Neonatal Exposure to the Dipeptidyl Peptidase-IV Inhibitors Diprotin A and Sitagliptin Induces Depression-Like Behavior, Anxiety, and Latent Aggression in Adolescent and Adult Rats

Emotional and motivational disorders in adults are often considered to be the result of altered neurodevelopment. Clinical and experimental data provide evidence that serine protease dipeptidyl peptidase-IV (DPP-IV, EC 3.4.14.5) is involved in the pathophysiology of psycho-emotional disorders. Recently, we have shown that adolescent and adult rats exhibit an increase in anxiety and depression-related behaviors after neonatal administration of a synthetic non-competitive inhibitor of DPP-IV, methionyl-2(S)-cyano-pyrrolidine. In the present study, we tested the effects of two competitive, selective DPP-IV inhibitors, sitagliptin (4 mg/kg) and diprotin A (2 mg/kg), administered at postnatal days 5 - 18 on the emotional and motivational behavior of adolescent and adult rats. We observed increased anxiety in one-month-old diprotin A- or sitagliptin-treated rats in the elevated plus maze;diprotin A also enhanced the animals’ anxiety score using a ranked scale for evaluating anxiety and phobias. In the sucrose consumption and preference test, depressive-like behavior was pronounced in both the diprotin A- and sitagliptin-treated one-month-old animals, while only the diprotin A-treated rats exhibited a decrease in sucrose consumption at the age of 2 months. The diprotin A-treated rats also demonstrated behavioral despair and decreased activity in the forced swimming test within 1 - 3 months of age. Increased aggression was observed in 1 - 3-month-old diprotin A-treated rats and in two-month-old sitagliptin-treated rats. These findings support the hypothesis that DPP-IV is involved in the genesis of emotional and motivational disorders. Additionally, the results show that diprotin А impairs the adolescent and adult rats’ behavior more significantly than sitagliptin when the animals were treated with the DPP-IV inhibitors in the early postnatal period.

Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of E3024, a Novel and Selective Dipeptidyl Peptidase-IV Inhibitor, in Healthy Japanese Male Subjects: Rash Development in Men and Its Possible Mechanism

E3024 (3-but-2-ynyl-5-methyl-2-piperazin-1-yl-3,5-dihydro-4H-imidazo[4,5-d]pyridazin-4-one tosylate) is a dipeptidyl peptidase-IV (DPP-IV) inhibitor that was expected to be an antidiabetic agent. Its safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) were investigated in a randomized, double-blind, placebo-controlled, ascending single-dose study in 48 healthy Japanese male subjects. Fasted subjects were orally administered E3024 (5, 10, 20, 40, or 80 mg) or placebo. E3024 was rapidly absorbed, with tmax values ranging between 0.33 and 3 h after dosing. The mean t1/2 ranged from 5.34 to 11.68 h. AUC0-inf and Cmax increased dose-proportionately. PK-PD relationship of E3024 was evaluated by using an Imax model, indicating that plasma E3024 concentrations and inhibitory effects of plasma DPP-IV activity were well correlated. The IC50 value was calculated as 33.7 ng/mL, which was consistent with in vitro data. Thus, E3024 showed a good PK profile and inhibited DPP-IV dose-dependently. Of 30 subjects administered E3024, 12 (40%) experienced adverse events (AEs). Dose escalation to 160 mg was abandoned owing to undesired subjective/objective findings in 4 of 6 subjects receiving 40 mg and 5 of 6 subjects receiving 80 mg. The most prominent AE was rash, but there were no serious AEs or deaths. The maximum tolerated dose was considered to be 20 mg. We hypothesized that histamine was a cause of the rash induction, and examined blood histamine levels of normal Fischer rats treated with E3024. Blood histamine levels were increased significantly by E3024 at 500 mg/kg (p < 0.001), but not by vildagliptin or valine-pyrrolidide (DPP-IV inhibitors) at the same dose. No blood histamine increases were observed in genetically mast cell-deficient Ws/Ws rats treated with E3024 at 500 mg/kg. In in vitro assays, E3024 induced histamine release from normal rat peritoneal mast cells in a concentration-dependent manner, but not from basophils. The structure-activity relationship study suggested that a piperazine group N-linked to the 2-position of the 5,6-membered fused heterocyclic rings was a key structural element for triggering histamine release.

