一种新的降压药——咪唑啉受体拮抗剂

一种新的降压药—咪唑啉受体拮抗剂ＩｍｉｄａｚｏｌｉｎｅＲｅｃｅｐｔｏｒＡｎｔａｇｏｎｉｓｔ－ＡＮｅｗＡｎｔｉｈｙｐｅｒｔｅｎｓｉｖｅＤｒｕｇ今年６月，在英国格拉斯哥召开的第１６届国际高血压学术会议上，介绍了一种新型降压药—咪唑啉受体拮抗剂，国内学者尚...     

咪唑啉受体在人体内的分布及功能

大量研究表明 ,多种动物的不同组织内均存在咪唑啉受体 ,作用于此类受体 ,可产生多种不同的选择性作用。本文着重阐述了咪唑啉受体在人体内的分布及其功能     

利美尼定——一种亲咪唑啉受体的新型抗高血压药物

利美尼定是一种新型的中枢性抗高血压药物，除与α２－肾上腺素能受体结合外，与咪唑啉受体有更大的亲和力。它通过与咪唑啉受体的结合而发挥降压作用，同时也减轻了与α－２－肾上腺素能受体结合带来的副作用。     

选择性5—羟色胺4受体激动剂研究进展

本对５－羟色安４受体激动剂吲哚烷基胺类ＨＴＦ的基本结构、药代动力学、药效学、对胃肠运动的调节机制以及不良反应等作一综述。     

多巴胺受体激动剂治疗中晚期帕金森病的临床研究

帕金森病(PD)是以运动减少、震颤和肌强直为主要表现的一种神经变性疾病,晚期致残率较高。左旋多巴替代治疗一直是基本的治疗药物。近年研究表明多巴胺(DA)受体激动剂不但能缓解其临床症状,还可以克服左旋多巴的不足,且具有神经保护作用[1],主张将DA受体激动剂用于早发(<50岁发病)的PD患者或者与左旋多巴制剂联合应用治疗中晚期PD[2]。本研究观察了34例应用DA受体激动剂(吡贝地尔缓释剂,商品名:泰舒达)或复方左旋多巴制剂(多巴丝肼,商品名:美多芭)治疗的中晚期PD患者,初步探索DA受体激动剂治疗中晚期PD的临床疗效。1资料与方法1.1病…     

多巴胺受体激动剂治疗帕金森病的基础研究进展

帕金森病 (PD)是以脑内黑质多巴胺 (DA)能神经元缺失为主要特点的慢性进行性变性疾病。 40多年来L dopa制剂一直被认为是治疗PD的最有效的药物 ,它对各种PD症状都有较好的疗效 ,但长期和 /或大量应用易出现疗效减退、“剂末现象”、“开关现象”等并发症的发生〔1〕。产生这些现象的原因尽管目前尚未完全阐明 ,但与L dopa本身的缺陷及疾病的不断进展有密切的联系。DA受体激动剂可以克服L dopa的不足 ,并可以加强L dopa的疗效 ,延缓并发症的出现。DA受体激动剂是目前发展最快的PD治疗药物。1　DA受体激动剂的分类DA受体是 2 0世纪 7…     

咪唑安定在机械通气中的应用

机械通气患者在救治过程中常见的应激反应为焦虑、恐惧和躁动等,患者应激反应的程度及能否控制直接关系到其预后。因此,有效的镇静对于机械通气患者非常重要。1 镇静剂对机械通气患者的作用 由于气管插管的强烈刺激,机械通气患者常发生烦躁不     

钙敏感受体激动剂的临床研究进展

继发性甲状旁腺功能亢进症(SHPT)是慢性肾脏病(CKD)常见的并发症,慢性肾脏病导致患者矿物质和骨代谢异常,其严重性主要是导致心血管钙化,与透析患者的生存预后密切相关.活性维生素D类药物用于临床治疗继发性甲状旁腺功能亢进症常常伴发高血钙、高血磷而增加心血管钙化的危险.多数药物治疗无效的继发性甲状旁腺功能亢进症患者只能接受甲状旁腺切除术治疗.钙敏感受体激动剂的问世改变了继发性甲状旁腺功能亢进症药物治疗的难题,使多数重症继发性甲状旁腺功能亢进症患者避免了手术风险.我们对钙敏感受体激动剂的临床应用作一介绍.     

第三代β受体阻滞剂卡维地洛

第三代β受体阻滞剂卡维地洛江西景德镇市第三医院内科欧阳伟综述吴钟山审校卡维地洛（ｃａｒｖｅｄｉｌｏｌ或ＢＭ１４１９０，简称ＣＤＬ）是一种具有多种附加作用的第三代β阻滞剂，化学名为１［咔唑基－（４）－氧］－３－［（２－甲氧苯氧甲基）氨基］－丙醇－（２）...     

