This retrospective real-world cohort study aims to evaluate the effectiveness, safety, and tolerability of the combination of sibutramine and topiramate in the treatment of obesity and overweight associated with metabolic comorbidities in adult patients treated in an outpatient clinical setting. Obesity is a chronic, multifactorial, and progressive disease associated with substantial metabolic, cardiovascular, and psychosocial burden. Although newer anti-obesity therapies such as GLP-1 receptor agonists and dual agonists have demonstrated high efficacy, their elevated cost significantly limits accessibility in low- and middle-income populations and restricts widespread implementation in routine clinical practice. Consequently, there is an increasing need for affordable, accessible, and clinically effective pharmacological strategies for obesity management.
Sibutramine is a serotonin and norepinephrine reuptake inhibitor that promotes appetite suppression and increased satiety, while topiramate is a neuromodulatory agent with anorexigenic effects mediated through GABAergic and glutamatergic pathways. The pharmacological combination of these agents has been increasingly used in clinical practice because of their complementary mechanisms of action and relatively low cost. Previous studies and observational data have suggested meaningful weight reduction and acceptable tolerability with this combination under appropriate medical supervision.
The present study is designed as a retrospective observational cohort based on the review of medical records from adult patients treated between January 2023 and December 2025 at a private outpatient clinic in Brazil. Eligible participants include adults aged 18 years or older with obesity (body mass index [BMI] ≥30 kg/m²) or overweight (BMI ≥27 kg/m²) associated with at least one metabolic comorbidity, including type 2 diabetes mellitus, prediabetes, dyslipidemia, or hypertension. Patients must have received concomitant treatment with sibutramine and topiramate for a minimum period of three months and have documented clinical follow-up with at least two consultations containing anthropometric and clinical information.
Patients with pregnancy, breastfeeding, uncontrolled hypertension, significant cardiovascular disease, severe psychiatric disorders, epilepsy, nephrolithiasis, glaucoma, severe renal or hepatic disease, or concomitant use of medications known to significantly interfere with body weight will be excluded. Records lacking sufficient anthropometric or clinical follow-up information will also be excluded from analysis.
Data extracted from medical records will include demographic variables, baseline body weight, BMI, treatment duration, medication doses, percentage weight change over time, adherence to follow-up, eating behavior control, and adverse events reported during treatment. All information will be anonymized before analysis. No identifiable personal information, including names, telephone numbers, addresses, or identification numbers, will be collected. Data will be stored in password-protected electronic databases accessible only to the principal investigator.
The primary outcome is the percentage change in body weight and BMI during treatment with the sibutramine-topiramate combination. Secondary outcomes include the proportion of patients achieving clinically significant weight loss thresholds (≥5%, ≥10%, and ≥15%), early treatment response defined as ≥3% body weight reduction within the first month, treatment adherence, tolerability profile, frequency of adverse events, and subgroup analyses according to age, sex, baseline BMI, and medication dose.
Statistical analyses will include descriptive statistics, paired parametric or nonparametric comparisons, and exploratory regression analyses to identify predictors of therapeutic response. Statistical significance will be established at p<0.05.
Because this is a retrospective observational study using exclusively secondary data from medical records, the protocol is classified as minimal risk. There will be no direct patient contact, no intervention, and no modification of standard medical care. The study was approved by the Research Ethics Committee of the Hospital Universitário Cassiano Antônio de Moraes / Federal University of Espírito Santo (HUCAM/UFES), Brazil, under approval number 8.403.776 and CAAE 94334125.7.0000.5071.

开始日期2026-06-01

申办/合作机构-

NCT05209984

/ Withdrawn临床3期

A Phase 3, Randomized, Double-blind, Double-dummy, Parallel-group, Active Drug and Placebo-controlled, Safety, Efficacy and Superiority of Sibutramine IR/Topiramate XR in Overweight Adults With Comorbidities/Obesity

A phase 3, multicenter, randomized, double-blind, double-dummy, parallel-group, active-drug- and placebo-controlled clinical trial to assess the safety, efficacy and superiority of the new fixed-dose combination sibutramine IR/topyramat XR in weight reduction in overweight adults with comorbidity(ies) or obesity

开始日期2026-04-01

申办/合作机构

Eurofarma Laboratórios SA

IRCT201012275483N1

/ CompletedN/AIIT

The effect of low calorie diet with and without sibutramine on metabolic syndrome risk factors and sonographic findings in non alcoholic fatty liver

开始日期2010-04-18

申办/合作机构-

100 项与盐酸西布曲明水合物相关的临床结果

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100 项与盐酸西布曲明水合物相关的转化医学

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100 项与盐酸西布曲明水合物相关的专利（医药）

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806

项与盐酸西布曲明水合物相关的文献（医药）

2025-08-30·JOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE

Global insights into food fraud from location‐based analysis: food adulteration in Turkey

Article

作者: Ozalp, Veli Cengiz ; Kavruk, Murat ; Aydın, Ali ; Balcı, Tuğçe Nur ; Özel, İrem Çağla

Abstract:

Background:

Food fraud and adulteration pose critical global challenges impacting economic stability and public health. This study examines the prevalence and characteristics of food fraud incidents in Turkey, an international player in the food supply chain. Controls carried out from production to consumption reveal many fraudulent events worldwide.

Results:

Data collected by the Ministry of Agriculture and Forestry of Türkiye from 2012 to 2022, covering 4007 incidents and 7180 specific cases of adulteration, form the basis of this analysis. The study categorizes food fraud by region, product group and type of fraud, revealing trends and patterns. Key findings indicate a higher incidence of fraud in milk, meat and vegetable oil products, including the detection of drug‐based adulteration having potential for serious health consequences.

Conclusion:

At most importance, we demonstrated the importance of risk‐based food inspections and the development of new detection technologies to enhance food safety. The results are fundamental for more effective food inspections in terms of risk‐based conformity assessment approaches or developing new methods, devices and analysis kits in terms of scientific and technological approaches. Still, they can also significantly improve future food safety measures. These insights are aimed at informing global food safety strategies and policymaking, contributing to a safer and more transparent food supply chain. © 2025 The Author(s). Journal of the Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

2025-07-01·Personalized Medicine in Psychiatry

Approaches to mitigate weight gain associated with antipsychotic use

作者: Meriden, Zina ; Tran, Faith ; Urbonas, Rebecca ; Barnes, Alexaundria

Antipsychotics are vital in the management of multiple psychiatric disorders.Weight gain is a common adverse effect that can impact quality of life and long-term adherence to treatment.The goal of this literature review is to explore posited mechanisms for antipsychotic-induced weight gain (AIWG) and review proposed nonpharmacol. and pharmacol. interventions to mitigate this weight gain.An electronic literature search was performed on PubMed to identify full-text, English-language articles that discussed AIWG.Selected articles were published between 2000 and 2024.Findings from 68 articles were reviewed and discussed. 27 strategies/agents of varying efficacies were identified.Non-pharmacol. interventions exhibit data in being effective against AIWG.Switching to an antipsychotic with a more favorable side-effect profile can be an appropriate option, but it is associated with an increased risk of relapse.Metformin is the most widely accepted and researched adjunctive treatment, followed by liraglutide and samidorphan.Dulaglutide, semaglutide, topiramate, betahistine, amantadine hydrochloride, berberine, probiotics, dietary fiber, nanoparticle formulation, and reboxetine show promising results in the attenuation of AIWG but need further research to understand their efficacy, metabolic effects, and safety.Melatonin, vitamin D, orlistat, modafinil, and naltrexone currently have very little data and have yet to exhibit compelling results.Lorcaserin, rimonabant, and sibutramine have all been removed from the market in the United States and are not recommended.Data on AIWG is diverse, but scarce.Further research is needed to better understand the pathophysiol. of AIWG and explore long-term effectiveness and safety of promising pharmacol. therapies in this vulnerable patient population.

