Arteether

关注并星标CPHI制药在线       青蒿素（Artemisinin）是从菊科植物黄花蒿叶中提取的含过氧化基团结构的倍半萜内酯化合物。青蒿素的主要衍生物包括蒿甲醚（Artemethere）、蒿乙醚（Arteether）、青蒿琥酯（Artesunate）、二氢青蒿素（Dihydro artemisinin）等。青蒿素类药物主要以治疗疟疾为主，随着研究的不断深入，研究发现青蒿素类化合物还有许多其他作用，如抗肿瘤、抑菌杀虫、解热、抗炎、免疫调节等。药理作用1抗疟作用研究发现，青蒿素类化合物发挥抗疟活性的作用机制包括：①青蒿素在血红蛋白Fe2+的催化下，发生过氧桥键断裂，生成氧和碳自由基，这些自由基可以随有机烷基化结合位点附近的氨基酸残基，阻断疟原虫的营养吸收，同时迅速形成自噬泡将缺乏营养而导致氨基酸饥饿的原虫排出体外，发挥消灭疟原虫的作用；②在一定量Fe2+的催化作用下，青蒿素产生以碳为中心的自由基，被激活的青蒿素依靠其疏水骨架靶向作用于疟原虫钙ATP蛋白6（PfATP6），引起疟原虫胞浆内钙离子浓度上升，发挥杀虫抗疟作用。③青蒿素类药物对疟原虫配子体也具有杀灭作用，能够抑制不同阶段的配子体发育，快速杀死疟原虫的初期配子体，同时截断未成熟配子体的发育。       2抑菌、杀虫作用青蒿素类注射液对猪的多种血液寄生虫病都具有良好的防治效果，特别是对猪附红细胞体、猪弓形体、猪巴通氏体、猪锥虫病等都有较好的治疗作用，同时对鸡的球虫病等也有很好的疗效。青蒿素及其衍生物可阻断虫体早期阶段的营养物质的消化吸收代谢，造成氨基酸缺乏，最终导致虫体的细胞膜受损而死亡。进一步研究发现，青蒿素及其衍生物能有效抑制球虫裂殖子微线基因相关 mRNA 的转录和表达，从而达到减少球虫数量的目的。此外，青蒿素类还能有效促进机体内淋巴细胞的转化，显著增加血液中红细胞、白细胞和血红蛋白数量。另有研究发现，青蒿素可改变线粒体的膜电位，使其在细胞周期的G0/G1期停滞，最终导致杜氏利什曼原虫前鞭毛体细胞死亡。       3解热、 抗炎作用青蒿及其衍生物对缓解热应激也有积极效果。研究结果显示，与处于热应激环境中相比，当饲粮中添加酶解青蒿后可以显著提高肉鸡对饲料中粗脂肪、粗蛋白和有机物的表观利用率，使肠道中酶活性增加，对缓解鸡热应激有积极的效果。在肉鸡饲粮中添加酶解青蒿可以缓解热应激引起的血液 pH 值升高、生产性能下降及血清中皮质酮、谷丙转氨酶、谷草转氨酶升高，并且可以通过提高血清和肝脏抗氧化酶活性及调节相关mRNA 表达水平发挥增强抗氧化能力及缓解热应激的作用。有学者研究并比较了青蒿素和二氢青蒿素的抗炎作用及其分子机制：二氢青蒿素通过下调诱导型一氧化氮合酶（iNOS）蛋白表达，抑制巨噬细胞释放炎症因子肿瘤坏死因子-α（TNF-α）、白细胞介素-6（IL-6）和炎症介质 NO 而发挥抗炎活性；而青蒿素可能通过代谢为二氢青蒿素而发挥抗炎作用。研究发现青蒿素可通过调节核转录因子-κB（NF-κB）和丝裂原活化蛋白激酶（MAPK）信号通路来发挥抗炎作用。       4抗肿瘤作用目前普遍认为青蒿素类化合物能够发挥抗肿瘤作用的机制为：①抑制新生血管生成；②诱导细胞凋亡；③阻滞细胞周期；④Fe2+介导的细胞毒作用；⑤与致癌基因和抑癌基因相关；⑥作用于特殊靶蛋白；⑦对抗多药耐药。研究发现，青蒿素衍生物可在体外抑制宫颈癌 HeLa细胞的增殖并促进其凋亡，其作用机制分别与下调细胞外调节蛋白激酶1/2（ERK1/2）蛋白磷酸化水平和上调p38 蛋白磷酸化水平有关。双氢青蒿素能抑制人胶质瘤 U251 细胞增殖的机制与其抑制 Wnt/β-catenin 通路，从而抑制上皮间质转换（EMT）进程有关。抑制胰 腺癌 JF-305 细胞增殖的作用机制可能与其升高 JF-305 细胞中活性氧（ROS）的水平引起的线粒体凋亡途径有关。青蒿琥酯诱导人胃癌 HGC27 细胞凋亡可能与抑制Wnt/β-catenin 信号通路活化有关。       5免疫调节作用研究结果表明，青蒿素及其衍生物不仅能够直接作用于T淋巴细胞，而且能显著抑制T 淋巴细胞丝裂原 ConA 诱导的小鼠脾 脏淋巴细胞的增殖。青蒿素的衍生物青蒿琥酯可通过降低大鼠脑水肿指数和血脑屏障通透性，阻碍内皮细胞紧密连接蛋白 Occludin 和 ZO-1 蛋白表达的下调，同时减轻蛛网膜下出血后模型大鼠早期脑组织损伤，提高神经功能。研究发现，青蒿素对实验性自身免疫性重症肌无力（EAMG）大鼠具有免疫调节作用，其机制与其通过直接或间接降低血清R97-116 抗体水平、抑制淋巴结单个核细胞分泌 γ干扰素（IFN-γ）和IL-17促炎性因子有关。青蒿素能明显抑制刀豆蛋白 A（ConA）诱导的 T 淋巴细胞增殖，减轻 IV 型或迟发型超敏反应（DTH）模型小鼠免疫器官的脏器指数，减轻耳肿胀度，推测青蒿素是通过下调机体细胞免疫应答发挥免疫抑制作用。此外，青蒿素及其衍生物对系统性红斑狼疮具有较好的疗效，研究发现双氢青蒿素通过上调DNA甲基转移酶1（DNMT1）表达和下调 Gadd45a 表达，升高系统性红斑狼疮（SLE）小鼠 CD4+ T细胞基因组 DNA 甲基化水平，从而减少自身免疫抗体产生，进而发挥治疗 SLE 的作用。剂型虽然青蒿素类药物抗疟作用突出且具其他药理功能，但在临床上，青蒿素类药物大多存在溶解度差、生物利用度低、首过效应高、疟原虫复燃率高、给药频繁等问题，因此，青蒿素类药物的剂型研究成为当前热点。随着制药科技的发展，很多新技术运用到青蒿素及其衍生物的制剂中来，为青蒿素多方面的治疗作用提供了可能的途径，如纳米制剂、固体分散体、包合物、微乳、经皮给药制剂等。       