Brain Edema

随着气温升高，手足口病即将进入高发季节。手足口病是由多种肠道病毒引起的5岁及以下儿童常见急性传染性疾病，4-7月为手足口病春夏季感染高峰。病原学肠道病毒属于小RNA病毒科肠道病毒属。手足口病（HFMD）由肠道病毒引起，主要致病血清型包括柯萨奇病毒(Coxsackievirus，CV)A组4～7、9、10、16型和B组1～3、5型，埃可病毒(Echovirus)的部分血清型和肠道病毒71型(Enterovirus A71，EV-A71)等，其中以CV-A16和EV-A71最为常见，其中EV-A71具有致病性强、传染性高、嗜神经等特点,可致严重甚至致命的神经系统及心肺并发症，重症及死亡病例多由EV-A71所致。流行病学1、常见亚型：亚基因型EV-A71_C4、CVA16_B1b、CVA6_D3a、CVA10_ F目前在中国占主导地位。2、传染源：患儿和隐性感染者，可通过感染者的粪便、咽喉分泌物、唾液和疱疹液等广泛传播。3、传播途径：密切接触，通过接触被病毒污染的手、毛巾、手绢、牙杯、玩具、食具、奶具以及床上用品、内衣等引起感染；呼吸道飞沫传播；饮用或食入被病毒污染的水和食物。4、易感人群：婴幼儿和儿童普遍易感，以5岁以下儿童为主。5、好发季节：该病全年都可以发病，在北方地区夏秋高发，但有逐渐提早的趋势。在南方地区以春夏为主高峰，秋冬季节为次高峰。临床表现1、潜伏期：多为2～10 d，平均3～5 d。2、出疹期：主要表现为发热，手、足、口、臀等部位出疹，可伴有咳嗽、流涕、食欲不振等症状。典型皮疹表现为斑丘疹、丘疹、疱疹。皮疹周围有炎性红晕，疱疹内液体较少，不疼不痒，皮疹恢复时不结痂、不留疤。不典型皮疹通常小、厚、硬、少，有时可见瘀点、瘀斑。某些型别肠道病毒如CV-A6和CV-A10所致皮损严重，皮疹可表现为大疱样改变，伴疼痛及痒感，且不限于手、足、口部位。此期属于手足口病普通型，绝大多数在此期痊愈。3、神经系统受累期：少数病例可出现中枢神经系统损害，多发生在病程1～5 d，表现为精神差、嗜睡、吸吮无力、易惊、头痛、呕吐、烦躁、肢体抖动、肌无力、颈项强直等。此期属于手足口病重症病例重型，大多数可痊愈。4、心肺功能衰竭前期：多发生在病程5 d内，表现为心率和呼吸增快、出冷汗、四肢末梢发凉、皮肤发花、血压升高。此期属于手足口病重症病例危重型。及时识别并正确治疗，是降低病死率的关键。5、心肺功能衰竭期：可在心肺功能衰竭前期的基础上迅速进入该期。临床表现为心动过速(个别患儿心动过缓)、呼吸急促、口唇紫绀、咳粉红色泡沫痰或血性液体、血压降低或休克。亦有病例以严重脑功能衰竭为主要表现，临床可见抽搐、严重意识障碍等。此期属于手足口病重症危重型，病死率较高。6、恢复期：此期体温逐渐恢复正常，对血管活性药物的依赖逐渐减少，神经系统受累症状和心肺功能逐渐恢复，少数可遗留神经系统后遗症。部分手足口病例(多见于CV-A6、CV-A10感染者)在病后2～4周有脱甲的症状，新甲于1～2月长出。辅助检查1、实验室检查（1）血常规及C-反应蛋白(CRP)多数病例白细胞计数正常，部分病例白细胞计数、中性粒细胞比例及CRP可升高。（2）病原学及血清学临床样本（咽拭子、粪便或肛拭子、血液等标本）肠道病毒特异性核酸检测阳性或分离到肠道病毒。急性期血清相关病毒IgM抗体阳性。恢复期血清CV-A16、EV-A71或其他可引起手足口病的肠道病毒中和抗体比急性期有4倍及以上升高。（3）血生化   部分病例丙氨酸氨基转移酶（ALT）、天门冬氨酸氨基转移酶（AST）、肌酸激酶同工酶（CK-MB）轻度升高，病情危重者肌钙蛋白、血糖、乳酸升高。（4）脑脊液神经系统受累时，脑脊液符合病毒性脑膜炎和/或脑炎改变，表现为外观清亮，压力增高，白细胞计数增多，以单核细胞为主（早期以多核细胞升高为主），蛋白正常或轻度增多，糖和氯化物正常。2、影像学检查（1）影像学：轻症患儿肺部无明显异常。重症及危重症患儿并发神经源性肺水肿时，两肺野透亮度减低，磨玻璃样改变，局限或广泛分布的斑片状、大片状阴影，进展迅速。（2）颅脑CT和/或MRI颅脑CT检查可用于鉴别颅内出血、脑疝、颅内占位等病变。神经系统受累者MRI检查可出现异常改变，合并脑干脑炎者可表现为脑桥、延髓及中脑的斑点状或斑片状长T1长T2信号。并发急性弛缓性麻痹者可显示受累节段脊髓前角区的斑点状对称或不对称的长T1长T2信号。（3）心电图可见窦性心动过速或过缓，Q-T间期延长，ST-T改变。（4）脑电图神经系统受累者可表现为弥漫性慢波，少数可出现棘(尖)慢波。（5）超声心动图重症患儿可出现心肌收缩和/或舒张功能减低，节段性室壁运动异常，射血分数降低等。诊断标准在临床诊断病例基础上，具有下列之一者即可确诊。1、肠道病毒（CV-A16、EV-A71等）特异性核酸检查阳性。2、分离出肠道病毒，并鉴定为CV-A16、EV-A71或其他可引起手足口病的肠道病毒。3、急性期血清相关病毒IgM抗体阳性。4、恢复期血清相关肠道病毒的中和抗体比急性期有4倍及以上升高。重症病例的早期识别重症病例诊疗关键在于及时准确地识别第2期和第3期，阻止发展为第4期。年龄3岁以下、病程3天以内和EV-A71感染为重症高危因素，下列指标提示患儿可能发展为重症病例危重型：1、持续高热：体温大于39℃，常规退热效果不佳；2、神经系统表现：出现精神萎靡、头痛、眼球震颤或上翻、呕吐、易惊、肢体抖动、吸吮无力、站立或坐立不稳等；3、呼吸异常：呼吸增快、减慢或节律不整，安静状态下呼吸频率超过30～40次/分；4、循环功能障碍：心率增快（＞160次/分）、出冷汗、四肢末梢发凉、皮肤发花、血压升高、毛细血管再充盈时间延长（＞2秒）5、外周血白细胞计数升高：外周血白细胞计数≥15×109/L，除外其他感染因素；6、血糖升高：出现应激性高血糖，血糖＞8.3mmol/L；7、血乳酸升高：出现循环功能障碍时，通常血乳酸≥2.0mmol/L，其升高程度可作为判断预后的参考指标。