Protamine sulfate is a standard agent used to reverse heparin anticoagulation during cardiovascular procedures such as coronary artery bypass grafting (CABG). Although rare, it can be associated with severe adverse reactions. We present a case of a 68-year-old male with type 2 diabetes, who was on insulin lispro protamine and underwent elective CABG. Shortly after protamine administration to reverse heparin during extracorporeal circulation (ECC), the patient experienced anaphylactic shock, manifesting as tachycardia, hypotension, facial flushing, periorbital edema, and elevated serum tryptase levels. Despite prompt treatment with volume resuscitation, epinephrine, and corticosteroids, the patient's condition remained unstable, necessitating a second period of ECC for additional bypass grafting. The case contributes to the clinical literature by providing an illustrative example of how protamine hypersensitivity can complicate postoperative recovery, emphasizing the importance of vigilance and comprehensive management strategies in preventing and addressing such reactions.

2023-04-01·International endodontic journal

25‐Hydroxycholesterol induces odontoclastic differentiation through RANK–RANKL upregulation and NF‐κB activation in odontoblast‐like MDPC‐23 cells: An in vitro study

Article

作者: Lim, HyangI ; Oh, Ji‐Su ; Kim, Jae‐Sung ; Kang, Kyeong‐Rok ; Yu, Sun‐Kyoung ; Kim, Do Kyung ; Park, Joo‐Cheol ; Kim, Heung‐Joong ; Seo, Jeong‐Yeon

Abstract:

Aim:

The physiological effects and cellular mechanism of 25‐hydroxycholesterol (25‐HC), which is an oxysterol synthesized from cholesterol by cholesterol‐25‐hydroxylase (CH25H) expressed under inflammatory conditions, are still largely unknown during odontoclastogenesis. This study aimed to evaluate 25‐HC‐induced odontoclastogenesis and its cellular mechanisms in odontoblast‐like MDPC‐23 cells.

Methodology:

To investigate 25‐HC‐induced odontoclastogenesis of MDPC‐23 cells and its cellular mechanism, haemotoxylin and eosin staining, tartrate‐resistant acid phosphatase (TRAP) staining, dentine resorption assay, zymography, reactive oxygen species (ROS) detection, immunocytochemistry, and nuclear translocation were performed. The experimental values are presented as mean ± standard deviation and were compared using analysis of variance, followed by post hoc multiple comparisons (Tukey's test) using SPSS software version 22 (IBM Corp.). A p‐value <.05 was considered statistically significant.

Results:

Lipopolysaccharide or receptor activator of nuclear factor‐κB ligand (RANKL) induced the synthesis of 25‐HC via the expression of CH25H in MDPC‐23 cells (p < .01). Multinucleated giant cells with morphological characteristics and TRAP activity of the odontoclast were increased by 25‐HC in MDPC‐23 cells (p < .01). Moreover, 25‐HC increased dentine resorption through the expression and activity of matrix metalloproteinases in MDPC‐23 cells. It not only increased the expression of odontoclastogenic biomarkers but also translocated cytosolic nuclear factor‐κB (NF‐κB) to the nucleus in MDPC‐23 cells. Additionally, 25‐HC not only increased the production of ROS (p < .01), expression of inflammatory mediators (p < .01), pro‐inflammatory cytokines, receptor activator of NF‐κB (RANK), and RANKL but also suppressed the expression of osteoprotegerin (OPG) in MDPC‐23 cells. In contrast, CDDO‐Me, a chemical NF‐κB inhibitor, decreased TRAP activity (p < .01) and downregulated the expression of the odontoclastogenic biomarkers, including RANK and RANKL, in MDPC‐23 cells.

Conclusion:

25‐HC induced odontoclastogenesis by modulating the RANK–RANKL–OPG axis via NF‐κB activation in MDPC‐23 cells. Therefore, these findings provide that 25‐HC derived from cholesterol metabolism may be involved in the pathophysiological etiological factors of internal tooth resorption.

2022-08-01·Clinical and experimental pharmacology & physiology

Expression of anti and pro‐inflammatory genes in human endothelial cells activated by 25‐hydroxycholesterol: A comparison of rivaroxaban and dabigatran

Article

作者: Broncel, Marlena ; Pawlos, Agnieszka ; Gorzelak‐Pabiś, Paulina ; Woźniak, Ewelina ; Wojdan, Katarzyna

Abstract:

Atherosclerosis is associated with a haemostatic imbalance characterized by excessive activation of pro‐inflammatory and pro‐coagulant pathways. Non‐vitamin K antagonists oral anticoagulant (NOACs) may reduce the incidence of cardiovascular events, cerebral ischemia, thromboembolic events and atherosclerosis. Chronic inflammation, vascular proliferation and the development of atherosclerosis is also influenced by 25‐hydroxycholesterol (25‐OHC). The aim of the study was to assess the effect of rivaroxaban and dabigatran on the messenger RNA (mRNA) expression of anti‐inflammatory cytokines transforming growth factor β (TGF‐β), interleukin (IL)‐37, IL‐35 as well as of pro‐inflammatory cytokines IL‐18 and IL‐23, in endothelial cells damaged by 25‐OHC. Human umbilical vascular endothelial cells (HUVECs) were treated with 25‐OHC (10 μg/mL), rivaroxaban (100, 500 ng/mL), dabigatran (100, 500 ng/mL), 25‐OHC + rivaroxaban, and 25‐OHC + dabigatran. The mRNA expression of TGF‐β, IL‐37, IL‐35 subunits EBI3 and p35, IL‐18, and IL‐23 was analysed using real‐time polymerase chain reaction (PCR). The results showed that 25‐OHC decreased TGF‐β and IL‐37 mRNA expression and increased EBI3, p35, IL‐18, IL‐23 mRNA expression in endothelial cell as compared to an untreated control (P < .05). Messenger RNA expression of TGF‐β and IL‐37 significantly increased following stimulation with rivaroxaban and dabigatran as compared to an untreated control (P < .01). In HUVECs pre‐treated with oxysterol, rivaroxaban and dabigatran increased mRNA expression of TGF‐β, IL‐37 and decreased mRNA expression of EBI3, p35, IL‐23 and IL‐18 as compared to 25‐OHC (P < .01). Our finding suggests that both rivaroxaban and dabigatran inhibit the inflammatory activation caused by oxysterol in vitro.

项与精蛋白锌重组赖脯胰岛素生物类似药 (25R) (甘李药业) 相关的新闻（医药）

2024-01-02

·BioSpace

Inventprise Completes Vaccination of Participants in a Phase 2 Dose Ranging Study of its 25 Valent Pneumococcal Vaccine Candidate

The 25 valent pneumococcal conjugate vaccine is designed to broaden protection against life-threatening childhood pneumonia and other serious pneumococcal diseases. REDMOND, Wash.--(BUSINESS WIRE)-- Biotechnology company Inventprise Inc.n today announced the completion of vaccination in their Phase 2 dose ranging study of its 25-valent pneumococcal conjugate vaccine (IVT PCV-25) in young adults. The study is being conducted in four sites in Canada. This Phase 2 study is an important step in the efforts to develop an affordable, expanded-coverage pneumococcal conjugate vaccine (PCV). This vaccine is designed to help prevent pneumococcal disease caused by serotypes not covered in the current PCVs and to help provide protection to people globally, including in low- and middle-income regions where the pneumococcal disease burden is greatest. As a leading cause of deadly childhood pneumonia, sepsis, meningitis, and debilitating middle-ear infections, the pneumococcus bacterium is responsible for an estimated 300,000 deaths per year in children less than five years of age worldwide. Adults over the age of 65 and people with preexisting health problems are also at risk for pneumonia. PCVs are lifesaving tools for children and older adults and PCVs approved for use in these age groups currently cover 10 to 20 pneumococcal varieties (or serotypes), but do not include some important disease-causing serotypes. The Inventprise PCV includes 25 serotypes—expanding the potential to prevent several deadly and emerging serotypes not yet addressed by existing PCVs. Sponsored by Inventprise and conducted in collaboration with the international nonprofit organization PATH, Canadian Center for Vaccinology (Halifax), Vaccine Evaluation Center (British Columbia), Colchester Research Group (Nova Scotia) and Centre de recherche Saint-Louis (Quebec), this Phase 2 study is evaluating three different dose levels of IVT PCV‑25 compared to Prevnar20®, in 220 young adults aged 18-49 years. Endpoints include solicited and unsolicited adverse events, along with both binding and functional antibody responses. Satisfactory results in this adult population will support initiation of Phase 2 study in infants, planned for midyear 2024. A Phase 2 study in older adults is also planned to take place in the second half of 2024. Inventprise is producing the IVT PCV-25 vaccine at its new, highly automated manufacturing facilities in Washington State. Funding for development of IVT PCV-25 has been achieved with support from the Bill & Melinda Gates Foundation. “PCVs are the world’s most complex vaccines and increasing the number of serotypes and manufacturing capacity has been challenging since conjugate vaccines were first developed,” says Yves Leurquin, President & CEO, Inventprise. “With this 25-valent PCV, we have worked to overcome many of the challenges by optimizing formulations and manufacturing processes to enhance immune responses and enable higher coverage for children worldwide. We are looking forward to moving ahead to evaluation in infants,” says Dr. Subhash Kapre, Executive Chairman, Inventprise. “This study was designed to evaluate safety and antibody responses following single doses of three different formulations of IVT PCV-25 in young adults to pave the way for future studies in infants and older adults. In Canada, as well as elsewhere in the world, there continues to be significant rates of disease due to serotypes not covered in licensed vaccines so we are very interested in the potential for broader coverage,” says Dr. Joanne Langley, the study’s principal investigator at the Canadian Center for Vaccinology. About Inventprise Inc. Inventprise is a biopharmaceutical company leveraging its innovative platform technology to develop vaccines against infectious diseases with an initial focus on invasive pneumococcal disease. Inventprise platform technologies are designed to enable high valent vaccines to induce broad, robust, and durable protection against pathogenic strains of infectious diseases. Inventprise has a robust pipeline of investigational vaccines including candidates to prevent group B streptococcus (GBS) and Shigella. Inventprise was founded by Subhash Kapre, PhD in 2012 to advance novel, affordable and highly impactful vaccines using proprietary technology, with the initial goal of providing lifesaving interventions globally, including to low and middle-income countries. Inventprise maintains facilities in Redmond and Woodinville, Washington. View source version on businesswire.com: Contacts For Media Inquiries Ph. +1 425-708-8699 media@inventprise.com Source: Inventprise Inc. View this news release online at:

疫苗临床2期

2022-08-01

·Insight数据库

无需注射的严重低血糖疗法！礼来高血糖素鼻用粉雾剂国内报上市

8 月 1 日，据 CDE 官网显示，礼来高血糖素鼻用粉雾剂的上市申请获受理（受理号：JXHS2200063）。来自：CDE 官网礼来 Baqsimi 国内报上市Baqsimi（胰高血糖素）鼻粉剂最早于 2019 年 7 月获 FDA 批准上市，用于 4 岁及以上糖尿病患者严重低血糖的紧急治疗，成为首个批准用于紧急治疗严重低血糖的胰高血糖素疗法，无需注射即可给药。今日，Baqsimi 在国内的申报上市申请获受理。严重低血糖是指患者血糖水平下降到某一水平，出现困惑或失去知觉，或出现其他需要他人帮助治疗的症状。严重低血糖通常发生在使用胰岛素治疗的糖尿病患者身上。此前市面上已有许多产品针对需要胰岛素的患者，但发生严重低血糖症时，通常的做法是先用胰高血糖素注射剂进行治疗。Baqsimi 是一种鼻粉剂，使用喷雾器通过鼻腔给药，与注射剂相比，此种给药方式可能会简化治疗过程，这在严重低血糖发作期间可能是至关重要的，特别是患者可能失去意识或可能癫痫发作。Baqsimi 通过刺激肝脏将储存的葡萄糖释放到血液中来增加体内的血糖水平，具有与胰岛素相反的作用，而胰岛素是降低血糖水平。礼来曾披露的 2 项研究评估了 Baqsimi 鼻粉剂胰高血糖素治疗严重低血糖的疗效和安全性。这 2 项研究分别入组 83 例和 70 例糖尿病患者，比较了单剂量 Baqsimi 与单剂量胰高血糖素注射治疗对胰岛素诱导低血糖的血糖反应。结果显示，Baqsimi 能充分提高血糖水平。而在一项入组了 48 例年龄在 4 岁以上 1 型糖尿病患者的儿科研究中，也观察到了相似结果。研究中，与 Baqsimi 相关的最常见的不良反应是恶心、呕吐、头痛、上呼吸道刺激、水眼、眼睛发红和瘙痒。Baqsimi 的副作用类似于注射用胰高血糖素，由于给药方式的不同，还会出现鼻和眼相关症状，如眼睛湿润和鼻塞。需要注意的是，Baqsimi 不能用于嗜铬细胞瘤（一种罕见的肾上腺组织肿瘤）患者或胰岛瘤（一种胰腺肿瘤）患者，也不能用于已知对胰高血糖素或 Baqsimi 中非活性成分过敏的患者，因为可能导致过敏反应。Baqsimi 的药品标签中附有一则警告信息，提示对于长期禁食、肾上腺功能不全或长期低血糖的患者，应谨慎使用 Baqsimi，因为这些情况会导致肝脏中可释放的葡萄糖水平较低。糖尿病领域礼来布局 5 款重磅产品当前，礼来在糖尿病领域布局有多款重磅产品。据礼来 2021 财报显示，2021 年礼来销售额 TOP 15 的产品中就有 5 款为糖尿病药物。分别为度拉糖肽、重组赖脯胰岛素、重组人胰岛素、恩格列净以及甘精胰岛素。来自：Insight 整理度拉糖肽注射液度拉糖肽注射液是一款每周注射 1 次的长效 GLP-1 受体激动剂，2014 年 9 月获 FDA 批准上市。在国内，度拉糖肽于 2019 年 2 月首次获批上市，适用于成人2型糖尿病患者的血糖控制，包括单药以及接受二甲双胍和/或磺脲类药物治疗血糖仍控制不佳的患者。度拉糖肽注射液国内开发进度甘特图来自：Insight 数据库网页版（点击放大，可查看大图）作为礼来的一款糖尿病明星产品，度拉糖肽自上市以后表现出不凡的市场竞争能力。度拉糖肽（Trulicity）在 2021 年第 4 季度全球销售额 18.84 亿美元，同比增长 25%；全年收入 64.72 亿美元，同比增长 28%。