1纳米制剂纳米给药系统为一系列粒径在纳米级的新型微小给药系统的统称，根据纳米颗粒分散运动状态及其性质的特殊性，纳米给药系统主要有纳米粒、脂质体、纳米乳、聚合物胶束、纳米混悬剂等。该系统具有良好的肿瘤靶向性，较长的体内循环时间，易被细胞摄取，可控制药物释放以及改善药物溶解度，增加药物稳定性等特点。①纳米乳 (nano emulsion) 是由表面活性剂、助表面活性剂、油相、水相组成的一种稳定透明的胶体分散系统，其粒径在10～100 nm之间。有学者在研究用青蒿琥酯治疗牛、羊泰勒焦虫病及双芽焦虫病时，乳化剂选择聚山梨醇酯-80，助表面活性剂选择正丁醇，油酸乙酯为油相制备青蒿琥酯纳米乳注射剂。解决了青蒿琥酯在水中的溶解度不大、口服不能避免肝 脏的首过效应、市售青蒿琥酯钠盐放置不稳定、临床使用不方便的问题。②纳米粒（nanopartilcles，NP）由天然或合成高分子材料制成，是一种粒径介于1～100nm固态胶体粒子，包括纳米球（Nanospheres）和纳米囊（Nanocapsules）。活性组分（药物、生物活性材料等）溶解、包裹于粒子内部，或者吸附、附着于粒子表面。利用改良自乳化/溶剂扩散法将青蒿琥酯制成适用于人体可生物降解的纳米粒，并将肿瘤细胞表面特异性的可识别配体 Tf 结合在载药纳米载体上，实现对肿瘤组织（细胞）的靶向治疗，动物体内实验表明该新型纳米制剂具有血液及骨髓的靶向性。采用初生态微晶法制备了载有蒿甲醚的纳米胶囊，能解决蒿甲醚不溶于水、代谢快及利用率低的缺点，可显著提高药效。③纳米脂质体。纳米结构脂质载体 (nanostructured lipid carrier，NLC) 是以一定比例的液态油或其他不同的脂质 (如卵磷脂、甘油三酯等 )为载体，将药物包裹于类脂核中的固态胶体给药体系，粒径在50～1000nm之间的一种新型纳米给药系统。有学者采用动物肿瘤膜型研究双氢青蒿素纳米脂质载体与双氢青蒿素混悬液对肝癌瘤株的抑制作用，证实双氢青蒿素纳米脂质载体较普通混悬液对白血病细胞 K562及胶质瘤细胞U87具有更强的增殖抑制作用，为开发高效低毒的双氢青蒿素抗癌药物提供依据。利用青蒿琥酯纳米脂质体干预血管内皮 生长因子 (VEGF) 及血管内皮 细胞生长因子受体2(VEGFR2) 在HepG2 中的表达，证明青蒿琥酯纳米脂质体能够抑制肿瘤血管的生成达到抗肿瘤作用，且作用强于青蒿琥酯原料药，有应用于肝癌治疗的潜在价值。       2固体分散体固体分散体是指药物高度分散在适宜的载体材料中类似于液体系统形成的一种固态物质。固体分散体使得药物以无定型太、微晶态、分子分散态或胶体分散态存在，分散度很大，当与胃肠中液体接触后，溶出速度加快，药物的吸收加快，生物利用度提高。根据载体性质的不同和释药特点的不同，固体分散体又分为速释型固体分散体、缓控释型固体分散体和肠溶型固体分散体。①速释型固体分散体是利用亲水性载体材料制备的固体分散体。药物在载体材料中高度分散，由于载体材料的亲水性，药物具有良好的润湿性，使药物达到快速释放，提高了药物的溶解度、加快药物溶出速率，提高了药物的生物利用度。这对于难溶性药物而言，是解决溶出问题非常好的方案，例如有学者将低水溶性药物双氢青蒿素用聚乙烯吡咯烷酮作为载体制备成固体分散体，用X射线衍射（XRD）和差示扫描热量法（DSC）进行了对比检测，发现双氢青蒿素以非晶体复合体存在，并且溶解度比原料药增加了50倍，生物活性明显提高。②缓控释型固体分散体是以水不溶性或脂溶性载体制备的固体分散体。这种体系可以看作是溶解扩散体系。③肠溶型固体分散体是利用肠溶性载体制成便于肠道释放的固体分散体，由于载体材料溶解的特殊pH 条件，使得结肠靶向释药型固体分散体可在胃和小肠不释放或较少释放，到达结肠才快速释药。       3环糊精包合物环糊精包合物是将药物分子作为砌块进入环糊精超分子体系，构建出的有复杂结构和特殊功能的组装体，从而使难溶性药物被环糊精包合后，增强在水中的溶解度和稳定性，从而改善药物的生物利用度。采用蒸发沉淀法分别制得了青蒿素纳米粒以及青蒿素 β-环糊精包合物，两者均能显著提高青蒿素的溶解度以及溶出速率。有学者合成青蒿琥酯-环糊精的键接前药，采用MTT法进行细胞活性测定，证明该系列新化合物具有良好的抗结直肠癌活性，且具有一定靶向性。       4经皮给药制剂经皮给药制剂是指将药物制备成经皮肤给药的制剂，目前有软膏剂和压敏胶贴片两种。这种制剂能使药物迅速穿透皮肤，进入血液循环而起全身治疗作用，避免了肝脏的"首过效应"和胃肠道的破坏。有学者制备了蒿甲醚可溶解微针透皮贴片，与肌内注射相比，生物利用度相近的情况下，血药浓度更加平稳，开发出具有缓释效果的抗疟新剂型。       参考资料：       [1]李海波,秦大鹏,葛雯,王振中,曹亮,肖伟,于洋,姚新生.青蒿化学成分及药理作用研究进展[J].中草药,2019,50(14):3461-3470.       [2]张文飞,管武太,陈芳,张世海,邓跃林,史合群,许国焕.青蒿素及其衍生物在畜禽生产中的应用研究进展[J].饲料工业,2019,40(15):22-27.DOI:10.13302/j.cnki.fi.2019.15.004.      [3]李文婷,张国丽,张锐武,段国蕾,杨兆祥.青蒿素类药物新剂型研究进展[J].农村经济与科技,2019,30(12):299-300.       作者简介：小米虫，药品质量研究工作者，长期致力于药品质量研究及药品分析方法验证工作，现就职于国内某大型药物研发公司，从事药品检验分析及分析方法验证。【企业推荐】智药研习社近期课程报名来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com▼更多制药资讯，请关注CPHI制药在线▼点击阅读原文，进入智药研习社~

