A Multicenter, Randomized, Double Blind, Placebo Controlled Phase II Clinical Study to Evaluate the Safety and Efficacy of SHPL-49 Injection in the Treatment of Acute Ischemic Stroke

This study is designed to determine the safety and efficacy of SHPL-49 intravenous infusion for 7 consecutive days in the treatment of acute ischemic stroke subjects.

开始日期2023-12-29

申办/合作机构

上海和黄药业有限公司

[+1]

CTR20234035 / Active, not recruiting临床2期

SHPL-49注射液治疗急性缺血性脑卒中有效性和安全性的Ⅱ期临床试验-多中心、随机、双盲、安慰剂平行对照试验

主要研究目的:探索连续7天静脉滴注不同剂量SHPL-49注射液治疗发病后8h内急性缺血性脑卒中受试者的有效性。次要研究目的:探索连续7天静脉滴注不同剂量SHPL-49注射液治疗发病后8h内急性缺血性脑卒中受试者的安全性。

开始日期2023-12-29

申办/合作机构

上海和黄药业有限公司

CTR20221800 / Completed临床1期

一项评价健康受试者单次和连续7天多次静脉输注SHPL-49注射液的安全性、耐受性和药代特征的单中心、随机、双盲、安慰剂对照、剂量递增试验

主要目的：评估单次和连续7天多次静脉输注不同剂量SHPL-49注射液的安全性和耐受性。次要目的：评估单次和连续7天多次静脉输注不同剂量SHPL-49注射液的药代动力学（PK）特征；探索性目的：初探SHPL-49注射液给药在体内的代谢产物及物质平衡。

开始日期2022-08-22

申办/合作机构

上海和黄药业有限公司

100 项与 SHPL-49 相关的临床结果

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100 项与 SHPL-49 相关的转化医学

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100 项与 SHPL-49 相关的专利（医药）

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项与 SHPL-49 相关的文献（医药）

2024-11-01·Biomedicine & Pharmacotherapy

Microglia-mediated endothelial protection: the role of SHPL-49 in ischemic stroke

Article

作者: Zhang, Pei ; Zhao, Yu ; Zhang, Jiange

It was previously shown that SHPL-49, a glycoside derivative of salidroside formed through structural modification, exhibited neuroprotective effects in a rat cerebral ischemia model of permanent middle cerebral artery occlusion (pMCAO). Additionally, SHPL-49 enhanced the mRNA expression of vascular endothelial growth factor-a (Vegf-a) in macrophages. Microglia, functioning as resident macrophages within the brain, promptly respond to cerebral ischemia and engage in interactions with the cells of the Glial-Vascular Unit to orchestrate nerve injury responses. We postulated that the neuroprotective effects of SHPL-49 were mediated through microglia-dependent amelioration of endothelial dysfunction following cerebral ischemia. The present study demonstrates that SHPL-49 effectively mitigated microglia-dependent endothelial dysfunction in the pMCAO model by upregulating the expression of VEGF and suppressing the release of MMP-9 from microglia. Further MRI analyses confirmed that SHPL-49 significantly reduced nerve and endothelial function when microglia were depleted in the brains of pMCAO rats. The above phenomenon was also confirmed in the in vitro experiment investigating microglia-mediated brain endothelial cell function. Furthermore, we discovered that SHPL-49 activates the VEGFR2/Akt/eNOS pathways in endothelial cells and suppresses the p38 MAPK/MMP-9 pathways in microglia cells, thereby facilitating brain endothelial cell protection. Altogether, we have demonstrated that SHPL-49 effectively ameliorates endothelial dysfunction induced by cerebral ischemia through a microglia-dependent mechanism, thereby providing more valuable insights and references for the clinical evaluation of SHPL-49 injection for ischemic stroke.

