Carbamazepine

DOR/ISL is the first non-INSTI, two-drug regimen to demonstrate non-inferiority and a similar safety pro Week 48 to BIC/FTC/TAF in adults living with HIV-1 who had not previously received antiretroviral treatment DOR/ISL maintained virologic suppression at Week 96 in adults with virologically suppressed HIV-1 who switched from other oral antiretroviral therapies, including BIC/FTC/TAF RAHWAY, N.J.--(BUSINESS WIRE)-- $MRK #MRK --Merck (NYSE: MRK), known as MSD outside of the United States and Canada, today announced the presentation of results from three pivotal Phase 3 trials evaluating the investigational, once-daily, oral, two-drug regimen of doravirine/islatravir [DOR/ISL (100 mg/0.25 mg), (MK-8591A)] in adults with HIV-1. The findings were shared in late-breaking presentations at the 33rd Conference on Retroviruses and Opportunistic Infections (CROI) being held in Denver. “We are proud to continue building on our 40-year history of HIV research with the presentation of compelling new data from our HIV pipeline at CROI this year,” said Dr. Eliav Barr, senior vice president, head of global clinical development and chief medical officer, Merck Research Laboratories. “Islatravir blocks HIV-1 replication through multiple mechanisms, including reverse transcriptase translocation inhibition, and could serve as the anchor for a series of two-drug, non-INSTI, daily and weekly treatment regimens. If approved, DOR/ISL will be the first of these regimens in our portfolio and may provide an important new option to help meet the evolving treatment needs of people living with HIV.” The Phase 3, double-blind, clinical trial MK-8591A-053 evaluating DOR/ISL versus bictegravir/emtricitabine/tenofovir alafenamide i [(50 mg/200 mg/25 mg),(BIC/FTC/TAF)] in adults living with HIV-1 who had not previously received antiretroviral treatment (treatment-naïve), met its primary efficacy endpoint of percentage of participants achieving viral suppression (HIV-1 RNA 100,000 copies/mL). The primary efficacy endpoint was the percentage of participants with HIV-1 RNA 100,000 copies/mL, 10.3% had HIV-1 RNA >500,000 copies/mL and 17.2% had baseline CD4+ T-cell count 100,000 copies/mL (94.0% vs 87.6%, respectively) and >500,000 copies/mL (90.3% vs 84.4%, respectively). Drug-related AEs were reported in 14.1% of participants on DOR/ISL and 18.0% on BIC/FTC/TAF and discontinuations due to AEs (1.1% vs. 2.2%) were similar in both groups. Immune reconstitution was similar in DOR/ISL vs. comparator with no between-group differences in mean increases in CD4+ T-cell counts or total lymphocyte counts (TLC). About the Phase 3 data from MK-8591A-052 MK-8591A-052 is a Phase 3, randomized, active-controlled, double-blind, clinical trial to evaluate the efficacy and safety of a switch to investigational, once-daily DOR/ISL (100 mg/0.25 mg) in adults with HIV-1 infection that has been virologically suppressed on BIC/FTC/TAF (50 mg/200 mg/25 mg). In this trial, 513 adults with HIV-1 who had virologic suppression for three months or more on BIC/FTC/TAF, no history of treatment failure and no known resistance to DOR were randomized (2:1) and switched to DOR/ISL (n= 342) or continued treatment with BIC/FTC/TAF (n=171). The primary efficacy endpoint, the percentage of participants with HIV-1 RNA ≥50 copies/mL at