The goal of this placebo-controlled double-blind Phase 2 clinical trial is to test in people with early Alzheimer's Disease.
The main questions it aims to answer are:
* Does treatment with fasudil, a ROCK-inhibitor, lead to significant improvement in working memory (based on computer-based working memory composite scores) compared to placebo in individuals with early Alzheimer's disease (AD) over 12 months?
* What is the effect of fasudil treatment for 12 months on other cognitive functions, brain metabolism measured by Fluorodeoxyglucose Positron Emission Tomography (FDG-PET), and other relevant clinical functions and biomarkers in individuals with early Alzheimer's disease (AD)?
* Treatment will be escalated to a maintenance dose of 120 mg total daily dose for up to 50 weeks, with regular clinic visits for efficacy and safety evaluations.
* Assessments will include cognitive tests, FDG-PET scans, and biomarker analyses, with follow-up by the Data and Safety Monitoring Board for ongoing safety review.
The study will compare participants receiving fasudil with those receiving placebo to see if fasudil treatment leads to improvements in cognitive functions, brain metabolism measured by FDG-PET.

开始日期2024-08-01

申办/合作机构

Helse Stavanger HF

[+2]

CTIS2024-517413-33-00 / RecruitingIIT

Safety, Tolerability and Symptomatic Efficacy of the ROCK-Inhibitor Fasudil in Patients with Parkinson's Disease (ROCK-PD) - ROCK-PD-0000-LIN-007

开始日期2023-09-11

申办/合作机构-

JPRN-jRCTs041220024 / Suspended临床1期IIT

A Phase 1 study of Fasudil in combination with Methotrexate, Adriamycin and Cisplatin (MAP) targeting cancer stem cell.

开始日期2022-05-31

申办/合作机构-

100 项与甲磺酸法舒地尔相关的临床结果

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100 项与甲磺酸法舒地尔相关的转化医学

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100 项与甲磺酸法舒地尔相关的专利（医药）

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1,233

项与甲磺酸法舒地尔相关的文献（医药）

2025-05-01·Neural Regeneration Research

Pharmacological intervention for chronic phase of spinal cord injury

Article

作者: Tohda, Chihiro

Spinal cord injury is an intractable traumatic injury. The most common hurdles faced during spinal cord injury are failure of axonal regrowth and reconnection to target sites. These also tend to be the most challenging issues in spinal cord injury. As spinal cord injury progresses to the chronic phase, lost motor and sensory functions are not recovered. Several reasons may be attributed to the failure of recovery from chronic spinal cord injury. These include factors that inhibit axonal growth such as activated astrocytes, chondroitin sulfate proteoglycan, myelin-associated proteins, inflammatory microglia, and fibroblasts that accumulate at lesion sites. Skeletal muscle atrophy due to denervation is another chronic and detrimental spinal cord injury–specific condition. Although several intervention strategies based on multiple outlooks have been attempted for treating spinal cord injury, few approaches have been successful. To treat chronic spinal cord injury, neural cells or tissue substitutes may need to be supplied in the cavity area to enable possible axonal growth. Additionally, stimulating axonal growth activity by extrinsic factors is extremely important and essential for maintaining the remaining host neurons and transplanted neurons. This review focuses on pharmacotherapeutic approaches using small compounds and proteins to enable axonal growth in chronic spinal cord injury. This review presents some of these candidates that have shown promising outcomes in basic research (in vivo animal studies) and clinical trials: AA-NgR(310)ecto-Fc (AXER-204), fasudil, phosphatase and tensin homolog protein antagonist peptide 4, chondroitinase ABC, intracellular sigma peptide, (-)-epigallocatechin gallate, matrine, acteoside, pyrvate kinase M2, diosgenin, granulocyte-colony stimulating factor, and fampridine-sustained release. Although the current situation suggests that drug-based therapies to recover function in chronic spinal cord injury are limited, potential candidates have been identified through basic research, and these candidates may be subjects of clinical studies in the future. Moreover, cocktail therapy comprising drugs with varied underlying mechanisms may be effective in treating the refractory status of chronic spinal cord injury.

2024-11-01·BIOPHYSICAL CHEMISTRY

Simulating the anti-aggregative effect of fasudil in early dimerisation process of α-synuclein

Article

作者: Menon, Sneha ; Mondal, Jagannath

The aggregation of the protein α-synuclein into amyloid deposits is associated with multiple neurological disorders, including Parkinson's disease. Soluble amyloid oligomers are reported to exhibit higher toxicity than insoluble amyloid fibrils, with dimers being the smallest toxic oligomer. Small molecule drugs, such as fasudil, have shown potential in targeting α-synuclein aggregation and reducing its toxicity. In this study, we use atomistic molecular dynamics simulations to demonstrate how fasudil affects the earliest stage of aggregation, namely dimerization. Our results show that the presence of fasudil reduces the propensity for intermolecular contact formation between protein chains. Consistent with previous reports, our analysis confirms that fasudil predominantly interacts with the negatively charged C-terminal region of α-synuclein. However, we also observe transient interactions with residues in the charged N-terminal and hydrophobic NAC regions. Our simulations indicate that while fasudil prominently interacts with the C-terminal region, it is the transient interactions with residues in the N-terminal and NAC regions that effectively block the formation of intermolecular contacts between protein chains and prevent early dimerization of this disordered protein.

2024-11-01·LANCET NEUROLOGY

Safety, tolerability, and efficacy of fasudil in amyotrophic lateral sclerosis (ROCK-ALS): a phase 2, randomised, double-blind, placebo-controlled trial

Article

作者: Remane, Yvonne ; Zurek, Gabriela ; Koch, Jan C ; Zeller, Daniel ; Ludolph, Albert C ; Bidner, Helen ; Weber, Markus ; Kuttler, Josua ; Corcia, Philippe ; Metelmann, Moritz ; Dorst, Johannes ; Neuwirth, Christoph ; Attarian, Shahram ; Leha, Andreas ; Großkreutz, Julian ; Braun, Nathalie ; Meyer, Thomas ; Cordts, Isabell ; Benatar, Michael ; Weyen, Ute ; Wuu, Joanne ; Soriani, Marie-Hélène ; Rogers, Mary-Louise ; Deschauer, Marcus ; Weishaupt, Jochen H ; Günther, René ; Schmidt, Jens ; Feneberg, Emily ; Lingor, Paul ; Weydt, Patrick ; Camu, William ; De La Cruz, Elisa ; Friede, Tim

BACKGROUND:

Fasudil is a small molecule inhibitor of Rho-associated kinase (ROCK) and is approved for the treatment of subarachnoid haemorrhage. In preclinical studies, fasudil has been shown to attenuate neurodegeneration, modulate neuroinflammation, and foster axonal regeneration. We aimed to investigate the safety, tolerability, and efficacy of fasudil in patients with amyotrophic lateral sclerosis.

