抑制三磷酸腺苷柠檬酸裂解酶的降胆固醇新药——bempedoic acid

Bempedoic acid(ETC-1002)是由美国生物制药公司Esperion公司研发的一种新型口服降脂药物,目前正在进行临床Ⅲ期研究。Bempedoic acid通过抑制三磷酸腺苷柠檬酸裂解酶来降低胆固醇合成。该药单独或与阿托伐他汀、依泽替米贝进行二联或者三联用药,可将低密度脂蛋白降低17%～45%,同时还可以降低非高密度脂蛋白胆固醇、C-反应蛋白和载脂蛋白B的水平。与他汀类药物相比,bempedoic acid仅在肝脏中代谢为活性形式,而在非骨骼肌中不代谢转化。因此不会导致他汀类药物使用过程中经常出现的肌肉不良反应。本文对其基本信息、作用机制、临床试验信息进行概述。     

新型口服降脂药物——Bempedoic Acid

Bempedoic Acid是一种新型口服降血脂药物,于2020年在美国和欧洲获批上市,用于治疗已接受最大耐受剂量他汀类药物,而低密度脂蛋白胆固醇(LDL-C)仍没有达标的杂合子家族性高胆固醇血症(HeFH)或动脉粥样硬化性心血管疾病(ASCVD).Bempedoic Acid是一种三磷酸腺苷-柠檬酸裂解酶(ACL)抑...     

羟苯氨酮强心作用的生化机理研究

目的：研究羟苯氨酮(oxyphenamone, Oxy)强心作用的生化机理。方法：采用Na⁺,K⁺-ATP酶活性和cAMP-PDE活性、肌浆网Ca²⁺-ATP酶活性和cAMP含量以及心肌肌原纤维Ca²⁺,Mg²⁺-ATP酶活性等测定法,研究Oxy对它们的影响,并与milrinone和MCI-154作比较。 结果：Oxy对Na⁺,K⁺-ATP酶和PDE无抑制作用,也不影响心肌cAMP含量,但能显著增强心肌肌原纤维对Ca²⁺的敏感性,高浓度时轻度抑制心肌肌浆网Ca²⁺-ATP酶活性。结论：Oxy的强心作用方式不同于强心苷、β受体激动剂和PDE抑制剂等强心药,可能为一种新的钙增敏性强心药物。     

水飞蓟宾通过调控AMPK活性抑制自由脂肪酸诱导的肝细胞炎症因子分泌

目的研究水飞蓟宾对自由脂肪酸(FFA)诱导肝细胞炎症因子分泌的抑制作用,并探讨其是否通过调节腺苷单磷酸活化蛋白激酶(AMPK)信号通路实现。方法将HepG2细胞分为对照组、模型组和水飞蓟宾组。水飞蓟宾组(80和160μmol·L-1)预孵育HepG2细胞4h后,用500μmol·L-1的FFA处理HepG2细胞24h。Real-time PCR和Elisa法测定炎症因子IL-1β和TNF-α的mRNA及蛋白表达,油红O染色检测脂质生成情况,Western Blot测定AMPK和p-AMPK的蛋白相对表达量。用AMPK抑制剂或水飞蓟宾孵育细胞后用FFA处理,Elisa法测定炎症因子的生成情况。结果水飞蓟宾组可降低FFA诱导炎症因子生成增加,降低肝细胞中脂质含量的积累。Western Blot测定结果发现,水飞蓟宾可增加AMPK的磷酸化,AMPK抑制剂可逆转水飞蓟宾对炎症因子生成的抑制作用。结论水飞蓟宾组可通过AMPK信号通路抑制FFA诱导肝细胞炎症因子的表达。     

啤酒酵母转化腺苷生成ATP的HPLC测定方法的研究

为了建立和优化啤酒酵母转化腺苷生成三磷酸腺苷反应液中AR、AMP、ADP、ATP的分离及含量的测定方法.采用HPLC法,色谱柱:Welch Ultimate AQ-C18(250 mm×4.6mm,5μm);流动相A:0.05 mol/L磷酸盐缓冲溶液(pH 6.8)-0.6％甲醇溶液(V/V=89∶ 11);流动相B...     