Week 48 (non-inferiority margin 4%), was met, demonstrating non-inferiority to BIC/FTC/TAF; 1.5% of participants who switched to DOR/ISL had a viral load of ≥50 copies/mL at Week 48, compared to 0.6% on BIC/FTC/TAF (treatment difference 0.9%, 95% CI -1.9, 2.9). Results at Week 48 were recently published in The Lancet . At Week 96, DOR/ISL continued to demonstrate similar efficacy compared to BIC/FTC/TAF; 1.5% of participants on DOR/ISL had a viral load of ≥50 copies/mL compared to 1.2% of participants on BIC/FTC/TAF (treatment difference 0.3%, 95% CI -2.8, 2.4); 88.9% of participants on DOR/ISL maintained virologic suppression (HIV-1 RNA <50 copies/mL) compared to 90.1% of participants continuing BIC/FTC/TAF (treatment difference -1.2%, 95% CI -6.5, 5.0). No hypothesis testing was performed for these secondary endpoints. The safety pro DOR/ISL at Week 96 continued to be similar to BIC/FTC/TAF with no new safety findings. No additional drug-related serious adverse events were reported in any group between Week 48 and Week 96. At Week 96, rates of discontinuation due to AEs were similar for both groups (3.2% vs. 2.9%). There were no differences between trial arms in CD4+ T-cell count or TLC changes through Week 96. About the Phase 3 data from MK-8591A-051 MK-8591A-051 is a Phase 3, open-label randomized, active-controlled, clinical trial to evaluate the efficacy and safety of a switch to investigational, once-daily DOR/ISL (100 mg/0.25 mg) in adults with HIV-1 infection that has been virologically suppressed using bART. In this trial, 551 adults with HIV-1 RNA <50 copies/mL for three months or more on oral 2- or 3-drug ART, with no history of treatment failure and no known virologic resistance to DOR, were randomized 2:1 and switched to DOR/ISL (n= 366) or continued bART (n=185), stratified by bART regimen. The primary efficacy endpoint, percentage of participants with HIV-1 RNA ≥50 copies/mL at Week 48 (non-inferiority margin 4%), was met, demonstrating DOR/ISL to be non-inferior to bART; 1.4% of participants who received DOR/ISL had a viral load of ≥50 copies/mL at Week 48, compared to 4.9% on bART (treatment difference -3.6%, 95% CI -7.8, -0.8). After Week 48 of the comparative portion of the study, all participants received open-label DOR/ISL through Week 144. Results at Week 48 were recently published in The Lancet . At Week 96, 1.9% of participants who continued on DOR/ISL for 96 weeks had HIV-1 RNA ≥50 copies/mL and 1.1% of participants who switched from bART to DOR/ISL at Week 48. Additionally, 92.6% of participants who were on DOR/ISL through 96 weeks and 96.6% of participants who switched to DOR/ISL at Week 48 maintained virologic suppression (HIV-1 RNA <50 copies/mL) at Week 96. At Week 96, there were similar rates of drug-related AEs between those who continued on DOR/ISL (13.7%) for 96 weeks and for those who switched from bART to DOR/ISL at Week 48 (11.3%) and rates of discontinuations due to AEs for those on DOR/ISL for 96 weeks (1.1%) and for those who switched from bART to DOR/ISL at Week 48 (0.6%) were similar. The mean percent change in total lymphocyte and CD4 counts were similar for participants who continued on DOR/ISL and switched from bART to DOR/ISL. No participants discontinued treatment due to decreased CD4+ T-cell count or TLC. About Islatravir (MK-8591) and Merck’s HIV Research Islatravir (MK-8591) is Merck’s investigational nucleoside analog that blocks HIV-1 replication by multiple mechanisms including inhibition of reverse transcriptase translocation, resulting in immediate chain termination and induction of structural changes in the viral DNA. Islatravir is under evaluation in multiple ongoing early and late-stage clinical trials in combination with other antiretrovirals for potential daily and once-weekly treatments for HIV-1, with islatravir serving as the anchor medicine in these two-drug regimens. Islatravir in combination with Gilead’s lenacapavir is in Phase 3 development as a novel oral once-weekly treatment for HIV-1 [ISLEND-1 ( NCT06630286 ) and ISLEND-2 ( NCT06630299 )], and islatravir in combination with our company’s investigational non-nucleoside reverse transcriptase inhibitor (NNRTI) ulonivirine (MK-8507) is in Phase 2b development (MK-8591B-060, NCT06891066 and MK-8591B-062, NCT07266831 ) as an oral once-weekly treatment. MK-8527 is the company’s investigational, novel, once-monthly, oral candidate for pre-exposure prophylaxis (PrEP) for HIV-1. The Phase 3 EXPrESSIVE-11 (MK-8527-011, NCT07044297 ) trial is evaluating the safety and efficacy of MK-8527 as PrEP to reduce the risk of sexually acquired HIV-1 infection among people likely to be exposed to HIV-1 in 16 countries. The Phase 3 EXPrESSIVE-10 (MK-8527-010, NCT07071623 ) trial is evaluating the safety and efficacy of MK-8527 as PrEP to reduce the risk of sexually acquired HIV-1 infection among women and adolescent girls in sub-Saharan Africa. Both trials are now enrolling. For an overview of Merck’s HIV treatment and prevention clinical development program, please click here . Indications and usage for PIFELTRO ® (doravirine) and DELSTRIGO ® (doravirine, lamivudine, and tenofovir disoproxil fumarate) in the U.S. PIFELTRO is indicated in combination with other antiretroviral (ARV) agents for the treatment of HIV-1 infection in adult patients with no prior ARV treatment history or to replace the current ARV regimen in those who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable ARV regimen with no history of treatment failure and no known substitutions associated with resistance to doravirine. DELSTRIGO is indicated as a complete regimen for the treatment of HIV-1 infection in adult patients with no prior ARV treatment history or to replace the current ARV regimen in those who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable ARV regimen with no history of treatment failure and no known substitutions associated with resistance to the individual components of DELSTRIGO. Selected Safety Information Warning: Posttreatment Acute Exacerbation of Hepatitis B Virus (HBV) for DELSTRIGO All patients with HIV-1 should be tested for the presence of HBV before initiating ARV therapy. Severe acute exacerbations of HBV have been reported in people with concomitant HIV-1 and HBV who have discontinued products containing lamivudine or tenofovir disoproxil fumarate (TDF), which are components of DELSTRIGO. Patients coinfected with HIV-1 and HBV who discontinue DELSTRIGO should be monitored with both clinical and laboratory follow-up for at least several months after stopping DELSTRIGO. If appropriate, initiation of anti-HBV therapy may be