2025-06-01·FOOD CHEMISTRY

High-throughput screening of new psychoactive substances and related compounds in food by UHPLC-Q/Orbitrap

Article

作者: Huang, Xia ; Wan, Yuping ; Shi, Peiyu ; Wu, Wenlin ; Xiao, Quanwei ; Liu, Shiyao ; Guo, Tianrong ; Chen, Xiaoqi ; Zhou, Yan ; Zhang, Min ; Xia, Bing

Currently, there is concern about food products to which new psychoactive substances (NPS) have been added illegally. However, rapid, high-sensitivity, and high-throughput screening methods for such harmful substances have not been reported yet. In this study, a high-throughput non-targeted screening strategy was developed based on UHPLC-Q/Orbitrap. First, optimized pretreatment methods for typical high-risk matrices were established. Second, an accurate, efficient, and scalable high resolution mass spectrometry database containing 206 NPS and related compounds was constructed. The fragmentation pathways of three different types of fentanyl-related compounds were then systematically investigated to enhance compound identification. Additionally, a non-targeted screening strategy was developed using warning ions derived from 24 fentanyl-related compounds, streamlining the identification of NPS. This strategy was applied to 100 food samples with possible illegal additives and demonstrated its effectiveness. In summary, this study provides robust technical support for regulatory authorities in combating the illegal addition of food products.

