Mexiletine Hydrochloride

二尖瓣狭窄是临床执业医师考试中的高频必学疾病，近 10 年考过 19 次。来看一道 2023 年的考题，看看你做对了吗？执考平均 48 秒做 1 题，请答题：女性，54岁，心悸气短10年，加重伴大咳血1天，查体：颈静脉怒张，双肺可闻及湿啰音，心率120次/分，心律不齐，第一心音亢进，可听见开瓣音，P₂亢进，心尖部舒张期隆隆样杂音，双下肢轻度水肿，心电图示心房颤动伴快心室率，胸部x线片示心影呈梨形心。应首选治疗药物是：A. β受体拮抗剂B. 利尿剂C. 普罗帕酮D. 美西律E. 西地兰答案解析1. 关键题眼：心房颤动；快心室率 2. 正确选项（E）患者老年女性，有心力衰竭表现（颈静脉怒张，双肺可闻及湿啰音，双下肢轻度水肿），心电图示房颤伴快心室率，心尖部舒张期隆隆样杂音+梨形心（提示二尖瓣狭窄），伴有快速心房颤动／心房扑动的收缩性心力衰竭是应用洋地黄的最佳指征，故首选西地兰。 3. 错误选项（A）对于窦性心律病人，如其呼吸困难发生在心率加快时，可使用负性心率药物，如β受体拮抗剂或非二氢吡啶类钙通道阻滞剂，故不选。 4. 错误选项（B）如病人存在肺淤血导致的呼吸困难，应减少体力活动，限制钠盐摄入，间断使用利尿药，故该患者不使用。 5. 错误选项（C）普罗帕酮可用于预防和治疗室性和室上性异位搏动，室性或室上性心动过速，预激综合征，电复律后室颤发作等，故该患者不适用。 6. 错误选项（D）美西律主要用于室性期前收缩及室性心动过速、心室纤颤及急性心肌梗死或洋地黄所致心律失常，故不选。 内容来源于：丁香医考 App 临床执业笔试题库。更多完整解析+考友神评论，点击左下方「阅读原文」去丁香医考 App 查看👇👇

horillaz/ Getty Images With its recent data drop for an oligonucleotide candidate, Dyne Therapeutics signals it may become a frontrunner in this disease space alongside Avidity Biosciences, Lupin and AMO Pharma. Last month, Dyne Therapeutics announced positive results in a Phase I/II trial of its candidate DYNE-101. The milestone places Dyne among the companies closest to developing a disease-modifying treatment for myotonic dystrophy type 1. Myotonic dystrophy type 1 (DM1) is a form of muscular dystrophy caused by DMPK mutations on chromosome 19. It affects muscles and many organs across multiple systems that depend on muscular activity. Also known as Steinert disease, it is characterized by the inability to relax muscles at will. DM1 affects 140,000 people in the United States alone, and although there are drugs that address its symptoms, there are no currently approved disease-modifying treatments for the condition. There are, however, more than two dozen investigational drugs in development for DM1. Among the companies looking to fill the unmet need is Dyne, whose DYNE-101 is an antisense oligonucleotide fused with a fragment antibody that binds to the transferrin receptor 1 in muscles. In the Phase I/II ACHIEVE trial , key findings included DMPK RNA level reductions, CASI-22 improvements, early and sustained improvement in myotonia as measured by grip myotonia assessment, and multiple other strength and timed assessments. The trial utilized a multiple ascending dose cohort to identify 6.8 mg/kg every 8 weeks as the optimal dose for future studies. Dyne stated in its press release that it plans to initiate a global registrational expansion cohort of the trial to potentially support a submission for FDA Accelerated Approval in the first half of 2026. Meanwhile, Avidity Biosciences is developing AOC 1001, an antibody oligonucleotide conjugate that targets the DMPK gene to treat DM1. Also known as del-desiran, this investigational treatment is currently being studied in the Phase III HARBOR trial and Avidity has announced plans to submit marketing applications in 2026. In March 2024, Avidity announced positive long-term del-desiran data from the Phase II MARINA-OLE trial showing reversal of disease progression in people living with DM1 across multiple endpoints compared to a matched natural history study population over one year. Those endpoints included grip myotonia assessment, muscle strength and activities of daily living. According to Avidity, additional data from the ongoing Phase I/II MARINA trial for AOC 1001, in which patients were split into placebo-controlled single-dose and multiple ascending dose arms, will be released in the first quarter of this year. While clinical-stage investigational oligonucleotide-based therapy candidates are catching up, repurposed drugs such as metformin, tideglusib and mexiletine are also undergoing Phase III trials to treat DM1. Metformin , a biguanide currently approved for type 2 diabetes mellitus, is currently slated for Phase III trials in DM1. In previous Phase II trials, metformin increased the 6-minute walking distance for DM1 patients versus placebo. While it has positive benefits ranging from anticancer effects to cardiovascular protection to neuroprotection, metformin is also associated with adverse effects such as gastrointestinal discomfort and lactic acidosis in high doses. Another approach is AMO Pharma ’s tideglusib (also known as AMO-02), a glycogen synthase kinase 3 beta inhibitor currently in Phase III clinical trials. Despite not reaching its primary endpoint in the Phase II/III REACH-CDM trial due to a strong placebo effect, tideglusib had achieved clinically and statistically significant benefits in various functional and objective assessments as of May 2024. As a result, after meeting with the FDA, AMO Pharma is forging ahead with a Phase III trial of tideglusib. Elsewhere, Lupin is working on repurposing mexiletine, a class I antiarrhythmic drug that is currently in Phase III trials for DM1. In contrast to previous trials that used mexiletine capsules for immediate-release effects, Lupin intends to use mexiletine granules for prolonged-release oral suspension formulations for its Phase III HERCULES and ATLAS trials. Like tideglusib, mexiletine reached Phase III despite less-than-stellar mid-stage results. In its case, Phase II trial data demonstrated no significant change in 6-minute walk distance at 6 months for patients on mexiletine capsules compared to placebo. Also worthy of mention is ARTHex. While clinical data is scant for the company’s ATX-01, it was enrolling patients into its Phase I/IIa ArthemiR trial as of October 2024. The drug is based on microRNA technology. As progress currently stands, antibody-oligonucleotide conjugates appear to be more effective at targeting the genetic source of DM1 and have a more convincing mechanism of action than small molecules and repurposed drugs. However, even though genetic therapies are advancing quickly, the DM1 space is risky. Consider that Ionis Pharmaceuticals stopped working on its antisense compound IONIS-DMPK-2.5Rx in January 2017 after failing to achieve adequate concentration levels in muscles in Phase I/II trials. If all goes well in the late-stage gene therapy space for DM1, expect new treatments to hit the market within the next three to four years at the earliest.