warranted. Contraindications PIFELTRO and DELSTRIGO are contraindicated when coadministered with drugs that are strong cytochrome P450 (CYP)3A enzyme inducers (including the anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, and phenytoin; the androgen receptor inhibitor enzalutamide; the antimycobacterials rifampin and rifapentine; the cytotoxic agent mitotane; and the herbal product St. John’s wort (Hypericum perforatum)), as significant decreases in doravirine plasma concentrations may occur, which may decrease the effectiveness of DELSTRIGO and PIFELTRO. DELSTRIGO is contraindicated in patients with a previous hypersensitivity reaction to lamivudine. Warnings and Precautions Severe Skin Reactions Severe skin reactions, including Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN), have been reported during the postmarketing experience with doravirine-containing regimens. Discontinue PIFELTRO or DELSTRIGO, and other medications known to be associated with severe skin reactions, immediately if a painful rash with mucosal involvement or a progressive severe rash develops. Clinical status should be closely monitored, and appropriate therapy should be initiated. New or Worsening Renal Impairment Renal impairment, including cases of acute renal failure and Fanconi syndrome, have been reported with the use of TDF. DELSTRIGO should be avoided with concurrent or recent use of a nephrotoxic agent (e.g., high-dose or multiple NSAIDs). Cases of acute renal failure after initiation of high-dose or multiple NSAIDs have been reported in people living with HIV with risk factors for renal dysfunction who appeared stable on TDF. Prior to or when initiating DELSTRIGO, and during treatment, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus. Discontinue DELSTRIGO in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome. Discontinue DELSTRIGO if estimated creatinine clearance declines below 50 mL/min. Bone Loss and Mineralization Defects In clinical trials in adults living with HIV, TDF was associated with slightly greater decreases in bone mineral density (BMD) and increases in biochemical markers of bone metabolism. Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher. Cases of osteomalacia associated with proximal renal tubulopathy have been reported with the use of TDF. The effects of TDF-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk in adults are unknown. Immune Reconstitution Syndrome Immune reconstitution syndrome can occur, including the occurrence of autoimmune disorders with variable time to onset, which may necessitate further evaluation and treatment. Drug Interactions Because DELSTRIGO is a complete regimen, coadministration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended. Coadministration of PIFELTRO with efavirenz, etravirine, or nevirapine is not recommended. If DELSTRIGO is coadministered with rifabutin, take one tablet of DELSTRIGO once daily, followed by one tablet of doravirine (PIFELTRO) approximately 12 hours after the dose of DELSTRIGO. If PIFELTRO is coadministered with rifabutin, increase PIFELTRO dosage to one tablet twice daily (approximately 12 hours apart). Consult the full Prescribing Information prior to and during treatment for more information on potential drug-drug interactions. Dosage and Administration/Specific Populations Renal