106

项与盐酸西布曲明水合物相关的新闻（医药）

2026-09-17

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中医药调控AMPK信号通路治疗类风湿关节炎的研究进展

摘要：类风湿关节炎(rheumatoid arthritis,RA)是一种以滑膜炎、关节侵蚀和软骨损伤为表现的系统性自身免疫性疾病,病情严重时可影响心脏、肺部等器官以及神经系统,对患者的身心健康构成重大威胁。中医药治疗RA具有多靶点、多途径的作用特点,且不良反应发生率较低,在临床应用中展现出独特优势。研究表明中药活性成分及其复方可通过调控腺苷酸活化蛋白激酶(AMPK)信号通路,抑制炎症因子表达、减轻骨组织破坏,并缓解关节疼痛症状,从而有效控制RA病情进展。基于此,本文旨在深入探讨AMPK信号通路与RA之间的关系,总结中医药调控AMPK信号通路治疗RA的研究进展,以期为RA的临床治疗及新型药物的研发提供参考。关键词：类风湿关节炎;AMPK信号通路;研究进展引用格式： [1]孙文超,刘春龙,扈有芹.中医药调控AMPK信号通路治疗类风湿关节炎的研究进展[J].中国中医基础医学杂志,2025,31(12):2285-2289. DOI:10.19945/j.cnki.issn.1006-3250.20250623.001. 中医 ZGZYJC 类风湿关节炎(rheumatoid arthritis,RA)是临床最常见的自身免疫性疾病,与免疫过度激活有关,主要影响关节和关节周围软组织,患者会出现疼痛、肿胀及屈伸不利等症状[1]。若治疗不及时,严重者可出现关节畸形,累及心、肺等内脏器官和神经系统,预后十分不良[2]。流行病学调查显示,我国RA发病率约为0.32%～0.36%[3],该病可发生于各年龄段,其中40岁以上人群的发病率相对较高,且女性患病率为男性的2～3倍[4]。RA病因不清,发病机制复杂,临床治疗以缓解症状和延缓病情进展为主要目标,常用药物包括缓解病情抗风湿药、糖皮质激素及生物制剂等。然而,长期使用这些药物可能导致肝肾功能损害、骨髓抑制、皮疹、脱发及药物依赖等不良反应[5-6]。近年来,中医药在RA治疗方面取得显著进展,其多途径、多靶点的作用机制以及较高的安全性已获得广泛认可[7-8],为临床实现增效减毒提供了新的治疗选择。研究表明,通过分离提取获得的中药活性成分可调控多种信号通路,从而发挥治疗RA的作用[9-11]。腺苷酸活化蛋白激酶(AMPK)是众所周知的细胞能量传感器之一,可调节各种细胞类型的代谢途径[12],且在调节细胞生长、迁移和免疫反应等方面发挥作用[13]。本文就AMPK通路及近年来中药经AMPK信号通路治疗RA的实验研究进行归纳概括,旨在为治疗RA提供思路。1 AMPK信号通路概述 AMPK是一种进化上高度保守且在真核细胞中普遍表达的丝氨酸/苏氨酸蛋白激酶,它各由一个α-催化亚基、β-调节亚基及γ-调节亚基构成异源三聚复合物体[14],其中α-亚基有α1和α2两个亚型,β-亚基有β1和β2两个亚型及γ-亚基有γ1、γ2和γ3三个亚型,三者分别以1:1:1的比率相互作用,可形成12种不同的组合形式[15]。AMPK被发现可以追溯到1973年,Ki-han Kim等首次观察到乙酰辅酶A羧化酶(ACC)的部分纯化制剂在与ATP孵育后以时间依赖性方式失活[15],据报道3-羟基-3-甲基戊二酰辅酶A(HMG-CoA)还原酶也有类似的情况发生[16]。后续研究证实这两者是同一种产物,最终将其命名为AMPK。AMPK是调控细胞内能量平衡的能量传感器之一,对ATP/AMP比值的变化感知非常敏锐[17],在机体能量较低的情况下,AMPK中hr-172位点在α-亚基的催化下发生磷酸化,从而激活AMPK信号通路。2 AMPK信号通路与RA AMPK通路与RA联系密切,研究发现在新诊断的RA 患者外周血白细胞中,AMPK的表达水平显著降低[18],一些药物通过激活AMPK信号传导显示出抗类风湿作用[19-20]。RA是以对称性关节肿痛、晨僵为主要临床表现的免疫系统疾病,而滑膜细胞大量增生黏附于关节软骨表面形成的血管翳是引起关节病变、软骨破坏的主要原因及病理基础,细胞自噬失调与该过程密切相关。自噬是一种细胞内过程,它决定蛋白质的最终去向及其功能。AMPK信号通路在细胞自噬调控中起关键作用[21]。AMPK通过其下游靶点哺乳动物雷帕霉素靶蛋白(mTOR)调控蛋白质合成与代谢,二者在功能上存在密切关联。有研究发现RA患者滑膜组织中mTOR活性显著升高[22],这使得mTOR成为RA治疗的重要研究方向[23]。同时,AMPK的激活可导致mTOR活性的抑制,进而调控细胞自噬和凋亡过程。其中,unc-51样自噬激活激酶1(ULK1)作为自噬起始的关键调控因子,其磷酸化状态受AMPK/mTOR等多条信号通路调控[24]。具体而言,AMPK通过诱导ULK1磷酸化促进自噬启动,而mTOR则通过抑制ULK1活性阻碍自噬进程。此外,AMPK通路也通过调控细胞自噬参与疼痛调节过程。作为ULK1和Ⅲ型磷脂酰肌醇3-激酶(PIK3C3)的上游激酶,AMPK可通过双重机制调控自噬:一方面,内源性镇痛物质如集落刺激因子1(CSF1)和脂多糖(LPS)可促进ULK1磷酸化和LC3-Ⅱ表达,诱导自噬并增加促炎因子释放[25];另一方面,AMPK直接磷酸化ULK1的Ser317、Ser555和Ser777位点[26-27],同时通过抑制mTORC1通路间接激活自噬。AMPK还可通过磷酸化PIK3C3来增强自噬活性[28]。总的来说,AMPK可能通过控制自噬过程中的各种激酶来调节疼痛。AMPK活性抑制可导致痛觉过敏,这一过程与NOD 样受体蛋白3(NLRP3)炎性小体的激活密切相关,同时伴随血清白细胞介素(IL)-1β和IL-18水平的显著升高[29]。 RA骨破坏主要是由于大量炎性细胞因子如IL-6、肿瘤坏死因子(TNF)-α等激活破骨细胞所致。AMPK/核因子-κB受体活化因子配体(RANKL)/骨保护素(OPG)系统是骨代谢过程中的一个重要信号通路,RANKL促进破骨细胞的分化,OPG通过与RANKL竞争性结合,减少RANKL与RANK之间的相互作用,从而抑制破骨细胞的成熟和活化,防止骨流失[30],而AMPK通过调节RANKL表达水平也能达到骨保护的目的[31]。另外,董伟[32]研究表明细胞在高糖环境下,唑来膦酸盐通过调控AMPK/OPG/RANKL通路可以实现骨分化与生成的提高。国外研究证实AMPK激活剂可上调OPG表达并降低RANKL mRNA水平,从而促进成骨细胞增殖[33]。再者,RA患者关节腔内缺氧主要源于滑膜细胞过度增殖和炎症细胞浸润[34]。为适应缺氧环境,细胞主要从氧化磷酸化转变为糖酵解途径以维持能量供应[35],糖酵解是糖代谢中的一种,当RA滑膜细胞中的糖酵解代谢途径增加时,代谢物乳酸的存在会加剧关节组织中缺氧的出现,促进滑膜细胞异常活化,并进一步促进滑膜增生和血管新生。糖酵解抑制剂2-脱氧葡萄糖(2-DG)可能通过激活AMPK通路减少抗凋亡蛋白B淋巴细胞瘤-2(Bcl-2)的表达,从而抑制血管内皮细胞活化[36]。综上所述,AMPK信号通路在RA的病理过程中发挥多重调控作用,不仅参与滑膜炎症反应,还影响骨代谢过程,并与疼痛调节密切相关。AMPK信号通路贯穿RA发生发展的全过程,这为探索中医药治疗RA的作用机制提供了新的研究方向。深入阐明AMPK信号通路在RA中的作用机制,将为开发基于该通路的中医药治疗方案奠定重要理论基础。