截至 2021 年 12 月，度拉糖肽在美国市场的注射 GLP-1 总处方量份额占到近 48%，较之 2020 年增长了 35%，快于市场平均增幅。重组赖脯胰岛素重组赖脯胰岛素是一种新型的胰岛素类似物，起效快，作用持续时间更短，更符合生理餐时的胰岛素分泌曲线，其制剂重组赖脯胰岛素注射液、精蛋白锌重组赖脯胰岛素混合注射液 (25R) 和精蛋白锌重组赖脯胰岛素混合注射液 (50R) 均能更好地控制血糖，并减少低血糖的发生。礼来的重组赖脯胰岛素注射液商品名为优泌乐（Humalog），最早于 1996 年 4 月获 FDA 批准上市，用于治疗糖尿病。2005 年，优泌乐在国内获批上市。精蛋白锌重组赖脯胰岛素混合注射液（25R），商品名为优泌乐 25（HumalogMix25），于 1999 年 12 月由 FDA 批准用于治疗糖尿病，2010 年在国内上市。精蛋白锌重组赖脯胰岛素混合注射液（50R），商品名为优泌乐 50（HumalogMix50），于 1999 年 12 月由 FDA 批准用于治疗糖尿病，2008 年在国内上市。重组赖脯胰岛素近年销售额虽以个位数比例逐年缓慢下滑，但目前仍为礼来带来巨大的营收，成为 2021 年礼来销售额 TOP2 产品。恩格列净恩格列净（Jardiance）是礼来和勃林格殷格翰合作一款 SGLT-2 抑制剂，于 2017 年首次在国内获批上市，用于治疗成人 2 型糖尿病患者。此后，于今年 6 月，恩格列净新适应症获批上市，用于治疗伴或不伴糖尿病、射血分数降低的成人心力衰竭患者。恩格列净国内项目概览来自：Insight 数据库网页版（点击放大，可查看大图）恩格列净 2021 年 Q4 实现全球收入 4.32 亿美元（+38%），全年实现收入 14.91 亿美元（+29%），这些增长主要源于需求的增长。甘精胰岛素礼来甘精胰岛素（商品名：Basaglar）是来得时（赛诺菲，甘精胰岛素 [rDNA 来源] 注射液）的生物类似药，两者均为适用于糖尿病治疗的长效人胰岛素类似物。Basaglar 的一级氨基酸序列与来得时的活性成分相同，且与来得时的剂型相同。其与人胰岛素的不同之处在于，胰岛素 A 链的 1 处氨基酸被取代（A21 位置天冬酰胺被甘氨酸取代）以及 B 链 C-末端加入 2 个精氨酸。与传统胰岛素相比，长效胰岛素类似物（甘精胰岛素）比中效胰岛素（NPH）等既往药物治疗提供更多的获益，包括降低夜间的低血糖发生率、更好的空腹血糖控制并改善生活质量。Basaglar（甘精胰岛素）100units/mL 于 2014 年 09 月首次获得欧洲药品管理局的上市授权。目前已在 87 个国家获得上市授权，包括欧盟（包括欧洲经济区）、美国、加拿大、澳大利亚、日本和瑞士等。目前，在欧美市场，甘精胰岛素注射液的主要供货商除原研厂商赛诺菲外，礼来的Basaglar 也占据一定的市场，据礼来财报显示，Basaglar 2021 年的全球销售额也有 8.93 亿美元。点击以下卡片进入 Insight 小程序查看「礼来」产品管线免责声明：本文仅作消息分享，并不构成投资建议，也不代表 Insight 数据库的立场，文章观点仅供分享行业见解，请广大投资者谨慎。编辑：HebePR 稿对接：微信 insightxb投稿：微信 insightxb；邮箱 insight@dxy.cn点击阅读原文免费试用 Insight 数据库

财报生物类似药

100 项与精蛋白锌重组赖脯胰岛素生物类似药 (25R) (甘李药业) 相关的药物交易

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