动脉粥样硬化炎性标志物及相关药物研究进展

动脉粥样硬化(AS)是一种慢性炎症过程,对于炎症与AS间这一新的认识,加深了人们对AS的理解,也为临床提供了重要指征.本文综述与AS有关的炎性标志物及相关治疗药物研究评价,以期对临床治疗方案的选择提供帮助.     

ABCA1：动脉粥样硬化治疗的新方向

动脉粥样硬化是导致心血管疾病的主要原因，血浆中的HDL水平与AS呈现高度负相关性。ABCA1是ATP-结合盒转运蛋白超家族中的一员，能介导转运胆固醇至细胞膜与载脂蛋白结合形成HDL，从而从外周细胞转运胆固醇至肝脏，再从胆汁分泌中清除，防止胆固醇在巨噬细胞中沉积，防止AS的发生。有ABCA1基因突变引起的tangier病纯合子发生AS的几率几乎比正常人高6倍。由此可见，ABCA1在胆固醇转运，HDL代谢和防动脉粥样硬化中都起到一定作用。     

抗氧化：防治动脉粥样硬化的新途径

动脉粥样硬化(atherosclerosis,AS)是一类严重威胁人类健康的疾病,是心脑血管疾病的重要病理基础,因而抗AS药的研究日益受到重视.AS传统的治疗措施多为对危险因素(高脂血症,高血压等)的治疗.近年来AS发生的氧化修饰脂蛋白学说日益受到重视.氧化修饰低密度脂蛋白(oxidizedmodified low density lipoprotein,OX-LDL)在AS中具有重要作用,因此,防止LDL氧化的药物成为近年研究抗AS的新途径.我们就近年来抗氧化剂对AS发生发展过程的影响作一阐述.1 AS发生的氧化修饰脂蛋白学说AS主要以内皮细胞损伤、血管平滑肌细胞增殖及内膜下移为特点.内皮细胞损伤为AS发生的始动环节.造成内皮细胞损伤的因素很多,其中高胆固醇血症仍被认为是最重要的危险因素之一.现已证实胆固醇的致AS效应主要在于胆固醇中的LDL,特别是OX-LDL.OX-LDL是由天然LDL(n-LDL)经过氧化修饰形成的.动脉壁中主要的3种类型细胞即内皮细胞、血管平滑肌细胞(SMC)及单核细胞都可氧化LDL.OX-LDL具有以下生物学特性:①细胞毒性作用,可使内皮细胞变性、坏死、脱落,造成内皮细胞损伤;②促进SMC增殖,OX-LDL可促进     

恩格列净降低糖尿病合并动脉粥样硬化患者主要心血管事件风险价值的长期队列观察研究

目的:观察和分析恩格列净降低糖尿病(DM)合并动脉粥样硬化(AS)患者主要心血管事件风险的价值.方法:选取2016年9月至2019年12月延安大学附属医院心脑血管病医院收治的136例DM合并AS患者.根据降糖治疗方案,将86例使用恩格列净的患者纳入观察组,50例未使用恩格列净的患者纳入对照组.采取常规降糖及对症治疗,两...     

补阳还五汤联合生脉散颗粒对高血压颈动脉粥样硬化患者临床疗效观察

<正>各种心脑血管疾病如心肌梗死、脑梗死等在目前人类病死原因中占首位,而动脉粥样硬化(atherosclerosis)在其中起着重要的作用,因此有效防治AS有利于保障人民群众的身体健康。高脂血症是指由物质代谢异常引发的病症,胆固醇(TC)、甘油三酯(TG)指标异常为主要特征。高脂血症不但可降低生活质量,还可诱发心血管疾病,危害健康。故而,临床需加强该病诊断、治疗,在调节血脂代谢,保护血管的同时,尽量防止动脉粥样硬化,提高     

调血脂性抗动脉粥样硬化药物的研究进展

<正> 抗动脉粥样硬化药(AASD)是防治动脉粥样硬化(AS)病变的药物。近20年来这类药物的发展很快,主要原因为: 1.AS是心脑血管病的主要病理基础,而心脑血管的发病率、致残率和死亡率均高,是人体健康和生命的最大威胁; 2.防治AS是防治心脑血管的根本性措施; 3.药物是防治AS的主要工具之一;     

动脉粥样硬化动物模型研究现状

动脉粥样硬化(AS)是引发多种心脑血管疾病的重要原因,建立一个良好的AS动物模型是研究AS发病机制,寻找有效的预防和治疗手段的重要前提.人们在不断的探索中已经成功建立了多种AS动物模型,现就目前这方面的工作作一综述.     

