作者: Shi, Rui ; Monnet, Xavier ; Donadello, Katia ; Fouqué, Gaelle ; Bruscagnin, Chiara ; Rosalba, Daniela ; Teboul, Jean-Louis ; Lai, Christopher ; Pham, Tài ; Hagry, Julien

BACKGROUNDTo detect preload responsiveness in patients ventilated with a tidal volume (Vt) at 6 mL/kg of predicted body weight (PBW), the Vt-challenge consists in increasing Vt from 6 to 8 mL/kg PBW and measuring the increase in pulse pressure variation (PPV). However, this requires an arterial catheter. The perfusion index (PI), which reflects the amplitude of the photoplethysmographic signal, may reflect stroke volume and its respiratory variation (pleth variability index, PVI) may estimate PPV. We assessed whether Vt-challenge-induced changes in PI or PVI could be as reliable as changes in PPV for detecting preload responsiveness defined by a PLR-induced increase in cardiac index (CI) ≥ 10%.METHODSIn critically ill patients ventilated with Vt = 6 mL/kg PBW and no spontaneous breathing, haemodynamic (PICCO₂ system) and photoplethysmographic (Masimo-SET technique, sensor placed on the finger or the forehead) data were recorded during a Vt-challenge and a PLR test.RESULTSAmong 63 screened patients, 21 (33%) were excluded because of an unstable PI signal and/or atrial fibrillation and 42 were included. During the Vt-challenge in the 16 preload responders, CI decreased by 4.8 ± 2.8% (percent change), PPV increased by 4.4 ± 1.9% (absolute change), PI_finger decreased by 14.5 ± 10.7% (percent change), PVI_finger increased by 1.9 ± 2.6% (absolute change), PI_forehead decreased by 18.7 ± 10.9 (percent change) and PVI_forehead increased by 1.0 ± 2.5 (absolute change). All these changes were larger than in preload non-responders. The area under the ROC curve (AUROC) for detecting preload responsiveness was 0.97 ± 0.02 for the Vt-challenge-induced changes in CI (percent change), 0.95 ± 0.04 for the Vt-challenge-induced changes in PPV (absolute change), 0.98 ± 0.02 for Vt-challenge-induced changes in PI_forehead (percent change) and 0.85 ± 0.05 for Vt-challenge-induced changes in PI_finger (percent change) (p = 0.04 vs. PI_forehead). The AUROC for the Vt-challenge-induced changes in PVI_forehead and PVI_finger was significantly larger than 0.50, but smaller than the AUROC for the Vt-challenge-induced changes in PPV.CONCLUSIONSIn patients under mechanical ventilation with no spontaneous breathing and/or atrial fibrillation, changes in PI detected during Vt-challenge reliably detected preload responsiveness. The reliability was better when PI was measured on the forehead than on the fingertip. Changes in PVI during the Vt-challenge also detected preload responsiveness, but with lower accuracy.

2024-07-03·British Journal of Neurosurgery4区 · 医学

The effect of anti-thrombotics on the postoperative bleeding rate in patients undergoing craniotomy for brain tumor