3 中医药经AMPK信号通路治疗RA研究进展 RA在中医学中归属为“痹证”“尪痹”等范畴。《素问·痹论篇》载“风寒湿三气杂至,合而为痹也”,著名中医药专家焦树德认为“复感三邪,内舍肝肾”,因此笔者认为RA主要是由风、寒、湿三邪相合而外袭机体,加之体内肝肾功能不足,外实内虚,发为痹证。实验证实中药有效成分及复方可通过调控AMPK通路在治疗RA中发挥关键作用,故总结以下,以供参考。3.1 中药有效成分白芍总苷是从白芍中提取的糖苷类活性物质,具有镇痛、抗炎、抗氧化和免疫调节等作用。白芍总苷不仅临床治疗RA效果良好,还具有护肝作用,与西药联合使用能降低不良反应出现的频率[37]。徐婉等[38]发现白芍总苷能够改善胶原诱导性关节炎(CIA)模型大鼠关节破坏,降低致炎因子TNF-α、IL-6、IL-1α的生成及RANKL的表达,提高p-AMPK和OPG的表达,其可能通过激活AMPK蛋白磷酸化进而调控RANKL/OPG信号通路来发挥对RA的靶向骨保护作用。黄连苦寒,具有清热燥湿、泻火解毒之功,小檗碱是其生物碱类化合物中最主要的有效成分,主要通过抑制相关靶蛋白阻碍炎症信号的传导,使下游蛋白的表达受到影响,进而显现出良好的抗炎作用。AMPK是小檗碱的作用靶点之一,实验发现在佐剂诱导关节炎(AA)大鼠模型中,小檗碱可上调滑膜巨噬细胞中p-AMPK的表达,同时下调缺氧诱导因子(HIF)-1α的表达,进而调控巨噬细胞极化,改善AA大鼠的炎症反应,故小檗碱的抗关节炎作用可能与通过AMPK/HIF-1α 通路调节巨噬细胞的能量代谢有关[39]。蛇床子素是从蛇床子成熟果实中提取的天然香豆素类化合物,具有多种药理活性,可抗炎止痛、抗肿瘤、抗衰老、抗菌杀虫止痒等,对免疫系统也有调节作用。Jiang等[40]研究发现,蛇床子素通过激活AMPK通路抑制NLRP3炎症小体的激活及减少炎症因子的分泌,明显改善CIA大鼠关节的炎性细胞浸润、软骨破坏和滑膜增生等病理改变,并降低关节炎指数评分。瑞香素最早是从长白瑞香中提取而来的一种天然活性成分,药理学研究表明其有抗炎、抗癌、镇静等疗效。冷雨等[41]通过实验证实瑞香素可能通过激活AMPK/mTOR信号通路促进IL-1β诱导的关节软骨细胞自噬,抑制细胞凋亡进程,从而发挥关节软骨保护作用。啤酒花又称忽布、蛇麻花,有健胃消食、利尿安神、抗痨消炎之功用,其活性成分黄腐酚被证明有防治RA的效果[42]。通过给CIA大鼠注射黄腐酚,可促进AMPK通路激活,上调核因子E2相关因子2(Nrf2)抗氧化信号,降低线粒体活性氧(ROS)水平,从而抑制NLRP3炎性小体反应,受到NLRP3炎性小体调控的IL-1β分泌也相应降低,故炎症减轻,关节炎疼痛得到缓解。五味子的重要活性成分五味子木脂素药理作用广泛,不仅对人体的多个器官及系统具有保护作用,还具有抗炎免疫、抗肿瘤和抗菌等功效。范紫微等[43]发现五味子木脂素能使AMPK的表达水平升高,阻滞mTOR的生成,而调控自噬小体与溶酶体结合的自噬相关(ATG)5,ATG7和ATG12表达水平也显著提高,其机制可能与促进AA大鼠滑膜细胞的自噬水平相关。大黄素是大黄中提取的活性成分之一,在各种疼痛模型中均表现出有效的抗疼痛和抗炎作用。Cheng等[44]研究发现大黄素能够与AMPK结合呈现出相对稳定的对接结果,通过促进其活性,抑制 NLRP3炎性小体反应,提高抗氧化反应,提高 CIA 小鼠的疼痛阈值,并恢复其运动协调性。柚皮素具有抗炎、抗癌和调节免疫活性等作用。研究发现,柚皮素激活 AMPK通路会启动自噬并抑制巨噬细胞活化,多种炎症介质的释放也相应减少[45]。常用藏药翼首草中含量最高的成分吴茱萸苷被证实通过提高AMPK磷酸化上调沉默信息调节相关酶1(Sirt 1)的表达,借此抑制核转录因子(NF)-κB信号的活化,从而降低成纤维样滑膜细胞的增殖和迁移,改善炎症反应[46]。且有研究证明紫草素通过调控p-AMPK和p-ULK1水平升高及p-mTOR表达降低,从而调节AMPK/mTOR/ULK1通路诱导细胞凋亡和自噬细胞死亡,导致自噬水平升高进而减少RA滑膜成纤维细胞持续增殖,延缓RA病情进展[47]。3.2 中药复方及外治法王为兰教授认为RA多因外来风寒湿邪或内生湿邪,困于机体不解,化热伤阴,灼津酿毒,致成痹热,以清热解毒、化浊除湿、通督止痛为治疗原则,由此创立了清热养阴除湿汤,用于RA急性期治疗。清热养阴除湿汤可能通过调控AMPK信号通路,调节T细胞能量代谢紊乱状态,改善其合成代谢功能,恢复细胞氧化还原稳态,从而降低炎症反应、缓解RA症状[48]。蠲痹汤出于程钟龄《医学心悟》,有祛风除湿、蠲痹止痛之效,临床上用于治疗RA、骨关节炎等效果显著。郑永智等[49]研究发现,经蠲痹汤干预后,大鼠软骨细胞的炎症反应与凋亡被抑制,有效保护软骨细胞被进一步损害,其作用机制可能与靶向调控AMPK/磷酸酶及张力蛋白同源物诱导的蛋白激酶1(PINK1)/E3泛素连接酶(Parkin)通路所介导的线粒体自噬有关。刘健教授结合自身多年临床经验,提出RA以脾虚为本、湿浊痰瘀为标的病机理论,主张采用健脾化湿通络法从脾论治RA,其中自制黄芩清热除痹胶囊经研究证明具有抗氧化、抗炎作用,其机制可能是通过抑制IL-1β等促炎因子的分泌,从而激活AMPK信号通路,直接磷酸化叉形头转录因O亚型3a(FOXO3a)增强其转录活性,提高机体抗氧化能力,保护细胞免受氧化应激损伤[50]。艾灸作为中医传统外治法之一,不仅温经通络,还可抗炎、调整人体免疫的功能,在治疗RA方面疗效显著。刘梨等[51]研究发现通过艾灸大鼠“足三里”“关元”穴位,可激活AMPK通路,促进自噬、缓解炎症反应,其机制可能与AMP含量、AMPK和液泡蛋白质分选34(VPS34)表达量、ULK1和ATG13mRNA表达水平提高有关。4 结语与展望 RA是临床中常见的全身性自身免疫性疾病之一,我国RA的患病率约在0.32%～0.36%,患病群体规模庞大,开发更有效且低风险的治疗药物是当前RA治疗的首要任务。中医药以其疗效确切、成本低廉和安全性高的优势,在RA诊治中发挥着重要作用。AMPK信号通路在细胞能量代谢方面起关键作用,具有潜在治疗价值,多种中药有效成分及复方在实验中已直接或间接证明了其可以通过调节AMPK通路抑制炎症反应、调节糖脂代谢、调节自噬过程和调控AMPK上下游的信号通路等方式,减轻RA症状,起到延缓病情发生发展的作用。通过分析,本文发现还有以下不足:①中药品类繁多,具有补肾壮骨、补益肝肾、清热利湿、活血通痹等功效的中药甚多,其他相似功效中药是否同样通过AMPK信号通路治疗RA需深入探索;②本文所举实验大多为动物实验研究,缺乏临床试验证据,其药物进入人体后的有效浓度、量效关系尚有待进一步探索;③部分中医药调控AMPK信号通路治疗RA的研究结果停留在相关性研究,研究深度欠缺;④AMPK作为能量传感调节剂,与多条通路相关,需进一步探索通路间的交互作用。未来通过科研工作者的持续探索,有望进一步阐明RA的发病机制,为RA的治疗提供新的理论依据和治疗策略,提升临床治疗效果。利益冲突:本文不存在任何利益冲突。参考文献： [1] BROWN P,PRATT A G,HYRICH K L.Therapeutic advances in rheumatoid arthritis[J].BMJ,2024,384:e070856. 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2026-09-14