2024-11-01·Phytomedicine

Salidroside derivative SHPL-49 attenuates glutamate excitotoxicity in acute ischemic stroke via promoting NR2A-CAMKⅡα-Akt /CREB pathway

Article

作者: You, Suxin ; ZHAN, Changsen ; Zhang, Pei ; Zhan, Changsen ; ZHANG, Jiange ; Zhang, Jiange ; Xu, Wenwen ; SHEN, Yue ; XU, Wenwen ; Shen, Yue ; Xie, Dong ; XIE, Dong ; YOU, Suxin ; ZHANG, Pei

BACKGROUNDIschemic stroke is a significant cause of death and disability with a limited treatment time window. The reduction of early glutamate excitotoxicity using neuroprotective agents targeting N-methyl-d-aspartic acid (NMDA) receptors have attracted recent research attention. SHPL-49, a structurally modified derivative of salidroside, was synthesized by our team. Previous studies have confirmed the neuroprotective efficacy of SHPL-49 in rats with ischemic stroke. However, the underlying mechanisms need to be clarified.METHODSWe conducted in vivo experiments using the permanent middle cerebral artery occlusion rat model to investigate the role of SHPL-49 in glutamate release at different time points and treatment durations. Glutamate transporters and receptor proteins and neural survival proteins in the brain were also examined at the same time points. In vitro, primary neurons and the coculture system of primary neurons-astrocytes were subjected to oxygen-glucose deprivation and glutamate injury. Proteomics and parallel reaction monitoring analyses were performed to identify potential therapeutic targets of SHPL-49, which were further confirmed through in vitro experiments on the inhibition and mutation of the target.RESULTSSHPL-49 significantly reduced glutamate release caused by hypoxia-ischemia. One therapeutic pathway of SHPL-49 was promoting the expression of glutamate transporter-1 to increase glutamate reuptake and further reduce the occurrence of subsequent neurotoxicity. In addition, we explored the therapeutic targets of SHPL-49 and its regulatory effects on glutamate receptors for the first time. SHPL-49 enhanced neuroprotection by activating the NMDA subunit NR2A, which upregulated the cyclic-AMP response binding protein (CREB) neural survival pathway and Akt phosphorylation. Since calcium/calmodulin-dependent kinase IIα (CaMKIIα) is necessary for synaptic transmission of NMDA receptors, we explored the interaction between CaMKIIα and SHPL-49, which protected CaMKIIα from hypoxia-ischemia-induced autophosphorylation damage.CONCLUSIONOverall, SHPL-49 enhanced neuronal survival and attenuated acute ischemic stroke by promoting the NR2A-CAMKⅡα-Akt/CREB pathway. Our study provides the first evidence demonstrating that the neuroprotective effect of SHPL-49 is achieved by promoting the NR2A subunit to extend the treatment time window, making it a promising drug for ischemic stroke.

2024-10-01·Journal of Pharmaceutical and Biomedical Analysis

First-in-human study to assess the safety, tolerability, and pharmacokinetics of intravenous SHPL-49 following single- and multiple-ascending-dose administration in healthy adults

Article

作者: Wang, Yongjun ; Xu, Shuhong ; Wang, Weicong ; Xu, Chunmin ; Zhao, Min ; Li, Shuya ; Wang, Jiaqing ; Yang, Cuicui ; Li, Jian

SHPL-49 is an innovative glycoside derivative that is synthesized by structural modifications of salidroside，demonstrating therapeutic effects on animal models of ischemia in pre-clinical experiments. A phase I, single-center, randomized, double-blind, placebo-controlled, single and multiple dose administration study of SHPL-49 was conducted in healthy Chinese volunteers. In single-ascending-dose (SAD) study, 32 subjects randomized 6:2 to receive SHPL-49 (30 mg, 75 mg, 150 mg, 300 mg) or placebo with 30 minutes infusion. In multiple-ascending-dose (MAD) study, subjects were randomized 6:2 to receive SHPL-49 (75 mg, 150 mg, 300 mg) or placebo with 30 minutes infusion every 8 h for 7 days. Safety evaluations were conducted throughout the studies. Plasma and urine concentrations of SHPL-49 were detected and its metabolites were identified. Pharmacokinetic parameters were calculated using noncompartmental methods. SHPL-49 was generally safe and well-tolerated at single ascending doses (30-300 mg) and multiple ascending doses (75-300 mg). All adverse events were mild and resolved without any intervention. No serious adverse events were reported. In the SAD study, SHPL-49 exhibited dose-proportional plasma pharmacokinetics, with peak plasma concentration (C_max) ranging from 673.83 to 6275.00 ng/mL, area under the plasma concentration-time curve (AUC_0-t) ranging from 338.57 to 3732.67 h·ng/mL, and elimination half-life (t_1/2) ranging from 0.49 to 0.67 h. In the MAD, the exposure was also dose-proportional and there was no significant accumulation following multiple dosing. Four metabolites were identified in urine and plasma. SHPL-49 shows a favorable pharmacokinetic, safety, and tolerability profile in healthy Chinese volunteers following a single- and multiple-ascending- dose administration in this study. For future therapeutic investigations, it is recommended to administer SHPL-49 intravenously at 8-hour intervals with a dosage range of 150-300 mg.