4区 · 医学

Article

作者: Guzman, Raphael ; Ullmann, Muriel ; Mariani, Luigi ; Soleman, Jehuda

OBJECTIVEThe peak prevalence of many brain tumors is in elderly patients. These patients are often treated with platelet inhibitors (PIs) or anticoagulants (ACs), creating a challenge for neurosurgeons concerning the perioperative management. The aim of this study is to analyze the effect of PI/AC treatment on the postoperative bleeding rates in patients undergoing craniotomy due to a brain tumor.METHODSRetrospective analysis of 415 consecutive patients undergoing craniotomy/craniectomy due to a brain tumor. Ninety-nine patients with PI/AC treatment (PI/AC group consisting of 64 PI, 29 AC, and six multiple) and 316 patients without PI/AC (control group) were primarily compared for hemorrhage rate. Secondary outcome measures were clinical outcome and mortality. The association between short preoperative discontinuation (≤5 days), early postoperative resumption time (≤5 days), as well as short total discontinuation time (≤5 days) of PI/AC and postoperative bleeding rates was analyzed.RESULTSPostoperative bleeding rates were comparable between the groups (12.2% and 13.5% in the PI/AC and control group, respectively; p=.74). The majority of bleeds were asymptomatic (85.2%). No significant difference in the postoperative mortality rate was observed (1.0% and 1.6% in the PI/AC and the control group, respectively; p=.67). Shorter discontinuation time of PI/AC was not significantly associated with higher postoperative bleeding rates (preoperative: 12.1% vs. 12.3%; p=.94, postoperative: 11.1% vs. 12.5%, respectively; p=.87, total: 16.7% vs. 12%, respectively; p=.73).CONCLUSIONSPatients treated with PI/AC undergoing craniotomy for the resection of brain tumor do not seem to have increased rates of postoperative bleeding or mortality. We did not find a significant correlation between short discontinuation time of PI/AC in the perioperative period and postoperative bleeding.

2024-07-01·Journal of Cataract & Refractive Surgery

In vivo assessment of antimicrobial activity and toxicity of repeated 1% povidone–iodine applications vs a single 5% povidone–iodine application

Article

作者: Hajj, Abeer ; Teren, David ; Abulafia, Adi ; Assayag, Elishai ; Shwartz, Orna ; Gelman, Evgeny ; Neuman, Gil ; Zadok, David

Purpose:To demonstrate the noninferiority in antimicrobial effectiveness of thrice-repeated applications of 1% povidone–iodine (PI) compared with a single application of 5% PI on the ocular surface in vivo and to evaluate potential toxicity of PI to the corneal epithelium.Setting:Department of Ophthalmology, Shaare Zedek Medical Center, Jerusalem, Israel.Design:Prospective, randomized, double-blind study.Methods:Patients randomly received either a single application of 5% PI or repeated irrigations of 1% PI on the ocular surface preoperatively. Bacterial colony counts were quantitatively analyzed by taking standardized conjunctival swabs before and after irrigation, and differences in bacterial colony counts were compared between the 2 groups. The presence of superficial punctate keratopathy was evaluated in all patients by the National Eye Institute grading system.Results:The study comprised 102 eyes of 102 patients. Both 1% and 5% PI yielded a marked decrease in bacterial colonies compared with before application (P < .001). The repeated application of 1% PI showed a significantly lower bacterial count compared with the single application of 5% PI (P < .05) and resulted in significantly less damage to the corneal epithelium compared with a single 5% PI application (P < .001).Conclusions:Preoperative repeated applications of 1% PI effectively eradicated ocular surface bacteria equal to that of 5% PI with a less deleterious effect on the corneal epithelium. Our findings suggest that 1% PI may be a promising alternative to 5% PI.