长期口服卡托普利对小鼠脑组织自由基及相关酶的影响

目的:探讨长期口服卡托普利对小鼠脑组织自由基及相关酶的影响,为其临床应用提供实验依据。方法:取30只小鼠,随机均分为正常对照组(水)和卡托普利组(卡托普利,11.08～14.92mg·kg-1·d-1),按饮水给药方式连续给药14周,测定脑组织中自由基与相关酶(丙二醛(MDA)、超氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶(GSH-Px)、钠-钾泵三磷酸腺苷酶(Na+-K+-ATP酶)、钙-镁泵三磷酸腺苷酶(Ca2+-Mg2+-ATP酶))水平。结果:与正常对照组比较,卡托普利组小鼠脑组织中MDA水平降低(P<0.05);SOD、GSH-Px水平均无明显变化;Ca2+-Mg2+-ATP酶、Na+-K+-ATP酶活性有降低的趋势,但无统计学意义。结论:长期口服卡托普利可减少脑组织自由基含量,增强机体抗氧化能力,但脑组织神经细胞膜功能有受损的可能。     

通过环磷酸腺苷信号通路治疗焦虑症的研究进展

目的:综述近年来国内外通过第二信使环磷酸腺苷(c AMP)信号通路治疗焦虑症的相关研究进展,寻找治疗焦虑症新的潜在靶点。方法:以AnxietyCyclic adenosine monophosphateAdenylate cyclasePhosphodiesteraseProtein kinase A等组合作为关键词,查阅2000-2014年Pub Med、Science Direct、Springer等数据库,检索药物通过作用第二信使c AMP通路治疗焦虑症的研究文献,对其相关研究进展进行汇总分析。结果与结论:共检索到相关文献236篇,其中有效文献33篇。c AMP信号通路治疗抑郁症的潜在靶点可能位于腺苷酸环化酶(AC)、磷酸二酯酶(PDE)和c AMP依赖的蛋白激酶A(PKA)。通过敲除Ca2+调节的AC基因、抑制或激活相关G蛋白偶联受体、抑制AC活性、降低细胞内c AMP水平可产生一定的抗焦虑样作用;而PDE抑制剂和PKA激动药则可通过增加特定脑区内的c AMP水平产生抗焦虑样作用,但其治疗焦虑症的作用机制有待更深入的研究。     

吡格列酮对高脂喂养大鼠骨骼肌组织脂质异位沉积的影响

目的:观察吡格列酮(Pio)对高脂喂养大鼠骨骼肌组织脂质异位沉积的影响。方法:30只Wistar大鼠平均分为对照组、胰岛素抵抗组和吡格列酮干预组,对照组给予基础饲料,其余2组均给予高脂饲料喂养,其中吡格列酮干预组同时给予吡格列酮20 mg·kg^-1·d^-1灌胃,各组均喂养16周后检测各组大鼠血游离脂肪酸(FFA)水平及骨骼肌组织中三酰甘油(TG)含量,同时应用蛋白免疫印迹法检测骨骼肌组织一磷酸腺苷活化蛋白激酶α(AMPKα)磷酸化水平。结果:与对照组比较,胰岛素抵抗组大鼠胰岛素敏感性显著降低,血FFA水平及骨骼肌组织TG含量增高,骨骼肌组织中AMPKα磷酸化水平降至对照组水平的52.9%;与胰岛素抵抗组比较,吡格列酮干预组大鼠胰岛素敏感性明显提高,血FFA水平及骨骼肌组织TG含量显著下降,骨骼肌组织中AMPKα磷酸化水平显著提高至对照组的81.3%。但是与对照组比较,吡格列酮干预组大鼠血FFA水平及骨骼肌组织TG含量仍然较高,而且胰岛素敏感性及骨骼肌组织中AMPKα磷酸化水平仍然显著降低。结论:高脂饮食诱导胰岛素抵抗,吡格列酮干预可以通过降低血FFA水平及减轻骨骼肌组织脂质异位沉积改善其胰岛素抵抗。     