Role of dipeptidyl peptidase 4 inhibitors in the new era of antidiabetic treatment

The last few years important changes have occurred in the field of diabetes treatment.The priority in the therapy of patients with diabetes is not glycemic control per se rather an overall management of risk factors,while individualization of glycemic target is suggested.Furthermore,regulatory authorities now require evidence of cardiovascular(CV)safety in order to approve new antidiabetic agents.The most novel drug classes,i.e.,sodium-glucose transporter 2 inhibitors(SGLT2-i)and some glucagon-like peptide-1 receptor agonists(GLP-1 RA),have been demonstrated to reduce major adverse CV events and,thus,have a prominent position in the therapeutic algorithm of hyperglycemia.In this context,the role of previously used hypoglycemic agents,including dipeptidyl peptidase 4(DPP-4)inhibitors,has been modified.DPP-4 inhibitors have a favorable safety profile,do not cause hypoglycemia or weight gain and do not require dose uptitration.Furthermore,they can be administered in patients with chronic kidney disease after dose modification and elderly patients with diabetes.Still,though,they have been undermined to a third line therapeutic choice as they have not been shown to reduce CV events as is the case with SGLT2-i and GLP-1 RA.Overall,DPP-4 inhibitors appear to have a place in the management of patients with diabetes as a safe class of oral glucose lowering agents with great experience in their use.

Cardiovascular efficacy and safety of dipeptidyl peptidase-4 inhibitors:A meta-analysis of cardiovascular outcome trials

BACKGROUND Dipeptidyl peptidase-4(DPP-4)inhibitors are a generally safe and well tolerated antidiabetic drug class with proven efficacy in type 2 diabetes mellitus(T2DM).Recently,a series of large,randomized controlled trials(RCTs)addressing cardiovascular outcomes with DPP-4 inhibitors have been published.AIM To pool data from the aforementioned trials concerning the impact of DPP-4 inhibitors on surrogate cardiovascular efficacy outcomes and on major cardiac arrhythmias.METHODS We searched PubMed and grey literature sources for all published RCTs assessing cardiovascular outcomes with DPP-4 inhibitors compared to placebo until October 2020.We extracted data concerning the following“hard”efficacy outcomes:fatal and non-fatal myocardial infarction,fatal and non-fatal stroke,hospitalization for heart failure,hospitalization for unstable angina,hospitalization for coronary revascularization and cardiovascular death.We also extracted data regarding the risk for major cardiac arrhythmias,such as atrial fibrillation,atrial flutter,ventricular fibrillation and ventricular tachycardia.RESULTS We pooled data from 6 trials in a total of 52520 patients with T2DM assigned either to DPP-4 inhibitor or placebo.DPP-4 inhibitors compared to placebo led to a non-significant increase in the risk for fatal and non-fatal myocardial infarction[risk ratio(RR)=1.02,95%CI:0.94-1.11,I2=0%],hospitalization for heart failure(RR=1.09,95%CI:0.92-1.29,I2=65%)and cardiovascular death(RR=1.02,95%CI:0.93-1.11,I2=0%).DPP-4 inhibitors resulted in a non-significant decrease in the risk for fatal and non-fatal stroke(RR=0.96,95%CI:0.85-1.08,I2=0%)and coronary revascularization(RR=0.99,95%CI:0.90-1.09,I2=0%),Finally,DPP-4 inhibitors demonstrated a neutral effect on the risk for hospitalization due to unstable angina(RR=1.00,95%CI:0.85-1.18,I2=0%).As far as cardiac arrhythmias are concerned,DPP-4 inhibitors did not significantly affect the risk for atrial fibrillation(RR=0.95,95%CI:0.78-1.17,I2=0%),while they were associated with a significant increase in the risk for atrial flutter,equal to 52%(RR=1.52,95%CI:1.03-2.24,I2=0%).DPP-4 inhibitors did not have a significant impact on the risk for any of the rest assessed cardiac arrhythmias.CONCLUSION DPP-4 inhibitors do not seem to confer any significant cardiovascular benefit for patients with T2DM,while they do not seem to be associated with a significant risk for any major cardiac arrhythmias,except for atrial flutter.Therefore,this drug class should not be the treatment of choice for patients with established cardiovascular disease or multiple risk factors,except for those cases when newer antidiabetics(glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors)are not tolerated,contraindicated or not affordable for the patient.