治疗目前尚无特效抗肠道病毒药物，手足口病的治疗仍以对症支持治疗为主。研究显示，干扰素α喷雾或雾化、利巴韦林静脉滴注早期使用可有一定疗效，若使用利巴韦林应关注其不良反应和生殖毒性。不应使用阿昔洛韦、更昔洛韦、单磷酸阿糖腺苷等药物治疗。1、一般治疗注意隔离，避免交叉感染；清淡饮食；做好口腔和皮肤护理。积极控制高热，体温超过38.5℃者，采用物理降温（温水擦浴、使用退热贴等）或应用退热药物治疗。惊厥病例需要及时止惊2、液体疗法重症病例可出现脑水肿、肺水肿及心功能衰竭，应控制液体入量，给予生理需要量60～80ml/（kg·d）（脱水剂不计算在内），建议匀速给予，即2.5～3.3ml/（kg·h），注意维持血压稳定。休克病例在应用血管活性药物同时，给予生理盐水5～10ml/（kg·次）进行液体复苏，15～30分钟内输入，此后酌情补液，避免短期内大量扩容。仍不能纠正者给予胶体液（如白蛋白或血浆）输注。有条件的医疗机构可依据中心静脉压（CVP）、动脉血压（ABP）等指导补液。3、降颅压常用甘露醇，严重颅内高压或低钠血症患儿可考虑联合使用高渗盐水（3%氯化钠）。有心功能障碍者，可使用利尿剂，如呋塞米1～2mg/kg静脉注射。4、血管活性药物心肺功能衰竭前期患儿血流动力学改变为高动力高阻力型，以使用扩血管药物为主。心肺功能衰竭期血压下降时，可应用正性肌力及升压药物治疗。5、静脉丙种球蛋白有脑脊髓炎和持续高热等表现者以及危重病例可酌情使用，剂量1.0g/（kg·d），连用2天。6、糖皮质激素有脑脊髓炎和持续高热等表现者以及危重病例酌情使用。7、机械通气（1）机械通气指征：出现以下表现之一者，可予气管插管机械通气：①呼吸急促、减慢或节律改变；②气道分泌物呈淡红色或血性；③短期内肺部出现湿性啰音；④胸部X线检查提示肺部明显渗出性病变；⑤脉搏血氧饱和度（SpO2）或动脉血氧分压（PaO2）下降；⑥面色苍白、紫绀、皮温低、皮肤发花、血压下降；⑦频繁抽搐或昏迷。（2）撤机指征①自主呼吸恢复正常，咳嗽反射良好；②氧合指数（PaO2/FiO2）≥200mmHg，PEEP＜10cmH2O时，开始做撤机评估；③血气分析好转，胸片肺部渗出与肺水肿好转；④意识状态好转；⑤循环稳定。预防1、一般预防措施保持良好的个人卫生习惯。勤洗手，不要让儿童喝生水，吃生冷食物。儿童玩具和常接触到的物品应当定期进行清洁消毒。避免儿童与患手足口病儿童密切接触。2、接种疫苗EV-A71型灭活疫苗可用于6月龄～5岁儿童预防EV-A71感染所致的手足口病，基础免疫程序为2剂次，间隔1个月，鼓励在12月龄前完成接种。撰文 | 梅斯医学编辑 | Swagpp● 震惊！大三甲医生惨痛教训：35岁住院医，工作6年，跟风读研后反而找不到工作了！网友：为读研而读研你太傻！学历贬值你不懂?● 柳叶刀最新：全球生育率持续下降，逼近临界值！25年后，近50%国家的自然增长率为负，中国人口将持续减少● 重磅！！国家卫健委：2024年将推进“先诊疗后付费”等新模式！依靠信用，“花呗”版看病真的来了！意味着什么？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！

Soluble Beta Amyloid Aggregates Called Oligomers or Protofibrils Initiate and Drive Pathogenesis of Alzheimer’s Disease All Other Biochemical Effects and Neurodegenerative Changes Observed in Alzheimer’s Brain Are a Direct Response to or Downstream Effect of Initial toxic Insult by Amyloid Oligomers Other Neurodegenerative Disorders Follow Similar Path in which Normal Brain Proteins Become Trapped in Aging Brain Due to Impaired Clearance and then Misfold and Aggregate into Neurotoxic Species that Exhibit Prion-Like Behavior Inhibition of Amyloid Misfolding and Aggregation by ALZ-801/Valiltramiprosate Could Slow Disease Progression in Alzheimer’s Patients FRAMINGHAM, Mass.