METHODS:

ROCK-ALS was a phase 2, randomised, double-blind, placebo-controlled trial conducted at 19 amyotrophic lateral sclerosis centres in Germany, France, and Switzerland. Individuals (aged 18-80 years) with at least probable amyotrophic lateral sclerosis (as per the revised El Escorial criteria), a disease duration of 6-24 months, and a slow vital capacity greater than 65% of predicted normal were eligible for inclusion. Patients were randomly assigned (1:1:1) to receive 30 mg (15 mg twice daily) or 60 mg (30 mg twice daily) fasudil or matched placebo intravenously for 20 days over a 4-week period. Follow-up assessments were performed at 45, 90, and 180 days after treatment initiation. The co-primary endpoints were safety until day 180 (defined as the proportion without drug-related serious adverse events) and tolerability during the treatment period (defined as the proportion who did not discontinue treatment due to suspected drug-related adverse events). The primary analyses were carried out in the intention-to-treat population, which included all participants who entered the treatment phase. This trial is registered at ClinicalTrials.gov (NCT03792490) and Eudra-CT (2017-003676-31) and is now completed.

FINDINGS:

Between Feb 20, 2019, and April 20, 2022, 120 participants were enrolled and randomised; two individuals assigned fasudil 30 mg withdrew consent before the baseline visit. Thus, the intention-to-treat population comprised 35 in the fasudil 30 mg group, 39 in the fasudil 60 mg group, and 44 in the placebo group. The estimated proportion without a drug-related serious adverse event was 1·00 (95% CI 0·91 to 1·00) with placebo, 1·00 (0·89 to 1·00) with fasudil 30 mg, and 1·00 (0·90 to 1·00) with fasudil 60 mg; the difference in proportions was 0·00 (95% CI -0·11 to 0·10; p>0·99) for fasudil 30 mg versus placebo and 0·00 (-0·10 to 0·10; p>0·99) for fasudil 60 mg versus placebo. Treatment tolerability (the estimated proportion who did not discontinue) was 0·93 (95% CI 0·81 to 0·99) with placebo, 1·00 (0·90 to 1·00) with fasudil 30 mg, and 0·90 (0·76 to 0·97) with fasudil 60 mg; the difference in proportions was 0·07 (95% CI -0·05 to 0·20; p=0·25) for fasudil 30 mg versus placebo, and -0·03 (-0·18 to 0·10; p=0·70) for fasudil 60 mg versus placebo. Eight deaths occurred: two in the placebo group, four in the fasudil 30 mg group, and two in the fasudil 60 mg group. The most common serious adverse events were respiratory failure (seven events), gastrostomy (five events), pneumonia (four events), and dysphagia (four events). No serious adverse events or deaths were attributed to study treatment. Adverse events, which were mainly related to disease progression, occurred in 139 participants in the placebo group, 108 in the fasudil 30 mg group, and 105 in the fasudil 60 mg group.

INTERPRETATION:

Fasudil was well tolerated and safe in people with amyotrophic lateral sclerosis. The effect of fasudil on efficacy outcomes should be explored in larger clinical trials with a longer treatment duration, oral administration, and potentially higher dose of the trial drug.

FUNDING:

Framework of the E-Rare Joint Transnational Call 2016 "Clinical research for new therapeutic uses of already existing molecules (repurposing) in rare diseases".

