Vomiting

Topas Therapeutics, a small German biotech company attempting to quell overactive immune systems, has revealed the first data from a study of its “tolerance induction” therapy for celiac disease. The results, to be presented at the Digestive Disease Week conference on Monday, come more than six months after Topas first declared success in the study via a press release , without divulging any data. The company discussed the therapy and shared the data with Endpoints News in an exclusive interview ahead of the conference, though many questions remain about the results. The 38-person trial focused on the safety of the company’s experimental nanoparticle treatment over seven weeks, its ability to steer immune cells toward a less inflammatory state, and patient-reported changes in gastrointestinal symptoms. Topas executives told Endpoints that the therapy was successful against those goals, even though granular data on safety and patient outcomes was missing from the presentation. They conceded that bigger and longer studies are still needed, but added that any relief from celiac disease would be a breakthrough. “There is both very much a medical need and big commercial opportunity in celiac,” Topas CEO Hugo Fry told Endpoints. Celiac disease is caused by an unwanted immune reaction to gluten, which is abundant in food. There’s no treatment or cure for the condition that, by some estimates, may affect as many as 1 in 100 people. Despite that, there are relatively few drug developers working on treatments. Topas is one of three companies, along with Anokion and Takeda, developing a potential immune tolerizing therapy in a Phase 2 study. Rather than merely tamping down on inflammation, the efforts aim to retrain the immune system to ignore triggers like gluten. “Tolerization is at that disease-modifying, almost curative end of the spectrum,” Fry said. It aims to do so by presenting nanoparticles decorated with tidbits of peptides that resemble the problematic parts of proteins that set off the immune system, known as antigens. For the celiac therapy, dubbed TPM502, the company uses three nanoparticles, each with a different antigenic peptide from the gluten protein. In many ways, the goal is opposite to that of a vaccine, which presents antigens to build the body’s reaction and create an immune response. Instead, Topas’ infused nanoparticles target specific cells in the liver that serve as a calming zone for T cells, where they learn to live peacefully alongside antigens that don’t warrant being attacked. “That’s the body’s natural hub of induced tolerization,” Fry said. “And it pushes them through that natural route.” Celiac was a good place to start looking for signals that the tolerization approach was working because doctors can easily provoke the immune system to flare up by having participants consume gluten, said Topas chief medical officer Cristina de Min. The company tested four doses of its nanoparticle therapy, ranging from 0.72 micromolar to 7.2 micromolar, in 26 patients. The other 12 patients got a placebo. Participants got the drug or placebo on day 1 and day 15 of the study and then consumed gluten a week later. De Min said that “the drug was remarkably safe,” largely resulting in side effects that resemble gluten consumption in celiac disease, including headache, pain, nausea and vomiting in 27 patients. But the company didn’t break this safety data down by side effect, or between participants who got the drug versus placebo. The company also said that there were three “grade 3” adverse events, the second highest severity, but didn’t say what they were. To get an idea of whether the treatment was working, Topas measured the release of the inflammatory immune protein IL-2 in response to being “challenged” with gluten. Only the highest dose of the therapy resulted in a significant decrease in IL-2 release. But when studying the gene expression of T cells before and after the therapy, the company found that all dose levels helped turn on genes that tamped down on inflammation and reduced genes that promoted inflammation. Topas also asked patients to rate their gastrointestinal symptoms before and after the treatment. The company said that people who got higher doses of the therapy had reduced symptoms, but the presentation was light on specific details. Topas emphasized that the study was not designed to test for efficacy. Another major caveat was the study’s strict inclusion criteria. Topas screened 391 people and recruited only one-tenth of them. Many prospective participants were excluded because they didn’t produce high enough levels of IL-2 in response to gluten consumption. “We wanted to make sure that only patients with measurable response would be involved,” de Min said. Even more patients were excluded because they didn’t have the certain immune system genotype that Topas focused on in this study. Topas is planning a Phase 2b study that will include a broader range of immune genotypes, accounting for 85% to 90% of people with celiac disease. Topas also wants to develop a tolerization therapy for type 1 diabetes, Fry said. But doing so will require more funding, and Fry is setting out to raise a €70 million Series D round. The company is currently funded through 2026 and isn’t planning to start a new study before then, he said.

