长效GLP-1受体激动药索马鲁肽治疗2型糖尿病疗效和安全性的系统评价

目的:系统评价长效胰高血糖素样肽-1(GLP-1)受体激动药索马鲁肽对比安慰剂或其他降糖药治疗2型糖尿病的疗效和安全性,为临床治疗提供循证参考。方法:计算机检索PubMed、Embase、Medline、Cochrane图书馆,检索时限为自建库起至2018年9月,收集索马鲁肽(试验组)对比安慰剂或其他降糖药(对照组)治疗2型糖尿病疗效和安全性的随机对照试验(RCT),对符合纳入标准的临床研究进行资料提取并采用Cochrane系统评价手册5.1.0进行质量评价后,使用Rev Man 5.3软件对治疗前后患者的糖化血红蛋白(HbA_1c)水平及达标率、空腹血糖(FPG)水平、收缩压、舒张压、体质量指数(BMI)、体质量、脉搏频率水平、低血糖和胃肠道反应发生率等指标进行Meta分析。结果:共纳入12项RCT,合计9 966例患者。Meta分析结果显示,试验组相比于对照组能更有效降低HbA_1c水平[MD=-1.03,95%CI(-1.22,-0.85),P<0.001]和FPG水平[MD=-1.14,95%CI(-1.53,-0.76),P<0.001],增加受试患者HbA_1c达标率[RD=0.40,95%CI(0.31,0.49),P<0.001],同时还可降低收缩压[MD=-2.61,95%CI(-3.23,-1.98),P<0.001]、舒张压[MD=-0.56,95%CI(-0.96,-0.16),P=0.006]、BMI[MD=-1.25,95%CI(-1.51,-0.99),P<0.001],减轻体质量[MD=-3.60,95%CI(-4.24,-2.96),P<0.001],增加脉搏频率[MD=2.16,95%CI(1.51,2.81),P<0.001],差异均有统计学意义;索马鲁肽的主要不良反应为胃肠道反应,其发生率高于对照组[RD=0.20,95%CI(0.15,0.26),P<0.001]、低血糖事件的发生率与对照组比较,差异则无统计学意义[RD=0.00,95%CI(-0.01,0.02),P=0.44]。结论:索马鲁肽可明显降低2型糖尿病患者的HbA_1c、FPG、体质量、血压水平,增加脉搏频率,提高服用患者的HbA_1c达标率;同时,虽然其致胃肠道反应发生率高于对照组,但不会增加低血糖发生的风险,提示该药具有较好的耐受性和安全性。     

小分子GLP-1R激动剂对骨质疏松模型小鼠的改善作用

目的:探讨小分子胰高血糖素样肽1受体(GLP-1R)激动剂6,7-二氯-2-磺酰烷基-3-仲烷氨基喹喔啉(DMB)对骨质疏松模型小鼠的改善作用.方法:将C57BL/6J小鼠随机分为假手术组、模型组、阳性对照组(17β-雌二醇,10μg/kg)和DMB组(1 mg/kg),每组10只.假手术组小鼠行双侧剖腹术但不摘除卵巢...     

GLP-1受体激动剂超说明书用药情况调查及合理性分析

目的 了解GLP-1受体激动剂超说明书用药情况,促进临床合理用药。方法 采用回顾性调查法,抽取内分泌科2015年12月3日-2016年12月14日使用过GLP-1受体激动剂进行治疗的住院病例,按照药品说明书,判断其超说明书用药情况,对超说明书用药进行分类和统计,并评价其合理性。结果 共调查内分泌科住院患者51例,有97例次存在超说明书用药情况,其中超适应证47例次（48.45%）,主要表现在联合用药方面,另有50例次（51.55%）属于用法用量超说明书。结论 GLP-1受体激动剂在临床超说明书使用的现象较普遍,某些有其合理性和必要性,但也有不合理用药情况,临床需引起高度重视。     