项与甲磺酸法舒地尔相关的新闻（医药）

2024-09-28

·米内网

知名医院摊上事了！25个药品价格“跳水”，医药大省集采结果出炉，恒瑞、君实1类新药亮眼

看点 view 本周，2024上半年医药工业统计数据出炉，中纪委点名医院招标腐败，知名医院涉骗保遭严查；药品市场迎变局，447个产品拟中选医药大省集采，25个品种主动降价，29款国谈药医保支付价公开；企业大新闻，两大国资药企“牵手”推动中医药现代化，一创新药企业闯关IPO折戟，恒瑞医药、君实生物1类新药亮眼......医药行业一周大事件，精彩不容错过！米内一周TOP榜米内数据口服高血压药TOP20，施慧达、华润双鹤突围 23个独家品种厉害了！扬子江2大品种亮眼软膏剂TOP20洗牌，华润三九、华邦上榜药企动态倍特拿下25个重磅品种，126个过评品种霸屏奥赛康首仿药大涨454%，5款重磅新品获批石药发力改良型新药，超600亿市场起波澜审评药闻海思科1类新药来袭！抢攻1400亿市场 5亿畅销产品，石四药入局抢食 9亿大品种，浙江药企获批了覆盖全国18省！“六病共管”集采蓄势待发 9月24日，三明采购联盟第六次联席会议暨开展“六病共管”用药（第一批）集采工作会议在福建省三明市召开，会议指出：“六病共管”用药集采被列入国家招采重点工作；鼓励集采药品落地向民营医疗机构、零售药店和村卫生室延伸；大力推进集采药品追溯码工作，遏制医保药品“回流”、“重复销售”等违规行为；黑龙江全省加入三明采购联盟等。截至目前，三明采购联盟成员已覆盖全国18个省份、42个地级市、4个全国医改示范县，覆盖区域人口逾1.8亿人。（三明采购联盟）延伸阅读： “六病共管”是三明市与上海瑞金医院的深度合作管理模式，该项目以三明医改为背景，依托瑞金医院的优质资源，从人出生到死亡的全生命周期中，选取肿瘤、心脑血管、呼吸、代谢、生殖医学以及老年医学六类高发病率疾病，由瑞金医院和三明市医疗机构共同对患者进行诊疗和管理。“六病共管”项目于今年2月正式启动，目前瑞金医院已与三明市10余家总医院开展协作。中纪委再发文，点名医院招标腐败 9月26日，中央纪委国家监委发布题为《深度关注|营造风清气正招投标环境》的头条文章，其中提到，部分省（市）公共资源交易中心场所管理不严、现场监督不实、交易秩序混乱，有的评标专家在评标过程中肆无忌惮，频繁违法。比如：江苏省公共资源交易中心工作人员腐败窝案中，某开评标现场管理人员利用职务便利，经常随意进出招投标现场，并通过暗示评标专家、泄露答辩题目、向投标企业提供评标专家名单、协助将项目运作到省平台交易等方式帮助企业中标，受贿共计690余万元。今年以来，中纪委围绕招投标腐败问题密集发文，其中评标专家管理被多次点名。（中央纪委国家监委） 2024上半年医药工业发展“遇冷”，子行业表现各异 9月26日，中国医药企业管理协会披露《2024年上半年医药工业经济运行情况》，2024上半年，我国规模以上医药工业增加值同比增长1.2%；规模以上企业实现营业收入14465.5亿元，同比下降1.4%；实现利润2111.2亿元，同比下降1.2%。分子行业看，化学原料药和化学制剂营业收入小幅下降，但利润实现了正增长，分别为+8.2%和+5.7%；中药饮片是唯一营收（+6.1%）、利润（+2.8%）均实现正增长的子行业；生物制品摆脱了新冠疫苗影响因素，营业收入恢复正增长（+0.7%）；中成药、卫生材料及医药用品、医疗仪器设备及器械、制药专用设备等4个子行业营收和利润均为负增长。（中国医药企业管理协会） 5款独家中成药申请保护获准 9月24日，国家药监局发布公告称，对5款独家中成药给予二级保护，其中，批准贵州汉方药业的芪胶升白胶囊、山东凤凰制药的复方川芎片、重庆华森制药的六味安神胶囊、哈尔滨市康隆药业的炎宁糖浆为首家中药二级保护品种，对青岛华仁太医药业的蒲元和胃胶囊延长二级保护期。（国家药监局）本周获批中药二级保护的品种两大国资药企“牵手”，推进中医药现代化 9月23日，重药控股官方微信公众号发布消息，由华润三九（华润医药子公司）和重庆医药（重药控股子公司）共同出资组建的重庆医药集团九隆现代中药有限公司（下文简称“重药九隆”）正式开业投产，主营业务包括中药配方颗粒、中药饮片、中药材以及中成药生产等。重药九隆成立于2020年10月，项目于2022年5月开工建设，总投资约4亿元，目前由华润三九持股51%，重庆医药持股49%。（企业官微）延伸阅读：今年6月，经过股权无偿划转后，重药控股间接控股股东变更为通用技术集团，实际控制人变更为国资委，其与华润三九的合作可以视为一次国资“牵手”。 447个产品拟中选！医药大省集采结果出炉 9月27日，福建省医保局发布《福建省第五批药品集中带量采购公告（第7号）》，对本省第五批药品集采拟中选清单进行公示，公示时间为9月28日至10月10日。据悉，本次集采共有447个产品拟中选，其中，接续采购产品有129个，新一轮采购产品有318个。经对比，接续采购目录中的西尼地平口服常释剂型、美洛西林舒巴坦(4:1)注射剂，及新一轮采购目录中的氟比洛芬贴剂、青霉素注射剂拟流标。（福建省医保局）狙击超200亿市场，恒瑞1类新药临床报喜 9月24日、26日，恒瑞医药连发两则公告称，旗下1类新药HRS-2129片、3类仿制药氟[18F]美他酚注射液获批临床。其中，HRS-2129片拟用于治疗急慢性疼痛，目前国内外尚无同类产品获批上市，米内网数据显示，2023年中国三大终端六大市场（统计范围详见本文末）止痛药销售规模首破200亿元，同比涨逾8%。氟[18F]美他酚注射液是一款放射性诊断剂，拟用于评估阿尔茨海默病或其他原因导致的认知障碍的成年患者脑内β-淀粉样蛋白聚集形成的神经炎斑密度的PET成像。（米内网整理） 29个国谈药，医保支付标准公开 9月23日，山西省药械集采网发布《关于对2023年国谈药品（竞价药品）同通用名药品（第二批）医保支付标准进行公示的函》，拟公开29个国谈药医保支付标准，不乏沙库巴曲缬沙坦钠片、注射用头孢他啶阿维巴坦钠、复方氨基酸注射液(14AA-SF)等2023年在中国三大终端六大市场销售额超10亿元的大品种。按品规及最小包装数量统计，正大天晴药业、齐鲁制药、海南广升誉制药等均有3个及以上产品在列。（山西省药械集采网）最高88%！25个品种主动降价 9月23日，河南省医药集中采购平台发布了一则下调药品价格公示。据梳理，此次共有20家企业、25个药品提交了降价申请，医保品种占比超过八成。其中，丙酚替诺福韦片剂、法舒地尔注射剂等品种降幅较大，均超过70%，而成都国为医药的纳美芬注射剂价格仅下降0.003%，为本次降幅最小的产品。（米内网整理）超11亿大品种！君实1类新药再下一城 9月25日，君实生物发布公告称，公司自主研发的1类新药特瑞普利单抗于近日获欧盟委员会批准上市，用于转移性鼻咽癌（NPC）一线治疗，及晚期/复发或转移性食管鳞癌（ESCC）一线治疗。此前，特瑞普利单抗已先后于2018年和2023年在中国、美国等地获批上市。（公司公告）米内数据：特瑞普利单抗是国内首个获批上市的国产PD-1单抗，2020年通过谈判进入医保后市场实现快速放量，2023年在中国三大终端六大市场销售额超过11亿元，同比增长37.11%。采购不合规！一医药企业被罚157万 9月25日，重庆市药监局公开的一则行政处罚决定书中显示，益百家医药（重庆）有限公司未从药品上市许可持有人或者具有药品生产、经营资格的企业购进强骨生血口服液、复方木芙蓉涂鼻软膏、射干利咽口服液，依据《中华人民共和国药品管理法》相关规定，重庆市药监局依法对其作出没收违射干利咽口服液16681盒、强骨生血口服液1809盒、复方木芙蓉涂鼻软膏186盒，罚款合计约157万元等行政处罚。（重庆市药监局）原拟募13亿元！善康医药闯关IPO折戟 9月24日，上海证券交易所官网显示，深圳善康医药科技股份有限公司（下文简称“善康医药”）主动撤回科创板上市申请，IPO终止。据悉，善康医药主要从事以预防阿片类毒品复吸、治疗酒精使用障碍为代表的成瘾治疗药物等创新药的研发、生产和销售。今年6月，公司的核心产品盐酸纳曲酮植入剂（2.2类新药）获批上市，用于预防阿片类物质依赖患者脱毒后的复吸，有效时长达150天，是国内目前唯一一款进入商业化阶段的长效戒毒药物。（中国经济网）延伸阅读：善康医药原计划选择“科创板第五套”标准上市，即“预计市值不低于40亿元，主要业务或产品需经国家有关部门批准，医药企业需至少有一项核心产品获准开展Ⅱ期临床等相关条件”。公司此次原拟募资13.27亿元，用于新药研发项目、创新药高端制剂生产基地建设项目、营销网络建设项目、补充流动资金项目等。知名医院出事了！法人、院长等被采取刑事措施 9月24日，无锡市医保局发布情况通报称，近日，无锡市医保局会同公安、卫健委等部门继续对无锡虹桥医院涉嫌骗取医保问题进行全面调查，目前该医院骗保情况基本查实。9月22日，无锡市医保局取消其医保定点资格，公安机关刑事立案。9月23日，无锡虹桥医院法定代表人、院长等15名涉案人员已被公安机关依法采取刑事强制措施。该民营医院现已停业。（无锡市医保局）注：米内网《中国三大终端六大市场药品竞争格局》，统计范围是：城市公立医院和县级公立医院、城市社区中心和乡镇卫生院、城市实体药店和网上药店，不含民营医院、私人诊所、村卫生室，不含县乡村药店；上述销售额以产品在终端的平均零售价计算。投稿及报料请发邮件到872470254@qq.com稿件要求详询米内微信首页菜单栏商务及内容合作可联系QQ：412539092 【分享、点赞、在看】点一点不失联哦