--(BUSINESS WIRE)-- Alzheon, Inc., a clinical-stage biopharmaceutical company developing a broad portfolio of product candidates and diagnostic assays for patients suffering from Alzheimer’s disease (AD) and other neurodegenerative disorders, today announced the publication of a peer-reviewed research paper, “The Single Toxin Origin of Alzheimer’s Disease and Other Neurodegenerative Disorders Enables Targeted Approach to Treatment and Prevention” in the Special Issue Dementia: From Molecular Pathophysiology to Novel Therapeutic Approaches of the International Journal of Molecular Sciences, available through open access at: . “Novel biomarkers and disease-modifying treatments have advanced our understanding of Alzheimer’s and provide support for our thesis that the aggregation of misfolded native proteins initiates and drives the pathogenic cascade that leads to Alzheimer’s disease and other age-related neurodegenerative disorders. In addition, our single toxin theory of brain neurodegeneration identifies new targets and approaches for the development of disease-modifying treatments,” said Martin Tolar, MD, PhD, Founder, President, and CEO of Alzheon. “Therapies such as oral ALZ-801/valiltramiprosate that inhibit beta amyloid misfolding and aggregation in this initial step of the amyloid cascade offer a tremendous opportunity to advance the standard of care for Alzheimer’s disease. The results from our pivotal APOLLOE4 Phase 3 trial later this year evaluating ALZ-801 will provide an important data point for this approach and set the stage for the potential NDA submission this year and commercial launch in 2025.” Authored by Alzheon scientists, the publication reviews the pathogenic cascade leading to AD and offers insights into pathogenesis, as well as therapeutic approaches that can lead to disease modification and clinically meaningful benefits for patients with Alzheimer’s and other neurodegenerative disorders. The publication profiles four anti-amyloid treatments that have progressed to late-stage clinical trials in AD and highlights the discoveries led by Alzheon scientists that enabled these advances: Identification of soluble amyloid oligomers as the upstream triggers of brain neurodegeneration and as drivers of Alzheimer’s pathogenesis. The biological definition of AD based on biomarkers, which enabled improved diagnostic accuracy using the A/T/N (amyloid/tau/neurodegeneration) criteria. The application of biomarkers, in particular p-tau, synaptic markers, and brain volumetrics for the evaluation of disease course and therapeutic efficacy in AD trials. An improved understanding of the role of