29岁的林女士，这一年多来总是双眼反复发红、刺痛、畏光，几乎每个月都要跑一次眼科门诊。她被诊断为“虹膜睫状体炎”，点了无数眼药水，症状稍缓后又反复。“是不是干眼症太严重？”、“是不是过敏？”、“是不是老熬夜？”她问过许多医生，也试过各种护眼方式，但病情始终反复。直到这一次来院复查，眼科医生发现她眼部异常并不仅仅是炎症那么简单。双眼表层巩膜呈散在结节状充血，后部角膜缘竟出现了新生血管和“影子血管”，更关键的是：她还提到了“最近常常头晕”！“有没有听力下降？耳鸣？耳闷？”医生一问，林女士一愣：“确实有点耳闷，没太在意。”种种线索拼在一起，医生高度怀疑：这不是单纯的眼病，而是罕见的Cogan综合征！累及眼、听觉-前庭系统的综合征1945年Cogan首次详细描述一种听觉-前庭障碍伴发非梅毒性基质性角膜炎的独立临床病例，将其命名为Cogan综合征。该病是一种累及眼、听觉-前庭系统的综合征，属于自身免疫性疾病，主要表现为非梅毒性角膜基质炎、前庭功能障碍、听力下降以及全身症状。该病临床上较罕见，好发于青壮年，无年龄差异，文献报道白种人居多。角膜基质炎大多数患者都会出现眼红、畏光及眼痛等，很少无症状。该病患者大多数都是双眼相继或同时发病，症状随病程进展逐日加重。分型Cogan综合征分为典型与非典型两种类型。典型Cogan综合征表现为非梅毒性角膜炎和美尼尔听觉-前庭障碍。诊断典型的综合征主要依据非梅毒性角膜基质炎、急性发作的感音神经性听力损失、类似美尼尔病的前庭症状及发病两年内听力进行性损失致聋。眼部症状除了基质性角膜炎外，还可有结膜炎、虹膜炎和睑板腺囊肿等。非典型的Cogan综合征眼部损伤多表现为不伴基质性角膜炎的其他病变。另一种非典型的Cogan综合征眼部表现具有典型的基质性角膜炎症状，但耳部症状为非美尼尔听觉-前庭障碍，或者眼耳症状不同时发生（一般2年内先后发生）。至今该病仍然没有确切的诊断标准，但是可以根据患者的症状体征及鉴别诊断对其进行确诊。临床表现该病首发症状可以是眼部炎症性反应，也可以是眼部症状伴发内耳症状。1.内耳症状：表现为骤然出现的类似美尼尔病样发作：眩晕，恶心，呕吐，共济失调，耳鸣，突发性感音神经性聋。内耳症状可与眼部症状同时出现，也可以晚于眼部症状数周或2年内先后出现。2.眼部表现：可出现较多变异，但最典型的眼部症状是非梅毒性间质性角膜炎，表现为眼红、畏光、眼睛不适、疼痛和视物模糊。在裂隙灯下可见斑片状颗粒状角膜浸润，反复发作患者可出现云状角膜变性。3.耳部损害：听力进行性下降为最主要的耳部损害，发病2年内，有54%典型的和37%非典型的Cogan综合征患者会发生单耳或双耳的耳聋。经过抗炎与全身激素治疗，听力较视力下降的改善较差。4.全身其他系统：引起其他系统症状。如，呼吸系统的上呼吸道感染，可见胸痛、呼吸困难等；心血管系统可见主动脉炎、心包炎或者心律失常、高血压等；消化系统可见腹部疼痛不适、消化不良、腹泻、便血、肝脾肿大等；以及皮肤可见红斑、风疹，也可出现多发性关节炎或关节痛。治疗糖皮质激素是治疗CS的基本药物，宜早期大量应用，起效后逐渐减量维持。糖皮质激素无效时可联用免疫抑制剂。结膜炎、巩膜炎、角膜炎、前葡萄膜炎局部应用糖皮质激素有效。无效时可用环孢霉素A滴眼液，严重眼部炎症需服用泼尼松。参考资料1. 范梓晰，靳荷，黄里佳,等. Cogan综合征二例. 中国实用眼科杂志，2015，33(02):200-201.2. 李雪静,陈楠.老年Cogan综合征1例[J].中国现代医学杂志,2019,29(09):126.3.毛秋月,杨涛,彭安全,等.Cogan综合征诊治的研究进展[J].中华耳科学杂志,2023,21(01):115-120.来源 | 梅斯医学编辑 | wanny神经系统罕见病交流群↓点击下方“阅读原文”，下载梅斯医学APP吧！

