肠促胰岛素相关药物的临床作用研究进展

肠促胰岛素是一类在食物刺激下由肠道细胞分泌并能促使胰岛素分泌的激素,与之相关并已用于临床的药物主要包括胰高血糖素样肽-1类似物和二肽基肽酶-4抑制剂两类。本文简要介绍肠促胰岛素相关药物的临床作用研究进展。     

肠促胰岛素相关药物的不良反应

胰高血糖素样肽-1受体激动剂和二肽基肽酶-4抑制剂是已获准用于2型糖尿病治疗的肠促胰岛素相关药物。但因此类药物的使用时间尚短,故其安全性仍受到广泛关注。本文概要介绍肠促胰岛素相关药物的不良反应。     

基于肠促胰岛素的药物的研究进展

基于肠促胰岛素的药物包括胰高血糖素样肽-1(glucagon-like peptide-1,GLP-1)受体激动剂和二肽基肽酶-4抑制剂,目前已获准用于治疗2型糖尿病,而其未来的发展方向可能主要在于如何优化自身特点和扩展临床适应证,具体包括延长GLP-1受体激动剂的有效作用时间、开发能口服的GLP-1受体激动剂、寻找可促进GLP-1分泌的新靶点、开发其他胃肠-胰腺生物活性肽类新药以及探求此类药物在1型糖尿病、肥胖症、心血管疾病和神经退行性疾病治疗领域中的临床应用前景等。     

基于肠促胰岛素的抗糖尿病药物发展概况

肠促胰岛素的发现为糖尿病治疗提供了一个新的途径,各大制药公司已相继推出了自己的药品,根据作用机制可分为二肽基肽酶-4抑制剂和胰高血糖素样肽-1类似物或受体激动剂。这些药物具有有效降低血糖、安全性和耐受性良好以及不增加体重等优点,是2型糖尿病治疗的新选择。     

基于肠促胰岛素的抗糖尿病药物市场概况

胰高血糖素样肽-1受体激动剂和二肽基肽酶-4抑制剂是两类基于肠促胰岛素的抗糖尿病新药,均通过提高体内胰高血糖素样肽-1活性而呈现血糖调控作用。这两类新药在全球及中国市场增长迅速,其中西格列汀作为二肽基肽酶-4抑制剂的代表性药物,已成为全球非胰岛素类抗糖尿病药物中的最大品牌药物。     

肠促胰岛素类药物的安全性评估

肠促胰岛素类药物包括GLP-1受体激动剂和DPP-4抑制剂。由于本类药物不同于其他传统降糖药物的独特作用机制,近年来的研究及临床应用取得了飞速进展。但是,人体内多脏器表达GLP-1受体、DPP4的底物众多,长期应用肠促胰岛素类药物的安全风险尚存在不确定性。故本文分别从胰腺、甲状腺、心血管系统、消化系统等方面,对本类药物近期的安全性研究进行了综述和分析。结果提示本类药物治疗引发胰腺炎和肿瘤的潜在风险是目前临床最大的担忧,有必要对肠促胰岛素类药物的临床应用进行长期的监测,为临床应用的安全性提供可靠数据。     

肠促胰岛素激素类2-型糖尿病药物研究进展

近年来糖尿病患者递增,糖尿病已经成为严重危害人类健康的疾病。新型2-型糖尿病药物的研发已成为当前药物研究的一大热点。研究表明葡萄糖依赖性促胰岛素分泌多肽（glucose-dependent-insulinotropie polypeptide,GIP）和胰高血糖素样肽-1（glucagons like peptide-1.GLP-1）是人类重要的肠促胰岛素激素,GLP-1和GIP对于保持人体葡萄糖稳态平衡意义重大。目前根据GLP-1和GIP的作用机制研发出胰高血糖素样肽-l类似物和受体激动剂以及二肽基肽酶-4（DPP-4）抑制剂,均具有广阔的临床价值及市场前景。     

胰高血糖素样肽-1的生物学及相关药物研究

19世纪60年代发现了肠道对葡萄糖具有调节作用。这种生理现象主要是由两个被称为"肠促胰素"的肠内因子:胰高糖素样肽-1(7-37)/(7-36)酰胺和葡萄糖依赖性促胰岛素多肽(1-42)介导的。GLP-1与GLP-1受体的结合,刺激cAMP生成,增加葡萄糖依赖性胰岛素分泌。研究还证明在体外人的胰岛制备中,GLP-1介导β-细胞凋亡的减弱和胰岛素反应性增强。很明显GLP-1/GLP-1受体轴是葡萄糖代谢的关键性生理调节器,因此GLP-1受体激动剂和DPP-4抑制剂成为治疗糖尿病药物研发的焦点。     