SDF-1/CXCR4与糖尿病大血管病变关系的研究

动脉粥样硬化（atherosclerosis,AS）是糖尿病大血管病变的基本特征,糖尿病AS的特点主要表现为病变血管分布更加广泛,粥样病变更加弥散,管腔狭窄程度更加严重以及斑块更加容易破裂.基质细胞衍生因子-1（stromal cell derived factor 1,SDF-1）是一种趋化因子,能介导血液中的炎症细胞与血管内皮细胞黏附并向血管内膜下迁移,从而发挥生物学作用.有越来越多的研究表明,SDF-1在AS的斑块与血栓形成、内膜的增厚、管腔狭窄等病理过程中起着重要作用,因此SDF-1有望成为治疗AS的新靶点,研究SDF-1/CXCR4对治疗糖尿病大血管病变有着重要意义.…… 作者简介：梁玉娥（1987-）,女,广西来宾人,硕士研究生,主要进行糖尿病大血管动脉粥样硬化病变的研究;E-mail：lye2011@163.com.     

torcetrapib与动脉粥样硬化

动脉粥样硬化(AS)是引起心肌梗死、脑梗死及冠心病等心脑血管疾病死亡的主要原因。近来对胆固醇酯转移蛋白(CETP)的抑制作用已成为治疗AS的新靶点,torcetrapib是治疗AS和脂蛋白紊乱的新的CETP抑制剂。家兔实验表明,torcetrapib对CETP活性的抑制达70%~80%,且能使HDL-C水平增加50%~100%。临床试验表明,torcetrapib单独服用或伍用其他抑制剂,均能使HDL-C水平增加,LDL-C水平降低,达到AS的治疗目标。     

葛根素抗动脉粥样硬化作用及其机制的研究进展

近年来,随着人们生活水平的提高和工作节奏的加快,心脑血管病的发病率和病死率都呈明显的上升趋势.动脉粥样硬化(atherosclerosis,AS)是心脑血管病的主要病理基础,引起动脉粥样硬化的危险因素很多.葛根素的药理作用研究较多,大量临床资料证实,葛根素对动脉粥样硬化所致心血管疾病有确切疗效.近年来,对葛根素研究的热...     

Current therapeutics for spondyloarthritis

Introduction: Ankylosing spondylitis (AS) belongs to a clinically related group of disorders named spondyloarthritis (SpA) that mainly affect the axial skeleton and present with specific extra-articular manifestations. The therapeutic management of AS and other SpA has considerably progressed over the past 10 years.

Areas covered: This paper provides a review of the available treatments for AS including traditional treatments (NSAIDs, sulfasalazine and methotrexate, local corticosteroids) and biological therapies (TNF-α antagonists), as well as nonpharmacological procedures (education and physical therapy) and specific recommendations for this therapeutic management.

Expert opinion: NSAIDs remain the first-line treatment in patients with AS, especially with axial disease. There is an increasing amount of evidence showing the short-term and long-term efficacy of TNF-α antagonists in AS, with the control of pain, extra-articular manifestations and spinal inflammation as evidenced by MRI. By contrast, there is no proof for the control of radiographic progression at the spine with these agents. An early diagnosis is now possible using the new classification criteria for SpA. However, it remains to be established if an early intervention might control the progression of the disease. Since about 20 – 25% of patients are considered as nonmajor responders to TNF-α blockers, there is an unmet need for developing new biological therapies. Targeting the IL-17 pathway may be an interesting option. International recommendations for the management of AS by the Assessment of Spondyloarthritis (ASAS) group were recently updated and discussed the respective place of each current therapeutic option in AS.     

An overview of investigational new drugs for treating ankylosing spondylitis

Introduction: Ankylosing spondylitis (AS) is a chronic inflammatory rheumatic condition. Pharmacological treatment relies on nonsteroidal anti-inflammatory drugs, disease-modifying anti-rheumatic drugs (in case of peripheral involvement) and anti-TNF agents in case of inadequate response. To date, there are no alternate options, and about 30% of the patients do not adequately respond to anti-TNF therapy.

Areas covered: This overview is based on recent publications and programmed studies. The author provides the reader with an overview of AS, its current management and provide details of novel insights into the disorder. From there, the authors highlight novel treatments under investigation before providing their expert opinion on the field.

Expert opinion: The first results with biodrugs targeting the IL-23/Th17 pathway are encouraging, and secukinumab will likely be available in the forthcoming years to treat AS. Other targets may be evaluated in this axis. The author believes that additional head-to-head studies are needed find the place of these new drugs in AS treatment strategies. Further studies are also needed to better evaluate their long-term outcome and safety.     

