This clinical trial studies if a bowel management program with a retrograde rectal enema (RRE) for the treatment of low anterior resection syndrome (LARS) in rectal cancer patients is better than medical management alone. Rectal cancer treatment can include a procedure where part of the rectum with cancer is removed and the remaining part of the rectum is reconnected to the colon, this is called a low anterior resection of the rectum. LARS is a common condition that can develop after undergoing a low anterior resection of the rectum. LARS consists of any change in how the body performs defecation, the discharge of feces from the body, after undergoing a resection procedure. Patients with LARS may experience fecal urgency, incontinence, increased frequency, constipation, feelings of incomplete bowel movement, or bowel emptying difficulties. Patients may experience individual symptoms of LARS or a combination of them. A bowel management program assists patient's with identifying a specific bowel management regimen that works best for managing symptoms of LARS. A RRE consists of inserting a catheter through the anus into the rectum. The RRE is designed to assist fecal emptying. Medical management of LARS can include the use of fiber, loperamide hydrochloride, or pelvic floor physical therapy. Fiber may help relieve constipation, feelings of incomplete bowel movement, or bowel emptying difficulties. Loperamide hydrocholoride may help lessen fecal urgency, incontinence, or increased frequency. Pelvic floor physical therapy may help restore strength in the rectum possibly helping to improve symptoms of LARS. Participating in a bowel management program with a RRE may be more effective in treating LARS than medical management alone.

开始日期2025-03-31

申办/合作机构

Ohio State University Comprehensive Cancer Center

CTIS2024-515531-29-00

/ Not yet recruiting

- N-LOP-24-289

开始日期2024-11-05

申办/合作机构-

ISRCTN18843536

/ Recruiting临床2期IIT

Impact of 20% phenytoin and 5% loperamide cream on neuropathic pain: a prospective double-blind randomized controlled study

开始日期2024-03-13

申办/合作机构-

100 项与盐酸洛哌丁胺相关的临床结果

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100 项与盐酸洛哌丁胺相关的转化医学

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100 项与盐酸洛哌丁胺相关的专利（医药）

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2,281

项与盐酸洛哌丁胺相关的文献（医药）

2025-02-01·JOURNAL OF ETHNOPHARMACOLOGY

In vivo evaluation of anti-diarrheal activity of hydroalcoholic extract and solvent fractions of the leaf of Leucas deﬂexa Hook.f (Lamiaceae) in rodents

Article

作者: Abera, Tadele ; Hammeso, Workineh Woldeselassie ; Fisseha, Nebeyi ; Nureye, Dejen ; Woldeselassie, Behailu Desalegn

ETHNOPHARMACOLOGICAL RELEVANCE:

The emergence of antibiotic-resistant bacteria has intensified the search for novel antidiarrheal drug. Plant-derived extracts offer promising alternatives due to their ability to modulate gut motility and enhance water absorption. The leaves of Leucas deflexa Hook.f., a plant native to Ethiopia, have been traditionally utilized in the treatment of diarrheal diseases. Nonetheless, its traditional application has yet to be scientifically confirmed.

AIM OF THE STUDY:

Hence, the aim of the present study was to evaluate antidiarrheal activity of the crude extract and fractions of the leaf of Leucas deﬂexa Hook.f (Lamiaceae).

MATERIALS AND METHODS:

Healthy Swiss albino mice were randomly divided into five groups per experimental model: castor oil-induced diarrhea, gastrointestinal motility, and anti-enteropooling assays. The control group received distilled water (10 ml/kg), while the positive control was treated with loperamide (3 mg/kg). The remaining groups were administered various dosages (LD100, LD200, and LD400 mg/kg) of a hydroalcoholic extract or its fractions from Leucas deflexa Hook.f.

RESULT:

The crude extract and chloroform fraction substantially (P < 0.001) delayed the onset of diarrhea, reduced fecal frequency, and decreased total fecal weight at all administered doses compared to the negative control. The butanol and aqueous fractions exhibited a substantial antidiarrheal effect at doses of 200 mg/kg and 400 mg/kg, respectively. All treatments, including the crude extract, chloroform, butanol, and aqueous fractions, substantially (P < 0.001) reduced the volume and weight of intestinal contents at various doses. Additionally, the chloroform, aqueous fraction, and crude extract at doses of 100, 200, and 400 mg/kg substantially inhibited gastrointestinal motility compared to the negative control.