肠促胰素类药物与2型糖尿病患者体重控制

超重或肥胖已成为全球日益严重的公共健康问题,其中2型糖尿病的发生与肥胖息息相关。临床观察资料表明,新型肠促胰素类药物二肽基肽酶-4（dipeptidyl peptidase-4,DPP-4）抑制剂或胰高血糖素样肽-1（glucagon-like peptide-1,GLP-1）受体激动剂,在有效降糖的同时,并不增加患者体重,甚至能使患者体重降低,为目前2型糖尿病患者治疗提供了更佳的选择。     

基于肠促胰岛素治疗糖尿病的药物研究进展

肠促胰岛素包括胰高血糖素样肽-1(Glucagon-like peptide-1,GLP-1)和葡萄糖依赖性促胰岛素释放多肽(Glucose-dependent insulinotropic polypeptide, GIP)两种分子,能够在肠道摄入食物后通过血糖依赖机制促进胰岛素的分泌。胰高血糖素样肽-1受体激动剂(Glucagon-like peptide-1 receptor agonists, GLP-1RAs)类药物凭借其良好的降糖活性、显著的体重控制作用以及明显的心血管收益在糖尿病的治疗中占据重要地位,基于另一肠促胰岛素GIP的疗法能否在糖尿病患者中发挥降糖作用仍不确定。GIP/GLP-1双重受体激动剂在临床试验中展现出了较好的治疗效果,针对糖尿病这一复杂的综合代谢性疾病,单分子多重受体激动剂似乎更具有潜力。文章介绍了基于肠促胰岛素的已上市药物,综述近年来处于临床试验阶段的基于肠促胰岛素治疗糖尿病的分子,以期为基于肠促胰岛素治疗糖尿病提供更多研究思路。     

Management of Type 2 diabetes: the role of incretin mimetics

Type 2 diabetes is characterised by insulin resistance and progressive β-cell dysfunction (which leads to hyperglycaemia), the risk of progressive worsening of glycaemic control and an increased risk of both macrovascular and microvascular complications. Existing treatment strategies target deficient insulin secretion and insulin resistance, but do not generally address the underlying progressive β-cell dysfunction that is common to Type 2 diabetes. Traditionally, Type 2 diabetes is first treated with medical nutrition therapy (reduced food intake and increased physical activity), followed by stepwise addition of oral antidiabetes therapies and, ultimately, exogenous insulin, as required. Unfortunately, these approaches have not been shown to delay the need for additional therapies, nor do they generally prevent or delay the inexorable decline in β-cell function. Patients with Type 2 diabetes commonly experience deterioration in glycaemic control, and may have substantial weight gain due to the diabetes therapies that contribute to worsening obesity. In addition, insulin-providing therapies, such as sulfonylureas and exogenous insulin, carry the risk of hypoglycaemia, and cannot fully address the complex hormonal irregularities that characterise Type 2 diabetes, including the role of glucagon hypersecretion. New therapeutic approaches are being developed that couple durable glycaemic control with improved control of body weight. These approaches include development of the incretin mimetics, which are a novel class of agents that share several of the glucoregulatory effects of incretin hormones, such as glucagon-like hormone-1. Deficiency of glucagon-like hormone-1 secretion is known to be present in those with abnormal glucose tolerance. Agents that manipulate the physiological actions of incretin hormones, such as glucagon-like hormone-1, may significantly benefit patients with Type 2 diabetes.     

左氧氟沙星药代动力学/药效动力学参数与金黄色葡萄球菌耐药的相关性研究

目的：探讨左氧氟沙星药代动力学/药效动力学（PK/PD）参数与金黄色葡萄球菌耐药的相关性。方法：建立兔组织笼金黄色葡萄球菌感染模型,给予不同剂量的左氧氟沙星灌胃治疗。抽取组织笼内组织液进行药代动力学测定,计算PK/PD参数,同时监测组织笼内细菌药物敏感性变化。结果：PK/PD参数AUC24/MIC、AUC24/MPC、Cmax/MIC、Cmax/MPC、T〉MPC和Tmsw和耐药发生相关（MIC：最小抑菌浓度,MPC：防耐药变异浓度,MSW：耐药突变选择窗）,T〉MIC与耐药的发生无相关性。当AUC24/MIC在20～150h时,容易发生耐药,保持药物AUC24/MPC〉25h可以限制耐药的发生。体内MSW的上、下限分别为AUC24/MPC=25h和AUC24/MIC=20h。结论：AUC24/MPC、Cmax/MPC和T〉MPC可能是预测耐药发生的独立参数。     

Pharmacokinetic/pharmacodynamic modeling: What it is!

