者分为两组,分别应用艾塞那肽(27例)和传统方案(23例)治疗,在用药3个月后,观察空腹和餐后血糖、糖化血红蛋白(HbA1c)、低血糖发生率、体质量变化、血糖波动及胰岛功能情况.结果 与对照组相比,艾塞那肽组的空腹和餐后血糖、HbA1c、体质量均明显下降(均P<0.05),低血糖发生率低.结论 艾塞那肽可明显改善T2DM患者的血糖及胰岛功能,降低HBA1c,使血糖达标,同时还可持续降低体质量,尤其对于初诊肥胖患者疗效显著. 相似文献
246.
Background Incretin-based therapies provide additional options for treating type 2 diabetes. We aimed to evaluate the efficacy and tolerability of exenatide monotherapy in obese patients with type 2 diabetes.
Methods A 26-week, metformin controlled, parallel-group study was conducted among antidiabetic drug-naive obese patients aged >18 years, and with type 2 diabetes. Participating patients were randomly assigned to receive exenatide or metformin treatments.
Results Fifty-nine patients (age (50.5±8.6) years, body mass index (BMI) (30.2±1.6) kg/m2, and hemoglobin A1C (HbA1C (8.2±1.2)%) were enrolled in the study. Glucose control and weight reduction improved in both groups receiving treatment. HbA1C and oral glucose tolerance test (OGTT) 2 hour glycemia reduction with exenatide was superior to that obtained with metformin ((–2.10±1.79)% vs. (–1.66±1.38)%, (–5.11±2.68) mmol/L vs. (–2.80±2.70) mmol/L, P <0.05). Fast plasma glucose (FPG) reduction was not significantly different between the two groups ((–1.8±2.0) mmol/L vs. (–1.6±1.7) mmol/L, P >0.05). Patients treated with exenatide achieved HbA1C of <7% (97% of patients) and <6.5% (79%) at end-point, vs. 93% and 73% with metformin (P >0.05). Greater weight reduction was also achieved with exenatide ((–5.80±3.66) kg) than with metformin ((–3.81±1.38) kg, P <0.01). Homeostasis model assessment of beta-cell function (HOMA-B) was not significantly increased, but the insulinogenic index and HOMA for insulin sensitivity (HOMA-S) were greatly improved in the exenatide group (P <0.05). Nausea was the most common adverse effect in exenatide treatment (30% vs. 8%; P <0.05), but most cases were of mild to moderate intensity. One case in the exenatide group was withdrawn early because of severe nausea. Hypoglycemia events were often observed during the first 4 weeks, with 12% of patients in the exenatide and 3.2% in metformin groups, respectively (P <0.05). No incidents of severe hypoglycemia were reported.
Conclusions Exenatide demonstrated more beneficial effects on HbA1C, weight reduction and insulin resistance during 26 weeks of treatment, but there were more hypoglycemic events and mild-to-moderate nausea compared with metformin. These results suggested that exenatide monotherapy may provide a viable treatment option in newly developed type 2 diabetes. 相似文献
247.
目的 比较艾塞那肽与二甲双胍治疗新诊断2型糖尿病的疗效及其对血糖波动的影响。方法 将68例新诊断2型糖尿病患者随机分为2组,分别为二甲双胍组35例,艾塞那肽组33例。治疗12周,比较2组治疗前后空腹血糖(FBG),餐后2 h血糖(2 h PG)、糖化血红蛋白(HbA1c)、血脂、体重指数,以及血糖波动指标日内平均血糖波动幅度(MAGE)、最大血糖波动幅度(LAGE)、平均餐后血糖波动幅度(MPPGE)的变化。结果 治疗12 周后,两组FBG、2 h PG、HbA1c、血糖波动指标较治疗前均明显下降,两组治疗后无统计学差异;两组治疗后三酰甘油(TG)较治疗前明显降低(P<0.05),二甲双胍组(1.88±0.57)mmol/L,艾塞那肽组(1.58±0.21)mmol/L,相比二甲双胍组,艾塞那肽组下降更为明显(P<0.05);体重指数艾塞那肽组治疗前体重(25.14±2.21)kg/m2,治疗后(23.16±1.46)kg/m2,治疗前后比较具有统计学差异(P<0.05)。结论 艾塞那肽与二甲双胍对新诊断2型糖尿病控制血糖效果具有同等的疗效,艾塞那肽在降低三酰甘油及体重方面更为显著。 相似文献
248.
Simeon I. Taylor MD May E. Montasser PhD Ashley H. Yuen MD Hubert Fan BS Zhinoosossadat Shahidzadeh Yazdi MD Hilary B. Whitlatch MD Braxton D. Mitchell PhD Alan R. Shuldiner MD Ranganath Muniyappa MD Elizabeth A. Streeten MD Amber L. Beitelshees PharmD 《Diabetes, obesity & metabolism》2023,25(9):2586-2594
249.
Annemarie B. van der Aart-van der Beek PharmD Ellen Apperloo MD Niels Jongs PhD Dennis B. Rouw MD C. David Sjöström MD Iris Friedli PhD Lars Johansson PhD Daniël H. van Raalte MD Klaas Hoogenberg MD Hiddo J. L. Heerspink PhD 《Diabetes, obesity & metabolism》2023,25(6):1758-1768