Risk of pancreatic adverse events associated with the use of glucagon-like peptide-1 receptor agonist and dipeptidyl peptidase-4 inhibitor drugs: A systematic review and metaanalysis of randomized trials

AIM: To systematically assess risk of pancreatic adverse events with glucagon-like peptide-1(GLP-1) receptor agonist and dipeptidyl peptidase-4(DPP-4) inhibitor drugs.METHODS: We searched Pub Med, Embase, CINAHL, Cochrane review of clinical trials, pharmaceutical company clinical trials register, United States Food and Drug Administration website, European Medicines Agency website and Clinical Trials.gov for randomized controlled trials from inception to October 2013. Randomized control trial studies were selected for inclusion if they reported on pancreatic complication events and/or changes in pancreatic enzyme levels(serum amylase and serum lipase) as adverse events or as serious adverse events for patients who were on GLP-1 receptor agonist and DPP-4 inhibitor drugs. Two independent reviewers extracted data directly. We performed Peto odds ratio(OR) fixed effect meta-analysis of pancreatic adverse events a, and assessed heterogeneity with the I^2 statistic.RESULTS: Sixty-eight randomized controlled trials were eligible. A total of 60720 patients were included in our analysis of the association of risk of pancreatic complication events with GLP-1 agents. A total of 89 pancreatic related adverse events occurred among the GLP-1 agents compared to 74 events among the controls. There was a statistically significant increased risk of elevation of pancreatic enzymes associated with GLP-1 agents compared with control(Peto OR = 3.15, 95%CI: 1.56-6.39, P = 0.001, I2 = 0%). There was no statistically significant difference in the risk of pancreatic adverse event associated with GLP-1 agent compared with controls(Peto OR = 1.00, 95%CI: 0.73-1.37, P = 1.00, I2 = 0%). There were a total of 71 pancreatitis events in patients on GLP-1 agents and 56 pancreatitis events occurred in the control patients. There were 36 reports of pancreatic cancer in these studies. Of these cases, 2 used linagliptin, 2 used alogliptin, 1 used vildagliptin, 7 used saxagliptin while 6 used sitagliptin. The remaining 18 cases occurred among controls.CONCLUSION: Although GLP-1 based agents are associated with pancreatic enzyme elevation, we were unable to confirm a significant risk of pancreatitis or pancreatic cancer.

DPP-4 inhibitors and GLP-1RAs:cardiovascular safety and benefits

Glucagon-like peptide-1 receptor agonists(GLP-1RAs)and dipeptidyl peptidase-4 inhibitors are commonly used treatments for patients with type 2 diabetes mellitus(T2DM).Both anti-diabetic treatments function by playing key modulatory roles in the incretin system.Though these drugs have been deemed effective in treating T2DM,the Food and Drug Administration(FDA)and some members of the scientific community have questioned the safety of these therapeutics relative to important cardiovascular endpoints.As a result,since 2008,the FDA has required all new drugs for glycemic control in T2DM patients to demonstrate cardiovascular safety.The present review article strives to assess the safety and benefits of incretin-based therapy,a new class of antidiabetic drug,on the health of patient cardiovascular systems.In the process,this review will also provide a physiological overview of the incretin system and how key components function in T2DM.