APOE4 genotype in Alzheimer’s pathogenesis and its effects on efficacy and safety of anti-amyloid treatments. To date, only agents that either block formation of or preferentially clear soluble amyloid aggregates have shown clinical efficacy in Alzheimer’s clinical trials, suggesting that amyloid oligomers are the primary causative agents in AD pathogenesis. Other neurodegenerative disorders follow the same pattern of protein dysregulation, impaired clearance, and increased aggregation, leading to neurotoxicity and loss of function. In these diseases, a normal essential protein starts accumulating in the brain, misfolding and aggregating into soluble oligomers. These oligomers behave like prions, propagating and seeding further aggregation across synaptic networks, form pathognomonic protein aggregates that are toxic to specific neuronal populations and cause the degeneration of neuronal networks. The destruction of brain structures by oligomer assemblies results in characteristic clinical syndromes described in Alzheimer’s disease and Parkinson’s disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, and many other neurological diseases. These well-conserved pathways of brain neurodegeneration offer multiple opportunities for potential disease-modifying interventions to slow the progression or even prevent the onset of clinical symptoms if administered early in the course of the pathogenic process. Therapeutic strategies to treat and prevent neurodegenerative disorders include interventions to improve the clearance of toxins from the brain and the use of agents that inhibit the misfolding of proteins, aggregation into oligomers, the toxicity of pathogenic aggregates, and prion propagation. “The degree of amyloid oligomer selectivity appears to be the key factor that, together with the pharmacokinetic properties, determines the magnitude of the benefit and risk pro each anti-amyloid agent,” said co-author Susan Abushakra, MD, Chief Medical Officer of Alzheon. “ALZ-801 provides advantages over injectable antibodies as an oral agent that efficiently crosses the blood brain barrier, selectively interacts with amyloid monomers to inhibit their misfolding, and blocks the formation of neurotoxic soluble amyloid oligomers in a concentration-dependent manner, without affecting insoluble amyloid plaques or fibrils. Along with its well-differentiated