带量采购IPO

2024-06-17

·BioSpace

Raya Therapeutic Announces Supportive Clinical Results of Fasudil (RT1968) in ALS Patients

MONTREAL, June 17, 2024 /PRNewswire/ - Raya Therapeutic Inc., ("Raya") a mission-driven company focused on the treatment of ALS and other neurodegenerative diseases, is pleased to announce supportive clinical data for its lead compound, fasudil (RT1968, in the treatment of Amyotrophic Lateral Sclerosis (ALS)), as disclosed in a conference abstract for the ENCALS meeting by the investigators of the ROCK-ALS Phase 2 clinical trial. As shared in the conference abstract, the ROCK-ALS Phase 2 study was a randomized, double-blind, placebo-controlled trial that enrolled 120 patients across sites in Germany, France, and Switzerland. Subjects were randomly assigned (1:1:1) to receive 30 mg of fasudil, 60 mg of fasudil, or placebo intravenously (iv) over 20 treatment days. Assessments were performed at 45, 90 and 180 days after treatment initiation. Primary endpoints were tolerability and safety, and secondary endpoints included, among others, motor unit number index (MUNIX), which estimates how many motor neurons innervate a muscle, and slow vital capacity (SVC), which is a measure of respiratory function. In the intention-to-treat population (118 participants), safety and tolerability were not significantly different between groups. In the secondary outcomes, MUNIX showed a significantly reduced decline with Fasudil 60 mg at 26 and 90 days, and for Fasudil 30 mg at 90 days after treatment initiation. In addition, there was a directional difference in a slower loss of SVC favoring the 60 mg of fasudil treatment at day 26, which was statistically significant in a post-hoc subgroup analysis of females at all time points, as stated in the conference abstract. The authors, who include the principal investigators of this investigator-initiated trial, conclude the following regarding the results of this trial in the abstract: "Fasudil treatment was well tolerated and safe in ALS patients. MUNIX evaluation suggests a slower loss of motor units in fasudil-treated patients compared to placebo suggesting a benefit of fasudil to be explored in further clinical trials." These preliminary results were shared in the conference abstract and have not yet been peer-reviewed. "We are excited by the encouraging data from the ROCK-ALS trial of fasudil and remain steadfast in our mission to develop breakthrough therapies for ALS and other neurodegenerative disorders," said Anjan Aralihalli, President and founder of Raya. Based on these encouraging findings, Raya will now test fasudil in more extensive studies with a larger patient cohort to further assess the compound's efficacy in ALS. In addition, Raya has reformulated fasudil into a novel formulation to enhance ease of use, especially for the approximately 80% of ALS patients that suffer from dysphagia. Anjan Aralihalli continues: "With a comprehensive combination strategy on the horizon, along with plans to initiate clinical trials next year for both mono and combination therapies, we are optimistic about the future prospects of fasudil and our entire pipeline. We are especially grateful to our licensor, University Medical Center Göttingen (UMG), for their pivotal support and collaboration as the principal sponsor of this Phase 2 study. Their commitment and support have been instrumental in advancing fasudil for ALS patients." For more information about Raya and its innovative pipeline, visit or LinkedIn Members of the Raya management team will be attending the ENCALS Annual Meeting in Stockholm, Sweden from June 17-20. About Raya Raya is a mission-driven company focused on the treatment of ALS, leveraging the latest techniques for the selection and development of disease-modifying therapies. The company has a robust pipeline of five distinct clinical stage compounds that each target different pathways involved in motor neuron degeneration seen in ALS patients. The compounds were in-licensed following a rigorous selection process based on biological plausibility, clinical target engagement and functional clinical effects reflective of efficacy. This diversified approach may enable the development of combination therapies which may have a significant impact on disease progression. To develop further combination therapies, Raya entered into a strategic research collaboration with argenx last summer ( ). This partnership explores synergistic effects of their combined drug candidates in the hope of developing more effective treatment options for ALS patients. Raya is further supported by global experts and will leverage a unique patient-friendly platform trial design offering new hope in the fight against ALS. About Fasudil Fasudil is a small molecule inhibitor of the rho-associated kinase (ROCK) and is approved for the treatment of subarachnoid hemorrhage in a few Asian countries. In preclinical studies, fasudil attenuates neurodegeneration, modulates neuroinflammation, and fosters axonal regeneration. About UMG (University Medical Center Göttingen) The UMG located in Göttingen, Lower Saxony, Germany is one of the leading university medical facilities in Germany. It is comprised of a Medical Faculty engaged in research and teaching, a University Hospital providing patient care and Research allowing for the swift transfer of innovative therapy options into patient care and education.

