Box-Behnken效应面法优化磷酸西格列汀片处方设计

目的：筛选磷酸西格列汀片直接压片法的最佳处方。方法：采用Box-Behnken效应面法（BBD）优化磷酸西格列汀片的处方设计,以原料药粒径、MCC占填充剂比例及崩解剂用量为考察因素,以休止角、均匀度、溶出度为评价指标,制备样品作质量考察。结果：最优处方原药粒径100 nm,MCC占填充剂比例为45%,崩解剂用量为2.7%。根据最优处方制备的小试样品,均匀度为（2.53±0.18）%,休止角为（38.9±0.5）°,10 min溶出度为（82.3±2.2）%,与理论值的差距＜10%。3批中试样品,各评价指标与理论值的差距均＜10%,符合质量要求。结论：通过BBD法优化的磷酸西格列汀片处方,具有良好的流动性、混合均匀度,制得片剂具有快速溶出特征。     

Mechanism-based pharmacokinetic/pharmacodynamic modeling of the effects of sitagliptin on DPP-4 activity,insulin and glucose in diabetic rats

Dipeptidyl peptidase-4 (DPP-4) inhibitors exert their antihyperglycemic effects through repressing inactivation of certain incretin hormones and thus increasing insulin secretion and controlling glucose level. In this study, the plasma concentrations of sitagliptin, a potent DPP-4 inhibitor, after a single oral dose of 300 mg/kg in streptozotocin-induced type 2 diabetic rats were determined by HPLC. A one-compartment pharmacokinetic (PK) model with first order absorption was developed to describe the PK profile of sitagliptin, and the drug concentrations at the doses given in the pharmacodynamic (PD) study were simulated accordingly. The dynamic changes in DPP-4 activity, insulin concentration and blood glucose level in diabetic rats at doses of 1, 5 and 10 mg/kg were measured, and a mechanism-based PK/PD model was established subsequently. In this model, the inhibitory effect of sitagliptin on DPP-4 activity was demonstrated using the Hill’s function with direct link, and the downstream increase in insulin secretion and inhibition of glucose production were characterized using indirect response (IDR) models. This model interpreted the mechanism of antihyperglycemic action of sitagliptin, and may be modified and applied to other species or other agents in this class.     

磷酸西格列汀片处方工艺研究

目的 筛选磷酸西格列汀片的最佳处方工艺。方法 设计不同处方工艺,通过检测溶出曲线及粉体学数据,确定最佳处方工艺。结果 自制片的4个处方中,粉体学数据及压片流畅性均较好,其中湿法制粒工艺两个处方溶出比参比制剂慢,粉末直压工艺中当交联羧甲基纤维素钠为16 mg时溶出曲线与参比制剂拟合较好。结论 通过对磷酸西格列汀片的处方工艺研究,最终确定了磷酸西格列汀片的工艺和崩解剂用量。     

Clinical Effects of Exposure to DPP-4 Inhibitors as Reported to the National Poison Data System

DPP-4 inhibitors (sitagliptin, saxagliptin, and linagliptin) are approved for the treatment of diabetes. They are considered safe due to their hyperglycemia dependent mechanism of action. We examined all isolated exposures to DPP-4 inhibitors reported to the National Poison Database System since 2006 to determine if significant toxicity occurs after exposure with attention to pediatric and intentional overdoses. NPDS data regarding DPP-4 ingestions in all age groups between January 2006 and March 2013 was collected. Cases were reviewed, and the following inclusion criteria applied: (1) reported ingestion of a DPP-4 inhibitor and (2) known clinical outcome. Exclusion criteria included the following: (1) exposure to more than a single substance, (2) no known outcome, and (3) clinical outcome judged to be unrelated to the exposure. One thousand four hundred seventy-six cases were reviewed while 826 were excluded. Of 650 included cases, 562 developed no clinical effects. Mild effects were noted in 77. There were no deaths. Moderate/major effect cases were investigated: two medication-naive nondiabetic individuals with accidental exposures developed clinically significant hypoglycemia requiring treatment. One diabetic patient on a DPP-4 inhibitor developed prolonged hypoglycemia requiring admission and continuous exogenous dextrose. Of 650 included exposures to DPP-4 inhibitors, 639 (98.3%) had either no or minor clinical effects. Three resulted in clinically significant hypoglycemia requiring intervention. None of the moderate or major clinical outcomes were the result of intentional overdoses for the purpose of self-injury. No exploratory ingestions resulted in moderate or major effects. Based on this data, exposure to DPP-4 inhibitors may rarely result in clinically significant hypoglycemia.     

西格列汀联合二甲双胍治疗初诊2型糖尿病的疗效观察

目的 探讨西格列汀联合二甲双胍治疗初发、肥胖2型糖尿病的临床疗效.方法 选取2012年1月至2013年12月期间在我院治疗的180例初发、肥胖2型糖尿病患者为研究对象,将其随机分为治疗组和对照组,其中治疗组92例,对照组88例.对照组患者给予格列美脲＋二甲双胍治疗,治疗组给予二甲双胍＋西格列汀治疗.入组前常规进行肝肾功能、血糖血脂、糖化血红蛋白、胰岛细胞分泌功能、胰岛素抵抗等评估,治疗期24周.治疗结束后分析两组患者的在体重、空腹血糖、餐后2小时血糖、糖化血红蛋白、胰岛细胞分泌功能、胰岛素抵抗指数等方面的差异.结果 治疗组患者各项监测指标（空腹及餐后血糖、糖化血红蛋白、胰岛细胞分泌功能、胰岛素抵抗指数）明显好于对照组患者（P＜0.05）,且治疗组的总有效率92.40％ （85/92）和对照组患者72.73％ （64/88）相比占优势,两组患者比较差异具有统计学意义（P＜0.05）.两组患者在体重、低血糖发作方面无明显差异（P＞0.05）.结论 二甲双胍联合西格列汀治疗初发、肥胖2型糖尿病患者安全有效,值得借鉴.     