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FDA的DDI表格：底物/抑制剂/诱导剂到底怎么选、怎么读

打开FDA官网那张"Table of Substrates, Inhibitors and Inducers"，很容易被当成一份简单的清单。这张表本质是一份经过临床证据筛选的"参考地图"，不是可以直接落地的操作手册：同一页里有体外探针、有临床探针，有给底物看的、也有给促变药（perpetrator，引起相互作用的一方）看的，分级阈值还分通用和CYP3A特殊两套。看错一个门槛，可能把一个强抑制剂当成弱抑制剂放过。 2020年1月23日，FDA同时定稿发布了两份DDI指南——《体外药物相互作用研究》和《临床药物相互作用研究》（均为细胞色素P450酶和转运体介导）[1,2]。2024年5月，ICH M12作为全球统一的DDI指导原则正式定稿[3]。国内NMPA也在2021年1月更新了《药物相互作用研究技术指导原则（试行）》[4]。规则在趋同，但表格怎么读、探针药怎么选，依然是CRO和药企研发每天要面对的具体问题。这篇就拆解这张表的读法，把藏在表头背后的判断逻辑讲透。表格给的是"哪些药可以作为证据"，而不是"你的化合物该怎么做"。把参考工具当操作手册用，是DDI策略里最常见的一类误判。 FDA这张表，到底是什么先搞清楚这张表的性质。它挂在FDA的"Drug Interactions Labeling"栏目下，是一份动态维护的参考清单，不属于具有法律约束力的指南文件。FDA自己反复强调，所有列表都"非详尽"——这意味着表上没有的药，不代表没有相互作用；表上有的药，也只是"有充分临床证据支持其分类"的那一批。表格按用途分成两大板块。一块是给体外研究用的：体外探针底物、体外抑制剂、体外诱导剂，这些是你在实验室里做酶表型鉴定、抑制剂筛选时选的阳性对照和工具药。另一块是给临床研究用的：临床指针底物（index substrate）、临床抑制剂、临床诱导剂。这两套表的逻辑完全不同，用错地方就会出问题。还有一点常被混淆：FDA官网上其实有两张容易搞混的表。一张面向药物研发，叫"Table of Substrates, Inhibitors and Inducers"，颗粒度细、体外和临床全覆盖；另一张面向医护人员，叫"Examples of Drugs that Interact with CYP Enzymes and Transporter Systems"，是给处方决策用的速查清单，更简洁也更贴近临床场景。研发阶段拿错表，等于把别人为临床速查写的措辞，硬套到体外实验设计上。体外那套表里，FDA推荐的CYP探针底物是经典组合：CYP1A2用非那西丁（phenacetin，O-脱乙基反应），CYP2C9用甲苯磺丁脲或S-华法林，CYP2C19用S-美芬妥英，CYP2D6用右美沙芬或丁呋洛尔，CYP3A4/5用咪达唑仑（midazolam）和睾酮（testosterone）。注意CYP3A这里用了两个结构不相关的底物——FDA明确建议，CYP3A的抑制评估要用两种底物平行做，如果两个都被抑制，才需要往体内推进。临床那套表则是另一批药：CYP1A2的临床指针底物是替扎尼定（tizanidine）和咖啡因，CYP3A是咪达唑仑、三唑仑、辛伐他汀，CYP2D6是地昔帕明和右美沙芬。替扎尼定和咖啡因都在表上，但在评估CYP1A2抑制时，两者的"分辨率"天差地别，这个后面用真实案例讲。强中弱不是形容词，是有数字门槛的 "强抑制剂""弱诱导剂"这种说法，日常讨论里经常被当形容词用。在监管语境下，它们是精确的定量标签，门槛写在指南里。 FDA 2020版指南、ICH M12和NMPA 2021版指导原则给出的CYP抑制剂/诱导剂分类标准已经高度一致，具体如下：类别抑制剂：敏感指针底物AUC升高诱导剂：敏感指针底物AUC下降强 ≥5倍 ≥80% 中 ≥2倍且<5倍 ≥50%且<80% 弱 ≥1.25倍且<2倍 ≥20%且<50% （数据来源：FDA 2020临床DDI指南[2]、ICH M12[3]、NMPA 2021指导原则[4]）几个容易忽略的限定词。分类通常基于治疗剂量范围内的最高剂量和最短给药间隔——同一药物在低剂量下可能只是中等抑制剂，加量后可能变成强抑制剂，效应有剂量依赖性。诱导剂的阈值方向是"下降"，一个让AUC掉了70%的诱导剂算中等，掉了85%才算强。弱抑制剂的1.25倍下限也不是随便定的，它对应的是"与默认的80%–125%无效应边界刚好咬合"。这套阈值只管CYP酶。转运体和非CYP代谢酶（UGT、MAO等）目前没有官方统一的强中弱分类系统——ICH M12在5.3.2节明确写了这一点。所以当有人问"环孢素算不算强转运体抑制剂"时，严谨的答案是：它是一个强效的OATP1B1/BCRP/P-gp抑制剂，但这个"强"是描述性的，不像CYP那样有监管定义的数字门槛。底物也分三六九等：敏感、中等敏感、窄治疗窗抑制剂有分级，底物同样有。区分底物类型，比记住抑制剂分级更影响DDI研究的成败。敏感底物（sensitive substrate）指的是：与某代谢途径的强抑制剂合用时，AUC升高达到或超过5倍的药物。中等敏感底物对应AUC升高2到5倍。还有一类叫窄治疗窗底物（narrow therapeutic range substrate），它的判据不是AUC涨了多少，而是"暴露量增加可能引发严重安全性问题"——典型如治疗窗极窄、AUC一涨就可能导致尖端扭转型室速的底物。这两类底物在开发中的处理方式完全不同。如果候选药是敏感底物，DDI研究的结论会很直接、影响也大；如果是窄治疗窗底物，即便AUC只涨了1.5倍，也可能需要在说明书里写禁忌或剂量调整。敏感底物决定的是"相互作用有多容易被看穿"，窄治疗窗底物决定的是"看穿了之后有多要命"。前者关乎研究设计，后者关乎安全边界。底物的敏感度不是拍脑袋定的。一个底物算不算敏感，核心看特定代谢途径对它的代谢分数（fm，fraction metabolized）——当某条通路的fm超过80%，完全抑制这条通路通常会让AUC升高5倍以上，这样的底物才有资格当"指示器"。fm偏低、或者有多条清除途径兜底的药物，即便通路上被抑制，暴露量也未必明显变化。 FDA表格里，CYP3A的敏感底物一栏列得最长：咪达唑仑、三唑仑、辛伐他汀、洛伐他汀、布司哌隆、非洛地平、西地那非等。这不是说CYP3A的底物多，而是因为CYP3A是最主要的药物代谢酶，约一半的临床药物走这条路，被研究得也最透。挑cocktail探针药：在特异性和灵敏度之间走钢丝当你的候选化合物可能同时影响多个酶时，逐个做单项DDI研究代价太大。cocktail（鸡尾酒）研究法把多个探针底物一次性给药，在一次试验里同时评估对多种酶/转运体的影响，效率高得多。挑探针药有两条硬标准，ICH M12在3.2.6节写得清楚：探针底物对特定的CYP酶或转运体要有特异性；探针底物之间不能有DDI。不满足这两条，就得清楚知道它的非特异性有多大、探针之间有没有互作，并在解读结果时把这些因素纳进去。常用的组合有两套经典版本。Basel cocktail覆盖CYP1A2、2B6、2C9、2C19、2D6、3A4；Geneva cocktail在此基础上加了非索非那定（fexofenadine）来测P-gp。转运体cocktail方面，地高辛（P-gp）、呋塞米（OAT1/3）、二甲双胍（OCT2/MATE）、瑞舒伐他汀（OATP1B1/1B3和BCRP）按优化剂量组合已有验证数据，被证明彼此无互作。微剂量cocktail是另一个方向：用10微克咪达唑仑加375微克达比加群酯、10微克匹伐他汀等极低剂量，安全性更高，适合早期探索。但这里有个坑——微剂量得到的结果不一定能外推到治疗剂量，ICH M12专门提醒过这一点。达比加群在微剂量和临床剂量下的外推差异，就是常被引用的反例。图1：cocktail探针药组合示意图——Basel/Geneva cocktail的酶覆盖网络，以及各探针药的靶点映射 ① 共享靶点（青色实线，3 个）：CYP1A2（咖啡因）、CYP2C19（奥美拉唑）、CYP3A4/3A5（咪达唑仑）——两套鸡尾酒用的是同一个探针药，这也是两套方案之间可以直接互认的部分。 ② 各自选择（琥珀虚线，3 个）：这是两套方案最核心的差异所在—— 2B6：Basel 用依非韦伦，Geneva 用安非他酮 2C9：Basel 用氯沙坦，Geneva 用氟比洛芬 2D6：Basel 用美托洛尔，Geneva 用右美沙芬 ③ Geneva 独有（玫红）：非索非那定 → P-gp。Basel 不含转运体探针，Geneva 把外排转运体也纳进了同一个面板。分级的尽头：临床替代方案与"不做的艺术" 体外研究先当第一道筛子。FDA和NMPA都给了明确的体外阈值：可逆抑制用R₁判断，肝脏R₁≥1.02、肠道R₁,gut≥11就需警惕；时间依赖性抑制（TDI，time-dependent inhibition）用R₂判断，R₂≥1.25提示有风险；诱导则看mRNA变化是否≥2倍，或静态模型预测的AUCR是否≤0.8。这些数字背后的逻辑是——只有体外信号强到一定程度，才值得花钱进临床。到了临床层面，替代方案越来越丰富。