Impairment Because DELSTRIGO is a fixed-dose combination tablet and the dosage of lamivudine and TDF cannot be adjusted, DELSTRIGO is not recommended in patients with estimated creatinine clearance less than 50 mL/min. Adverse Reactions The most common adverse reactions with DELSTRIGO (incidence ≥5%, all intensities) were dizziness (7%), nausea (5%), and abnormal dreams (5%). The most common adverse reactions with PIFELTRO (incidence ≥5%, all intensities) were nausea (7%), dizziness (7%), headache (6%), fatigue (6%), diarrhea (6%), abdominal pain (5%), and abnormal dreams (5%). By week 96 in DRIVE-FORWARD, 2% of adult participants in the PIFELTRO group and 3% in the darunavir+ritonavir (DRV+r) group had adverse events leading to discontinuation of study medication. By week 96 in DRIVE-AHEAD, 3% of adult participants in the DELSTRIGO group and 7% in the efavirenz (EFV)/emtricitabine (FTC)/TDF group had adverse events leading to discontinuation of study medication. In DRIVE-FORWARD, mean changes from baseline at week 48 in LDL-cholesterol (LDL-C) and non-HDL-cholesterol (non-HDL-C) were pre-specified. LDL-C: -4.6 mg/dL in the PIFELTRO group vs 9.5 mg/dL in the DRV+r group. Non-HDL-C: -5.4 mg/dL in the PIFELTRO group vs 13.7 mg/dL in the DRV+r group. The clinical benefits of these findings have not been demonstrated. In DRIVE-AHEAD, mean changes from baseline at week 48 in LDL-C and non-HDL-C were pre-specified. LDL-C: -2.1 mg/dL in the DELSTRIGO group vs 8.3 mg/dL in the EFV/FTC/TDF group. Non-HDL-C: -4.1 mg/dL in the DELSTRIGO group vs 12.7 mg/dL in the EFV/FTC/TDF group. The clinical benefits of these findings have not been demonstrated. In DRIVE-SHIFT, mean changes from baseline at week 24 in LDL-C and non-HDL-C were pre-specified. LDL-C: -16.3 mg/dL in the DELSTRIGO group vs -2.6 mg/dL in the PI + ritonavir group. Non-HDL-C: -24.8 mg/dL in the DELSTRIGO group vs -2.1 mg/dL in the PI + ritonavir group. The clinical benefits of these findings have not been demonstrated. In DRIVE-AHEAD, neuropsychiatric adverse events were reported in the three pre-specified categories of sleep disorders and disturbances, dizziness, and altered sensorium. Twelve percent of adult participants in the DELSTRIGO group and 26% in the EFV/FTC/TDF group reported neuropsychiatric adverse events of sleep disorders and disturbances; 9% in the DELSTRIGO group and 37% in the EFV/FTC/TDF group reported dizziness; and 4% in the DELSTRIGO group and 8% in the EFV/FTC/TDF group reported altered sensorium. The safety of DELSTRIGO in virologically suppressed adults was based on week 48 data from participants in the DRIVE-SHIFT trial. Overall, the safety pro virologically suppressed adult participants was similar to that in participants with no ARV treatment history. Serum ALT and AST Elevations: In the DRIVE-SHIFT trial, 22% and 16% of participants in the immediate switch group experienced ALT and AST elevations greater than 1.25 X ULN, respectively, through 48 weeks on DELSTRIGO. For these ALT and AST elevations, no apparent patterns with regard to time to onset relative to switch were observed. One percent of participants had ALT or AST elevations greater than 5 X ULN through 48 weeks on DELSTRIGO. The ALT and AST elevations were generally asymptomatic, and not associated with bilirubin elevations. In