药物引起的胃肠道出血，可要注意了！来源 | 医脉通作者 | 小满这是安安（化名）第二次因为胃肠道出血到医院就诊了。01无诱因的胃溃疡出血，到底怎么回事？安安，28岁，1个月前因为胃痛和胃肠道出血在当地医院就诊，医生给她开了泮托拉唑，嘱咐她每天服用40mg的剂量。她回家以后按照医生给的建议服用药物。但一个月后，她再次发生了胃肠道出血，被转诊至本院。为什么吃了“泮托拉唑”后，还是会发生胃肠道出血？因为之前安安就诊时并没有做详细检查，所以医生决定先给安安做一个详细的检查。很快，她的检查结果就出来了。内窥镜检查：发现胃内有多处溃疡（图1）。图1 内窥镜检查图像消化性溃疡是一种由胃酸和胃蛋白酶对消化道黏膜的自我消化作用引起的慢性疾病，主要发生于胃和十二指肠，其核心机制是胃液侵袭性增强与黏膜防御能力下降的失衡。其中非甾体抗炎药物（NSAIDs）的使用和幽门螺杆菌（H. pylori，Hp）感染胃溃疡和十二指肠溃疡的主要危险因素。医生被安安的内窥镜下巨大的溃疡吓到了，于是再次向她求证是否有胃溃疡史或服用胃肠道药物。安安仔细想了又想，说：“我以往没有得过任何胃肠道疾病或胃溃疡，而且我也没有服用过任何致溃疡的药物。”为了一探究竟，医生对安安溃疡处进行了多次取样，并做了进一步检查：幽门螺杆菌（Hp）的测试结果：阴性。腹部CT扫描结果：正常。血常规检查结果：血清钙、胃泌素和嗜铬粒蛋白A水平也均在正常范围内（表1）。表1 安安的实验室检查结果于是医生给安安继续开了泮托拉唑，继续每天40mg两次给药。然而，回家以后的安安在服用药物以后，并没有得到好转，她的腹痛在持续4周以后，仍不消退。于是医生考虑是顽固性溃疡，又在治疗方案里添加了法莫替丁，用法为每天40mg。然而4周后，安安的征状仍然没有得到改善。医生们陷入了困局，无诱因的胃溃疡出血，治疗又无效果，病因到底在哪里？02她说出的一种病史，难道就是病因？突然，安安向医生告知了她患有抑郁症，这难道是病因？医生沉思了一会，回复她：“心情会影响到消化器官，但药物治疗也会有作用的。”“药物，对，药物，安安，你有服用哪些药物？”“安非他酮。”“安非他酮？！”医生又陷入沉思。因为“安非他酮”是一种多巴胺再摄取抑制剂，是一种常用的抗抑郁药和戒烟辅助剂，其常规用量推荐是：从每天150mg的最小剂量开始，增加至维持剂量为每天300mg，最大给药剂量450mg。安非他酮在治疗剂量下耐受性良好，但其常见的副作用包括口干、恶心、激动和失眠。虽然没有证据表明安安的胃溃疡与“安非他酮”有关，但医生还是要求安安的精神科医生给她停用了安非他酮。万幸，在安非他酮停药两周后，安安的腹痛得到了明显的缓解。两个月后，安安再次接受内窥镜检查，结果显示，消化性溃疡减少到几乎初始大小的一半（图2）。图2 停药2月后内窥镜检查图像但可惜的是，安安拒绝了接受第三次内窥镜检查，因为她的腹痛完全消失了。03安非他酮，为何会引起胃溃疡？消化性溃疡多由胃酸损伤引发，常见于胃及十二指肠，主因幽门螺杆菌感染或NSAIDs使用。本文患者安安第一次入院开了泮托拉唑，但并未减轻痛苦，后入院通过检查，排除Hp等常规风险因素，又通过排查过往的所有服药等经历，锁定安非他酮，停药联合抑酸治疗显著改善症状。但在以往的安非他酮副作用病例报告中，并没有找到引起消化性溃疡的报告。而在安非他酮的说明书中，也只明确提到临床常见的不良事件有激越、口干、失眠、头痛/偏头痛、恶心/呕吐、便秘和震颤，偶见吞咽困难、肝损伤/黄疸、直肠疾病、结肠炎、胃肠道出血、肠穿孔以及胃溃疡，则提示安非他酮可能与消化性溃疡存在潜在关联，但还需进一步研究验证。