内源性生物标志物（endogenous biomarker）可以在不额外给探针药的情况下反映酶或转运体的活性变化：4β-羟基胆固醇/胆固醇比值和尿液6β-羟基可的松/可的松比值反映CYP3A活性，血浆粪卟啉I（CPI）反映肝OATP1B1/1B3，血浆吡哆酸和N1-甲基烟酰胺分别对应OAT1/3和OCT2/MATE。如果给药后CPI的Cmax和AUC与基线比值小于1.25，就提示OATP1B抑制介导的临床DDI可能性低。PBPK（基于生理的药代动力学）模型也在承担越来越多的"减免"任务，强抑制剂的阴性结果往往可以用来豁免对中弱抑制剂的进一步研究。结果的外推也有方向性。强抑制剂的临床研究给出阴性结果，通常可以顺势豁免对中、弱抑制剂的进一步研究——最强的情况都没事，更弱的更不必单独做。反过来不成立：强抑制剂测出阳性，并不能直接推断中等或弱抑制剂也存在相互作用，那需要单独试验，或者靠经过验证的PBPK模型来支持。但替代方案有边界。内源性标志物并非都经过充分验证，灵敏度、特异性、日常波动都会受饮食、年龄、疾病状态干扰；PBPK在"转运体加代谢"这种复杂相互作用里外推并不可靠，OATP1B1的体外Ki值经常撑不起临床DDI的定量预测。用替代方案省下的临床研究，前提是你清楚它省得对不对。规则的价值不在于逼你多做几个试验，而在于帮你证明——有些试验，真的可以不做了。前提是，你得读得懂规则给出的每一个门槛。实操踩坑指南表格读过、阈值记住，真正让项目翻车的是下面这类具体操作。三个真实发表的案例，各有各的坑。案例一：选错探针底物，把强抑制剂看成了"没风险" 背景是上世纪90年代末，默沙东的罗非昔布（rofecoxib）在做DDI评估，需要判断它对CYP1A2的抑制作用。错误做法是用茶碱（theophylline）作为CYP1A2的探针底物。茶碱缺乏明显的首过效应，自身清除受CYP1A2影响的比例也不算高，对酶活性变化的"分辨力"很弱。后果是罗非昔布对茶碱的AUC只抬高了约1.5倍，结论看上去是"轻微或无临床意义"。直到换上替扎尼定（tizanidine）——一个首过效应强、暴露量对CYP1A2活性极度敏感的底物，同一个罗非昔布让替扎尼定的AUC暴涨约13.6倍。强抑制剂直到这时才现形。正确做法是：评估抑制剂对某条通路的影响，要选对该通路最敏感的指针底物，而不是手边最方便、最常用的那个底物。这条经验后来被写进了FDA的表格——CYP1A2的临床指针底物里，替扎尼定的优先级被明确标出。关键Takeaway：底物的敏感度决定了你能否看见相互作用，选错底物等于给研究戴上了墨镜。案例二：只看体外IC50，忽略代谢物机制，一款药因此撤市背景是拜耳的西立伐他汀（cerivastatin），它经CYP2C8和CYP3A4代谢，与吉非贝齐（gemfibrozil）联用会显著升高其暴露量。错误做法是：早期体外实验发现吉非贝齐对CYP2C8的抑制很弱，就按照当时的体外数据判断联用风险可控。问题在于，真正起作用的是吉非贝齐的葡糖醛酸苷代谢物——它是一个强效的时间依赖性抑制剂，而当时的体外体系没有把这条路径充分暴露出来。后果是联用后西立伐他汀的AUC升高了5到6倍，横纹肌溶解病例迅速累积，西立伐他汀在2001年全球撤市。正确做法是：体外评估不能只盯着母体化合物的IC50，代谢物（尤其是葡糖醛酸苷代谢物）的抑制活性要单独评，TDI机制要做预孵育实验才能捕捉。这条教训直接推动了FDA和后续指南把"代谢物介导的抑制"和"TDI"写成独立章节。关键Takeaway：体外的IC50是一个条件依赖的数字，母体化合物不抑制，不代表它的代谢物不抑制。案例三：给药时序错开，把强相互作用测成了"几乎没影响" 背景是西柚汁（grapefruit juice）对肠道CYP3A4的抑制——它是食物-药物相互作用研究的经典模型，也是CYP3A底物暴露量被放大的教科书案例。错误做法是：在一项早期研究中，受试者早晨喝西柚汁、晚上服用洛伐他汀（lovastatin），刻意把两者错开[8]。这个设计下，洛伐他汀的AUC只升高了约1.9倍。后果是结论被写成"西柚汁对洛伐他汀影响轻微"，一个本可致命的相互作用被低估成了边缘发现。另一项研究[9]把设计改成西柚汁与洛伐他汀同时服用、并在后续时段继续补充果汁后，同一个相互作用让AUC放大了约15倍。正确做法是：相互作用强度不是药物的固有属性，它由给药时序和暴露窗口共同决定。评估肠道CYP3A或转运体介导的相互作用时，促变药必须与底物在吸收窗口内重叠，错峰设计会系统性地把风险测小。关键Takeaway：剂量、时序和给药途径是DDI设计的三个变量，任何一项偏离真实用药场景，测出来的都可能是"假的阴性"。图2：DDI表格阅读路径图——从"确定研究对象是底物还是促变药"到"选体外/临床探针"到"对照阈值分级"的决策流程总结与展望核心是三个动作：分清你要查的是体外表还是临床表，分清研究对象是底物还是促变药，回到注释里核对具体的分级门槛。表是死的，读法是活的。规则层面正在快速趋同。ICH M12在2024年5月定稿，把FDA、EMA、日本等区域的DDI要求整合到一套框架下，强中弱分级阈值、cocktail要求、内源性标志物这些内容第一次有了全球统一的表述。对中国药企来说，这意味着未来一套体外加临床数据可能同时支持多个区域的申报，但前提是研究设计的细节跟得上。方法层面，替代技术的比重还会继续上升。内源性生物标志物会从"探索性工具"逐步走向常规应用，PBPK减免临床研究的接受度也在提高。对应的风险是——替代方案用得越多，对"门槛理解是否准确"的要求就越高。工具可以省事，判断省不了。真正拉开DDI研究质量的，从来不是谁记得更多的药名，而是谁更清楚那些药名背后的证据等级和适用边界。参考文献 [1] U.S. Food and Drug Administration. In Vitro Drug Interaction Studies — Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions: Guidance for Industry[S]. Silver Spring: FDA, 2020. [2] U.S. Food and Drug Administration. Clinical Drug Interaction Studies — Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions: Guidance for Industry[S]. Silver Spring: FDA, 2020. [3] International Council for Harmonisation. ICH M12: Drug Interaction Studies[S]. Geneva: ICH, 2024. [4] 国家药品监督管理局药品审评中心. 药物相互作用研究技术指导原则（试行）[S]. 北京: NMPA, 2021. [5] Tornio A, Filppula AM, Niemi M, et al. Clinical Studies on Drug-Drug Interactions Involving Metabolism and Transport: Methodology, Pitfalls, and Interpretation[J]. Clin Pharmacol Ther, 2019, 105(6): 1345-1361. [6] Fuhr U, Jetter A, Kirchheiner J. Appropriate Phenotyping Procedures for Drug Metabolizing Enzymes and Transporters in Humans and Their Simultaneous Use in the "Cocktail" Approach[J]. Clin Pharmacol Ther, 2007, 81(2): 270-283. [7] U.S. Food and Drug Administration. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers[EB/OL]. https://www.fda.gov/drugs/drug-interactions-labeling. [8] Rogers JD, Zhao Y, Liu L, et al. Grapefruit juice has minimal effects on plasma concentrations of lovastatin-derived 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors[J]. Clin Pharmacol Ther, 1999, 66(4): 358-366. [9] Kantola T, Kivistö KT, Neuvonen PJ. Grapefruit juice greatly increases serum concentrations of lovastatin and lovastatin acid[J]. Clin Pharmacol Ther, 1998, 63(4): 397-402.返回搜狐，查看更多