Ørsted has identified the 100 MW straw-fired unit at the Avedøre Power Station in Copenhagen as the best point source of sustainable CO2 for the next phases of the Green Fuels for Denmark Power-to-X facility in the Greater Copenhagen area which over time is planned to reach a total capacity of 1.3 GW and have a carbon emission abatement potential of 850,000 tonnes yearly. If the project at Avedøre Power Station is realised, it could become Ørsted’s first carbon capture facility. A future final investment decision for the carbon capture project is subject to the realisation of the parts of Green Fuels for Denmark that will produce e-methanol and e-kerosene. Ørsted owns and operates Avedøre Power Station. The combined heat and power plant consists of two wood pellet-fired units and a straw-fired unit that supply power to the Danish power grid and district heating to the Greater Copenhagen area. Ørsted and HOFOR recently announced an agreement that Ørsted will offtake the power production from HOFOR’s planned 250 MW Aflandshage offshore wind farm for parts of the Green Fuels for Denmark project. With the agreement to source renewable electricity in place, Ørsted has now identified the straw-fired unit at Avedøre Power Station as the best point source of sustainable carbon, and will now investigate the possibilities of advancing parts of the project’s first phases in order to deliver substantial amounts of sustainable fuels well before the previously planned 2027 operation date of the second phase. Recently, Green Fuels for Denmark took an important step closer to realisation as the project became part of the process of being named an Important Project of Common European Interest (IPCEI) in the EU programme initiated to kick-off the hydrogen economy in the EU. Green Fuels for Denmark is envisaged to be built in phases, beginning with approximately 10 MW, scaling up corresponding to the supply of electricity to reach 1,300 MW of total electrolysis capacity when fully developed. While the first phase of Green Fuels for Denmark will exclusively produce hydrogen for heavy-duty road transport, the next phase is planned to combine the production of renewable hydrogen with carbon capture to produce sustainable methanol and e-kerosene for shipping and aviation, respectively. CO2 from sustainable sourcesProvided