Pharmacology and Therapeutic Potential of Sigma1 Receptor Ligands

Sigma (σ) receptors, initially described as a subtype of opioid receptors, are now considered unique receptors. Pharmacological studies have distinguished two types of σ receptors, termed σ₁ and σ₂. Of these two subtypes, the σ₁ receptor has been cloned in humans and rodents, and its amino acid sequence shows no homology with other mammalian proteins. Several psychoactive drugs show high to moderate affinity for σ₁ receptors, including the antipsychotic haloperidol, the antidepressant drugs fluvoxamine and sertraline, and the psychostimulants cocaine and methamphetamine; in addition, the anticonvulsant drug phenytoin allosterically modulates σ₁ receptors. Certain neurosteroids are known to interact with σ₁ receptors, and have been proposed to be their endogenous ligands. These receptors are located in the plasma membrane and in subcellular membranes, particularly in the endoplasmic reticulum, where they play a modulatory role in intracellular Ca²⁺ signaling. Sigma₁ receptors also play a modulatory role in the activity of some ion channels and in several neurotransmitter systems, mainly in glutamatergic neurotransmission. In accordance with their widespread modulatory role, σ₁ receptor ligands have been proposed to be useful in several therapeutic fields such as amnesic and cognitive deficits, depression and anxiety, schizophrenia, analgesia, and against some effects of drugs of abuse (such as cocaine and methamphetamine). In this review we provide an overview of the present knowledge of σ₁ receptors, focussing on σ₁ ligand neuropharmacology and the role of σ₁ receptors in behavioral animal studies, which have contributed greatly to the potential therapeutic applications of σ₁ ligands.     

Therapeutic Potential of Aleglitazar,a New Dual PPAR-α/γ Agonist

Preventing morbidity and mortality from diabetes mellitus is of paramount importance as the incidence of this disease is increasing across the world. While microvascular complications of diabetes such as nephropathy, retinopathy, and neuropathy are reduced with intensive glycemic control, treatment of hyperglycemia has not been consistently shown to have effects on the macrovascular complications of diabetes such as coronary artery, cerebrovascular, and peripheral vascular disease. Preventive efforts have accordingly shifted toward the modification of other cardiovascular risk factors in diabetic patients. Agonism of the peroxisome proliferator-activated receptors (PPARs) has long been an attractive target for antidiabetic therapy due to the role of PPARs in glycemic control and lipid metabolism. PPAR-γ agonists such as rosiglitazone and pioglitazone are used in clinical practice for the treatment of diabetes, and there is some evidence that pioglitazone may have positive effects on cardiovascular complications by virtue of its favorable effects on lipid profiles. However, they have not been shown to reduce macrovascular events. PPAR-α agonism is the mechanism of action in the fibrate class of medications; these agents have been shown to increase high-density lipoprotein cholesterol (HDL-C) levels, reduce triglyceride levels, and improve cardiovascular outcomes. Given the prevalence of lipid abnormalities in patients with diabetes, dual PPAR-α/γ agonists (glitazars) could potentially benefit patients with diabetes. A phase II trial examining a novel dual PPAR agonist, aleglitazar, showed that therapy with this agent reduced hyperglycemia and favorably modified levels of HDL-C and triglycerides with an acceptable safety profile. Aleglitazar is currently being studied in large-scale clinical trials to assess whether it will reduce the risk of major cardiovascular endpoints (death, myocardial infarction, or stroke) among patients with diabetes and coronary artery disease. If ongoing studies confirm the theoretical benefit and safety of dual PPAR-α/γ agonism, aleglitazar may become the first therapy demonstrated to reduce macrovascular complications in patients with diabetes.     

Oxidative Stress and Neurodegenerative Diseases: A Review of Upstream and Downstream Antioxidant Therapeutic Options