项与 Pi 相关的新闻（医药）

2023-10-10

·CPHI制药在线

一文掌握国内双抗赛道研发进展

关注并星标CPHI制药在线双特异性抗体（BsAb，简称"双抗"）是通过细胞融合、重组DNA、蛋白质工程等技术制备的人工抗体，能够同时或先后特异性结合2种抗原或同一抗原的两个不同表位。与单抗相比，双抗通过双靶点信号阻断，能够防止耐药、介导更强的内吞作用等。鉴于双抗特有的优势，杀入双抗赛道的玩家越来越多。据公开数据统计，双抗相关临床试验数量以每年20.44%的速度持续增长。截至目前，全球已批准13款双抗上市。今年，双抗领域有哪些新的进展？全球已获批上市双抗产品（来源：公开资料） 2023年新获批双抗药物 2023年以来，共获批4款双抗药物。2023年5月19日，艾伯维与Genmab宣布，FDA批准其双抗新药Epcoritamab（商品名：Epkinly）上市，用于治疗复发或难治性弥漫大B细胞淋巴瘤，这是一款CD3/CD20双抗药物，能够同时靶向B细胞上的CD20蛋白和T细胞上的CD3蛋白，达到对CD20阳性的癌细胞杀伤的目的。 2023年6月15日，FDA批准罗氏的Glofitamab（商品名：Columvi）获批上市，用于复发性或难治性弥漫性大B细胞淋巴瘤（DLBCL），或起源于滤泡性淋巴瘤的大B细胞淋巴瘤（LBCL）成年患者，患者接受过二线或二线以上全身治疗，Epcoritamab是FDA批准的罗氏第2款CD3/CD20双抗。 2023年8月10日，FDA批准强生的双抗Talquetamab（商品名：Talvey）上市，用于先前至少接受过4种治疗（包括蛋白酶体抑制剂、免疫调节剂和CD38抗体）的复发或难治性多发性骨髓瘤（MM）成人患者。 Talquetamab是一款GPRC5D/CD3双抗。GPRC5D（G蛋白偶联受体C5家族亚型D）是一种在MM浆细胞表面高度表达的孤儿受体，其过度表达与MM患者的不良预后和肿瘤负荷密切相关，且与B细胞成熟抗原（BCMA）彼此独立表达，是继BCMA后下一个复发/难治性MM的强势靶点。 Talquetamab能够激活带有CD3受体的T细胞，并诱导其杀伤GPRC5D表达阳性的MM肿瘤细胞，发挥抗肿瘤作用。 2023年8月14日，FDA批准辉瑞的Elranatamab（商品名：Elrexfio）用于治疗复发性或难治性MM患者，这些患者之前接受过至少4种疗法，包括蛋白酶体抑制剂(PI)、免疫调节剂(IMiD) ，和抗CD38单克隆抗体。 Elranatamab是一种人源化IgG2a T细胞接合双特异性抗体，旨在靶向在肿瘤细胞上高表达的BCMA和T细胞表面的CD3。 2023年国内双抗企业融资情况除了已获批上市4款双抗药物外，今年以来，双抗赛道也产生了多笔融资，据不完全统计，2023年至今，国内双抗赛道有20余家完成融资。2023年国内双抗企业融资情况（来源：公开资料）双抗赛道新进展在资本的推动下，国内双抗赛道迎来了一些新进展。再鼎的特泊利单抗（Tebotelimab，MGD013）是一款靶向PD-1和LAG-3的双抗，能够同时阻断PD-1和LAG-3信号通路，以维持或恢复耗竭T细胞的功能。可用于治疗头颈部鳞状细胞癌、胃癌、乳腺癌、弥散性大B细胞淋巴瘤等。特泊利单抗原研由MacroGenics研发，2018年11月，再鼎医药与MacroGenics达成合作，获得Tebotelimab在大中华区独家开发及商业化授权。在今年公布的Tebotelimab对于既往靶向治疗和/或免疫治疗失败的晚期肝细胞癌（aHCC）患者的研究中，有13例患者在剂量递增阶段接受了Tebotelimab治疗，结果未观察到剂量限制毒性；研究中的客观缓解率（ORR）为3.3%，疾病控制率（DCR）为50.0%。免疫检查点抑制剂（ICI）经治组的缓解持续时间（DOR）为9.2个月，在ICI初治组仅有4例患者有反应，中位DOR为5.8个月。ICI经治组和ICI初治组的中位无进展生存（PFS）分别为2.4个月和3.1个月，两组均未达到中位总生存期（OS）。康宁杰瑞的 Elranatamab (KN046)是一种人源化IgG2a T细胞结合双抗，其靶向肿瘤细胞高表达的BCMA和T细胞表面的CD3。Elranatamab原研由辉瑞开发，用于治疗复发或难治性MM患者。 Elranatamab曾被FDA和EMA授予用于治疗MM的孤儿药认证。此外，FDA还授予了Elranatamab用于复发或难治性MM的快速通道和突破性疗法认证，EMA授予了Elranatamab用于复发或难治性MM的PRIME认证。今年上半年获得两轮融资的企业益科思特，其基于公司独有的FIST平台，设计出靶向CD3和CD19，适应症为非霍奇金淋巴瘤、复发或难治性前体B细胞急性淋巴细胞白血病(ALL)的双抗药物YK012，该药物于今年5月正式启动I期临床研究。绿竹生物基于其Fabite技术平台，开发了K193及K333双抗产品。其中K193是一款靶向CD19/CD3的双抗，正在国内进行I期临床研究，预计今年第四季度完成I期临床研究；计划于2027年第四季度完成II期临床试验，并于2027年向CDE提交NDA。K333是一款靶向CD33/CD3的双抗，目前正在进行临床前研究。自1960年Nisonoff等首次提出双抗的概念以来，双抗就成为了科学家们追逐的一个梦想。随着单克隆抗体技术，基因工程技术以及各类双抗平台的出现，目前无论是国内还是海外，双抗市场规模均呈现出飞速发展的趋势，未来双抗研发领域将迎来越来越多的临床突破。参考来源： 1. U.S. Food and Administration. FDA grants accelerated approval to epcoritamab-bysp for relapsed or refractory diffuse large B-cell lymphoma and high-grade B-cell lymphoma. Accessed May 24, 2023. 2. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-talquetamab-tgvs-relapsed-or-refractory-multiple-myeloma. 3.https://investors.pfizer.com/Investors/News/news-details/2023/Pfizers-ELREXFIO-Receives-U.S.-FDA-Accelerated-Approval-for-Relapsed-or-Refractory-Multiple-Myeloma/default.aspx. 4.https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/761309s000lbl.pdf. 扫码参与制药在线周年庆游园会来源：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~