目前临床上对于消化性溃疡，常用的治疗药物主要分为抑制胃酸分泌药物和黏膜保护治疗药物：1.抑制胃酸分泌药物。表2 消化性溃疡常用治疗药物（抑制胃酸分泌药物）一览表2.胃肠黏膜保护剂主要是弱碱性抗酸剂和铋剂，抗酸分泌治疗的基础上加用胃黏膜保护剂能快速缓解症状以及改善溃疡修复质量。弱碱性抗酸剂：包括铝碳酸镁、磷酸铝、硫糖铝、氢氧化铝凝胶等，其主要是通过黏附、覆盖在溃疡面、阻止胃酸及胃蛋白酶侵袭溃疡面和促进内源性PGs合成等，便秘或腹泻是其主要不良反应。铋剂：除具备弱碱性抗酸剂功效外，该药物还能抗Hp，多用于根除Hp联合治疗，短期服会有黑便，因防铋积蓄，少用于溃疡治疗。此外对于NSAIDs相关性溃疡：应尽可能暂停或减少NSAIDs剂量；如果病情需要继续服用，尽可能选用对胃肠道黏膜损害较小的NSAIDs或高选择性COX⁃2抑制剂，以减少不良反应；对计划长期服用NSAIDs的患者，如果Hp阳性推荐根除Hp治疗；停服NSAIDs后，可用常规治疗溃疡方案进行治疗；当未能中止NSAIDs治疗时，应选用抑酸剂进行溃疡治疗。通过该病例也是想提醒大家，对于难治性溃疡，建议转诊上级医院，排除未规律服药可能，需进一步内镜或病理检查。参考文献：[1] Kuna L,Jakab J,Smolic R,et al.Peptic Ulcer Disease:A Brief Review of Conventional Therapy and Herbal Treatment Options.J Clin Med.2019,8(2):179.Published 2019 Feb 3. doi:10.3390/jcm8020179[2] Zhang BB,Li Y,Liu XQ,et al.Association between vacA genotypes and the risk of duodenal ulcer: a meta-analysis. Mol Biol Rep. 2014;41(11):7241-7254. doi:10.1007/s11033-014-3610-y[3] Momayez Sanat Z,Mohammadi Ganjaroudi N,Pirsalehi A.Peptic Ulcer Disease Following Use of Bupropion:A Case Report. Clin Med Insights Case Rep.2023,16:11795476231153279. Published 2023 Feb 8.doi:10.1177/11795476231153279[4] Settle EC Jr.Bupropion sustained release:side effect profile.J Clin Psychiatry.1998,59 Suppl 4:32-36.[5] 消化性溃疡基层诊疗指南（2023年）[J].中华全科医师杂志,2023,22(11):1108-1115.责编｜亦一封面图来源｜视觉中国为“诱使”患者手术，医方“谎称”专家参与手术？患者死亡后，医院被加重处罚丨医眼看法幼儿肺炎后死亡，家属质疑系“打错针致死”，尸检发现黄豆……是过失，还是意外？医脉通是专业的在线医生平台，“感知世界医学脉搏，助力中国临床决策”是平台的使命。医脉通旗下拥有「临床指南」「用药参考」「医学文献王」「医知源」「e研通」「e脉播」等系列产品，全面满足医学工作者临床决策、获取新知及提升科研效率等方面的需求。☟戳这里，更有料！