Free radicals are common outcome of normal aerobic cellular metabolism. In-built antioxidant system of body plays its decisive role in prevention of any loss due to free radicals. However, imbalanced defense mechanism of antioxidants, overproduction or incorporation of free radicals from environment to living system leads to serious penalty leading to neuro-degeneration. Neural cells suffer functional or sensory loss in neurodegenerative diseases. Apart from several other environmental or genetic factors, oxidative stress (OS) leading to free radical attack on neural cells contributes calamitous role to neuro-degeneration. Though, oxygen is imperative for life, imbalanced metabolism and excess reactive oxygen species (ROS) generation end into a range of disorders such as Alzheimer’s disease, Parkinson’s disease, aging and many other neural disorders. Toxicity of free radicals contributes to proteins and DNA injury, inflammation, tissue damage and subsequent cellular apoptosis. Antioxidants are now being looked upon as persuasive therapeutic against solemn neuronal loss, as they have capability to combat by neutralizing free radicals. Diet is major source of antioxidants, as well as medicinal herbs are catching attention to be commercial source of antioxidants at present. Recognition of upstream and downstream antioxidant therapy to oxidative stress has been proved an effective tool in alteration of any neuronal damage as well as free radical scavenging. Antioxidants have a wide scope to sequester metal ions involved in neuronal plaque formation to prevent oxidative stress. In addition, antioxidant therapy is vital in scavenging free radicals and ROS preventing neuronal degeneration in post-oxidative stress scenario.Key Words: ROS, oxidative stress, antioxidants, neurodegenerative diseases, rns, amyloid, catalase, phagocytes.     

基础胰岛素联合GLP-1受体激动剂治疗2型糖尿病疗效和安全性分析

为了探讨基础胰岛素联合胰高糖素样肽-1(GLP-1)受体激动剂治疗2型糖尿病(T2DM)疗效和安全性,选取2017年1月至2019年1月该院T2DM患者200例,依据随机数字表分为A组和B组,每组100例,A组给予基础胰岛素治疗,B组在此基础上给予GLP-1受体激动剂(利司那肽)治疗,比较两组胰岛素功能[空腹胰岛素(FINS)、胰岛素抵抗指数(HOMA-IR)、胰岛β细胞功能(HOMA-β)]、血糖控制[空腹血糖(FBG)、餐后2 h血糖(2hPBG)、糖基化血红蛋白(HbA1c)]、治疗疗效、不良反应。A组和B组治疗后FINS、HOMA-IR、FBG、2hPBG、HbA1c明显低于治疗前,B组治疗后FINS、HOMA-IR、FBG、2hPBG、HbA1c明显低于A组,A组和B组治疗后HOMA-β明显高于治疗前,B组治疗后HOMA-β明显高于A组,差异有统计学意义(P<0.05);B组治疗有效率明显高于A组,差异有统计学意义(P<0.05);A组和B组不良反应率比较,差异无统计学意义(P>0.05)。基础胰岛素联合GLP-1受体激动剂可有效改善T2DM患者胰岛素功能、血糖控制效果,有利于提高疗效,且安全性好,可供临床应用参考。     

Discovery of MK-5046, a Potent,Selective Bombesin Receptor Subtype-3 Agonist for the Treatment of Obesity

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Development of a Population Pharmacokinetic Model for Taranabant, a Cannibinoid-1 Receptor Inverse Agonist

Taranabant is a cannabinoid-1 receptor inverse agonist developed for the treatment of obesity. A population model was constructed to facilitate the estimation of pharmacokinetic parameters and to identify the influence of selected covariates. Data from 12 phase 1 studies and one phase 2 study were pooled from subjects administered single and multiple oral doses of taranabant ranging from 0.5 to 8 mg. A total of 6,834 taranabant plasma concentrations from 187 healthy and 385 obese subjects were used to develop the population model in NONMEM. A standard covariate analysis using forward selection (α = 0.05) and backward elimination (α = 0.001) was conducted. A three-compartment model with first-order absorption and elimination adequately described plasma taranabant concentrations. The population mean estimates for apparent clearance and apparent steady-state volume of distribution were 25.4 L/h and 2,578 L, respectively. Statistically significant covariate effects were modest in magnitude and not considered clinically relevant (the effects of body mass index (BMI) and creatinine clearance (CrCL) on apparent clearance; BMI, age, CrCL, and gender on apparent volume of the peripheral compartment and age on apparent intercompartmental clearance). The pharmacokinetic profile of taranabant can adequately be described by a three-compartment model with first-order absorption and elimination. Clinical dose adjustment based on covariates effects is not warranted.Key words: NONMEM, obesity, pharmacokinetics, population, taranabant     