项与 SHPL-49 相关的新闻（医药）

2023-05-28

·米内网

【瞩目】中药产品矩阵持续发力，和黄药业步入出海2.0时代

精彩内容成立20多年以来，和黄药业一直坚持创新传统中药，推进中药现代化、国际化。米内网数据显示，公司现拥有超70款现代中药产品，其中独家大单品麝香保心丸2022年在中国公立医疗机构终端销售规模突破25亿元，胆宁片、正气片2款中药相继实现海外获批；注重传统中药的二次开发，2款在研新品步入Ⅱ期临床......秉承“传承精华、守正创新”的宗旨，和黄药业将打破传统路径的依赖，探索中药现代化、国际化的全新领域，推动企业的“二次腾飞”。手握25亿独家大单品中药是中华民族的瑰宝，也是中华文化的体现。近年来，在大多中药注射剂被列为辅助用药、重点监控用药的大背景下，叠加新冠疫情的冲击，米内网数据显示，中国城市公立医院、县级公立医院、城市社区中心以及乡镇卫生院（简称中国公立医疗机构）终端中成药在2018年达到峰值后（超2800亿元）出现下滑，现正处于“元气恢复期”。近年来中国公立医疗机构终端中成药销售趋势（单位：亿元）来源：米内网中国公立医疗机构药品终端竞争格局正值“十四五”规划中期，伴随《中医药振兴发展重大工程实施方案》、《“十四五”中医药文化弘扬工程实施方案》等激励政策的出台，中药行业发展有望迎来反转。总体看来，最为利好的当属独家中成药品种和创新中成药品种。独家品种中，又以配方保密的品种最具价值，国家保密等级又分为绝密、保密、保护品种。从各个绝密和保密品种对应的上市公司股价来看，片仔癀和云南白药过去10多年走出了长牛的走势，而同仁堂、广誉远则是于近期分别创下和接近历史新高。国内中药保密等级及品种来源：公开资料、米内网中国上市药品（MID）数据库注：数据统计截至2023年5月18日和黄药业的麝香保心丸也不例外，销售收入屡创佳绩。米内网数据显示，该药2020年在中国公立医疗机构终端销售规模首次突破20亿元大关，2022年再创超25亿元的佳绩，同比增长5.77%，是心脑血管疾病中成药的TOP5品种。近年来中国公立医疗机构终端麝香保心丸销售趋势（单位：万元）来源：米内网中国公立医疗机构药品终端竞争格局麝香保心丸前身为苏合香丸，最早见于宋代《太平惠民和剂局方》，在苏合香丸的基础上，1974年至1981年，上海复旦大学华山医院组建的专家团队，在中医药理论传承基础上，运用现代化药理研究方法，对原来的苏合香丸有效成分进行了逐一筛选，在保留原组方心血管活性成分、去除药效不明显或有害的成分后，采用独特的微粒丸技术，使苏合香丸最终以麝香保心丸的身份得以完美重生，并成为目前冠心病最常用的治疗药物之一。步入“中药出海”2.0时代当然，和黄药业的中药产品矩阵并非只有“单品”，旗下商业化潜力产品还包括胆宁片、正气片、安神补心丸及耳聋左慈丸等，上述4款产品2022年在中国城市实体药店终端销售增速均在二位数及以上，和黄药业的市场份额均位居前列。上述4款产品2022年在中国城市实体药店终端销售情况来源：米内网中国城市实体药店药品终端竞争格局3款在研新品在路上，以骨骼肌肉系统疾病用药、血液和造血系统药物为主，其中，健腰密骨片（用于肾虚血瘀型老年性骨质疏松症之腰痛）、参芪麝蓉丸（用于气虚血瘀肾亏型轻、中度脊髓型颈椎病）已进入Ⅱ期临床，SHPL-49注射液（用于急性缺血性脑卒中）已进入Ⅰ期临床。和黄药业在研产品情况来源：米内网中国临床试验数据库致力于创新中药开发的同时，和黄药业也在积极布局“中药出海”。