临床2期临床结果

2024-05-13

·梅斯医学

CIC 2024 | 张运院士：冠状动脉微血管疾病诊断和治疗的中国专家共识2023版

自2017年，中华医学会心血管病学分会基础研究学组、介入心脏病学组、女性心脏健康学组以及动脉粥样硬化和冠心病学组编写了国际上第一部“冠状动脉微血管疾病（CMVD）诊断和治疗的中国专家共识”以来，国际上关于CMVD的共识文件迅速增加，例如2019年，AHA发表了MINOCA诊断和治疗的科学声明，指出微血管性心绞痛、微血管痉挛和冠脉慢血流是MINOCA的重要病因。2020年，欧洲经皮心血管介入协会(EAPCI)和ESC联合发布了冠状动脉非阻塞性心肌缺血(INOCA)的共识性文件，提出CMVD和/或心外膜下冠脉痉挛是INOCA 的主要病因。2020年，ESC发表了心血管疾病中冠状动脉微血管功能异常的立场文件，将微血管性心绞痛归纳为慢性冠脉综合征的重要类型，提出了相应的诊断和治疗策略。尽管部分文件对CMVD的诊断和治疗提出了初步建议，但并未提供推荐分类和证据等级。2023版中国专家共识总结CMVD近年进展，更新旧版共识中过时的观点，规范CMVD诊断和治疗，以及凝练科学问题和研究方向。近日，在2024长安国际心血管病论坛（CIC2024）上，来自山东大学齐鲁医院的张运院士对《冠状动脉微血管疾病诊断和治疗的中国专家共识（2023版）》进行详细解读，该共识提出了新的CMVD分类，，推荐诊断途径、标准及治疗策略。本文梳理重点内容，以分享各位同道。CMVD的定义冠状动脉微血管疾病(coronary microvascular disease,CMVD)是指在动脉粥样硬化性和非动脉粥样硬化性致病因素的作用下，冠状前小动脉、小动脉和毛细血管的结构和功能异常所导致的急性和慢性心肌缺血的临床综合征。CMVD的临床分型心肌缺血相关的CMVD：冠状动脉阻塞性心肌缺血(IOCA)相关的CMVD冠状动脉非阻塞性心肌缺血(INOCA)相关的CMVD心肌梗死相关的CMVD：冠状动脉阻塞性心肌梗死(MIOCA)相关的CMVD冠状动脉非阻塞性心肌梗死(MINOCA)相关的CMVD血运重建相关的CMVD：急诊PCI相关的CMVD择期PCI手术相关的CMVDCABG相关的CMVD非动脉粥样硬化心脏病相关的CMVD：合并心肌肥厚的CMVD不合并心肌肥厚的CMVD冠状动脉血流的调节机制冠脉血流量是指心脏冠状动脉血液在单位时间内的流量。影响冠脉血流量大小的主要因素是心肌的活动。此外，神经和激素对冠状动脉血流量也具有一定的调节作用。调节冠脉血流量的因素主要有物理因素、代谢因素、神经体液因素和自身调节。其中最重要的是代谢因素，即心肌本身的代谢水平。不同冠脉节段的血管舒缩受不同机制调节：血流介导的血管扩张：主要发生在心外膜下冠状动脉和前小动脉；冠脉血流自动调节：机制可能为前小动脉远端的肌源性反应，即冠脉灌注压上升时前小动脉收缩，反之则扩张；心肌耗氧量：心肌耗氧量增加时，冠脉阻力血管可充分扩张以满足心肌的需求，称为功能性充血，NO、前列环素、内皮素等参与调节；心肌代谢产物：当心肌缺血缺氧时，代谢产物的堆积首先使冠状小>动脉扩张，冠脉阻力和前小动脉的压力下降，触发冠脉的肌源性反应，血管进一步扩张，触发血流介导的血管扩张，使心外膜下的冠脉和较大的前小动脉扩张(级联式反应)。冠脉血流储备1974年Gould 首次提出冠脉血流储备(CFR)的概念。CFR是指冠脉接近最大程度扩张时，冠脉血流量(coronary bloodflow，CBF)或心肌血流量(myocardⅡal blood flow，MBF)与静息状态下相应指标的比值，是测量冠脉储备功能的整体指标。CFR受到4个因素的影响：静息状态的冠脉血流量(静息状态血流量增大可使CFR降低)、单位体积心肌内阻力血管的横截面积(管壁增厚可使CFR降低)、冠脉血管外的压力(室壁张力增加可使CFR降低)和冠脉灌注压(血压下降可使CFR降低)。CMVD的发病机制CMVD发病机制较为复杂，在疾病发展进程中受诸多因素影响。新共识在此方面新增了冠脉血流的调节机制、微血管阻塞，同时对冠脉微循环结构和功能异常方面的机制进行了更新。1、冠状动脉微血管结构异常：遗传因素(RAAS、过氧化物酶体增殖物激活受体及内皮素等基因的多态性)；血流动力学因素(持续血压升高引起的剪切力变化)；神经体液机制(高血压状态下RAAS激活、细胞因子、黏附分子及内皮素等高表达以及炎性细胞积聚)。2、冠状动脉微血管阻塞(microvascular obstruction,MVO)3、冠状动脉微血管功能异常：内皮依赖性血管舒张异常非内皮依赖性血管舒张异常微血管痉挛心脏交感神经元功能障碍评价冠脉微血管功能的血管活性药物通过检测冠脉微血管对血管扩张剂的反应来评估其功能，常用指标是CFR。1、内皮非依赖型血管扩张剂：主要作用于血管平滑肌细胞腺苷：静注剂量140μg/Kg/min，冠脉内注射剂量2-16μg/Kg/min，注射时间1.5-6分钟。常见的副作用有AVB、SAB、支气管痉挛。半衰期仅10秒，副作用可很快消失。双嘧达莫：通过抑制腺苷降解而发挥作用，药理作用类似于腺苷。静注剂量0.56-0.84 mg/Kg。应用腺苷或双嘧达莫后CFR<2.5提示冠脉微血管舒张功能异常，临床上推荐CFR<2.0作为判断微血管功能障碍的临界值。2、内皮依赖型血管扩张剂：主要作用于血管内皮细胞乙酰胆碱的双重性：刺激内皮细胞释放NO扩张血管，结合毒碱样乙酰胆碱受体刺激平滑肌细胞收缩血管。内皮功能正常时，乙酰胆碱的扩血管作用占主导地位，但如出现内皮功能异常乙酰胆碱的缩血管作用占优势，从而导致血管痉挛。用法和用量：乙酰胆碱稀释后冠脉内递增式注射，注射1分钟后行冠脉造影，利用定量造影法测量冠脉内径以明确有痉挛，同时观察心绞痛症状和心电图变化。如注射后未见心外膜下冠脉痉挛但出现心绞痛症状和缺血型ST-T改变，可诊断为CMVD，同时应立即冠脉内注射硝酸甘油或尼可地尔以对抗冠脉微血管痉挛。瑞加诺生：选择性激活腺苷A2A受体使冠脉扩张，增加冠脉血流量，具有选择性扩张冠脉和起效迅速的特点。用法和用量：10秒内一次性固定剂量弹丸式快速静脉注射给药，0.4 mg/5 ml。