2026-09-11

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老药结构立新功！药明康德如何用这项技术为新型分子“撞开”一扇新门？| Bilingual

从20世纪40年代可的松（cortisone）在类风湿性关节炎治疗中惊艳亮相，到口服避孕药的诞生改变无数人的生活——被《经济学人》（The Economist）杂志评为20世纪科学与技术伟大的进步之一，再到如今广泛应用于抗肿瘤、免疫调节及代谢疾病等领域，甾体化合物在现代药物研发中始终占据着不可替代的地位。然而，随着新药靶点发现难度的增加、甾体分子结构日趋复杂，其研发与生产面临多重挑战。一方面，商业化可及的甾体药物中间体多集中于经典母核，新型结构适配的定制化中间体供给不足，提高了合成路线设计与工艺放大的门槛；另一方面，甾体骨架含多个连续手性中心，部分位点的反应选择性难以精准调控，不仅增加早期纯化成本，也易在规模放大过程中引发更多副反应，延长杂质研究周期。图片来源：123RF 深耕甾体化学：系统性构筑经验证的平台能力面对甾体化学的研发挑战，药明康德研发化学服务部（Research Chemistry Services，RCS）在十多年前便开始布局甾体化学能力，在攻克关键难题的过程中积累了丰富经验。依托长期的能力与经验沉淀，RCS近年来进一步构建了覆盖药物发现、分子优化到工艺开发与规模化生产的甾体化学综合技术平台。如今，平台累计合成超过1万种甾体类化合物。在复杂多手性中心构建与结构精准修饰方面，平台建立了20余种甾体手性中心构建方法，并配套丰富的甾体高级中间体与定制化路线设计能力，可高效支持从苗头化合物到先导化合物的优化、新结构开发到聚焦化合物库构建等早期研究需求。针对甾体分子的结构特点，RCS能够通过路线开发、杂质与代谢物合成、同位素标记及绝对构型解析等能力，实现对候选分子的系统性研究与优化。同时，平台支持毫克级至公斤级的化合物合成与交付，并通过早期工艺开发与放大研究，有效缩短开发周期。平台的能力已经在诸多项目中得到验证。曾有客户因棘手的工艺开发难题找到药明康德RCS团队：其目标甾体分子的原始合成路线步骤冗长，且存在区域选择性差、工艺放大难等问题。面对困局，RCS团队依托甾体合成经验与技术能力，重新审视并成功开发出一条全新路线——总路线从7步缩短至3步，总收率也提升了两倍以上。此次超预期的交付赢得了客户认可，也为双方建立了坚实的信任基础。随后，该客户在新业务开展时毫不犹豫地再次选择与RCS开展项目合作，共同推进更具挑战性的甾体分子项目。在另一个案例中，依托公司甾体化学综合技术平台及某关键中间体的成功应用，RCS团队仅用23天便完成客户目标甾体化合物的合成，相较行业常规约2个月的周期，时间大幅缩短。这些实践，既是药明康德甾体化学综合技术平台赋能能力的具体体现，也印证了平台能力与行业需求的深度契合。图片来源：123RF 持续精进：赋能新分子研发甾体药物的价值远不止于传统治疗领域，凭借独特的刚性多环骨架结构与生物学特性，甾体结构正成为突破新型分子成药瓶颈的关键功能单元。近年来，靶向蛋白降解剂、抗体偶联药物（ADCs）、寡核苷酸等新分子类型不断拓展可干预靶点的范围。在部分新分子设计中，甾体片段可作为关键结构单元，用于调节稳定性、靶向特异性或递送性能。这对甾体化学的高选择性衍生化改造能力提出了更高要求。为响应这类前沿新分子的研发需求，药明康德RCS甾体化学综合技术平台持续迭代其技术能力。目前，平台能够对ADCs和蛋白降解嵌合体等新型分子中的甾体片段进行高效且高选择性的衍生化改造。以某款基于甾体骨架的ADC载荷工艺开发项目为例，平台不仅快速完成了百毫克级合成验证，更通过路线优化大幅提升了总收率，充分验证了平台支持含甾体结构的新分子从早期设计到可放大合成的能力。目前，药明康德RCS已将甾体化学与新分子类型开发深度结合，可支持包含甾体骨架的抗体偶联药物、靶向蛋白降解剂、前药及氮芥类分子设计与合成，并与分析服务、反应条件筛选、重结晶平台、流动化学、光氧化还原及电化学等技术协同运行，实现从分子创新到可放大生产的无缝衔接。通过整合长期经验、模块化技术能力与跨平台协同，甾体化学平台能够为客户提供稳定、高效且可扩展的化学赋能，助力复杂甾体分子及新型偶联分子的研发与转化。甾体化学综合技术平台的演进，是药明康德一体化、端到端的CRDMO能力不断精进的缩影——通过在甾体化学领域的持续积累与迭代，助力合作伙伴提升研发效率、缩短项目周期，并提供从分子设计和优化到工艺开发与规模化生产的全流程解决方案。（如需了解药明康德研发化学服务或业务咨询，请点击文末“阅读原文”）未来，随着更多复杂甾体分子及新型分子模式的涌现，药明康德将持续通过一体化、端到端的CRDMO赋能平台，助力全球合作伙伴推动创新疗法更快惠及患者。 How WuXi AppTec Addresses the Challenges of Steroid Drug Discovery and Development Steroid compounds hold an important position in modern drug discovery and development, from the introduction of cortisone in the 1940s for rheumatoid arthritis, to the advent of the oral contraceptive pill, which transformed reproductive health and the lives of millions of people. Today, steroids remain widely used in the treatment of cancer, immune disorders, and metabolic diseases. However, the development and manufacturing of steroid compounds present distinct challenges as molecular structures become increasingly complex. First, commercially available steroid intermediates are largely limited to conventional core scaffolds, while customized intermediates suitable for novel structures remain scarce, complicating synthetic route design and process scale-up. Second, steroid scaffolds often contain multiple contiguous stereocenters, making it difficult to achieve precise regioselectivity and stereoselectivity at specific positions. These challenges can increase purification requirements during early development, promote side reactions during scale-up, and extend the time needed for impurity identification and control. Image source: 123RF Developing Proven Capabilities in Steroid Chemistry More than a decade ago, WuXi AppTec's Research Chemistry Services (RCS) began developing specialized capabilities in steroid chemistry to address the synthetic and process challenges associated with structurally complex steroid molecules. Building on this experience, RCS has established a comprehensive steroid chemistry platform covering discovery, optimization, process development, and large-scale production. Today, the platform has synthesized over 10,000 steroid molecules. To enable the construction and modification of complex steroid scaffolds, RCS has established over 20 methods for controlling stereochemistry at specific positions. These capabilities are complemented by customized route design and access to a diverse range of advanced steroid intermediates, supporting activities such as hit-to-lead optimization, novel scaffold development, and focused library generation. RCS also provides capabilities in synthetic route development, impurity and metabolite synthesis, isotope labeling, and absolute-configuration determination. Together, these capabilities enable the systematic characterization and optimization of steroid candidates based on their structural and physicochemical properties. The platform supports compound synthesis and delivery at scales ranging from milligrams to kilograms, as well as early process development and scale-up, helping clients advance programs efficiently through successive stages of development. In one project, a client sought support for a steroid molecule whose original synthetic route involved numerous steps, poor regioselectivity, and limited reproducibility during scale-up. RCS redesigned the route, reducing the total number of steps from 7 to 3 and more than doubling the overall yield. The team exceeded expectations and earned positive feedback from the client. Following completion of the project, the client engaged RCS for an additional and more technically challenging steroid synthesis program. In another project, RCS combined its steroid chemistry platform with the use of a key steroid intermediate to complete the synthesis of a target compound in 23 days. Given that the industry-standard timeline is approximately two months, the synthesis timeline was significantly shortened. These examples demonstrate how WuXi AppTec’s comprehensive steroid chemistry platform supports steroid drug development and how its integrated development capabilities align with industry needs. Image source: 123RF Extending Steroid Chemistry Capabilities to Emerging Therapeutic Modalities The value of steroid chemistry extends beyond the development of conventional steroid-based therapeutics. With their rigid polycyclic structures and distinctive physicochemical and biological properties, steroid scaffolds can serve as functional components in the design of emerging therapeutic modalities, helping researchers modulate molecular properties that may otherwise limit drug development. New modalities, including targeted protein degraders, antibody-drug conjugates (ADCs), and oligonucleotide therapeutics, are expanding the range of addressable targets and therapeutic design strategies. In some of these molecules, steroid-derived fragments can be incorporated as structural or functional components to modulate stability, targeting, or delivery. The development of such molecules requires steroid chemistry capabilities that enable precise, highly selective derivatization at specific positions on structurally complex steroid scaffolds. RCS's comprehensive steroid chemistry platform has evolved in response to the growing demands of these new modalities. It now supports the efficient and highly selective derivatization of steroid fragments used in ADCs and targeted protein degraders. In one case involving the development of an ADC payload based on a steroid scaffold, the platform delivered hundred‑milligram-scale compounds for validation and improved the overall yield through route optimization, demonstrating its ability to support steroid-containing new modalities from early design through scalable synthesis. WuXi AppTec’s RCS integrates steroid chemistry with the development of innovative therapeutic modalities, supporting the design and synthesis of ADCs, targeted protein degraders, prodrugs, and nitrogen mustard derivatives that incorporate steroid-derived structural or functional components. The platform also draws on complementary capabilities in analytical services, reaction-condition screening, recrystallization, flow chemistry, photoredox chemistry, and electrochemistry to support progression from molecular design to scalable synthesis. By integrating long-term experience, modular technical capabilities, and cross-platform synergy, the steroid chemistry platform provides clients with stable, efficient, and scalable synthetic solutions, accelerating the R&D of complex steroids and novel conjugate molecules. The continued development of RCS’s steroid chemistry capabilities reflects the broader evolution of WuXi AppTec’s integrated, end-to-end CRDMO model. Through ongoing technical refinement and cross-functional collaboration, RCS helps clients improve discovery and development efficiency, shorten project timelines, and obtain one-stop solutions covering molecular design, process development, and scale-up. As increasingly complex steroid molecules and emerging therapeutic modalities create new development demands, WuXi AppTec will continue to leverage its integrated CRDMO platform to help clients advance innovative therapies for patients worldwide. Key Takeaways: 1. WuXi AppTec’s Research Chemistry Services (RCS) has built an integrated steroid chemistry platform covering early discovery, molecular optimization, process development, and large-scale manufacturing. 2. With more than a decade of experience and over 10,000 steroid compounds synthesized, RCS has developed extensive expertise in addressing the stereochemical and synthetic challenges associated with complex steroid molecules. 3. Capabilities in route development, impurity and metabolite synthesis, isotope labeling, and absolute-configuration determination support the systematic characterization and optimization of steroid candidates. 4. RCS combines specialized steroid chemistry expertise with modular technical capabilities and cross-platform collaboration to support the design, synthesis, optimization, and scale-up of complex steroid compounds and novel conjugates. 5. The platform applies steroid chemistry to emerging therapeutic modalities, supporting ADCs, targeted protein degraders, prodrugs, and nitrogen mustard derivatives that incorporate steroid-derived components, while drawing on complementary capabilities in analytical services, reaction-condition screening, recrystallization, flow chemistry, photoredox chemistry, and electrochemistry. For more information about WuXi AppTec’s Research Chemistry Services or business collaboration inquiries, please click “Read More” at the end of this article. 参考资料： [1] FDA's Approval of the First Oral Contraceptive, Enovid. Retrieved June 10, 2026, from https://www.fda.gov/media/110456/download [2] Project W – The Power of the Pill. Retrieved June 10, from https://www.dwt.com/insights/2022/03/project-w-the-power-of-the-pill [3] Zhu, Jiacheng, Guoshun Luo and Hua Xiang. “Approved Steroidal Drugs (2000-2025): A Medicinal Chemistry Perspective.” Journal of medicinal chemistry (2026): n. pag. [4] 从避孕药到抗癌、抗抑郁：这个经典分子骨架，为何还能不断诞生新药？Retrieved June 10, 2026, from https://mp.weixin.qq.com/s?__biz=MzAwMDA5NTIxNQ==&mid=2650126164&idx=1&sn=6c9316570c22455fdcae5d9c898fc2a4&chksm=83e5a03d0cb826d7c9416f2eb3bc398ba63478001278832723a62b224c41fbc24871c342f09f [5] PENG H D, WANG Y Y, JIANG K, et al. A dual role reductase from phytosterols catabolism enables the efficient production of valuable steroid precursors. Angewandte Chemie International Edition, 2021, 60(10): 5414-5420. [6] DONOVA M V, EGOROVA O V. Microbial steroid transformations: current state and prospects[J]. Applied Microbiology and Biotechnology, 2012, 94(6): 1423-1447. 免责声明：本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。版权说明：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。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。分享，点赞，在看，传递医学新知