Dipeptidyl peptidase-4 inhibitor-induced autoimmune diseases:Current evidence

Dipeptidyl peptidase-4 inhibitors(DPP-4i)have an important place in the management of type 2 diabetes.The DPP-4 enzyme is ubiquitously distributed throughout the human body and has multiple substrates through which it regulates several important physiological functions.DPP-4 regulates several immune functions,including T-cell activation,macrophage function,and secretion of cytokines.Studies have reported an increase in autoimmune diseases like bullous pemphigoid,inflammatory bowel disease,and arthritis with DPP-4i use.The relationship of DPP-4i and autoimmune diseases is a complex one and warrants further research into the effect of DPP-4 inhibition on the immune system to understand the pathogenesis more clearly.Whether a particular cluster of autoimmune diseases is associated with DPP-4i use remains an important contentious issue.Nevertheless,a heightened awareness from the clinicians is required to identify and treat any such diseases.Through this review,we explore the clinical and pathophysiological characteristics of this association in light of recent evidence.

Efficacy of omarigliptin,once-weekly dipeptidyl peptidase-4 inhibitor,in patients with type 2 diabetes

BACKGROUND Omarigliptin is one of several once-weekly dipeptidyl peptidase-4 inhibitors(DPP-4is).Despite the high frequency of switching from various daily DPP-4is to omarigliptin in actual clinical practice,data regarding its efficacy in patients with type 2 diabetes(T2D)after switching are limited.AIM To analyze the efficacy of omarigliptin in Japanese patients with T2D who had previously received treatment with other glucose-lowering agents.METHODS Forty-nine T2D patients treated for the first time with omarigliptin were recruited retrospectively and divided into four groups defined as either add-on or switched from daily DPP-4is:switched from linagliptin,switched from sitagliptin,and switched from vildagliptin.During a 3-mo follow-up,the clinical parameters among these groups were assessed and compared,with the impact of the switch on glycemic variability as measured by continuous glucose monitoring also being evaluated in the switched groups.RESULTS Hemoglobin A1c levels saw a significant decrease of-0.32%±0.41%in the add-on group(P=0.002).However,the other groups’variables depended on the preswitch daily DPP-4i:switched from linagliptin,-0.05%±0.22%;switched from sitagliptin,-0.17%±0.33%;and switched from vildagliptin,0.45%±0.42%,which saw significant worsening(P=0.0007).Multivariate logistic regression analysis revealed that switching from vildagliptin to omarigliptin was independently associated with worsening glycemic control(P=0.0013).The mean and standard deviation of sensor glucose value,the mean amplitude of glycemic excursions,and the mean of daily difference significantly improved when switching the patient from either linagliptin or sitagliptin to omarigliptin.However,in patients switched from vildagliptin,not only did the glucose variability indices see no improvements,the mean of daily difference even underwent significant worsening.CONCLUSION Administering omarigliptin as add-on therapy or switching to it from sitagliptin and linagliptin,but not vildagliptin,improves glycemic control and thus should help in decision making when selecting DPP-4is for T2D patients.

基于医院卫生技术评估的5种二肽基肽酶4抑制剂的临床应用情况

目的通过医院卫生技术评估(HB-HTA)对5种二肽基肽酶4抑制剂(DPP-4i)(西格列汀、维格列汀、沙格列汀、利格列汀和阿格列汀)进行评估,为医疗机构药品的遴选、临床的合理安全使用提供依据。方法通过HB-HTA,依照百分制评分体系,参考药品说明书、临床指南和文献,从安全性、有效性、经济型、创新性、适宜性和可及性等方面分别对5种DPP-4i进行评估。结果西格列汀、维格列汀、沙格列汀、利格列汀和阿格列汀得分分别为85.0、75.0、77.0、80.0、78.5分。评分差异主要在安全性、经济性、适宜性和可及性方面。西格列汀综合得分最高。结论HB-HTA评估DPP-4i结果比较合理,为医院药品遴选、安全合理使用提供依据。

DPP4抑制剂在2型糖尿病中的临床应用及研究进展

2型糖尿病(Type 2 Diabetes Mellitus,T2DM)在我国具有较高的发病率,是中老年患者常见的一种慢性代谢疾病,可累及心脑血管等多个系统发生病变,危及生命安全,需及时治疗。二肽基肽酶-4(Dipeptidyl Peptidase-4,DPP4)可促进胰岛素生成,并分泌胰高血糖素,与T2DM有着密切关联,是目前我国T2DM治疗研究中的一个新方向。DPP4抑制剂是多项研究的结果,能够提高降糖效果,对多种降糖无效的患者均有显著作用。基于此,本文主要综述了DPP4抑制剂治疗T2DM的作用机制,分析DPP4抑制剂在T2DM中的应用及研究进展,以期为T2DM治疗提供参考。