Biotransformation of arsenic trioxide by AS3MT favors eradication of acute promyelocytic leukemia: revealing the hidden facts

Abstract

Arsenic trioxide (ATO) is one of the most effective drugs for treatment of acute promyelocytic leukemia (APL). It could specifically target the PML/RARα fusion oncoprotein stability and induces APL cell differentiation as well as apoptosis. Although many studies have been conducted to document the anticancer effects and mechanism of ATO, there is little information about the association between biotransformation of ATO to active arsenic metabolites and APL therapy. Generally, ATO can be rapidly converted into trivalent methylated metabolites by arsenic (+3 oxidation state) methyltransferase (AS3MT) mostly in liver and redistributed to bloodstream of APL patients who receiving ATO treatment, thereby leading to a balance between cytotoxicity and differentiation, which is proposed to be the key event in successful treatment of APL. In this review, we comprehensively discussed possible roles of AS3MT and methylated arsenic metabolites in APL therapy, so as to reveal the association between individual differences of AS3MT expression and activity with the therapeutic efficacy of ATO in APL patients.     

Proteomic analysis of serum-derived extracellular vesicles in ankylosing spondylitis patients

BackgroundAnkylosing spondylitis (AS) is a chronic inflammatory disease, whose pathogenesis is still unclear. Many studies show the proteins in extracellular vesicle (EVs) would change regularly in many diseases. The study aims to explore the proteins contents of serum-derived EVs in AS patients.MethodsEVs were separated by ExoQuick^TM kit. The protein profiles of AS patients and healthy subjects were analyzed by Label-free-liquid chromatography mass spectrometry (LC-MS/MS) technology. Enzyme-linked immunosorbent assay (ELISA) was used to verify the levels of the differently expressed proteins. Receiver operation characteristic (ROC) curves and bioinformatic analysis were conducted.ResultsSix hundred and ten serum-derived EVs proteins from AS patients were detected. Seventy-three diferentially expressed proteins were found in AS group, compared with healthy subjects. Of these, 31 proteins were up-regulated in AS group, while 42 proteins were down-regulated. ELISA result showed that EVs-derived serum amyloid A-1 (SAA1) was higher in AS group, which was consistent with the Label-free-LC-MS/MS data. ROC curves result revealed that the area under curve (AUC) value of EVs-derived SAA1 for AS was 0.768 (0.652–0.885). Bioinformatic analysis revealed that the differently expressed proteins in AS group were significantly involved in “complement and coagulation cascades”, “staphylococcus aureus infection”, “systemic lupus erythematosus” and “PI3K-Akt signaling pathway”.ConclusionsThe protein profiles of serum-derived EVs in AS patients and healthy subjects were different. EVs-derived SAA1 may be a potential biomarkes of AS. The function analysis indicated that the differentially expressed proteins may potentially participate in immune response.     

New treatment options and emerging drugs for axial spondyloarthritis: biological and targeted synthetic agents

Introduction: Ankylosing spondylitis (AS) and axial spondyloarthritis (ax SpA) are chronic inflammatory diseases mainly involving the axial skeleton. Pharmacological treatments for AS and ax SpA usually include local glucocorticoid injections, NSAIDs and anti-TNFα agents. Since around 30% to 40% of patients are non responders or intolerant to anti-TNFα agents, we need new therapeutic options for AS and ax SpA.

Areas covered: This review describes the new biological agents that can be used or are in development for AS or ax SpA as well as emerging synthetic targeted drugs.

Expert opinion: Based on the rationale of the involvement of the IL-23/Th17 axis in AS, novel biological agents have been developed and include secukinumab, an anti-IL-17A agent and ustekinumab, an anti-IL-23 antibody. New compounds in the class of synthetic drugs are apremilast, a PDE4 inhibitor, and inhibitors of kinase pathways. Secukinumab gave positive results in the treatment of AS. Ustekinumab yielded promising results in AS in an open labeled study. Apremilast is not effective in AS while results with kinase inhibitors are preliminary. Future studies will clarify the place of secukinumab in the therapeutic management of AS, its influence on radiographic progression and its effects on the non radiographic form of the disease.     