神经营养因子受体Trk小分子激动剂研究进展

神经营养因子作用于Trk受体酪氨酸激酶后能激活细胞内磷酸肌醇3-激酶、细胞外信号调节激酶等信号通路,促进神经元的存活和分化。开发非肽类小分子Trk激动剂以及神经营养因子模拟物,能够在激动Trk受体信号转导的同时避免神经营养因子的诸多缺点,为治疗神经系统疾病提供了新的治疗思路。     

甲状腺激素β受体激动剂在代谢性疾病中的应用前景

甲状腺激素β1受体(TRβ1)是甲状腺激素参与能量代谢、脂代谢和糖代谢的土要受体.TRβ激动剂选择性作用于TRβ1,动物实验表明TRβ激动剂KB-141、GC-1等可以减轻体重、调节血脂、改善精耐量、增加胰岛素的敏感性,不升高血压,且几乎不影响心率、骨骼肌和下丘脑-垂体-甲状腺轴的功能.凶此,TRβ激动剂有可能成为防治肥胖、血脂异常、糖尿病和代谢综合征等代谢性疾病的新药.     

Phase I studies of the safety,tolerability, pharmacokinetics and pharmacodynamics of the dual glucagon receptor/glucagon-like peptide-1 receptor agonist BI 456906

Aim

To report two phase I studies of the novel subcutaneous glucagon-like peptide-1 receptor/glucagon receptor (GLP-1R/GCGR) dual agonist BI 456906 versus placebo in healthy volunteers and people with overweight/obesity.

Materials and Methods

A phase Ia study (NCT03175211) investigated single rising doses (SRDs) of BI 456906 in 24 males with a body mass index (BMI) of 20–<30 kg/m². A phase Ib study (NCT03591718) investigated multiple rising doses (MRDs) of BI 456906 (escalated over 6 [Part A] or 16 [Part B] weeks) in 125 adults with a BMI of 27–40 kg/m².

Results

In the SRD study (N = 24), mean body weight decreased with increasing BI 456906 dose. In the MRD study, the maximum decreases in placebo-corrected mean body weight were at week 6 (–5.79%, dosage schedule [DS] 1; Part A) and week 16 (–13.8%, DS7; Part B). BI 456906 reduced plasma amino acids and glucagon, indicating target engagement at GCGRs and GLP-1Rs. Drug-related adverse events (AEs) increased with BI 456906 dose. The most frequent drug-related AE with SRDs was decreased appetite (n = 9, 50.0%), and two subjects (8.3%) did not complete the trial because of AEs (nausea and vomiting). During MRD Part A (N = 80), 10 subjects (12.5%) discontinued BI 456906, most commonly because of a cardiac or vascular AE (n = 6, 7.5%); during Part B (N = 45), eight subjects (17.8%) discontinued BI 456906, mainly because of AEs (n = 6, 13.3%), most commonly gastrointestinal disorders.

Conclusions

BI 456906 produced a placebo-corrected body weight loss of 13.8% (week 16), highlighting its potential to promote clinically meaningful body weight loss in people with overweight/obesity.     

Inverse agonist exposure enhances ligand binding and G protein activation of the human MT1 melatonin receptor, but leads to receptor down-regulation

Melatonin binds and activates G protein-coupled melatonin receptors. The density and affinity of the endogenous melatonin receptors change throughout the 24-hr day, and the exposure of recombinant melatonin receptors to melatonin often results in desensitization of the receptors. Receptor density, G protein activation and expression level were analyzed in CHO cell lines stably expressing the human MT1 receptors after 1 or 72 hr of exposure to melatonin (agonist, 10 nm) and luzindole (antagonist/inverse agonist, 10 microm). The 72-hr exposure to luzindole significantly increased the apparent receptor density in cell lines with both high and low MT1 receptor expression levels (MT1(high) and MT1(low) cells, respectively). In the constitutively active MT1(high) cells, luzindole pretreatment also stimulated the functional response to melatonin in [(35)S]GTPgammaS binding assays, whereas melatonin pretreatment attenuated the functional response at both time points. Receptor ELISA was used to analyze the cell membrane and total expression level of the MT1 receptor in intact and permeabilized cells, respectively. Luzindole pretreatment decreased the total cellular level of MT1 receptor in the MT1(high) cells at both time points but increased the cell surface expression of MT1 receptor at 72 hr. Melatonin significantly decreased MT1 receptor cell surface expression only in MT1(high) cells after a 1-hr treatment. These results indicate that melatonin treatment desensitizes MT1 receptors, whereas luzindole increases ligand binding and G-protein activation. Luzindole also stimulates downregulation of the MT1 receptor protein, interfering with the synthesis and/or degradation of the receptor.     