anti-oligomer characteristics, ALZ‑801 is the most advanced of the next generation of highly selective anti-oligomer agents in development and provides an innovative precision medicine solution in an emerging Alzheimer’s pipeline, with a path to potential approval in 2025.” About ALZ-801 ALZ-801/valiltramiprosate is a potential first-in-class, investigational oral disease-modifying therapy in Phase 3 development for the treatment of early Alzheimer’s disease. In mechanism-of-action studies, ALZ-801 fully blocked the formation of neurotoxic soluble beta amyloid (Aβ) oligomers at the Phase 3 clinical dose. ALZ-801 has shown potential for robust clinical efficacy in the highest-risk AD population – patients with two copies of the apolipoprotein ε4 allele (APOE4/4 homozygotes), and favorable safety with no increased risk of brain vasogenic edema. This population is the focus of Alzheon’s pivotal Phase 3 APOLLOE4 trial, which is now fully enrolled and will be completed in mid-2024. ALZ-801 Phase 2 Biomarker Trial Biomarker Effects of ALZ-801 in APOE4 Carriers With Early Alzheimer's Disease (NCT04693520): This ongoing trial was designed to evaluate the effects of 265 mg twice daily oral dose of ALZ-801 on biomarkers of AD pathology in subjects with Early AD, who have either the APOE4/4 or APOE3/4 genotype and constitute 65-70% of Alzheimer's patients. The trial also included evaluation of clinical efficacy, safety, tolerability, and pharmacokinetic pro ALZ-801 over 104 weeks of treatment. An ongoing long-term extension of the trial evaluates ALZ-801 for an additional 52 weeks of treatment for a total of 156 weeks. ALZ-801 APOLLOE4 Phase 3 Trial An Efficacy and Safety Study of ALZ-801 in APOE4/4 Early Alzheimer's Disease Subjects (NCT04770220): This ongoing trial is designed to evaluate the efficacy, safety, biomarker and imaging effects of 265 mg twice daily oral dose of ALZ-801 in Early AD subjects with two copies of the apolipoprotein ε4 allele (APOE4/4 homozygotes), who constitute approximately 15% of Alzheimer's patients. This is a double-blind, randomized trial comparing oral ALZ-801 to placebo treatment over 78 weeks. The APOLLOE4 trial is supported by a $51 million grant from the National Institute on Aging. About Alzheon Alzheon, Inc. is a clinical-stage biopharmaceutical company developing a broad portfolio of product candidates and diagnostic assays