The immune-modulator AS101 reduces anti-HLA antibodies in sera of sensitized patients: a structural approach

BackgroundSignificant efforts are dedicated to identification of agents that eliminate anti-HLA antibodies (Ab) from sera of transplant candidates. Antibody titer following in vitro incubation of sera with desensitizing agents has shown to reflect the probability that a patient would benefit from clinical de-sensitization protocols. AS101 is a non-toxic, synthetic, organic tellurium compound. The aim of this research was to assess the ability of AS101 to reduce anti-HLA Abs and to identify patients likely to benefit from this effect.MethodsSera of sensitized patients awaiting transplant were incubated in the presence of AS101. Measured mean fluorescence intensity (MFI) represents reactivity of anti HLA Abs in the serum, as detected by the Luminex platform. The repertoire of HLA antigen epitopes was recognized using HLA Matchmaker software.ResultsAS101 Incubation caused a significant Ab titer decrease in approximately two thirds of the samples. The median Class I and II MFI decrease among the responding samples was 16.7% and 14%, respectively (p < 0.05). HLA Matchmaker analysis of the patients' class I epitope sequences revealed apparent amino-acid differences between the patterns of the responding and non-responding patients.ConclusionIn vitro incubation of sera in the presence of AS101 causes a decrease in the anti-HLA Ab's reactivity in several patient samples. Sera most likely to demonstrate this effect are characterized by a moderate MFI level and a distinct antibody reactivity pattern specific for defined HLA antigen epitopes. These results support further investigation of AS101 as a potential agent for desensitization of humoral reactivity prior to transplantation.     

Integrated metabonomic–proteomic studies on blood enrichment effects of Angelica sinensis on a blood deficiency mice model

Context: Angelica sinensis (Oliv.) Diels (Umbelliferae) (AS) is a well-known Traditional Chinese Medicine (TCM) that enriches and regulates the blood.

Objective: An integrated metabonomic and proteomic method was developed and applied to study the blood enrichment effects and mechanisms of AS on blood deficiency (BD) mouse model.

Materials and methods: Forty mice were randomly divided into the control, BD, High-dose of AS (ASH), Middle-dose of AS (ASM), and Low-dose of AS (ASL) groups. BD model mice were established by injecting N-acetylphenylhydrazine (APH) and cyclophosphamide (CTX) (ip). The aqueous extract of AS was administered at three dose of 20, 10, or 5?g/kg b. wt. orally for 7 consecutive days before/after APH and CTX administration. Gas chromatography–mass spectrometry (GC-MS) combined with pattern recognition method and 2D gel electrophoresis (2-DE) proteomics were performed in this study to discover the underlying hematopoietic regulation mechanisms of AS on BD mouse model.

Results: Unlike in the control group, the HSP90 and arginase levels increased significantly (p?<?0.05) in the BD group, but the levels of carbonic anhydrase, GAPDH, catalase, fibrinogen, GSTP, carboxylesterase and hem binding protein in the BD group decreased significantly (p?l-alanine, arachidonic acid, l-valine, octadecanoic acid, glycine, hexadecanoic acid, l-threonine, butanoic acid, malic acid, l-proline and propanoic acid levels increased significantly (p?<?0.05) in the BD group, the levels of d-fructose in the BD group decreased significantly (p?<?0.05). The relative concentrations of 12 endogenous metabolites were also significantly affected by the ASL, ASM, and ASH treatments. Notably, most of the altered BD-related metabolites were restored to normal state after ASM administration.

Conclusion: AS can promote hematopoietic activities, inhibit production of reactive oxygen species, regulate energy metabolism, increase antiapoptosis, and potentially contribute to the blood enrichment effects of AS against APH- and CTX-induced BD mice.     

Nitroxyl inhibits overt pain-like behavior in mice: Role of cGMP/PKG/ATP-sensitive potassium channel signaling pathway

BackgroundSeveral lines of evidence have indicated that nitric oxide (NO) plays complex and diverse roles in modulation of pain/analgesia. However, the roles of charged and uncharged congeners of NO are less well understood. In the present study, the antinociceptive effect of the nitroxyl (HNO) donor, Angeli's salt (Na₂N₂O₃; AS) was investigated in models of overt pain-like behavior. Moreover, whether the antinociceptive effect of nitroxyl was dependent on the activation of cGMP (cyclic guanosine monophosphate)/PKG (protein kinase G)/ATP-sensitive potassium channels was addressed.MethodsThe antinociceptive effect of AS was evaluated on phenyl-p-benzoquinone (PBQ)- and acetic acid-induced writhings and via the formalin test. In addition, pharmacological treatments targeting guanylate cyclase (ODQ), PKG (KT5923) and ATP-sensitive potassium channel (glybenclamide) were used.ResultsPBQ and acetic acid induced significant writhing responses over 20 min. The nociceptive response in these models were significantly reduced in a dose-dependent manner by subcutaneous pre-treatment with AS. Furthermore, AS also inhibited both phases of the formalin test. Subsequently, the inhibitory effect of AS in writhing and flinching responses were prevented by ODQ, KT5823 and glybenclamide, although these inhibitors alone did not alter the writhing score. Furthermore, pretreatment with L-cysteine, an HNO scavenger, confirmed that the antinociceptive effect of AS depends on HNO.ConclusionThe present study demonstrates the efficacy of a nitroxyl donor and its analgesic mechanisms in overt pain-like behavior by activating the cGMP/PKG/ATP-sensitive potassium channel (K⁺) signaling pathway.     