comparison, 4% and 4% of participants in the delayed switch group experienced ALT and AST elevations of greater than 1.25 X ULN through 24 weeks on their baseline regimen. Pregnancy/Breastfeeding There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to PIFELTRO or DELSTRIGO during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Inform individuals with HIV-1 infection of the potential risks of breastfeeding, including: (1) HIV-1 transmission (in HIV-1–negative infants), (2) developing viral resistance (in HIV-1–positive infants), and (3) serious adverse reactions in a breastfed infant similar to those seen in adults. Merck’s Commitment to HIV For 40 years, Merck has been committed to scientific research and discovery in HIV leading to scientific breakthroughs that have helped change HIV treatment. Our work has been pioneering in the development of new options across multiple drug classes to help those impacted by HIV. Today, we are developing a series of antiviral options designed to help people manage HIV and protect people from HIV. We are researching for real life and want to ensure people are not defined by HIV. Our work focuses on transformational innovations, collaborations with others in the global HIV community, and access initiatives aimed at the goal of helping to end the HIV epidemic for everyone. About Merck At Merck, known as MSD outside of the United States and Canada, we are unified around our purpose: We use the power of leading-edge science to save and improve lives around the world. For more than 130 years, we have brought hope to humanity through the development of important medicines and vaccines. We aspire to be the premier research-intensive biopharmaceutical company in the world – and today, we are at the forefront of research to deliver innovative health solutions that advance the prevention and treatment of diseases in people and animals. We foster a diverse and inclusive global workforce and operate responsibly every day to enable a safe, sustainable and healthy future for all people and communities. For more information, visit and connect with us on X (formerly Twitter) , Facebook , Instagram , YouTube and LinkedIn . Forward-Looking Statement of Merck & Co., Inc., Rahway, N.J., USA This news release of Merck & Co., Inc., Rahway, N.J., USA (the “company”) includes “forward-looking statements” within the meaning of the safe harbor provisions of the U. Contacts Media Contacts: Eilyn Segura (203) 940-6259 Deb Wambold (215) 779-2234 Investor Contacts: Peter Dannenbaum (732) 594-1579 Damini Chokshi (732) 594-1577 Read full story here

声明： 本文仅为科普学习目的，不构成任何医疗建议。所有用药决策，请务必咨询专业医生。 话说在上世纪中叶，精神医学界迎来了一位重量级嘉宾——氯丙嗪，它开启了精神药物治疗的时代，无数患者因此受益。然而，这位“老大哥”脾气不太好，经常带来让人动作僵硬、手抖不停的“锥体外系反应”（EPS），像个无形的枷锁。 到了70年代，另一位“怪杰”氯氮平横空出世。它效果拔群，还不怎么惹“锥体外系反应”这个麻烦，简直是精神分裂症治疗的“王炸”。但这位“怪杰”有个致命缺陷——它可能导致严重的粒细胞缺乏，像是在患者体内埋下了一颗随时可能引爆的免疫炸弹，需要频繁抽血监测，搞得医生和患者都心惊胆战。 于是，整个80年代，全球的药物研发科学家们都有一个共同的梦想：创造一个既有氯氮平的“神效”，又没有其“夺命”风险，同时还能摆脱氯丙嗪类药物“僵尸副作用”的新药。 阿斯利康的“寻宝之旅” 就在这个背景下，英国的帝国化学工业公司（ICI）的制药部门，也就是后来大名鼎鼎的阿斯利康（AstraZeneca）的前身之一，也加入了这场“寻宝之旅”。他们的实验室里，一群科学家正埋头于一堆化学结构式中，试图在氯氮平的结构基础上“修修改改”，去其糟粕，取其精华。 时间来到1985年，一个代号为ICI 204,636的化合物在筛选中脱颖而出。这个化合物，就是我们今天的主角——喹硫平。早期的动物实验结果令人振奋：它表现出了明确的抗精神病活性，更关键的是，它引起动物模型出现僵直（EPS的类似表现）的倾向非常非常低。科学家们仿佛看到了黎明的曙光：这不就是我们梦寐以求的那个“理想型”吗？ 虽然具体的某一位“喹硫平之父”的名字在历史长河中并未被特别放大宣传，不像青蒿素和屠呦呦那样家喻户晓，但这背后无疑是一个由爱德华·瓦拉瓦（Edward Warawa）等杰出科学家领导的团队共同努力的结晶。