for patients suffering from Alzheimer’s disease and other neurodegenerative disorders. We are committed to developing innovative medicines by directly addressing the underlying pathology of neurodegeneration. Our lead Alzheimer’s clinical candidate, ALZ-801/valiltramiprosate, is a first-in-class oral agent in Phase 3 development as a potentially disease modifying treatment for AD. ALZ-801 is an oral small molecule that has been observed to fully block the formation of neurotoxic soluble amyloid oligomers in preclinical tests. Our clinical expertise and technology platform are focused on developing drug candidates and diagnostic assays using a precision medicine approach based on individual genetic and biomarker information to advance therapies with the greatest impact for patients. Alzheon Scientific Publications 1 Tolar M, et al: The Single Toxin Origin of Alzheimer’s Disease and Other Neurodegenerative Disorders Enables Targeted Approach to Treatment and Prevention, International Journal of Molecular Sciences, 2024; 25, 2727. 2 Tolar M, et al: Neurotoxic Soluble Amyloid Oligomers Drive Alzheimer’s Pathogenesis and Represent a Clinically Validated Target for Slowing Disease Progression, International Journal of Molecular Sciences, 2021; 22, 6355. 3 Abushakra S, et al: APOE ε4/ε4 Homozygotes with Early Alzheimer’s Disease Show Accelerated Hippocampal Atrophy and Cortical Thinning that Correlates with Cognitive Decline, Alzheimer’s & Dementia, 2020; 6: e12117. 4 Tolar M, et al: Aducanumab, Gantenerumab, BAN2401, and ALZ-801—the First Wave of Amyloid-Targeting Drugs for Alzheimer’s Disease with Potential for Near Term Approval, Alzheimer’s Research & Therapy, 2020; 12: 95. 5 Tolar M, et al: The Path Forward in Alzheimer’s Disease Therapeutics: Reevaluating the Amyloid Cascade Hypothesis, Alzheimer’s & Dementia, 2019; 1-8. 6 Hey JA, et al: Discovery and Identification of an Endogenous Metabolite of Tramiprosate and Its Prodrug ALZ-801 that Inhibits Beta Amyloid Oligomer Formation in the Human Brain, CNS Drugs, 2018; 32(9): 849-861. 7 Hey JA, et al: Clinical Pharmacokinetics and Safety of ALZ-801, a Novel Prodrug of Tramiprosate in Development for the Treatment of Alzheimer’s Disease, Clinical Pharmacokinetics, 2018; 57(3): 315–333. 8 Abushakra S, et al: Clinical Effects of Tramiprosate in APOE4/4 Homozygous Patients with Mild Alzheimer’s Disease Suggest Disease Modification Potential, Journal of Prevention of Alzheimer’s Disease, 2017; 4(3): 149-156. 