that a framework is established to promote the development of sustainable fuels, the 100 MW straw-fired unit at Avedøre Power Station could provide the amount of CO2 necessary for producing sustainable fuels in the next phases of Green Fuels for Denmark. Ørsted will now start investigating the best way forward to deploy carbon capture technology at the straw-fired unit at Avedøre Power Station, including optimising the electrolysis capacity of the second phase of Green Fuels for Denmark with the supply of renewable electricity. The straw-fired unit is fuelled by locally sourced agricultural by-products converting approx. 130,000 tonnes of straw each year to heat and power. The combination of using straw as fuel and utilising the surplus heat from both the carbon capture process and the Power-to-X process would result in up to 260 MW district heating, which would lead to both green and price-competitive district heating for the Greater Copenhagen area. Anders Nordstrøm, Vice President and head of Ørsted’s hydrogen and Power-to-X activities, said: “If Green Fuels for Denmark is realised, Copenhagen could become a showcase example of how new and existing energy technology can be combined to deliver on the vast European ambitions for sustainable fuels. Denmark can leverage its district heating systems, large sources of sustainable carbon, and massive offshore wind resources to create a new industrial stronghold and supply sustainable fuels to Danish logistics companies that are leading the green transformation of heavy transport. Green Fuels for Denmark is an ideal flagship project to realise this potential, and the agreement with Avedøre Power Station to source sustainable CO2 underlines Ørsted’s commitment to the project.” Ole Thomsen, Senior Vice President, Ørsted Bioenergy, says: “Converting our power stations from fossil fuels to sustainable biomass has been a centre-piece in Ørsted’s and Denmark’s green transformation. Utilising the potential for carbon capture at Avedøre Power Station could potentially be a showcase for even further decarbonisation at our power stations. Ørsted is currently exploring the potential for carbon capture at some of our other bioenergy plants, which would enable the carbon necessary for Power-to-X production plants to further contribute to the green transformation of our society.” The production of renewable hydrogen