他们的工作核心理念是，不能仅仅看药物和受体的结合强度，更要看它在复杂的生物体内的实际行为表现。这种理念指导他们发现，喹硫平与多巴胺D2受体的结合是一种“若即若离”的快速解离模式，这就像一个高情商的管理者，既能管住事儿（控制精神病性症状），又不会管得太死（避免EPS），为喹硫平温和的副作用特性奠定了理论基础。 从实验室到货架的漫漫长路 发现一个有潜力的化合物只是万里长征的第一步。接下来是漫长而烧钱的临床试验。从I期到III期，喹硫平在全球范围内接受了成千上万名患者的检验。研究数据不断证实了它的有效性和相对良好的安全性。 终于，在1997年，喹硫平以商品名“Seroquel”（思瑞康）获得了美国食品药品监督管理局（FDA）的批准，正式上市。这标志着第二代（非典型）抗精神病药物家族中，又增添了一位实力超群的核心成员。它的上市，为无数精神分裂症患者带来了新的希望，也让医生们在处方时多了一个更安全、更有效的选择。 从一个化学式到一个改变无数人命运的药物，喹硫平的诞生，是那个时代精神药理学发展的缩影，是一个关于“在前辈的肩膀上看得更远”的励志故事。 二、药物圈的“八卦时间”：关于喹硫平的趣闻轶事 1.“思瑞康”的名字玄机 喹硫平的商品名Seroquel，听起来就很高雅。坊间流传一种有趣的解读，认为它可能源于“Serenity”（宁静）和“Quell”（平息）的组合。想象一下，这个名字本身就像一剂安慰剂，暗示着它能“平息”大脑中的风暴，带来内心的“宁...静...”。虽然这并非官方解释，但不得不说，这个解读非常传神，也让这个药名充满了画面感。 2.“超级安眠药”的非官方认证 在临床实践中，喹硫平有一个人尽皆知的“隐藏身份”——超级助眠神器。由于它强大的组胺H1受体阻断作用（后面会详谈），小剂量的喹硫平（如25mg或50mg）能带来排山倒海般的睡意。因此，很多医生会“超说明书”地用它来对付那些顽固性失眠，尤其是在合并焦虑或抑郁情绪的患者中。它甚至在某些圈子里被戏称为“Sero-KILL”，意思是能“杀死”一切清醒的念头。当然，这只是玩笑话，也提醒我们它的镇静作用有多么强大，滥用是绝对不可取的。 3.营销风波与科学争议 任何一个明星药物都免不了身陷舆论漩涡。喹硫平在上市后的推广过程中，也曾因其营销策略和部分临床试验数据的解读而引发争议。有批评者认为，制药公司在宣传中可能过度强调了其优点，而对体重增加、糖尿病风险等代谢副作用的警示不够。这些争议事件也反映了商业利益与纯粹科学之间的复杂关系，提醒着医学界和公众需要始终保持批判性和审慎的态度。这就像一个当红明星，享受着聚光灯，也必须面对狗仔队的“长枪短炮”。 三、揭秘“多面手”的超能力：药理作用与适应症 如果把大脑中的神经递质受体比作一个个不同部门的“锁”，那喹硫平就像一个手持一大串钥匙的“社交达人”，它能和多个部门的“锁”打交道，但又亲疏有别，从而实现了复杂而精妙的调节作用。 药理作用：一位情商极高的“大脑外交官” 喹硫平属于“血清素-多巴胺受体拮抗剂”（SDA），但它的作用远不止于此。 lVS 多巴胺D2受体（主管兴奋、奖赏）：低调的管理者 这是治疗精神病性症状（如幻觉、妄想）的核心靶点。传统抗精神病药是死死地“锁住”D2受体，导致动作僵硬。而喹硫平则像个高情商领导，它和D2受体的结合是“暂时的”、“快速解离的”。这意味着它能恰到好处地降低多巴胺系统的“亢奋”，控制住症状，但又不会完全“锁死”，给了大脑一定的活动空间，所以锥体外系反应（EPS）的风险大大降低。 lVS 血清素5-HT2A受体（主管情绪、认知）：亲密的盟友 喹硫平与5-HT2A受体的亲和力比D2受体高得多。阻断这个受体有多重好处：首先，它本身就有抗精神病作用，能和D2阻断形成“双打组合”；其次，它能反过来促进大脑某些特定区域（如额叶皮层）的多巴胺释放，这有助于改善精神分裂症的“阴性症状”（如情感淡漠、思维贫乏）和认知功能；最后，这个作用还能进一步抵消D2阻断带来的EPS风险。简直是一石三鸟！ lVS 组胺H1受体（主管警觉、食欲）：一见如故的“酒肉朋友” 喹硫平对H1受体的亲和力极高，阻断它会带来两个立竿见影的效果：嗜睡和食欲增加/体重增加。这就是为什么它能当“安眠药”用，也是为什么很多患者服用后会变成“干饭人”。这个“朋友”让你睡得香，但也可能让你的腰围悄悄变粗。 lVS α1-肾上腺素能受体（主管血管收缩）：萍水相逢的“过客” 喹硫平也会阻断这个受体，导致血管扩张。当患者从躺着或坐着突然站起来时，血压可能来不及调整，就会出现头晕、眼黑，甚至摔倒。这就是所谓的“体位性低血压”。好在这个作用通常在用药初期比较明显，身体会慢慢适应。 l特别加分项：代谢产物“去甲喹硫平” 喹硫平在体内代谢后，会产生一个叫“去甲喹硫平”的活性物质。这个“儿子”比“老子”还多一项技能——它能抑制去甲肾上腺素的再摄取（NRI作用），这赋予了喹硫平额外的抗抑郁效果。所以，喹硫平不仅能抗精神病，还能抗躁狂、抗抑郁，堪称“三项全能选手”。 【趣味巧记】 你可以把喹硫平想象成一个**“爱睡觉（H1）、爱美食（H1）、有点晕（α1）、但脑子活（5-HT2A）、不得罪人（D2）”**的“多功能胖和尚”。这个形象是不是一下子就把它的主要特点都记住了？ 适应症：哪里需要哪里搬的“万金油” 基于其独特的药理作用，喹硫平成为了精神科的“多面手”，其官方批准的适应症主要包括： 1.精神分裂症（Schizophrenia）：这是它的“老本行”。对阳性症状（幻觉、妄想）和阴性症状（情感平淡、意志减退）都有效。 2.双相情感障碍（Bipolar Disorder）： l躁狂发作：无论是单独使用还是作为辅助治疗，都能快速控制躁狂症状。 l抑郁发作：这是喹硫平的一大特色。它是少数被明确批准用于治疗双相抑郁的药物之一，这很大程度上要归功于它的代谢产物去甲喹硫平的抗抑郁作用。 l维持期治疗：用于预防躁狂和抑郁的复发。 3.重度抑郁症（Major Depressive Disorder）的辅助治疗：当单一的抗抑郁药效果不佳时，加上喹硫平（通常是缓释剂型）可以起到“1+1>2”的增效作用。 四、“天使”的另一面：主要不良反应和注意事项 没有药物是完美的，喹硫平这位“外交官”也有自己的“小脾气”和“黑历史”。 最常见的不良反应：“三大金刚” 1.嗜睡与镇静：这是最最常见的不良反应，尤其在治疗初期和加量阶段。大部分患者晚上服用后能一觉睡到天亮，但也可能导致白天困倦、没精神。所以，服药期间，开车、操作精密仪器等需要高度集中注意力的活动，一定要格外小心！ 2.体重增加与代谢综合征：这是非典型抗精神病药物的“通病”，喹硫平也不例外。它通过影响组胺和血清素受体，让你食欲大开，同时可能改变身体的基础代谢。长期使用需要警惕“三高”风险：高血糖、高血脂、高体重（肥胖）。这就像一个“卡路里磁铁”，需要通过严格的饮食控制和规律运动来对抗。 3.头晕与体位性低血压：主要发生在刚开始服药或快速增加剂量时。记住一个口诀：“起身要慢，动作要缓”，给身体一个适应血压变化的时间。 其他需要关注的不良反应 l口干、便秘：抗胆碱能作用的体现，虽然比老药轻，但也很常见。多喝水、多吃蔬菜水果可以缓解。 l心跳加快：部分患者可能会感到心慌。 l锥体外系反应（EPS）：虽然风险低，但并非完全没有，尤其在高剂量下。 l催乳素升高：风险远低于利培酮等药物，但少数人也可能出现。 严重警告：“黑框警告” 这是FDA最高级别的警告，印在药品说明书最醒目的位置，必须引起重视。 l增加老年痴呆相关精神病患者的死亡风险：研究发现，使用非典型抗精神病药物治疗这类患者，会增加因心血管事件（如心衰、猝死）或感染（如肺炎）导致的死亡率。因此，喹硫平未被批准用于此目的。 l儿童、青少年和年轻成年人的自杀风险：在用于治疗抑郁症时，喹硫平可能会在治疗初期增加24岁以下患者的自杀意念和行为风险。