基于FAERS的二肽基肽酶-Ⅳ抑制剂皮肤不良事件信号挖掘与评价

目的为临床合理使用二肽基肽酶-Ⅳ(DPP-4)抑制剂提供参考。方法通过美国食品和药物管理局药品不良事件报告系统(FAERS)收集2010年至2021年各季度以全球已上市DPP-4抑制剂为首要怀疑药物的药品不良事件(ADE)报告,采用报告比值比(ROR)法挖掘DPP-4抑制剂的ADE信号,并利用《监管活动医学词典》(MedDRA)中的系统器官分类(SOC)提取并整理其中的皮肤ADE信号。结果以吉格列汀、奥格列汀、曲格列汀、安奈格列汀、依格列汀为首要怀疑药物的ADE报告数均为0份;以西格列汀、维格列汀、沙格列汀、阿格列汀、利格列汀、替格列汀为首要怀疑药物的ADE报告数分别为192131,2034,6787,3635,4532,2份,对应的皮肤ADE信号数依次为20,4,15,10,14,0个,且其中分别有18,2,7,9,8,0个ADE信号未在相应药品说明书中提及。在发生皮肤ADE的患者中,阿格列汀用药患者女性多于男性,其余4种药物反之;年龄多在65岁以上;维格列汀用药时长集中在0.5~1年,其余4种药物的用药时长集中在半年内或1年以上;西格列汀、维格列汀、沙格列汀、阿格列汀、利格列汀用药剂量依次集中在100,50,5,25,5 mg/d。使用西格列汀、阿格列汀的患者临床结局大多为住院,其余3种药物多为其他临床结局。结论DPP-4抑制剂可致多种皮肤ADE,临床用药时应密切监测。

二肽基肽酶I抑制剂的研究进展

中性粒细胞是先天免疫系统的重要组成部分,其功能失调和多种疾病密切相关.二肽基肽酶I是一种溶酶体半胱氨酸蛋白酶,介导中性粒细胞相关炎症过程,在多种炎症性疾病中发挥关键作用,因此成为炎症性疾病治疗药物开发的新颖靶点.文章从基于经验的药物设计、基于靶标的理性设计和靶标设计位点新选择三个方面综述了二肽基肽酶I抑制剂的研究进展,旨在为开发新型高效、低毒的二肽基肽酶I抑制剂提供参考.

DPP-4抑制剂治疗2型糖尿病合并非酒精性脂肪肝的作用研究进展

二肽基肽酶4(DPP-4)抑制剂是一种较新类型的糖尿病治疗药物,其主要的降糖机制是通过减少肠促胰素降低,来提高内源性胰高血糖素样肽1,进而促进胰岛素分泌与抑制胰高血糖素分泌,降低机体血糖水平。2型糖尿病(T2DM)与非酒精性脂肪肝(NAFLD)是临床常见的疾病类型,发病率居高不下。T2DM和NAFLD能够相互影响,相互促进,T2DM合并NAFLD不仅容易提高心血管疾病的患病风险与加重内分泌代谢紊乱,而且容易推动NAFLD病情进展,导致出现肝硬化、肝癌等恶性病变。目前大量研究显示,DPP-4抑制剂能够有效降低T2DM患者血糖水平和改善胰岛素抵抗,且对NAFLD具有较好的预防作用。本文从DPP-4抑制剂对治疗T2DM合并NAFLD的疗效与安全性方面进行综述。