Short-term inhibition of DPP-4 enhances endothelial regeneration after acute arterial injury via enhanced recruitment of circulating progenitor cells

Background

Endothelial injuries regularly occur in atherosclerosis and during interventional therapies of the arterial occlusive disease. Disturbances in the endothelial integrity can lead to insufficient blood supply and bear the risk of thrombus formation and acute vascular occlusion. At present, effective therapeutics to restore endothelial integrity are barely available.We analyzed the effect of pharmacological DPP-4-inhibition by Sitagliptin on endogenous progenitor cell-based endothelial regeneration via the SDF-1α/CXCR4-axis after acute endothelial damage in a mouse model of carotid injury.

Methods and Results

Induction of a defined endothelial injury was performed in the carotid artery of C57Bl/6 mice which led to a local upregulation of SDF-1α expression. Animals were treated with placebo, Sitagliptin or Sitagliptin + AMD3100. Using mass spectrometry we could prove that Sitagliptin prevented cleavage of the chemokine SDF-1α. Accordingly, increased SDF-1α concentrations enhanced recruitment of systemically applied and endogenous circulating CXCR4 + progenitor cells to the site of vascular injury followed by a significantly accelerated reendothelialization as compared to placebo-treated animals. Improved endothelial recovery, as well as recruitment of circulating CXCR4 + progenitor cells (CD133 +, Flk1 +), was reversed by CXCR4-antagonization through AMD3100. In addition, short-term Sitagliptin treatment did not significantly promote neointimal or medial hyperplasia.

Conclusion

Sitagliptin can accelerate endothelial regeneration after acute endothelial injury. DPP-4 inhibitors prevent degradation of the chemokine SDF-1α and thus improve the recruitment of regenerative circulating CXCR4 + progenitor cells which mediate local endothelial cell proliferation without adversely affecting vessel wall architecture.     

A comparative study of the role of crocin and sitagliptin in attenuation of STZ-induced diabetes mellitus and the associated inflammatory and apoptotic changes in pancreatic β-islets

Type 1 diabetes mellitus (T1DM) describes a complex group of metabolic disorders associated with elevated blood glucose levels and increased risks of complications development. Exploring new drug therapies would reduce the increased diabetes-associated morbidity and mortality and will reduce the excessive health care costs. Crocin is the major active ingredient of saffron. In the current study, DM was induced by single intraperitoneal injection of streptozocin (50 mg/kg).DM progression was associated with a significant increase in blood glucose level with reduced insulin and increased glucagon secretion. Pancreatic malondialdehyde (MDA) content significantly escalated, while superoxide dismutase (SOD) activity, reduced glutathione (GSH) concentration, catalase activity, thioredoxin level and serum total antioxidant capacity significantly declined. This was associated with a significant increase in pancreatic caspase-3 contents and pancreatic infiltration with inflammatory cells in β-islets. Both sitagliptin and crocin significantly reduced blood glucose levels, enhanced pancreatic insulin expression and secretion and suppressed glucagon secretion with enhancement of anti-oxidant defenses and reduction of oxidative burden, with evident anti-inflammatory impacts. Interestingly, the effect of crocin on DM indices, inflammatory and apoptotic changes was comparable to that of sitagliptin; the standard oral hypoglycemic agent. Nevertheless, crocin had a superior effect compared to sitagliptin on blood sugar level, β-islets diameter and insulin immune-reactivity. In conclusion, crocin reduced blood glucose level mainly via reduction of oxidative burden, modulation of apoptotic pathway and attenuation of pancreatic inflammation.     

西格列汀联合贝那普利治疗早期糖尿病肾病的效果及对血清IL-6、IL-18、TGF-β1的影响

目的 观察西格列汀联合贝那普利治疗早期糖尿病肾病(diabetic nephropathy,DN)的效果.方法 选取2018年7月—2019年10月在我院就诊的92例早期DN患者,根据治疗方法 不同分为观察组和对照组各46例,对照组采用非二肽基肽酶-4抑制剂类降糖药物联合贝那普利治疗,观察组在对照组基础上加用西格列汀...     

Sitagliptin: Anti-platelet effect in diabetes and healthy volunteers

Sitagliptin, a selective dipeptidyl peptidase-4 inhibitor drug is used to treat type-2 diabetes (T2DM). We investigated the anti-platelet activity of sitagliptin in patients with T2DM and in in vitro samples obtained from healthy humans. Patients with T2DM (27 male + 23 female) were selected and followed up before (control) and after treatment with sitagliptin for up to 3 months. Platelets were isolated from the blood of sitagliptin treated patients and controls. Patients with T2DM treated with sitagliptin for 1and 3 months, showed 10?±?2% and 30?±?5% inhibition of platelet aggregation, respectively. For the in vitro study, platelets from 10 normal humans (n?=?10) were isolated. Platelet aggregation, intracellular free calcium and tyrosine phosphorylation of multiple proteins were measured by aggregometer, spectrofluorometer and western blotting, respectively. Platelets pre-treated with 5 and 10?µg/ml of sitagliptin, showed 25?±?4% and 40?±?6% inhibition of thrombin-induced platelet aggregation, respectively. Sitagliptin decreased intracellular free calcium (2.5-fold) and tyrosine phosphorylation of multiple proteins in thrombin-induced platelet activation. Sitagliptin inhibited platelet aggregation in T2DM as well as in healthy humans. Sitagliptin has significant concentration-dependent anti-platelet activity. This activity was due to its inhibitory effect on intracellular free calcium and tyrosine phosphorylation.