CONCLUSION:

The results of this study corroborate the traditional use of Leucas deflexa leaves in the treatment of diarrhea. These findings give a scientific justification for further exploration of the underlying mechanisms and potential therapeutic applications of this plant extract.

2025-02-01·JOURNAL OF PAIN

Peripherally mediated opioid combination therapy in mouse and pig

Article

作者: Kitto, KF ; Bruce, DJ ; Larson, CM ; Lunzer, MM ; Clements, B M ; Wilcox, G L ; Pflepsen, K R ; Portoghese, P S ; Portoghese, PS ; Fairbanks, CA ; Wilcox, GL ; Peterson, CD ; Bruce, D J ; Akgün, E ; Lunzer, M M ; Kitto, K F ; Pflepsen, KR ; Clements, BM ; Larson, C M ; Fairbanks, C A ; Peterson, C D

The concomitant epidemics of chronic pain and opioid misuse in the United States have led to a call for novel analgesics with limited abuse potential. Previously, we have shown that co-delivery of a novel combination targeting both μ- and δ-opioid receptors in the peripheral and central nervous systems can produce synergistic analgesia. Loperamide, a peripherally restricted μ-opioid agonist, and oxymorphindole, a δ-opioid receptor partial agonist, synergize in multiple mouse models of hyperalgesia. We predicted this effect would generalize across species and therefore assessed this combination for analgesic synergy in a mouse model of post-incisional hypersensitivity. In mice, oxymorphindole and loperamide displayed significant analgesic synergy. Similar synergy was observed with N-benzyl-oxymorphindole and loperamide. In cross-bred pigs, we compared the analgesic effects of either morphine alone or the combination of oxymorphindole and loperamide or the combination of N-benzyl-oxymorphindole and loperamide. Both combinations showed increased potency as compared to morphine sulfate and effectively reduced hypersensitivity following injury without side effects. From these data we conclude that the combination of oxymorphindole and loperamide or the combination of N-benzyl-oxymorphindole and loperamide reverse incisional hyperalgesia, likely by acting in the periphery, in a large animal model without adverse effects on respiration or heart rate. PERSPECTIVE: This article presents novel opioid combinations, the μ-opioid agonist loperamide with a δ-opioid agonist, either oxymorphindole (OMI) or N-benzyl-oxymorphindole (BOMI), that relieve pain in mice and pigs without adverse side effects. These therapies could help clinicians manage pain in patients while reducing overall opioid burden and limiting side effects.

2025-01-01·NEUROGASTROENTEROLOGY AND MOTILITY

Laxative and purgative actions of phytoactive compounds from beetroot juice against loperamide‐induced constipation, oxidative stress, and inflammation in rats

Article

作者: Sebai, Hichem ; Jedidi, Saber ; Sammari, Houcem ; Dakhli, Nouha ; Ayari, Ala ; Arrari, Fatma

Abstract:

Background:

Chronic constipation is a gastrointestinal functional disorder which affects patient quality of life. Therefore, many studies were oriented to search herbal laxative agents. In this study, we investigated the phytochemical composition of beetroot juice (BJ) and its laxative potential in an experimental model of constipation and colonic dysmotility induced by loperamide (LOP) in Wistar rats.

Methods:

Animals were concurrently pretreated with LOP (3 mg/kg, b.w., i.p.) and BJ (5 and 10 mL/kg, b.w., p.o.), or yohimbine (2 mg/kg, b.w., i.p.), during 1 week. The laxative activity was determined based on the weight, frequency, and water content of the feces matter. The gastric‐emptying test and intestinal transit were determined. Colon histology was examined, and oxidative status was evaluated using biochemical‐colorimetric methods.

Key results:

The in vivo study revealed that LOP induced a significant inhibition of gastrointestinal motility, negative consequences on defecation parameters, oxidative stress, and colonic mucosa lesions. Conversely, administration of BJ reestablished these parameters and restored colonic oxidative balance. Importantly, BJ treatment protected against LOP‐induced inflammatory markers (pro‐inflammatory cytokines and WBC) and the increase in intracellular mediators such as hydrogen peroxide, free iron, and calcium levels.