MK-0626,a selective DPP-4 inhibitor,attenuates hepatic steatosis in ob/ob mice

AIM:To investigate the mechanism and in vivo effects of MK-0626,a dipeptidyl peptidase-4 inhibitor,on hepatic steatosis using ob/ob mice.METHODS:We analyzed obese(ob/ob)8-wk-old male mice that had been randomly divided into two groups of ob/ob mice(n=16 each)and were treated with1.5 or 3 mg/kg MK-0626 and two control groups of untreated ob/ob mice and lean littermates(n=16 each).All mice were fed a normal chow diet with or without MK-0626 for either four or eight weeks.Blood samples were collected,and total hepatectomy was performed.RESULTS:The administration of dietary MK-0626 ameliorated the hepatic lipid accumulation in ob/ob micetreated with 3 mg/kg MK-0626(3 MK),P<0.05,vs untreated ob/ob mice(ob/ob).The MK-0626 treatment reduced the serum alanine aminotransferase levels(both treatment groups,P<0.05 vs ob/ob)and glucoses/insulin levels/calculated HOMA scores(1.5 MK,P<0.05vs ob/ob;3 MK,P<0.01 vs ob/ob)and increased the serum adiponectin levels(3 MK,P<0.05 vs ob/ob)in a dose-dependent manner.The MK-0626 treatment increased the m RNA expression of peroxisome proliferator-activated receptorα/microsomal triglyceride transfer protein(1.5 MK,P<0.05 vs ob/ob;3 MK,P<0.01vs ob/ob)but reduced the sterol regulatory element binding transcription factor-1c/fatty acid synthase/stearoyl-Co A desaturase-1(both treatment groups,P<0.01 vs ob/ob).The MK-0626 treatment increased the activity of AMP-activated protein kinase(AMPK)(both treatment groups,P<0.01 vs ob/ob).CONCLUSION:MK-0626 could attenuate hepatic steatosis through enhancing AMPK activity,inhibiting hepatic lipogenic gene expression,enhancing triglyceride secretion from liver and increasing serum adiponectin levels.

Dipeptidyl peptidase Ⅳ(DPP Ⅳ):a novel emerging target for thetreatment of type 2 diabetes

The enzyme, dipeptidyl peptidase IV（DPP IV）, is a novel target for the treatment of type 2 diabetes. Dipeptidyl peptidase IV inhibition improves the impaired insulin secretion and decrease postprandial concentrations of glucagon by enhancing the incretin hormone levels lucagon-like peptide-1（GLP-1） and glucose-dependent insulinotropic polypeptide/gastric inhibitory polypeptide（GIP）. Recently, DPP IV inhibitors have attracted more and more attention, several of which have entered pre-clinical and clinical trials, and one has received approval for use as an anti-diabetic agent. Among the DPP IV inhibitors, two leading agents（sitagliptin and vildagliptin） have been shown to be effective in reducing glycosylated hemoglobin（HbAlc） and fasting plasma glucose（FPG） in patients with type 2 diabetes. This review summarizes the evidence supporting DPP IV inhibitors as potential antidiabetic agents.

Treatment of type 2 diabetes, lifestyle, GLP1 agonists and DPP4 inhibitors

In recent years the treatment focus for type 2 diabetes has shifted to prevention by lifestyle change and to more aggressive reduction of blood sugars during the early stage of treatment. Weight reduction is an important goal for many people with type 2 diabetes.Bariatric surgery is no longer considered a last resort treatment. Glucagon-like peptide-1 agonists given by injection are emerging as a useful treatment since they not only lower blood sugar but are associated with a modest weight reduction. The role of the oral dipeptidyl peptidase 4 inhibitors is emerging as second line treatment ahead of sulphonylureas due to a possible beneficial effect on the beta cell and weight neutrality.Drugs which inhibit glucose re-absorption in the kidney,sodium/glucose co-transport 2 inhibitors, may have a role in the treatment of diabetes. Insulin treatment still remains the cornerstone of treatment in many patients with type 2 diabetes.