茛菪类药对家兔红细胞膜钠泵及钙泵活性的影响

本实验研究了茛菪类药(含东莨菪碱和阿托品)对家兔红细胞膜钠、钾三磷酸腺苷酶(Na-K-ATPasc)及钙镁三磷酸腺苷酶(Ca-Mg-ATPasc)活性的影响。结果表明:静脉注射茛菪类药2ml/kg时,Na-K-ATPase活性与实验前比较有明显增强(P<0.05),Ca-Mg-ATPase活性有下降趋势。提示茛菪类药物能改变生物膜活性,其多相药理作用很可能是通过调整生物膜的活性来发挥疗效的。     

铝盐对乳鼠神经细胞膜ATPase活力的影响

铝是公认的慢性蓄积性神经毒物,它在老年性神经退行性疾病的毒作用已受广大学者的关注[1-4],但铝(主要形式为Al3 )是如何发挥其毒性作用的,目前尚少见报道。膜毒理是从亚细胞水平阐明毒作用机制的一个重要环节,本研究采用体内实验从铝盐对乳鼠神经细胞膜酶的相互作用后活力变化,初步探讨铝神经毒作用的机制。1材料与方法1·1材料健康出生7 d的Wistar小鼠乳鼠,由兰州医学院动物中心提供(甘动准字14-0006)。1·2试剂和仪器AlCl3·6H2O(上海金山化工厂),其余试剂均为国产分析纯。高速冷冻离心机(吉林图们),721分光光度计(四川仪器厂),水浴锅…     

Evaluating bempedoic acid for the treatment of hyperlipidaemia

Introduction: Despite the effectiveness of statins in the treatment of lipid disorders, residual risk still exists, and hitherto studies where additional drugs were added to statin therapy have been mainly negative or the outcomes were very modest. Therefore there is still a need for new and effective oral agents in the combination therapy of lipid disorders.

Areas covered: The review covers the current state of knowledge on the mechanism of action of bempedoic acid (ETC-1002) and results from recent clinical studies.

Expert opinion: ETC-1002 is a novel oral lipid-lowering therapy. The reduction of both low-density lipoprotein cholesterol (LDL-C) and high sensitivity C-reactive protein (hsCRP) demonstrated by ETC-1002 in clinical trials suggests that agent may have the potential for CV risk reduction. Adverse effects of current lipid-lowering agents can be dose-limiting, and combination approaches to lipid-lowering may often be utilized for optimal CV risk reduction. Because of this, new lipid-modulating drugs are urgently required. ETC-1002 has a unique mechanism of action (adenosine triphosphate-citrate lyase inhibition). It has been shown to be safe in combination with statins as well as ezetimibe, and appears to effectively lower LDL-C and has the potential to reduce the risk of muscle-related adverse events, which can limit the utilization and effectiveness of statin therapy.     

A new self-emulsifying formulation of mefenamic acid with enhanced drug dissolution

To enhance the dissolution of poorly soluble mefenamic acid, self-emulsifying formulation (SEF), composing of oil, surfactant and co-surfactant, was formulated. Among the oils and surfactants studied, Imwitor^® 742, Tween^® 60, Cremophore^® EL and Transcutol^® HP were selected as they showed maximal solubility to mefenamic acid. The ternary phase diagram was constructed to find optimal concentration that provided the highest drug loading. The droplet size after dispersion and drug dissolution of selected formulations were investigated. The results showed that the formulation containing Imwitor^® 742, Tween^® 60 and Transcutol^® HP (10:30:60) can encapsulate high amount of mefenamic acid. The dissolution study demonstrated that, in the medium containing surfactant, nearly 100% of mefenamic acid were dissolved from SEF within 5 min while 80% of drugs were dissolved from the commercial product in 45 min. In phosphate buffer (without surfactant), 80% of drug were dissolved from the developed SEF within 5 min while only about 13% of drug were dissolved in 45 min, from the commercial product. The results suggested that the SEF can enhance the dissolution of poorly soluble drug and has a potential to enhance drug absorption and improve bioavailability of drug.     