9 Kocis P, et al: Elucidating the Aβ42 Anti-Aggregation Mechanism of Action of Tramiprosate in Alzheimer’s Disease: Integrating Molecular Analytical Methods, Pharmacokinetic and Clinical Data, CNS Drugs, 2017; 31(6): 495-509. 10 Abushakra S, et al: Clinical Benefits of Tramiprosate in Alzheimer’s Disease Are Associated with Higher Number of APOE4 Alleles: The “APOE4 Gene-Dose Effect,” Journal of Prevention of Alzheimer’s Disease, 2016; 3(4): 219-228. View source version on businesswire.com: Contacts Media Glenn Pauly, Alzheon, Inc. 508.861.7709 media@alzheon.com Investor Ken Mace, Alzheon, Inc. 508.861.7709 investor@alzheon.com Source: Alzheon, Inc. View this news release online at:

转自：国家药监局 编辑：水晶3月22日， 国家药监局发布修订注射用戈那瑞林、复方妥英麻黄茶碱片、盐酸罂粟碱制剂（包括注射用盐酸罂粟碱、盐酸罂粟碱注射液、盐酸罂粟碱氯化钠注射液、盐酸罂粟碱片）说明书的公告。注射用戈那瑞林说明书修订：【禁忌】项、【不良反应】项、【注意事项】项内容。  复方妥英麻黄茶碱片说明书修订：【不良反应】项、【注意事项】项内容。注射用盐酸罂粟碱、盐酸罂粟碱注射液、盐酸罂粟碱氯化钠注射液说明书：【不良反应】项、【禁忌】项、【注意事项】项增加内容。盐酸罂粟碱片说明书：【不良反应】项和【禁忌】项增加内容。  1、注射用戈那瑞林根据药品不良反应评估结果，为进一步保障公众用药安全，国家药监局决定对注射用戈那瑞林说明书内容进行统一修订。现将有关事项公告如下：  一、所有上述药品的上市许可持有人均应当依据《药品注册管理办法》等有关规定，按照附件要求修订说明书，于2024年6月13日前报省级药品监督管理部门备案。  修订内容涉及药品标签的，应当一并进行修订；说明书及标签其他内容应当与原批准内容一致。在备案之日起生产的药品，不得继续使用原药品说明书。药品上市许可持有人应当在备案后9个月内对已出厂的药品说明书及标签予以更换。  二、药品上市许可持有人应当对新增不良反应发生机制开展深入研究，采取有效措施做好药品使用和安全性问题的宣传培训，指导医师、药师合理用药。  三、临床医师、药师应当仔细阅读上述药品说明书的修订内容，在选择用药时，应当根据新修订说明书进行充分的获益/风险分析。  四、患者用药前应当仔细阅读药品说明书，使用处方药的，应当严格遵医嘱用药。  五、省级药品监督管理部门应当督促行政区域内上述药品的上市许可持有人按要求做好相应说明书修订和标签、说明书更换工作，对违法违规行为依法严厉查处。  特此公告。  附件：注射用戈那瑞林说明书修订要求  国家药监局  2024年3月14日  附件  注射用戈那瑞林说明书修订要求  一、【禁忌】项下应修改为  1、对本品及所含成分过敏者禁用。  2、孕妇、激素依赖性肿瘤患者禁用。  二、【不良反应】项下应包含下列内容  上市后监测到本品的下列不良反应/事件：  免疫系统：类过敏反应、超敏反应、过敏性休克等；  胃肠系统：恶心、呕吐、腹痛等；  皮肤及皮下组织：皮疹、荨麻疹、瘙痒等；  血管与淋巴管类：潮红、苍白、发绀等；  呼吸系统、胸及纵隔：咳嗽、呼吸急促、呼吸困难等；  神经系统：头晕、头痛等；  全身及给药部位：胸部不适、寒战等。  三、【注意事项】项下应包含下列内容  上市后监测到本品有类过敏反应、过敏性休克的严重报告。用药前应仔细询问患者用药史和过敏史，在注射过程中以及在注射完成后30min内对患者进行密切观察；一旦出现过敏反应相关症状和体征，应立即停止给药并及时治疗。  （注：如原批准说明书安全性内容较本修订要求内容更全面或更严格的，应保留原批准内容。说明书其他内容如与上述修订要求不一致的，应当一并进行修订。） 2、复方妥英麻黄茶碱片 根据药品不良反应评估结果，为进一步保障公众用药安全，国家药监局决定对复方妥英麻黄茶碱片说明书内容进行统一修订。现将有关事项公告如下：  一、所有上述药品的上市许可持有人均应当依据《药品注册管理办法》等有关规定，按照附件要求修订说明书，于2024年6月13日前报省级药品监督管理部门备案。  修订内容涉及药品标签的，应当一并进行修订；说明书及标签其他内容应当与原批准内容一致。在备案之日起生产的药品，不得继续使用原药品说明书。药品上市许可持有人应当在备案后9个月内对已出厂的药品说明书及标签予以更换。  二、药品上市许可持有人应当对新增不良反应发生机制开展深入研究，采取有效措施做好药品使用和安全性问题的宣传培训，指导医师、药师合理用药。  