尼可地尔：硝酸酯类和腺苷三磷酸敏感性钾通道开放剂，激活细胞内的鸟苷酸环化酶，松弛血管平滑肌，兼具舒张心外膜动脉及冠脉微血管的功能。用法和用量：冠脉内弹丸式注射2~4 mg，作用效果及维持心肌最大充血状态的持续时间存在一定的剂量依赖性。CMVD的诊断CMVD的临床表现多样、机制复杂，且常规药物疗效有限，因此早期检出CMVD具有十分重要的临床意义。新共识更新了评价冠脉微血管功能的相关内容，指出诊断流程，同时整理了各亚类疾病的临床表现和诊断标准。临床评价冠状动脉微血管功能的检查主要包括：血管活性药物试验、无创伤性诊断技术和创伤性诊断技术等三类：血管活性药物试验：除了腺苷、双嘧达莫、乙酰胆碱，共识新增了腺苷A2A受体选择性激动剂Regadenoson和尼可地尔。无创伤性诊断技术：经胸超声冠脉血流显像（TTDE）、心肌声学造影（MCE）、单光子发射计算机断层成像（SPECT）、正电子发射型计算机断层显像（PET）、心脏磁共振成像（CMR）、CT灌注扫描（CTP）。 1）经胸多普勒超声(TTDE)：测量LAD近端分支的血流速度，诊断标准CFVR<2 2）心肌声学造影(MCE)：检测负荷后与负荷前的心肌血流量(MBF)，诊断标准CFR<2 3）单光子发射断层扫描(SPECT)：检测负荷后与负荷前的心肌血流量(MBF)，诊断标准CFR<2 4）正电子发射断层扫描(PET)：检测负荷后与负荷前MBF，诊断标准CFR<2 5）心脏核磁共振(CMR)：测量负荷后与负荷前MBF，计算心肌灌注储备指数(MPRI)，诊断标准MPRI<2 6）CT灌注显像(CTP)：诊断标准心肌灌注储备MPR<2诊断CMVD无创性技术的推荐创伤性诊断技术：冠脉造影、冠脉内温度-压力测量、冠脉内多普勒流速测量、冠脉痉挛诱导试验。 1）选择性冠状动脉造影(CAG)：TIMI血流分级：诊断标准TIMI分级≤2TIMI血流计帧法(TFC)：诊断标准TFC>25帧TIMI心肌显影分级(TMBG)，分为0-3级心肌显影密度分级(MBG)，分为0-3级TIMI心肌灌注帧数(TMPFC)：我国学者提出 2）温度稀释法：弹丸注射温度稀释法：诊断标准微血管阻力指数(IMR)>25连续温度稀释法：诊断标准微血管阻力储备(MRR)<2.1 3）冠状动脉内多普勒流速法：CFR<2.5,充血性微血管阻力(HMR)>1.7 mmHg/cm/s诊断CMVD有创技术的推荐图：CMVD诊断流程图CMVD的临床表现和诊断标准(一)心肌缺血相关的CMVD（1）INOCA相关的CMVD：也称原发性稳定性微血管心绞痛(MVA)临床表现：持续心肌缺血的症状，冠脉血流储备较低或有微血管痉挛的实验室证据，但没有心外膜冠脉的阻塞性病变。主要症状是劳力性胸痛，与严重冠脉狭窄患者的胸痛很难区分。以下特征提示CMVD：女性常见，大多数发生在绝经后；大多数患者经历分娩引起的胸痛，极少数在休息时出现胸痛；胸痛单次发作持续时间较长，50%以上发作持续10 min以上，停止运动后不适持续数分钟；硝酸甘油对胸痛无效，甚至使胸痛加重。诊断标准：典型的心肌缺血临床症状；具有至少一项心肌缺血的客观证据(心电图ST段压低、心肌负荷SPECT示可逆性心肌灌注缺损、多普勒超声检测CFR减低(<2.0)、CMR检测MPRI减低(<2.0)、PET检查发现有心肌缺血的代谢性证据；冠脉造影正常、管壁不规则或管腔狭窄≤50%；如临床高度疑诊CMVD但CFR≥2.0，可在严密监护下冠脉内注射乙酰胆碱进行负荷试验，如心外膜下冠脉无痉挛但出现心绞痛症状和心电图缺血型ST-T改变可确诊CMVD；排除非心源性胸痛和其他心脏病如变异性心绞痛、心肌病、心肌炎或心脏瓣膜病。（2）IOCA相关的CMVD临床表现：CMVD和心外膜冠脉阻塞性病变共同导致心绞痛症状；患者可能经历长时间的心绞痛发作；触发心绞痛的体力活动闽值具有高度变异性；舌下含服硝酸甘油无效；心绞痛的严重程度往往超过冠脉狭窄程度所预期的程度。诊断标准：典型的心肌缺血症状；PCI成功后早期负荷试验仍呈阳性；解除心外膜冠脉狭窄病变后，CFR<2.0或冠脉内乙酰胆碱激发试验后心外膜下冠脉无痉挛但出现典型心绞痛和心电图缺血型ST-T改变；择期 PCI患者，TIMI血流分级<3级和(或)TMPG<3级；PCI 后出院前 SPECT 显像显示心肌局部无灌注区或CMR显像显示心肌灌注缺损或延迟钆强化。(二)心肌梗死相关的CMVD（1）MINOCA相关的CMVD临床表现：休息或清晨时反复出现胸痛，以及轻度体力活动诱发的胸痛，可能持续1~2小时，硝酸甘油无效，胸痛发作时或动态心电图可记录到缺血和动态ST-T变化诊断标准；NSTEMI的临床表现；CMVD的实验室证据：CFR<2.0或CFR≥2.0但冠脉微血管痉挛试验阳性排除心外膜下阻塞性和痉挛性冠脉病变、一过性冠脉血栓形成、心肌病变或其他心血管疾病。（2）MIOCA相关的CMVD临床表现：成功PCI后发生CMVD相关的心绞痛，并伴有左室重构、心功能减退和心血管事件。诊断标准：具有冠脉阻塞性病变；CMVD的实验室证据；成功PCI后无创评估：SPECT显示心肌局部无灌注区，MRI显示心肌灌注缺损或延迟钆强化；成功PCI后有创评估：TIMI血流分级0-2级和/或TMBG 0-2级；IMR>40。(三)血运重建相关的CMVD（1）急诊PCI相关的CMVD临床表现：在接受直接PCI治疗的STEMI患者中，MVO的发生率为5%~50%。诊断标准：PCI术后TIMI血流分级0~2级；PCI术后TIMI心肌灌注分级0~2级；PCI术后90分钟心电图ST段抬高回落<50%；出院前SPECT显示局部心肌无灌注区，MRI显示心肌灌注缺损或延迟钆强化。（2）择期介入治疗相关的CMVD临床表现：PCI术后肌钙蛋白升高，心绞痛复发，发生MACE、死亡、MI和再次PCI的风险增加。诊断标准：成功PCI后仍有心绞痛症状；PCI术后冠脉内多普勒超声测量CFR<2.0；PCI术后即刻测量IMR≥25；CMR显示心肌灌注缺损或延迟钆强化。（3）CABG相关的CMVD临床表现：CABG术后反复发生心绞痛，在大多数情况下应考虑合并CMVD；心脏移植受者的异体冠脉血管病变中CMVD也很常见，它独立于心外膜冠状动脉病变，且与死亡风险有关。