目前，和黄药业的胆宁片、正气片已相继实现海外获批，分别在2016年12月及2023年4月获得加拿大天然药品上市许可。胆宁片秉承中医“六腑以通为用”、“胆病从肝论治”的治疗原则，具有疏肝利胆、清热通下的功效，是首个“功能主治”均被欧美国家认可的复方中药；正气片处方源于宋代《太平惠民和剂局方》中的藿香正气方，具有发散风寒、化湿和中之功效，用于伤风感冒、头痛胸闷、吐泻腹胀，是治疗胃肠型感冒的经典药物。尽管加拿大的药品市场逊于美国，但中药在加拿大获得上市许可绝非易事。据资料显示，加拿大是世界卫生组织认定的严格监管机构（SRA）国家之一，在上市前审批、上市途径申请、GMP及专论要求等方面都有着比美国与欧盟更为严苛的标准；提出申请的企业及产品必须同时通过生产质量管理、药品安全性、药品有效性等多方面、多层次的审查，要获得加拿大卫生部的天然药品产品许可证绝非易事。2款中药成功出口的经验，无疑进一步助力和黄药业迈向出海2.0时代，越来越多的优质中药有望加速面世，惠及全球更多患者。推动传统中药现代化看到如今的“中药出海”先行者——和黄药业如此出圈，这还得从它的前身——上海中药制药一厂40余年的发展历程说起。上海中药制药一厂建于1958年，由沪上4家百年药店雷允上、胡庆余、童涵春、蔡同德合并而成，是一家具有优良传统、丰富经验、剂型全面、技术领先的老牌中药企业。经过40余年的发展，上海中药制药一厂获得的成绩斐然，尤其是麝香保心丸、胆宁片等明星产品的面世，为后来和黄药业的“传承精华、守正创新”中药研发之路夯实了基础。在传承经典中药产品的道路上，依托和记黄埔强大的技术研发实力，和黄药业自建立以来（2001年），不断应用国际先进的科学技术和方法，对传统中药产品进行二次开发，如麝香保心丸指纹图谱技术、促进治疗性血管新生效果的发现、胆宁片脂肪肝适应症的扩展等；在传承的基础上不断创新，进一步阐明了复方中药的药效物质基础、作用机理和临床疗效，建立了现代中药全面质量控制体系，为中药现代化和国际化开创了崭新局面。目前，和黄药业还积极与国内著名科研院校共同开展以项目为纽带的科研合作，增强中医药学术含量，聚焦糖尿病及肥胖、老年疾病、免疫调节、消化系统、心血管等领域的新药开发，积极寻找有发展潜力的中药，进一步推动传统中药走向现代化。来源：米内网数据库、公司官网等注：米内网《中国公立医疗机构药品终端竞争格局》，统计范围是：中国城市公立医院、县级公立医院、城市社区中心以及乡镇卫生院，不含民营医院、私人诊所、村卫生室；米内网《中国城市实体药店药品终端竞争格局》，统计范围是：全国地级及以上城市实体药店，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。本文为原创稿件，转载请注明来源和作者，否则将追究侵权责任。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●温馨提示●因为微信公众号修改了推送规则，最近很多读者反映没有及时看到推文。把米内网设为“星标”，就能每天与我们不见不散啦，具体操作如下：【分享、点赞、在看】点一点不失联哦

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100 项与 SHPL-49 相关的药物交易

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