在此期间，家人和医生需要密切观察患者的情绪变化。 注意事项：医生和患者的“约定” l定期监测：初次服药及服药期间，应定期监测体重、腰围、空腹血糖、血脂和血压。这就像给你的健康状况做“年检”。 l避免突然停药：突然停药可能导致失眠、恶心、呕吐等戒断反应，或引起病情复发。一定要在医生指导下缓慢减量。 l告知病史：如果你有心脏病、癫痫、低血压、糖尿病、肝病等病史，一定要提前告诉医生。 l药物相互作用：喹硫平通过肝脏的CYP3A4酶代谢。如果同时使用能抑制这种酶的药物（如某些抗真菌药、抗生素），会使喹硫平的血药浓度升高，增加副作用风险；反之，使用诱导这种酶的药物（如卡马西平、苯妥英钠），则会降低其疗效。看病时，务必告知医生你正在使用的所有药物。 五、“华山论剑”：喹硫平与它的“兄弟们” 在非典型抗精神病药物这个“江湖”里，高手如云。我们来一场文字版的“华山论剑”，看看喹硫平与奥氮平、利培酮、阿立哌唑这几位“武林高手”相比，各有什么绝招和软肋。 参赛选手介绍： l喹硫平（Quetiapine）：外号“镇静和事佬”。武功特点是柔和全面，擅长安抚躁动，但有点贪吃嗜睡。 l奥氮平（Olanzapine）：外号“强效贪吃巨人”。内力深厚，招式威力巨大（疗效强），但副作用是食量惊人，是江湖中的“体重增长冠军”。 l利培酮（Risperidone）：外号“靠谱的老大哥”。功力扎实，是老一辈非典型药物的代表，但招式里还带着一点传统硬派功夫的影子（EPS和催乳素风险相对高）。 l阿立哌唑（Aripiprazole）：外号“新潮的活力派”。武功路数新颖，是多巴胺系统“部分激动剂”，不主张一味压制，讲究平衡，副作用是可能让人静不下来（静坐不能）。 第一回合：比拼疗效（内力深厚度） 在治疗精神分裂症阳性症状方面，大家的内力普遍被认为旗鼓相当，没有谁有绝对的压倒性优势。不过，“贪吃巨人”奥氮平在一些大规模研究（如CATIE研究）中，被认为综合疗效可能略胜一筹，患者的持续治疗时间更长。但这种微弱优势是以巨大的代谢副作用为代价的。对于改善阴性症状和认知功能，大家各有千秋，没有定论。“活力派”阿立哌唑理论上可能更有优势，但临床证据不一。在抗抑郁方面，“和事佬”喹硫平因其独特的代谢产物，在双相抑郁和重度抑郁辅助治疗领域独占鳌头，优势明显。 第二回合：比拼镇静作用（催眠功力） 这一局，“镇静和事佬”喹硫平和“贪吃巨人”奥氮平并列第一，它们的催眠功力深不可测，是失眠伴随精神障碍患者的福音。“靠谱老大哥”利培酮的镇静作用中等，属于“可以睡，但没那么沉”的水平。“新潮活力派”阿立哌唑则完全相反，它不仅不催眠，甚至可能让人精神、兴奋，导致失眠，适合白天需要保持清醒的患者。 第三回合：比拼体重与代谢（饭量与腰围） 这是大家最关心的环节。“贪吃巨人”奥氮平毫无悬念地夺得“增重之王”的称号，其引起体重增加和血糖血脂异常的风险最高。“镇静和事佬”喹硫平紧随其后，位列第二，也是代谢风险较高的选手。“靠谱老大哥”利培酮居中。“新潮活力派”阿立哌唑则是本场比赛的“瘦身达人”，对体重和代谢的影响最小。 第四回合：比拼锥体外系反应（动作灵活性） 在这一项，“靠谱老大哥”利培酮因为其对D2受体结合更紧，表现最差，是这四位高手中最容易引起手抖、僵硬等EPS的。尤其是剂量较大时，更像传统药物。“新潮活力派”阿立哌唑虽然EPS风险低，但它有一个独特的副作用——静坐不能，表现为内心烦躁，坐立不安，需要不停走动。“镇静和事佬”喹硫平和“贪吃巨人”奥氮平在这一局表现最佳，它们的EPS风险极低，动作非常灵活。 第五回合：比拼催乳素水平（内分泌影响） “靠谱老大哥”利培酮再次“垫底”，它是升高催乳素最明显的药物，可能导致女性月经紊乱、泌乳，男性乳房发育等问题。而其他三位选手——喹硫平、奥氮平、阿立哌唑，对催乳素的影响都非常小，几乎可以忽略不计。 总结一下这场“华山论剑”： l如果你需要强效镇静、治疗失眠，同时又能接受一定的体重增加风险，选喹硫平或奥氮平。 l如果你追求最强的疗效，且代谢问题可以靠后天努力控制，奥氮平可能是个选择。 l如果你看重经济性，对轻微的EPS或催乳素升高不那么敏感，利培酮是个性价比高的选项。 l如果你非常担心发胖、嗜睡，希望白天保持精力，甚至有点情绪低落，那么阿立哌唑可能更适合你。 没有最好的药，只有最合适的药。选择哪个，需要医生根据患者的具体病情、躯体状况、个人偏好和耐受性，进行个体化的权衡。 六、“实战演练”：一分钟看懂用药案例 人物：小陈，22岁，大四学生，最近一个月压力巨大。 症状：小陈开始变得多疑，总觉得同学在背后议论他，甚至能听到有人在耳边说他“没用”。晚上彻夜难眠，情绪激动，坐立不安，有时会突然对家人发脾气。学习完全无法集中，饭也吃不下。 医生诊断：首次发作的精神分裂症样障碍，伴有严重的失眠和激越。 医生的用药思考过程： 1.明确诊断，需要抗精神病药物治疗。 2.首次发作，优选副作用更温和的第二代药物，以保护患者的社会功能，提高依从性。 3.患者目前最突出的问题是失眠和情绪激动。我需要一个镇静作用强的药物，既能治疗精神病性症状，又能帮助他快速入睡，稳定情绪。 4.筛选候选药物： l阿立哌唑？不行，它偏激活，可能会加重失眠和激越。 l利培酮？镇静作用中等，而且EPS和催乳素风险相对高，对年轻人来说不是最优选。 l奥氮平？镇静作用强，疗效好，但体重增加太猛，小陈还年轻，未来生活质量很重要，先不作为首选。 l喹硫平？完美！ 镇静作用强，能解决失眠和激越；EPS风险低，不影响他日后的学习和生活；抗精神病效果也很好。虽然有体重增加的风险，但可以通过宣教让他注意。 5.制定方案：给予富马酸喹硫平片，从低剂量开始，比如睡前25mg或50mg，然后根据耐受性和疗效，在几天内逐渐增加到治疗剂量（如每日300-600mg）。 6.用药教育： l“小陈，这个药吃了会很困，所以一定要在晚上睡觉前吃，吃了就不要再玩手机了。” l“刚开始吃，早上起来或者上厕所突然站起来可能会有点晕，动作慢一点就没事了。” l“这个药可能会让你胃口变好，咱们得一起努力，管住嘴，迈开腿，定期称体重，别让体重‘失控’哦！” 通过这个案例，我们看到，医生选择喹硫平，正是看中了它“镇静和事佬”的特性，精准地解决了患者当下最痛苦的问题。 七、敲黑板划重点 & 大白话总结 【敲黑板划重点】 1.出身：喹硫平是80年代为了寻找氯氮平的“完美替代品”而诞生的第二代抗精神病药，1997年上市。 2.特长：药理作用广泛，是个“社交达人”，能和多巴胺、血清素、组胺等多种受体结合，实现抗精神病、抗躁狂、抗抑郁、强镇静等多重效果。 3.优点：锥体外系反应（EPS）和催乳素升高风险很低，对身体的“控制感”比较温和。 4.缺点：“三大金刚”副作用——嗜睡、体重增加、头晕（体位性低血压），其中代谢问题需长期警惕。 5.江湖地位：在众多同类药物中，以其强大的镇静作用和明确的抗双相抑郁效果而独树一帜，是精神科不可或缺的“多面手”。 6.使用原则：个体化选择，从小剂量开始，缓慢加量，定期监测体重和代谢指标，切忌自行突然停药。 【大白话总结全文】 好了，说了这么多，咱们用一句话总结一下喹硫平到底是个啥。 你可以把喹硫平想象成一个“憨厚能睡的大白”。 当你的大脑里有一群“小恶魔”（精神病性症状）在开派对，吵得你天翻地覆时，“大白”出场了。它不会像个粗暴的保安一样把所有人都打一顿（传统药物的EPS），而是用它那胖乎乎的身体温柔地把大家隔开（温和的D2阻断），同时播放舒缓的摇篮曲（强镇静作用），让整个场子瞬间安静下来，大家都昏昏欲睡。 不过呢，这位“大白”自己也特别爱吃零食（引起食欲增加），所以和它待久了，你可能也会不知不觉地跟着它一起长胖。而且它一出场，你就容易犯困，想干点精细活儿（比如开车）就难了。 所以，喹硫平就是一个能帮你把混乱大脑“哄睡着”的、温和但可能让你长胖的“超级安抚神器”。用不用它，怎么用好它，关键就看你最需要解决的是什么问题，以及你愿不愿意为了这份“宁静”而管好自己的嘴巴啦！