Assessment of effectiveness and safety of biosimilar infliximab (CT-P13) in a real-life setting for treatment of patients with active rheumatoid arthritis or ankylosing spondylitis

Objective: To assess the effectiveness and safety of infliximab biosimilar, CT-P13, administered in a real-life setting to adult patients with active rheumatoid arthritis (RA) or ankylosing spondylitis (AS).

Methods: This multi-center, non-interventional, observational study was conducted in Bulgaria, the Czech Republic, and Romania. A total of 151 patients with severe active RA (n?=?81) or AS (n?=?70) were enrolled and treated with CT-P13 for 24 weeks, according to current medical recommendations. Effectiveness was assessed using the 4-item Disease Activity Score 28 with C-reactive protein (DAS28-CRP) for RA patients, and the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) for AS patients. Safety was assessed by withdrawals and adverse events (AEs).

Results: A total of 129 patients (RA: 67; AS: 62) were included in the effectiveness analysis. CT-P13 treatment significantly improved DAS28-CRP scores at 12 and 24 weeks (p?=?.0001 vs baseline for both timepoints) in patients with RA and BASDAI scores at 12 and 24 weeks (p?=?.0001 vs baseline for both timepoints) in patients with AS. CRP levels were significantly reduced at 12 and 24 weeks (p?=?.0001 vs baseline for both timepoints). Among 713 infusions, 34 AEs were reported (4.8% of infusions), of which 11 were considered related to CT-P13 treatment. Two of seven serious AEs were considered possibly (hepatocellular injury) or definitely (dyspnoea due to allergic infusion reaction) treatment-related. Eight patients discontinued CT-P13 due to AEs and four patients were withdrawn due to therapeutic failure.

Conclusions: CT-P13 was effective and safe in a real-life setting in patients with active RA or AS.     

Economic evaluation of etoricoxib versus non-selective NSAIDs in the treatment of ankylosing spondylitis in the UK

ABSTRACT

Objectives: To evaluate the cost-effectiveness of etoricoxib, a cyclooxygenase (COX)‐2 selective inhibitor, versus non-selective nonsteroidal anti-inflammatory drugs (nsNSAIDs) in the treatment of ankylosing spondylitis (AS).

Methods: The cost-effectiveness of etoricoxib versus nsNSAIDs was evaluated from the UK National Health Service (NHS) and society perspective with a decision-analytic model. Patients stayed on initial therapy throughout 52 weeks unless they experienced an adverse event (AE) or lacked efficacy, in which case they switched to another nsNSAID or a tumor necrosis factor alpha antagonist. Efficacy data were obtained from a 1‐year etoricoxib clinical trial in AS. Bath AS Functional Index (BASFI) data were translated into Quality Adjusted Life Year (QALY) weights using a published data on the relation between BASFI and Short-form (SF) 36 Quality of life scores, as well as the relation between SF‐36 and utility. Safety data were based on meta-analyses of etoricoxib trials. Information on treatment pathways, resource consumption, and absenteeism from work was obtained from literature and experts. Model outcomes included QALYs, perforations, ulcers, or bleeds, cardiovascular events, and costs.

Results: Etoricoxib was cost-effective compared to nsNSAIDs in terms of cost per QALY saved (£5611). Probabilistic sensitivity analysis found a 77% probability of the incremental cost per QALY saved being within a threshold for cost-effectiveness of £20?000. The expected direct costs over the 52-week period were £1.23 (95% uncertainty distribution £1.10; £1.39) and £1.13 per day (£0.78; £1.55) for patients starting with etoricoxib and nsNSAIDs, respectively. When costs related to absenteeism were taken into account, the cost per QALY saved was £281.

Conclusions: Given the underlying assumptions and data used, this economic evaluation demonstrated that, compared to nsNSAIDs, etoricoxib is a cost-effective therapy for AS patients in the UK.