Although Pharmacokinetic/pharmacodynamic modeling has been around for decades, it is still in its infancy with respect to the future of its current manifestation. Due to the amount of time and other resources that must be committed for successful development and application of these methods, economic incentives must be made available to academic and industrial scientists through the NIH and FDA, respectively. The long-term returns should more than compensate for the investments in the form of scientific understanding of the concentration-effect relationships as well as more efficient and acceptable NDAs. Could this be the answer to the drug lag in the United States and other countries?     

Evaluation of species difference in peripheral lymphocyte reduction effect of CS‐0777, a sphingosine 1‐phosphate receptor modulator,based on a pharmacokinetic/pharmacodynamic model analysis

Pharmacokinetic (PK) and pharmacodynamic (PD) modeling was conducted for the reduction of peripheral lymphocytes after oral administration of CS‐0777 to healthy rats, monkeys and experimental autoimmune encephalomyelitis (EAE) induced rats. The phosphorylated active metabolite of CS‐0777, M1, is a selective sphingosine 1‐phosphate receptor‐1 modulator. A linear one‐ and two‐compartment model with a reversible metabolism process characterized the time courses of CS‐0777 and M1 concentrations in rats and monkeys, respectively. The relationship between lymphocyte counts and M1 concentrations in blood was well described by an indirect response model in all animals examined. An I_max of 0.815 and an IC₅₀ of 6.58 nM in healthy rats, an I_max of 0.807 and an IC₅₀ of 5.09 nM in the EAE rats, an I_max of 0.789 and an IC₅₀ of 0.484 nM in monkeys were estimated by the indirect PD model. Since the IC₅₀ values calculated in terms of the unbound plasma concentration in rats and monkeys were within a similar range, after correction of the IC₅₀ in blood described above with the blood to plasma concentration ratio and the plasma free fraction of M1, it was revealed that there is no species difference in the essential activity of M1 against lymphocyte reduction. The sensitivity of the lymphocytes to M1 was not affected by the EAE status. Comparison of the simulated lymphocyte reduction in EAE rats after multiple dosing with CS‐0777 and the actual EAE clinical scores implies that the significant suppressive effect on EAE did not require the elimination of all lymphocytes from the blood. Copyright © 2016 John Wiley & Sons, Ltd.     

药动药效联合模型定量分析方法的研究现状

药动药效联合模型在药理学研究中正在发挥越来越重要的作用。本文介绍了近年来该领域定量计算方面的一些新概念和新进展，包括药动学和药效学模型、药动药效联合模型的四个属性、Sheiner效应室理论应用时应该注意的问题及药动药效联合模型的计算程序等。     

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.     

Dipeptidyl peptidase IV inhibitors as new therapeutic agents for the treatment of Type 2 diabetes

Type 2 diabetes is the most prevalent form of diabetes. Incretin hormones play an important role in normal and pathological blood glucose homeostasis. The role of dipeptidyl peptidase IV (DPP IV) in the inactivation of glucagon-like peptide-1 (GLP-1), one of the most important incretins, is wellestablished. Therefore, DPP IV inhibitors are investigated as new therapeutic agents for the treatment of Type 2 diabetes. A summary of DPP IV inhibitors reported until 1998 and a more extensive discussion of more recent inhibitors found in literature and patent applications will be provided. The therapeutic potential of several aminoacyl pyrrolidides, aminoacyl thiazolidides and aminoacyl pyrrolidine-2-nitriles will be reviewed.     

Application of pharmacokinetic/pharmacodynamic and stochastic modelling to 6-mercaptopurine micronucleus induction in mouse bone marrow erythrocytes

This study investigates the kinetics of bone marrow micronucleated polychromatic erythrocytes and some mechanistic aspects of micronuclei induction using mathematical models. Female mice were administered a single intraperitoneal injection of the purine antagonist 6-mercaptopurine at 50 mg kg(-1). The time course evolution of the drug concentrations in the plasma and the micronucleated polychromatic erythrocyte kinetic rate in bone marrow were observed. Two mathematical models were developed for this study. The first model was built from a simultaneous pharmacokinetic/pharmacodynamic approach, but was invalidated after comparing its predictions to experimental data. The second model was a stochastic model based on some biological hypotheses involved in micronuclei induction. This model predicted a wavy kinetic rate of micronucleated polychromatic erythrocytes that was confirmed by a second data set obtained from a specifically built experimental design. The biological hypotheses were then discussed. It turned out from this work that mathematical modelling could be used as a tool to explore the cellular mechanisms of toxicity of the compound: for instance, the assumptions that 6-mercaptopurine induced micronuclei mainly in cells entering the S phase, and not only during the last cell cycle but during one of the earlier cycles preceding the extrusion of the main nucleus, were confirmed. Moreover, the use of the stochastic model would help to schedule more accurately the bone marrow or blood harvesting times in the in vivo rodent micronucleus test.