上市批准免疫疗法

2023-07-31

·PRNewswire

U.S. FDA Accepts Biologics License Application for GC Biopharma's GC5107B (Immune Globulin Intravenous (Human), 10% Liquid)

YONGIN, South Korea, July 31, 2023 /PRNewswire/ -- GC Biopharma (006280.KS), a global biopharmaceutical company dedicated to specialty plasma-derived therapeutics, today announced that the U.S. Food and Drug Administration (FDA) has accepted the Company's resubmission of the Biologics License Application (BLA) for its GC5107B (Immune Globulin Intravenous (Human) for patients with primary humoral immunodeficiency (PI). The Prescription Drug User Fee Act (PDUFA) target action date is January 13, 2024. If approved, GC Biopharma would be able to provide more treatment options for patients with PI in the U.S. GC Biopharma aims to enter the U.S. market in the second half of 2024 if GC5107B is approved by the FDA as anticipated. While the U.S. immunoglobulin market size is estimated at about US$ 10.4 billion in 2022 (as per MRB[1] 2022), there have been sporadic shortages as there are only a small number of immunoglobulin manufacturers considering the need for a massive investment in facility and sophisticated production know-hows. About GC5107B GC5107B is a liquid solution containing 10% immunoglobulin G (100 mg/mL) for intravenous infusion, manufactured from pooled human plasma from US donors. The manufacturing process includes three steps to reduce the risk of virus transmission. The steps are "Fractionation I+III, solvent/detergent (S/D) treatment, and Nanofiltration." About Primary H umoral Immunodeficiency Primary humoral immunodeficiency disease comprises a large, heterogenous group of disorders resulting from inborn errors of immunity. Patients with PI are unable to mount an immune response to pathogens and can experience recurrent bacterial, viral, fungal, and protozoal infections as a result. Global estimates project that up to 6 million people may be living with PI, but only 650,000 people worldwide have been diagnosed[2],[3],[4]. About GC Biopharma GC Biopharma (formerly known as Green Cross Corporation) is a biopharmaceutical company that delivers life-saving and life-sustaining protein therapeutics and vaccines. Headquartered in Yongin, South Korea, GC Biopharma is one of the leading plasma protein and vaccine product manufacturers globally and has been dedicated to quality healthcare solutions for more than half a century. This press release may contain forward-looking statements, which express the current beliefs and expectations of GC Biopharma's management. Such statements do not represent any guarantee by GC Biopharma or its management of future performance and involve known and unknown risks, uncertainties and other factors. GC Biopharma undertakes no obligation to update or revise any forward-looking statement contained in this press release or any other forward-looking statements it may make, except as required by law or stock exchange rule. GC Biopharma Contacts (Media) Sohee Kim [email protected] Yelin Jun [email protected] SOURCE GC Biopharma