诊断标准：CABG术后反复发生心绞痛；实验室检查：CFR<2.0；CMR显示心肌灌注缺损或延迟钆强化。(四)非动脉粥样硬化心脏病相关的CMVD（1）合并心肌肥厚的CMVDHCM、Fabry病、心脏淀粉样变、主动脉瓣狭窄等原发病表现；CMVD的实验室证据。（2）不合并心肌肥厚的CMVD应激性心肌病、扩张型心肌病、 HFpEF、糖尿病心肌病等原发病表现；CMVD的实验室证据。CMVD治疗策略和药物(一)INOCA相关CMVD的治疗控制危险因素：高血压、高脂血症、糖尿病、血栓栓塞。改善生活方式：戒烟、减轻体重、运动、心脏康复、避免应激。CMVD分层治疗：微血管心绞痛(MVA)的治疗血管痉挛型心绞痛(VSA)的治疗MVA合并VSA的治疗MVA和VSA的鉴别：行有创压力导丝的冠脉功能检测和乙酰胆碱负荷的内皮功能试验。MVA的诊断标准：腺苷负荷试验中冠脉压力导丝测量的FFR>0.8，CFR<2.0，IMR25，HMR ≥1.9；乙酰胆碱负荷试验中患者出现心绞痛症状、心电图ST段呈缺血性改变、冠状动脉内径缩窄<90%。VSA的诊断标准：腺苷负荷试验，冠脉压力导丝测量的FFR>0.8，CFR≥2.0，IMR<25，HMR <1.9；乙酰胆碱负荷试验中患者出现心绞痛症状、心电图ST段呈缺血性改变、冠状动脉内径缩窄≥90%。MVA合并VSA的诊断标准：腺苷负荷试验中冠脉压力导丝测量的FFR>0.8，CFR<2.0，IM≥25，HMR≥1.9；乙酰胆碱负荷试验中患者出现心绞痛症状、心电图ST段呈缺血性改变、冠状动脉内径缩窄≥290%。MVA的治疗推荐(Ⅰ-Ⅱa)β受体阻滞剂(Ⅰ,A)：高选择性β1受体抑制剂奈必洛尔，可增加NO释放而扩张冠脉，减轻心绞痛症状。卡维地洛同时具有α和β受体阻滞作用，对微血管病变有益。CCB(Ⅰ,B)：复合型L型和T型CCB咪拉地尔，可减少冠脉慢血流患者的心绞痛发作频率；氨氯地平或贝尼地平减轻MVA症状。尼可地尔(Ⅱa,B)：有效扩张冠脉微血管，对MVA效果较好。雷诺嗪(Ⅱa,B)：显著减少MVA患者心绞痛症状，增加运动耐量。曲美他嗪(Ⅱa,B)：显著增加INOCA合并微血管病变患者的运动耐量。ACEI/ARB(Ⅱa,B)：改善CMVD患者的心绞痛症状、提高CFR。伊伐布雷定(Ⅱa,B)：能够减轻INOCA患者的MVA症。中药 (Ⅱa,B)：通心络改善血管内皮功能；麝香保心丸增加CFR，降低IMR。MVA的治疗推荐(Ⅱb)内皮素受体拮抗剂(Ⅱb,B)：内皮素受体拮抗齐泊腾坦可改善CMVD患者的血管内皮功能。三环类药物(Ⅱb,B)：阿米替林、丙咪嗪或去甲丙咪嗪。非药物治疗(Ⅱb,B)：脊髓电刺激或增强型体外反搏。VSA的治疗推荐(Ⅱa-Ⅱb)CCB(Ⅱa,B)：VSA的药物治疗首选CCB对于冠脉痉严重者，CCB的剂量需要加倍。硝酸酯类(Ⅱa,B)：长效硝酸酯类单独或与CCB合用可缓解因VSA导致的顽固性心绞痛。尼可地尔(Ⅱa,C)：通过开放ATP敏感钾离子通道，扩张微血管。Rho激酶抑制剂(Ⅱb,B)：法舒地尔可抑制乙酰胆碱诱发的微血管痉挛，减少VSA发作。VSA的治疗推荐(Ⅱb-Ⅲ )磷酸二酯酶抑制剂(PDE)(Ⅱb,B)：PDE3抑制剂西洛他唑可抑制腺苷降解而发挥抗血小板、抗炎和扩张血管的作用，可缓解自发性VSA或麦角碱诱发的VSA以及CCB和硝酸酯无法缓解的顽固性心绞痛。PDE5抑制剂西地那非可改善冠心病患者内皮依赖性的血管舒张功能，改善CFR、缓解心绞痛。β受体阻滞剂(Ⅲ,C)：VSA患者应避免使用β受体阻滞剂，尤其是非选择性β受体阻滞剂(如普萘洛尔等)。MVA合并VSA的治疗推荐CCB(Ⅱa,B)：推荐氨氯地平、维拉帕米、地尔硫卓尼可地尔(Ⅱa,B)曲美他嗪(Ⅱa,B)ACEI或ARB (Ⅱa,B)他汀类药物(Ⅱa,C)(二)IOCA相关CMVD的治疗推荐改善生活方式：健康饮食、戒烟、体育锻炼、心脏康复治疗、控制体重、避免应和心理疏导等。抗动脉粥样硬化治疗CMVD的分层治疗及冠脉血运重建治疗(三)MINOCA相关CMVD的治疗推荐MINOCA相关CMVD的二级预防(四)MIQCA相关CMVD 的治疗推荐(五)STEMI介入治疗成功后CMVD的治疗(六)非动脉粥样硬化心脏病相关的CMVD的治疗（1）合并心肌肥厚的CMVD原发病治疗：高血压性心肌肥厚：ACEI/ARB(Ⅰ,A)，CCB(Ⅱa,B)肥厚型心肌病：室间隔切除或化学消融术(Ⅰa,B)主动脉瓣狭窄：主动脉瓣置换术(Ⅰ,A)CMVD治疗：ACEI/ARB(Ⅰ, A)，β受体阻滞剂(Ⅰ,A)，CCB(Ⅱb,B)（2）不合并心肌肥厚的CMVDACEI/ARB(Ⅰ,A)，β受体阻滞剂(Ⅰ,A)，别嘌呤醇(Ⅰb,B)问题和展望目前对CMVD发病机制的认识是基于AS动物模型和血管细胞的发现，CMVD动物模型的建立和微血管内皮细胞的培养是深入了解CMVD发病机制的基础。CMVD在不同人群和种族以及不常见病因的患者(如心肌病患者)中的流行病学数据缺乏。因此，需要在这些人群中加强流行病学研究。同时，未来发展无创性成像技术来评估整个左心室微血管的结构和功能非常必要。目前评估CMVD患者药物疗效的随机临床试验均使用替代终点(主要是CFR)，而使用硬终点如心血管死亡率的临床试验应是未来的发展方向。本文整理自山东大学齐鲁医院的张运院士CIC大会上发言撰文 | 阿拉斯加宝编辑 | 阿拉斯加宝● 热议！拒绝饿肚子下班！“关爱不是空话，请科室、带教老师给我们点饭！”华西刘进曾建议，规培生每年补贴10万！从吃饭开始，能做到吗？● 重磅！医德医风考核低于80分，不得申报高级职称、不得晋升！检举同事属实，每次加2分！重庆市出了新政策● 警惕这种氨基酸！Nature子刊：中山大学最新，这一“必需氨基酸”吃太多，恐加速肿瘤生长，抑制抗癌疗效！版权说明：梅斯医学（MedSci）是国内领先的医学科研与学术服务平台，致力于医疗质量的改进，为临床实践提供智慧、精准的决策支持，让医生与患者受益。欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。点击下方「阅读原文」立刻下载梅斯医学APP！