Effects of SA13353, a Transient Receptor Potential Vanilloid 1 Agonist,on Leukocyte Infiltration in Lipopolysaccharide-Induced Acute Lung Injury and Ovalbumin-Induced Allergic Airway Inflammation

We recently demonstrated that SA13353, a transient receptor potential vanilloid 1 (TRPV1) agonist, reduced the severity of the symptoms of kidney injury, arthritis, and encephalomyelitis in disease models. Here, we investigated the effects of orally administered SA13353 on leukocyte infiltration in lipopolysaccharide (LPS)-induced acute lung injury and ovalbumin-induced allergic airway inflammation. In LPS-induced lung injury, SA13353 attenuated neutrophil infiltration and the increase of TNF-α and CINC-1 levels. In allergic airway inflammation, SA13353 tended to inhibit leukocyte infiltration and attenuated the increase of IL-4 and IL-12p40. These results suggest that somatosensory TRPV1 may play an anti-inflammatory role in lung inflammation.     

The Role of ASIC1a in Epilepsy: A Potential Therapeutic Target

Background Epilepsy represents one of the most common brain diseases among humans. Tissue acidosis is a common phenomenon in epileptogenic foci. Moreover, its role in epileptogenesis remains unclear. Acid-sensing ion channel-1a (ASIC1a) represents a potential way to assess new therapies. ASIC1a, mainly expressed in the mammalian brain, is a type of protein-gated cation channel. It has been shown to play an important role in the pathological mechanism of various diseases, including stroke, epilepsy, and multiple sclerosis.Methods Data were collected from Web of Science, Medline, PubMed, through searching for these keywords: “Acid-sensing ion channels 1a” or “ASIC1a” and “epilepsy” or “seizure”.Results The role of ASIC1a in epilepsy remains controversial; it may represent a promising therapeutic target of epilepsy.Conclusion This review is intended to provide an overview of the structure, trafficking, and molecular mechanisms of ASIC1a in order to elucidate the role of ASIC1a in epilepsy further.     

Nanoparticles in the Brain: A Potential Therapeutic System Targeted to an Early Defect Observed in Many Neurodegenerative Diseases

Currently, there are no effective treatments or cures for many neurodegenerative diseases affecting an aging baby-boomer generation. The ongoing problem with many of the current therapeutic treatments is that most are aimed at dissolving or dissociating aggregates and preventing cell death, common neuropathology often seen towards the end stage of disease. Often such treatments have secondary effects that are more devastating than the disease itself. Thus, effective therapeutics must be focused on directly targeting early events such that global deleterious effects of drugs are minimized while beneficial therapeutic effects are maximized. Recent work indicates that in many neurodegenerative diseases long distance axonal transport is perturbed, leading to axonal blockages. Axonal blockages are observed before pathological or behavioral phenotypes are seen indicating that this pathway is perturbed early in disease. Thus, developing novel therapeutic treatments to an early defect is critical in curing disease. Here I review neurodegenerative disease and current treatment strategies, and discuss a novel nanotechnology based approach that is aimed at targeting an early pathway, with the rationale that restoring an early problem will prevent deleterious downstream effects. To accomplish this, knowledge exchange between biologists, chemists, and engineers will be required to manufacture effective novel biomaterials for medical use.     

Establishing the Therapeutic Index of Fluid Resuscitation in the Septic Patient: A Narrative Review and Meta-Analysis