免疫疗法

2023-07-28

·CPHI制药在线

Carvykti持续发力，CAR-T赛道会见证下一个传奇生物吗？

关注并星标CPHI制药在线近期强生发布了半年报，其中与传奇生物合作的CAR-T疗法Carvykti二季度销售额1.17亿美元，加上一季度的0.72亿美元销售额，上半年Carvykti合计销售收入达到1.89亿美元。作为第二款获批上市靶向BCMA（ B cell maturation antigen，B细胞成熟抗原）CAR-T疗法，Carvykti已经在欧美日完成商业化，今年Carvykti有望实现4.65亿美元销售收入。作为传奇生物现有的唯一一款商业化产品，Carvykti的利好消息迅速推动传奇生物的市值不断上扬，目前已经站上千亿人民币市值，给足了市场期待。作为Carvykti的靶点，BCMA在恶性浆细胞中高表达，在正常组织细胞（除浆细胞和部分成熟 B 细胞）和 CD34+干细胞上不表达，这使得其成为多发性骨髓瘤的靶向位点，从2020年8月GSK公司ADC Blenrep在获FDA批准上市开始（2022年11月宣布撤市），BCMA靶点随后又迎来了两款CAR-T疗法：2021年3月获批的Abecma（BMS/Bluebird）和Carvykti（强生/传奇）以及一款BCMA/CD3双特异性抗体teclistamab（强生），以上四款靶向BCMA的药物无一例外，适应症均为末线治疗多发性骨髓瘤。在过去二十年中，多发性骨髓瘤患者的治疗结局得到了显著改善，但其仍然是一种无法治愈的疾病，全球患者也面临着迫切的临床需求，所以 Blenrep（撤市前）、Abecma以及Carvykti（teclistamab目前销售额还未披露）的销售数据表现都算不错，其中Carvykti和Abecma的快速放量，在细胞疗法商业化困难的模式中，更显得难为可贵，BCMA见证了千亿传奇的诞生，那么下一站传奇又在何处呢？ 01Abecma和Carvykti的全面竞速战多发性骨髓瘤是全球第二大最常见的血液恶性肿瘤，血液瘤中发病率仅次于弥漫性大B细胞淋巴瘤。受限于现有治疗手段，目前多发性骨髓瘤仍无法治愈，几乎所有患者接受标准治疗后会出现复发或难治，针对多发性骨髓瘤的治疗主要目的为延长患者生存时间，及改善其生活质量。多发性骨髓瘤治疗发展总体分为两个阶段，免疫调节剂 (IMiDs)和蛋白酶体抑制剂 (PI)两类药物的面世，改变了传统化疗格局，开创靶向免疫治疗时代。全球已有数十款针对MM的治疗的上市药物，更多的创新药品种也不断涌现，目前末线治疗多发性骨髓瘤创新技术产品基本落在双抗、CAR-T以及ADC药物之上，Carvykti和Abecma自然会直接展开竞争。图：Carvykti和Abecma上市后季度销售额对比（梳理自公开数据） Abecma和Carvykti作为作为全球前两款获批的BCMA CAR-T疗法，两款产品在临床开发以及推进的思路也比较一致，在分别用二期临床数据推进至末线治疗多发性骨髓瘤获批后，Abecma和Carvykti又分别朝着前线治疗推进，在本年度两者又分别公布了三期数据。 • 2月，百时美施贵宝（BMS）宣布Abecma的KarMMa-3关键3期临床试验达到了主要终点和次要终点，该试验的患者均已接受2-4线包含三种不同类别的疗法（包含一种免疫调节药物、蛋白酶抑制剂与靶向CD38抗体）。与接受标准治疗方案（SOC）的患者相比，Abecma组的无进展生存期（PFS）为13.3个月，降低51%疾病进展或死亡的风险。有71%的Abecma组患者达成缓解，其中有39%的患者达到完全缓解（CR）或严格完全缓解（sCR）。 • 6月，传奇生物公布了Carvykti 3期CARTITUDE-4临床研究数据，治疗既往接受过1-3线治疗且来那度胺耐药的多发性骨髓瘤成人患者。结果显示在中位随访16个月时，Carvykti组中位PFS尚未达到，与SOC相比，Carvykti降低了患者74%的疾病进展或死亡风险，在既往接受过一线治疗患者中，降低了65%的疾病进展或死亡风险。在次要终点，Carvykti的总缓解率（ORR）达85%，73%的患者达到完全缓解（CR）或更好，总体的微小残留病（MRD）阴性率达到61%。