A new drug nanocarrier consisting of polyarginine and hyaluronic acid

The purpose of this study was to produce and characterize a variety of nanostructures comprised of the polyaminoacid polyarginine (PArg) and the polysaccharide hyaluronic acid (HA) as a preliminary stage before evaluating their potential application in drug delivery. PArg was combined with high- or low-molecular-weight HA (HMWHA or LMWHA, respectively) to form nanoparticles by simply mixing polymeric aqueous solutions at room temperature. The average size of the resulting nanocarriers was between 116 and 155 nm, and their zeta potential value ranged from +31.3 to −35.9 mV, indicating that the surface composition of the particle could be conveniently modified according to the mass ratio of the polymers. Importantly, the systems prepared with HMWHA remained stable after isolation by centrifugation and in conditions that mimic the physiological medium, whereas particles that incorporated LMWHA were unstable. Transmission electron microscopy showed that the nanostructures made with HMWHA were spherical. Finally, the systems were stable for at least three months at storage conditions (4 °C).     

Application of hyaluronic acid as carriers in drug delivery

Hyaluronic acid has good biocompatibility, biodegradability, and nonimmunogenicity. In addition, it has the ability to recognize specific receptors that are overexpressed on the surface of tumor cells, and cancer drugs can be targeted to the tumor cells to better kill them. Therefore, hyaluronic acid has attracted much attention as drug delivery vehicle. Herein, the application of hyaluronic acid as carrier in drug delivery was analyzed and summarized in detail. It showed that hyaluronic acid would have broad prospects for drug delivery.     

Ursodeoxycholic acid induced generalized fixed drug eruption

Fixed drug eruption (FDE) is a rare form of drug allergies that recur at the same cutaneous or mucosal site in every usage of drug. Single or multiple round, sharply demarcated and dusky red plaques appear soon after drug exposure. Ursodeoxycholic acid (UDCA: 3α,7β-dihydroxy-5β-cholanic acid) is used for the treatment of cholestatic liver diseases. Some side effects may be observed, such as diarrhea, dyspepsia, pruritus and headaches. We encountered only three cases of lichenoid reaction regarding the use of UDCA among previous studies. In this article, we reported a generalized FDE case related to UDCA intake in a 59-year-old male patient with cholestasis for the first time in the literature.     

An insight on hyaluronic acid in drug targeting and drug delivery

Hyaluronic acid (HA) has recently been studied for its use in drug delivery applications. Medically, HA is used as a surgical aid in ophthalmology. It also possesses therapeutic potential in the treatment of arthritis and wound healing. HA-binding receptors, CD44 and receptor for hyaluronan-mediated motility have attracted much enthusiasm, mainly because they are believed to be involved in cancer metastasis. This review unravels the role of HA in drug delivery and targeting. Designing of various novel drug delivery systems using HA as a biopolymer will also be reviewed in the present article.     

丙戊酸治疗药物监测研究进展

丙戊酸在临床上主要用于各型癫痫的治疗,但其体内代谢个体差异大,有效血药浓度达标率低。有效血药浓度是保证疗效和减少毒副作用的重要前提,临床常采取血药浓度监测来提高丙戊酸血药浓度达标率,以保证癫痫治疗的有效性和安全性。从丙戊酸血药浓度监测方法、丙戊酸血药浓度与疗效的相关性、丙戊酸血药浓度与不良反应的相关性和丙戊酸血药浓度影响因素4方面做一综述,为开展有关丙戊酸血药浓度监测及合理用药提供参考。     

抗菌药物联合抑制胃酸分泌药物治疗消化性溃疡疗效观察

目的观察抗菌药物联合抑制胃酸分泌药物治疗消化性溃疡的临床疗效。方法将156例消化性溃疡患者随机分为观察组和对照组各78例。观察组予抗菌药物联合抑制胃酸分泌药物治疗,对照组给予雷尼替丁联合庆大霉素治疗。30d后,对比2组临床疗效。结果观察组总有效率为97.4%高于对照组的88.5%,差异有统计学意义(P<0.05)。结论抗菌药物联合抑制胃酸分泌药物治疗消化性溃疡疗效显著,能极大提高溃疡愈合率并降低溃疡复发率,值得临床推广应用。     

治疗药物监测在丙戊酸临床应用中的研究进展

近年来,丙戊酸有关的治疗药物监测研究报道较多。在临床实践中治疗药物监测作为丙戊酸剂型选择和治疗方案调整的参考依据,可以提高丙戊酸临床疗效、减少药物不良反应,考察患者的服药依从性。丙戊酸在临床使用时进行治疗药物监测对丙戊酸的临床个体化、合理用药有着重要的指导意义。