This comprehensive review comparatively evaluates the safety and benefits of parenteral fluids used in resuscitation with a focus on sepsis. It also provides a random-effects meta-analysis of studies comparing restrictive resuscitation and usual care in sepsis with the primary outcome of mortality. In the septic patient, fluid therapy remains a complex interplay between fluid compartments in the body, the integrity of the endothelial barrier, and the inflammatory tone of the patient. Recent data have emerged describing the pharmacokinetics of fluid resuscitation that can be affected by the factors just listed, as well as mean arterial pressure, rate of infusion, volume of fluid infusate, nature of the fluid, and drug interactions. Fluid overload in sepsis has been associated with vasodilation, kidney injury, and increased mortality. Restrictive resuscitation after the initial septic insult is an emerging practice. Our search strategy of Medline databases revealed six randomized studies with 706 patients that examined restrictive resuscitation in sepsis. Results of this meta-analysis demonstrated no differences in mortality with restrictive resuscitation compared with usual care (30.6% vs 37.8%; risk ratio 0.83, 95% confidence interval 0.66–1.05, respectively) but was limited by the small number of studies and larger quantities of pre-randomization fluids. Another approach to address fluid overload is active (diuresis) de-resuscitation strategies that may shorten the need for mechanical ventilation and intensive care unit length of stay. Data suggest that colloids may confer mortality benefit over saline in the most severely ill septic patients. Compared with isotonic saline, balanced resuscitation fluids are associated with a lower incidence of acute kidney injury and mortality. The benefits of balanced resuscitation fluids are most evident when higher volumes of fluids are used for sepsis. Clinicians should consider these pharmacotherapeutic factors when selecting a fluid, its quantity, and rate of infusion.     

Discovery of MK-7725, A Potent,Selective Bombesin Receptor Subtype-3 Agonist for the Treatment of Obesity

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In Vitro ADME and Preclinical Pharmacokinetics of Ulotaront,a TAAR1/5-HT1A Receptor Agonist for the Treatment of Schizophrenia

Pharmaceutical Research - Ulotaront (SEP-363856) is a TAAR1 agonist with 5-HT1A agonist activity currently in clinical development for the treatment of schizophrenia. The objectives of the current...     

5-HT3 Receptor Antagonism: A Potential Therapeutic Approach for the Treatment of Depression and other Disorders

BackgroundDepression or Major depressive disorder (MDD) is a prolonged condition of sadness. MDD is the most common mental disorder that affects more than 264 million people worldwide. According to the monoamine hypothesis, serotonin (5-hydroxy tryptamine, 5-HT), dopamine (DA) and norepinephrine (NE) are the major neurotransmitters (NTs) involved in depression.MethodsThe methodology adopted for writing this review article is essentially based on the secondary literature search through a systematic literature review. This review mainly focussed on the role of 5-HT₃ receptor antagonists (5-HT₃RA) in depression and comorbid disorders like anxiety.ResultsOut of three major NTs mentioned above, serotonin has a predominant role in the pathophysiology of depression. The serotonin type-3 receptors (5-HT₃R) are well renowned to be expressed in the central nervous system (CNS) in regions which have significance in the vomiting reflex, perception of pain, the reward system, cognition, depression and anxiety control. 5-HT₃R are the receptors of serotonergic family that belong to ligand-gated ion channel. 5-HT₃RA inhibit the binding of serotonin to postsynaptic 5-HT₃R and increases its availability to other receptors like 5-HT_1A, _1B and _1D as well as 5-HT₂ receptors and produces anti-depressant-like effect. 5-HT₃RA also have an important role in mood and stress disorders. Some of the studies have shown the effectiveness of these agents in stress disorder.ConclusionThe present article focussed on the role of 5-HT₃R and their antagonists in the treatment of depression and anxiety. Further studies are warranted to prove their efficacy with respect to other standard anti-depressants.     

Safety and Pharmacokinetics of HTL0018318, a Novel M1 Receptor Agonist,Given in Combination with Donepezil at Steady State: A Randomized Trial in Healthy Elderly Subjects