AHA会议

100 项与甲磺酸法舒地尔相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	-	C04AX32	DB08162

研发状态

批准上市

10 条最早获批的记录,

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适应症	国家/地区	公司	日期
脑缺血	中国	武汉启瑞药业有限公司	2012-05-15
颅内血管痉挛	中国	武汉启瑞药业有限公司	2012-05-15

未上市

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
皮质基底节变性	临床2期	美国	Woolsey Pharmaceuticals, Inc.初创企业	2021-01-22
进行性核上性麻痹	临床2期	美国	Woolsey Pharmaceuticals, Inc.初创企业	2021-01-22
痴呆	临床2期	美国	Woolsey Pharmaceuticals, Inc.初创企业	2020-12-15
痴呆	临床2期	澳大利亚	Woolsey Pharmaceuticals, Inc.初创企业	2020-12-15
肌萎缩侧索硬化	临床2期	-	Raya Therapeutic Inc.	-

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临床结果

适应症

分期

评价

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT00498615 (CTgov)	临床3期	雷诺病 \| 系统性硬皮病	17	Fasudil (40 mg Fasudil)	憲簾繭窪顧積遞簾廠膚(窪獵艱築願願齋遞選鏇) = 簾簾繭醖鏇範鏇糧鏇獵艱餘鏇蓋選繭願鹽遞窪 (願鑰齋餘遞壓廠膚膚積, 壓範簾簾鬱鏇鹽築願憲 ~ 積鑰齋淵繭夢鹽壓網鹽) 更多	-	2014-11-04
NCT00498615 (CTgov)	临床3期	雷诺病 \| 系统性硬皮病	17	Fasudil (Placebo)	憲簾繭窪顧積遞簾廠膚(窪獵艱築願願齋遞選鏇) = 鏇艱膚築選餘餘糧淵鏇艱餘鏇蓋選繭願鹽遞窪 (願鑰齋餘遞壓廠膚膚積, 艱餘繭膚膚壓顧鹽淵觸 ~ 鏇蓋繭齋鬱膚網簾範廠) 更多	-	2014-11-04
ARVO2013	N/A	糖尿病性黄斑水肿	5	Intravitreal Fasudil + Bevacizumab	淵觸憲簾繭觸獵窪夢顧(鏇願醖糧顧構憲齋襯製) = 襯鹹蓋獵餘積壓糧築製簾齋窪淵製鏇夢構鹹鹽 (獵窪鏇觸獵選憲鹹蓋鏇 ) 更多	积极	2013-06-01