三、临床医师、药师应当仔细阅读上述药品说明书的修订内容，在选择用药时，应当根据新修订说明书进行充分的获益/风险分析。  四、患者用药前应当仔细阅读药品说明书，使用处方药的，应当严格遵医嘱用药。  五、省级药品监督管理部门应当督促行政区域内上述药品的上市许可持有人按要求做好相应说明书修订和标签、说明书更换工作，对违法违规行为依法严厉查处。  特此公告。  附件：复方妥英麻黄茶碱片说明书修订要求  国家药监局  2024年3月14日  附件  复方妥英麻黄茶碱片说明书修订要求  一、【不良反应】项下应包含以下内容  上市后监测到复方妥英麻黄茶碱片以下不良反应/事件（监测数据来自无法确定样本量的自发报告，难以准确估计其发生频率）：  胃肠系统：口干，齿龈增生，恶心，呕吐，腹部不适。  神经系统：头晕，嗜睡，震颤，共济失调，运动障碍。  皮肤及皮下组织类：皮疹，红斑，瘙痒。  眼器官类：视觉损害，眼球震颤。  其他：乏力，眩晕，失眠，心悸，超敏反应。  二、【注意事项】项下应包括以下内容  本品含有苯妥英钠，临床使用可能发生中枢神经系统不良反应，如眼球震颤、共济失调、言语不清、精神错乱等，且这种不良反应呈现剂量相关性。  苯妥英钠过量易发生毒性反应。最初的症状有眼球震颤、共济失调和构音障碍。已有不可逆的小脑功能障碍和小脑萎缩的报告。可能发生不良反应或毒性反应的苯妥英钠血药浓度存在明显的个体间差异；苯妥英钠临床有效水平通常为10-20μg/ml（40-80μmol/L），超过20μg/ml时易产生毒性反应。  临床使用本品应注意苯妥英钠的不良反应和药物过量风险，严格遵医嘱用药，不要自行增加用药剂量。如出现神经系统不良反应或中毒症状应立即就医。必要时，应当监测苯妥英钠的血药浓度。  （注：如原批准说明书的安全性内容较本修订要求内容更全面或更严格的，应保留原批准内容。说明书其他内容如与上述修订要求不一致的，应当一并进行修订。） 3、盐酸罂粟碱制剂  根据药品不良反应评估结果，为进一步保障公众用药安全，国家药监局决定对盐酸罂粟碱制剂（包括注射用盐酸罂粟碱、盐酸罂粟碱注射液、盐酸罂粟碱氯化钠注射液、盐酸罂粟碱片）说明书内容进行统一修订。现将有关事项公告如下：  一、所有上述药品的上市许可持有人均应当依据《药品注册管理办法》等有关规定，按照附件要求修订说明书，于2024年6月13日前报省级药品监督管理部门备案。  修订内容涉及药品标签的，应当一并进行修订；说明书及标签其他内容应当与原批准内容一致。在备案之日起生产的药品，不得继续使用原药品说明书。药品上市许可持有人应当在备案后9个月内对已出厂的药品说明书及标签予以更换。  二、药品上市许可持有人应当对新增不良反应发生机制开展深入研究，采取有效措施做好药品使用和安全性问题的宣传培训，指导医师、药师合理用药。  三、临床医师、药师应当仔细阅读上述药品说明书的修订内容，在选择用药时，应当根据新修订说明书进行充分的获益/风险分析。  四、患者用药前应当仔细阅读药品说明书，使用处方药的，应当严格遵医嘱用药。  五、省级药品监督管理部门应当督促行政区域内上述药品的上市许可持有人按要求做好相应说明书修订和标签、说明书更换工作，对违法违规行为依法严厉查处。  特此公告。  附件：1.注射用盐酸罂粟碱、盐酸罂粟碱注射液、盐酸罂粟碱氯化钠注射液说明书修订要求  2.盐酸罂粟碱片说明书修订要求  国家药监局  2024年3月14日  附件1  注射用盐酸罂粟碱、盐酸罂粟碱注射液、  盐酸罂粟碱氯化钠注射液说明书修订要求  一、【不良反应】项增加以下内容  上市后监测到盐酸罂粟碱注射剂的下列不良反应/事件（发生率未知）：  皮肤及皮下组织：皮疹（斑丘疹、斑疹、丘疹、荨麻疹）、瘙痒、多汗、皮肤潮红、皮肤肿胀。  全身性反应：寒战、畏寒、发热（甚至高热）、乏力、疼痛、肿胀。  神经系统：头晕、头痛、震颤、感觉减退、烦躁不安、抽动。  胃肠系统：口干、恶心、呕吐、消化不良、食欲减退、腹部不适、腹痛、腹胀、腹泻、便秘。  心血管系统：心悸、胸部不适、胸痛、QT间期延长、心律失常（心动过速、心动过缓、室性心律失常）、低血压、高血压。  血管与淋巴管类：静脉炎、发绀。  呼吸系统：呼吸困难、呼吸急促、窒息感、咳嗽。  免疫系统：过敏样反应、过敏性休克。  肝胆系统：肝功能异常（包括转氨酶升高、血胆红素升高）、肝损伤、肝细胞损伤。  眼部症状：视物模糊、视觉损害、眼睑水肿、眼痛。  肌肉骨骼及结缔组织：肢体疼痛、肌痛、肌无力、背痛。  肾脏及泌尿系统：排尿困难、尿潴留、尿失禁、尿频。  生殖系统：阴茎异常勃起。  二、【禁忌】项增加以下内容  1.对本品过敏者禁用。2.出血性脑梗死患者禁用。3.脑梗死发病后24小时至2周内有脑水肿及颅内压增高者禁用。  三、【注意事项】项增加以下内容  1.本品不宜与其他药物混合使用。如果确需联合使用其他药物的，应用适量间隔液对输液管道进行冲洗，避免发生药物间相互作用。  2.低血压患者使用过程中需要监测血压，滴速不宜过快。  （注：如原批准说明书的安全性内容较本修订要求更全面或更严格的，应保留原批准内容。说明书其他内容如与上述修订要求不一致的，应当一并进行修订。）  附件2  盐酸罂粟碱片说明书修订要求  一、【不良反应】项增加以下内容  上市后监测到本品的下列不良反应/事件（发生率未知）：  头晕、头痛、恶心、呕吐、腹痛、皮疹、瘙痒、出汗、肝功能异常。  二、【禁忌】项增加以下内容  1.对本品过敏者禁用。2.出血性脑梗死患者禁用。  （注：如原批准说明书的安全性内容较本修订要求更全面或更严格的，应保留原批准内容。说明书其他内容如与上述修订要求不一致的，应当一并进行修订。）