胰高血糖素样肽-1受体激动剂治疗多囊卵巢综合征的研究进展

多囊卵巢综合征(PCOS)是育龄期女性常见的一类内分泌紊乱疾病,可导致不孕.目前其病因尚未完全明确.高雄激素血症、胰岛素抵抗(IR)及高胰岛素血症等内分泌激素紊乱是其重要特征.现已证实,胰高血糖素样肽-1受体激动剂(GLP-1Ra)能够改善PCOS患者IR,减轻体重,并能影响其睾酮、黄体生成素、卵泡刺激素的分泌,因而可能干预PCOS的发生、发展.与此同时,GLP-1 Ra还能对PCOS伴发2型糖尿病、心血管系统疾病、非酒精性脂肪性肝病发挥作用.     

β2肾上腺素受体激动剂增强肺泡液体转运的信号转导机制进展

β2肾上腺素受体激动剂增强肺泡液体清除作用被高度关注,已在肺水肿和急性呼吸窘迫综合征患者中进行了多项临床实验.近年来其具体的信号转导机制的短时间作用和长时间作用两种途径都被进一步阐明,如前者高选择性Na+通道的膜插入机制,后者Na+,K+-ATP酶的转录后调节机制,为肺水肿治疗药物的开发奠定了理论基础.     

用Network Meta分析系统评价GLP-1受体激动剂类降糖药的心血管安全性

目的 使用Network Meta分析系统评价胰高血糖素样肽1（GLP-1）受体激动剂类降糖药的心血管安全性.方法 系统检索Medline、Embase、ClinicalTrials.gov和Cochrane Library数据库（截止2011年10月）中比较GLP-1受体激动剂与其他降糖药物或安慰剂的心血管安全性的随机对照研究（RCT）,采用传统Meta分析和Network Meta分析方法对纳入的RCT的研究结果进行合并.结果 共纳入45项研究,15 883例糖尿病患者,包括八种干预措施（六种GLP-1类药：艾塞那肽、利拉鲁肽、他司鲁肽、阿必鲁肽、利西拉来和LY2189265,以及安慰剂和传统降糖药）,研究总臂数为95.传统Meta分析和Network Meta分析结果相近,均未显示GLP-1受体激动剂与其他降糖药物或安慰剂之间心血管疾病安全性有统计学差异（P均＞0.05）.此外,结合直接和间接比较的Network Meta分析显示六种GLP-1类药之间两两比较的心血管安全性也均无统计学差异（P均＞0.05）.基于贝叶斯理论的Network Meta分析可对八种干预措施进行排序,显示安慰剂心血管风险最大.结论 尽管单个研究报道GLP-1类药有潜在的心血管保护效应,但目前Network Meta分析仍无法定论,仍有待专门设计的大型前瞻性研究加以验证.     

The impact of improved glycaemic control with GLP-1 receptor agonist therapy on diabetic retinopathy

Rapid improvement in glycaemic control with GLP-1 receptor agonist (RA) therapy has been reported to be associated with significant progression of diabetic retinopathy. This deterioration is transient, and continuing GLP-1 RA treatment is associated with reversal of this phenomenon. Pre-existent maculopathy, higher grade of retinopathy and longer duration of diabetes may be risk factors for persistent deterioration.     

Combination therapy with GLP‐1 receptor agonist and SGLT2 inhibitor

The SGLT2 inhibitors (SGLTi) and glucagon‐like‐1 receptor agonists (GLP‐1 RAs) effectively reduce HbA1c, but via very different mechanisms, making them an effective duet for combination therapy. Recently, drugs in both of these antidiabetic classes have been shown to reduce cardiovascular events, most probably by different mechanisms. SGLT2i appear to exert their CV protective actions by haemodynamic effects, while GLP‐1 RAs work via anti‐atherogenic/anti‐inflammatory mechanisms, raising the possibility that combined therapy with these 2 classes may produce additive CV benefits. The SGLT2i and GLP‐1 RAs also reduced macroalbuminuria, decreased the time for doubling of serum creatinine, and slowed the time to end‐stage renal disease. In this perspective, we review the potential benefit of combination SGLT2i/GLP‐1 RA therapy on metabolic‐cardiovascular‐renal disease in patients with type 2 diabetes mellitus.