HS-GC法测定利格列汀的7种残留溶剂

目的 建立顶空气相色谱法同时测定利格列汀中7种残留溶剂的分析方法。方法 采用顶空气相色谱(HS-GC)法,色谱柱为Agilent DB-624(30 m×0.53 mm, 3μm),程序升温,检测器为氢火焰离子化检测器(FID),氮气为载气。结果 在选定的色谱条件下,各溶剂峰均能完全分离,分别在相应浓度范围内与峰面积呈良好线性关系,各溶剂检测限均符合要求。结论 该方法操作简便、专属性强、灵敏、结果准确,适用于利格列汀的残留溶剂测定。

953例口服降糖药不良反应/事件报告分析

目的探讨口服降糖药品不良反应/事件(ADR/ADE)发生的一般规律和特点,为临床合理用药提供依据。方法采用回顾性研究方法,收集2012年1月1日至2022年12月31日武汉市ADR/ADE自发呈报系统数据库中10种口服降糖药ADR/ADE报告,采用描述性方法对报告信息、患者人口学特征、用药情况和累及系统-器官分布及临床表现等进行分析。结果共纳入口服降糖药ADR/ADE报告953例,涉及1405例次,数量呈逐年上升趋势,程度以“一般”为主(88.67%),“严重”占11.33%;以胃肠系统损害、皮肤及其附件损害和代谢与营养障碍最为多见,频次排序前3位的药物类别为α-糖苷酶抑制剂、噻唑烷二酮类和双胍联合噻唑烷二酮复方制剂。不同类别药物所致ADR/ADE的累及系统-器官和临床表现各具特点,钠-葡萄糖共转运蛋白2抑制剂以尿路损害和生殖器瘙痒为主,二肽基肽酶Ⅳ抑制剂以皮肤及皮肤附件疾病损害为主,格列奈类所致低血糖居多,其他类别最常见胃肠道不适,基本与药品说明书相符。结论口服降糖药的ADR/ADE涉及系统广泛,且呈逐年增多趋势,特别需关注新型口服降糖药,通过多方位药学服务,提升患者自我管理能力,加强ADR/ADE风险防范意识,及时识别并处理ADR/ADE,保障患者用药安全。

HPLC-DAD法检测降糖类保健食品中非法添加的二肽基肽酶-4抑制剂和钠-葡萄糖协同转运蛋白2抑制剂

目的利用高效液相色谱-二极管阵列检测器(HPLC-DAD)技术,建立降糖类保健食品中可能添加的维格列汀、沙格列汀、阿格列汀、利格列汀、恩格列净、达格列净、卡格列净和西格列汀等8种化学药物的检查方法。方法采用Agilent Zorbax C_(18)色谱柱(250 mm×4.6 mm,5μm),以乙腈-0.01 mol·L^(-1)磷酸二氢铵水溶液(含0.04%辛烷磺酸钠,用磷酸调pH至3.3)为流动相,进行梯度或等度洗脱,流速1.0 mL·min^(-1),柱温25℃,检测波长为210、220 nm。结果8种化学成分在对应质量浓度范围内与峰面积呈良好的线性关系(r≥0.9999);低、中、高3个质量浓度的平均回收率均在98.8%~100.7%,RSD在0.44%~0.76%;精密度和稳定性良好,RSD均小于1.0%;检测限为0.022~0.54μg·mL^(-1);定量限为0.070~1.7μg·mL^(-1)。结论该方法简便、准确、易于推广,适用于降糖类保健食品中8种可能非法添加的新型降糖化学药物的检测。

二肽基肽酶4抑制剂在风湿免疫病中的潜在作用

二肽基肽酶4(DPP4)抑制剂已广泛应用于2型糖尿病的二线治疗。DPP4抑制剂通过抑制DPP4酶提高循环中的肠促胰岛素激素、胰高血糖素样肽-1(GLP-1)和葡萄糖依赖性促胰岛素多肽(GIP)的完整生物活性形式水平。风湿免疫病是一组主要累及骨、关节和软组织的疾病,与自身免疫系统相关,造成关节等多个器官系统的损伤。免疫系统拥有复杂而精密的调控机制,因此在风湿免疫病治疗方面更需要个体化和精准化。随着近年来DPP4在纤维化和免疫调节中的作用被发现,DPP4抑制剂与风湿性疾病间的关系也越来越受到关注。该文综述DPP4抑制剂在免疫调控及风湿性疾病中应用的最新进展,为临床治疗中DPP4抑制剂的选择提供参考。