从以上数据不难看出，和末线治疗多发性骨髓瘤获批数据趋势保持一致，在2-4线多发性骨髓瘤获批的治疗数据上，传奇生物的Carvykti再胜一筹，在获批时间略晚的因素上，有了强生的加持，Carvykti在临床推进速度上已经追赶上了Abecma，在解决产能问题过后，凭借着临床数据和强生在多发性骨髓瘤上的产品市场优势，Carvykti未来也更被看好。与此同时根据传奇生物披露的数据来看，另一项 III 期临床 CARTITUDE-6 试验预计年底将会启动，未来Carvykti会将继续向一线疗法推进，Abecma和Carvykti在很长一段时间内会继续进行角逐。 02寻找下一站传奇仅用一款产品，就将传奇生物送上了千亿市值，环顾18A以及科创板的一圈生物医药企业的境遇，逻辑似乎也不难理解，只有真正意义上的创新，真正能解决临床需求的产品，才能被资本所拥抱。作为新兴的治疗领域，CAR-T在商业化道路上才走过六年时光，在获批的几款产品中已经或可能成为重磅炸弹的概率也超过了一半，而中国恰巧是目前全球CAR-T领域最火热的国家，在最有可能跑出黑马的领域中，相信大家会忍不住继续期待，下一个传奇在何处。在BCMA这一靶点之上已经见证了传奇，那么有理由相信，继续突破目前局限性的BCMA靶点疗法有可能继续带给市场惊喜。尽管BCMA CAR-T在多发性骨髓瘤这一适应症上取得了令人鼓舞的结果，但其通常表现出短期疗效，仍有大部分多发性骨髓瘤患者仍会出现疾病复发或进展。相关文献表明，耐药机制与抗BCMA CAR-T细胞、肿瘤细胞和复杂的肿瘤微环境之间的相互作用密切相关，涉及抗原逃逸和CAR-T细胞耗竭。目前也有几种潜在的策略来克服CAR-T细胞治疗的耐药性，包括使用双靶点CAR - T和第四代CAR-T疗法（Armored CAR-T），通过小分子药物和基因改造抑制细胞内耗竭相关信号，使用桥接治疗，以选择在疾病早期收集的T细胞进行CAR- T细胞制造。目前双靶点CAR-T疗法已经取得了前期的临床进展，BCMA/CD19、BCMA/CD38以及BCMA/CS1（SLAMF7）均已经有产品处于早期临床开发阶段，其中BCMA/CD19双靶点CAR-T细胞治疗在一小部分多发性骨髓瘤患者中显示出令人振奋的疗效，五名患者的ORR为95%，只有一个3级的细胞因子释放综合征（CRS）发生，没有神经毒性（NT）发生。以上只是抛砖引玉提出一个思路，传奇生物的成功不是偶然，也不单单只是Carvykti这一款产品带来的，但不可否认的是Carvykti在背负着细胞基因疗法商业化重重的枷锁中之上还取得了不俗的业绩，加上这一适应症市场仍旧有着众多未被满足的临床需求，不禁让人期待起后来者踩在巨人的肩膀上能取得怎样的成绩，下一站传奇，或者也已经在路上了。参考资料： 1.P. Rodriguez Otero, S. Ailawadhi, B. Arnulf, et al; Ide-cel or Standard Regimens in Relapsed and Refractory Multiple Myeloma; The New England Journal of Medicine;DOI: 10.1056/NEJMoa2213614； 2.Ciltacabtagene autoleucel: The second anti-BCMA CAR T-cell therapeutic armamentarium of relapsed or refractory multiple myeloma. Front Immunol. 2022;13:991092.； 3.CAR-T cell therapy in multiple myeloma: Current limitations and potential strategies, Front. Immunol. 14:1101495.doi: 10.3389/fimmu.2023.1101495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~

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