and sustainable fuels has a significant potential to reduce carbon emissions from hard-to-abate sectors, such as heavy transport. Sustainable fuels are currently more expensive to produce than fossil-based fuels. To reduce the cost, the production of sustainable fuels must be built out at industrial scale – just as we have seen with renewable energy technologies, such as offshore wind, onshore wind, and solar PV over the past decade. For this to be feasible, industry must join forces with governments to create the right framework that enables private investment in large-scale sustainable fuel production. About Green Fuels for DenmarkGreen Fuels for Denmark is Denmark's most ambitious vision for large-scale production of sustainable fuels and has a decarbonisation potential of 850,000 tonnes. Behind the project is a partnership consisting of A.P. Moller - Maersk, DSV Panalpina, DFDS, SAS, Copenhagen Airports, and Ørsted. Nel, Haldor Topsøe, and Everfuel have partnered up on the first phase of Green Fuels for Denmark and on developing the second phase. In addition, COWI is a knowledge partner on the project. The project is backed by Molslinjen, the City of Copenhagen, and the Capital Region of Denmark. Ørsted will continue to pursue opportunities to secure sustainable carbon and green power from additional sources for Green Fuels for Denmark towards the commissioning of the planned energy hub at the Danish island Bornholm. For further information, please contact:Media RelationsMichael Korsgaard+45 99 55 94 25mikon@orsted.dk Investor RelationsAllan Bødskov Andersen+45 99 55 79 96ir@orsted.dkAbout ØrstedThe Ørsted vision is a world that runs entirely on green energy. Ørsted develops, constructs, and operates offshore and onshore wind farms, solar farms, energy storage facilities, and bioenergy plants, and provides energy products to its customers. Ørsted ranks as the world’s most sustainable energy company in Corporate Knights' 2021 index of the Global 100 most sustainable corporations in the world and is recognised on the CDP Climate Change A List as a global leader on climate action. Headquartered in Denmark, Ørsted employs 6,311 people. Ørsted's shares are listed on Nasdaq Copenhagen (Orsted). In 2020, the group's revenue was DKK 52.6 billion (EUR 7.1 billion). Visit orsted.com or follow us on Facebook, LinkedIn, Instagram, and Twitter. Attachment