100 项与盐酸西布曲明水合物相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D02571	盐酸西布曲明水合物	A08AA10	DB01105

研发状态

批准上市

10 条最早获批的记录,

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适应症	国家/地区	公司	日期
肥胖	美国	Abbott Laboratories	1997-11-22

未上市

10 条进展最快的记录,

后查看更多信息

适应症	最高研发状态	国家/地区	公司	日期
脑血管疾病	临床3期	美国	Abbott Laboratories	2003-01-01
冠心病	临床3期	美国	Abbott Laboratories	2003-01-01
高血压	临床3期	美国	Abbott Laboratories	2003-01-01
外周动脉闭塞性疾病	临床3期	美国	Abbott Laboratories	2003-01-01
暴食症	临床3期	-	Abbott Laboratories	2000-08-01

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临床结果

适应症

分期

评价

查看全部结果

研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


Pubmed \| Diabetol Metab Syndr	N/A	肥胖	246	TopiramateSibutramine + TopiramateSibutramine	糧選鹹積鹹襯蓋鏇夢積(觸齋鏇範繭壓夢餘觸鑰) = Common adverse effects included paresthesia, memory impairment, bradyphrenia and elevated blood pressure 築網膚糧遞獵鏇築艱簾 (築鹹廠餘願獵鏇鹽範憲 )	积极	2025-07-21
NCT00234832 (Pubmed \| N Engl J Med)	临床3期	营养和代谢疾病	10,777	Sibutramine	醖衊觸鬱願糧壓襯壓積(鏇餘夢襯襯獵糧壓觸獵) = 淵積壓築顧獵窪醖夢鏇繭窪鹽糧齋觸鹹鏇糧構 (網獵廠壓鹽糧淵鏇鏇顧 ) 更多	不佳	2010-09-02
NCT00234832 (Pubmed \| N Engl J Med)	临床3期	营养和代谢疾病	10,777	Placebo	醖衊觸鬱願糧壓襯壓積(鏇餘夢襯襯獵糧壓觸獵) = 衊蓋觸願獵獵獵廠構壓繭窪鹽糧齋觸鹹鏇糧構 (網獵廠壓鹽糧淵鏇鏇顧 ) 更多	不佳	2010-09-02
NCT00234832 (SCOUT, CTgov)	临床3期	心血管疾病 \| 冠心病 \| 外周动脉闭塞性疾病 ... 更多	10,777	Sibutramine (Randomized Sibutramine)	鬱齋壓窪齋觸鬱構齋繭 = 遞憲鑰願遞蓋醖獵鏇衊選積醖網壓顧醖遞襯憲 (淵獵獵窪壓窪鬱膚遞範, 醖獵餘廠餘選獵願鬱蓋 ~ 膚築衊窪壓構齋餘遞膚) 更多	-	2010-04-15
NCT00234832 (SCOUT, CTgov)	临床3期	心血管疾病 \| 冠心病 \| 外周动脉闭塞性疾病 ... 更多	10,777	placebo (Randomized Placebo)	鬱齋壓窪齋觸鬱構齋繭 = 獵糧憲蓋鬱製繭鹽範願選積醖網壓顧醖遞襯憲 (淵獵獵窪壓窪鬱膚遞範, 獵壓艱鏇鏇觸窪範鹽範 ~ 繭製顧鹽餘憲鹽鬱鏇餘) 更多	-	2010-04-15
NCT00234832 (SCOUT, Pubmed \| BMC Endocr Disord)	临床3期	2型糖尿病	10,777	Sibutramine	獵鑰齋窪餘夢齋築遞觸(壓壓鏇網糧蓋鹽鹹窪壓) = 鹽餘鹹壓選範獵襯糧齋廠範鏇選構製願繭鑰簾 (構鑰積繭艱糧憲築衊鬱 ) 更多	-	2010-02-26
NCT00234832 (SCOUT, Pubmed \| Nutr Metab (Lond))	临床3期	糖尿病	10,777	Sibutramine plus lifestyle changes	選壓鑰顧夢繭顧範選艱(鹽願積鑰觸醖衊憲壓廠) = 鬱網憲鏇餘製顧願構餘壓壓蓋積顧膚製遞淵願 (範鬱糧製築醖積顧夢醖, -17.7; ~ 12.4)	-	2009-10-14