IntroductionHTL0018318 is a selective muscarinic M₁ receptor partial agonist under development for the symptomatic treatment of dementias, including Alzheimer’s disease. Clinically, HTL0018318 would likely be used alone or in conjunction with cholinesterase inhibitors (e.g. donepezil).ObjectiveWe investigated the safety, tolerability, and pharmacokinetics of HTL0018318 given alone and in combination with donepezil.MethodsThis was a randomized, double-blind, placebo-controlled trial in 42 (to deliver 36 with combination treatment) healthy elderly subjects investigating the effects of oral HTL0018318 15 and 25 mg given alone and combined with donepezil 10 mg at steady state on adverse events (AEs), vital signs, saliva production, sleep quality, pulmonary function, subjective feelings, and pharmacokinetics.ResultsAEs were reported by lower percentages of subjects after HTL0018318 alone than after donepezil alone. There was no increase in the percentage of subjects reporting AEs after co-administration than after donepezil alone. Supine systolic blood pressure was 1.6 mmHg (95% confidence interval [CI] −3.1 to −0.1) lower after HTL0018318 alone than after combination treatment. This was comparable with results from placebo alone: 1.7 mmHg (95% CI −3.2 to 0.2) lower than with combination treatment. Supine pulse rate was 3.3 bpm (95% CI 1.5–5.1) higher after HTL0018318 alone than with co-administration. HTL0018318 and donepezil did not meaningfully affect each other’s pharmacokinetics.ConclusionHTL0018318 was well tolerated when given alone and in combination with donepezil. HTL0018318 and donepezil do not demonstrate pharmacokinetic or pharmacodynamic interactions, indicating that HTL0018318 can be safely administered in combination with donepezil.Clinical trial registrationNetherlands Trial register identifier NL5915, registered on 28 October 2016.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40268-021-00352-5.     

Akathisia and Newer Second-Generation Antipsychotic Drugs: A Review of Current Evidence

Akathisia continues to present a significant challenge in clinical practice. As a class, so-called atypical, or second-generation, antipsychotics (SGAs) are the mainstay of treatment for schizophrenia and are commonly used to treat mood disorders. These medications have traditionally been distinguished from first-generation antipsychotics by their lowered risk of extrapyramidal side effects (EPS) such as dystonia, dyskinesia, akathisia, and pseudoparkinsonism. However, the occurrence of EPS, particularly akathisia, has been demonstrated to some degree in all commercially available SGAs. This review examines the incidence of akathisia in nine newer SGAs in patients with schizophrenia, bipolar disorder, and major depressive disorder (MDD). We performed a search of PubMed, ClinicalTrials.gov, Cochrane Central Register, and Google Scholar, as well as manufacturer websites and product labeling for published and unpublished clinical trials, meta-analyses, and systematic reviews. Studies evaluating adult patients with schizophrenia, bipolar disorder, or MDD were eligible for inclusion. Data on treatment-emergent akathisia rates were gathered from each study, and potential dose-response relationships were explored. A total of 177 studies were included in this review, comprising 58,069 patients across 414 treatment arms. Compared with placebo with a composite 3.7% incidence of akathisia, individual SGAs produced akathisia at total composite rates ranging from 2.9–13.0% across the included studies. High doses of an SGA were generally associated with an increased risk of akathisia. Clinicians should consider the risk of akathisia when choosing a treatment option and monitor for akathisia in patients beginning therapy with an SGA or following a dose increase of the SGA.     

The Tegafur-Based Dihydropyrimidine Dehydrogenase Inhibitory Fluoropyrimidines, UFT/Leucovorin (ORZEL and S-1: a Review of Their Clinical Development and Therapeutic Potential

Protracted intravenous regimens of fluorouracil (5-FU) may besuperior and better tolerated than intravenous bolus dosing. Aneffective oral regimen would allow a protracted course of 5-FUwithout the need for central venous lines and the associatedincrease in complications. Approximately 85% of 5-FU is degradedby dihydropyrimidine dehydrogenase (DPD); inhibition of thisenzyme pathway can increase the amount of circulating 5-FU. Two oralfluoropyrimidines commonly referred to as DPD inhibitoryfluoropyrimidines, or DIFs, UFT® plus leucovorin(LV) and S-1 are reviewed herein. These agents represent anapproach to more convenient, less toxic 5-FU therapy. In twomulticenter, randomized, phase III trials in patients withadvanced colorectal cancer, UFT/LV produced equivalent activitycompared with intravenous 5-FU/LV but with significantly lessmajor toxicity. The predominant side effect of UFT, diarrhea, isgenerally self-limited and easily managed. Myelosuppression andhand-foot syndrome were rarely noted in the schedules used inthese trials. S-1 has demonstrated promising activity in phaseII trials conducted in patients with gastric, colorectal, breast,and head and neck cancers. Ongoing trials are defining the rolesof these agents in a variety of malignancies.