Conclusions & inferences:

This study demonstrated that the bioactive compounds in BJ provided an anti‐constipation effect by modulating intestinal motility and regulating oxidative stress and inflammation induced by LOP intoxication.

项与盐酸洛哌丁胺相关的新闻（医药）

2025-01-08

·echemi

80 batches of drugs recalled urgently! A major decision by the National Medical Products Administration

Recently, the National Medical Products Administration announced an important decision to stop the production, sale, and use of Hyoscine Butylbromide Tablets, and to revoke its drug registration certificate. According to the announcement issued by the National Medical Products Administration on January 3, titled “Announcement on the Revocation of the Drug Registration Certificate for Hyoscine Butylbromide Tablets (2025 No. 2)”, Hyoscine Butylbromide Tablets, an antibacterial drug also known as Loperamide, will no longer circulate in the market of our country. This decision is effective immediately, and the products already on the market will be recalled by the marketing authorization holder and supervised by provincial drug regulatory authorities for destruction or other harmless disposal measures. A total of 80 batches of Hyoscine Butylbromide Tablets are involved. In addition, in another announcement issued by the National Medical Products Administration on December 2, 2024, it was also announced that 58 drug registration certificates, including 11 batches of Hyoscine Butylbromide Tablets, have been revoked. Based on Article 83 of the Drug Administration Law of the People's Republic of China and other relevant regulations, these drugs have been required to stop production and sale due to unclear efficacy, serious adverse reactions, or other hazards to human health. Hyoscine Butylbromide Tablets are a compound preparation, with the main active ingredients including Hyoscine Tincture, Sulfamethoxazole, and Trimethoprim, primarily used to treat dysentery caused by Shigella and other sensitive pathogenic bacteria causing enteritis. However, with the withdrawal of this drug from the market, other drugs such as Montmorillonite Powder will take on the responsibility for treating diarrhea. According to data from Miiine, the incidence of gastrointestinal diseases is on the rise and is becoming more prevalent among younger populations. In the first three quarters of 2022, the sales of anti-diarrheal drugs and intestinal anti-inflammatory/infection drugs in public hospitals in key provinces and cities in China exceeded 1.2 billion yuan, a year-on-year increase of 6.30%. The sales scale of Montmorillonite Powder in the three major terminal markets in China has exceeded 1 billion yuan, with the outpatient market being the main sales channel, rising by 60%, making it the Top 2 product in anti-diarrheal and intestinal anti-inflammatory/infection drugs. Statistics from Cyborg Blue show that 145 drug registration certificates were revoked in 2024. In the announcement on December 2, 2024, in addition to Hyoscine Butylbromide Tablets, it also included 3 batches of Losartan Potassium Tablets, 2 batches of Phenazone Tablets, 2 batches of Amlodipine Besylate Tablets, 2 batches of Entecavir Tablets, 2 batches of Compound Snake Gall and Chuan Bei Powder, and 2 batches of Rifampicin Capsules. Phenazone, as a pyrazolone analgesic and antipyretic, was launched early in our country, but its injection and nasal drops have severe adverse reactions, with risks outweighing benefits, and alternative medications are available, leading to its registration certificate being revoked in 2020. Although oral preparations like Phenazone Tablets still have certain clinical value, the National Medical Products Administration has implemented risk control measures by revising the instructions to add safety warnings, restricting applicable populations and indications. In the domestic market for antipyretic and analgesic drugs, Phenazone has a low market share and is declining. Data from Cyborg Blue shows that there are 861 approvals for "Phenazone Tablets," involving many companies and intense market competition. As related drug approvals are revoked, this market will face further fragmentation. Finally, according to the relevant provisions of the Regulations on the Implementation of the Drug Administration Law of the People's Republic of China and the Drug Registration Management Measures, the National Medical Products Administration decided on April 11, 2024, to revoke the registration certificates for 87 drugs, including Pancreatin Injection. Cyborg Blue’s analysis found that drugs such as 7 batches of Iohexol Injection, 6 batches of Insulin Glargine Injection, 4 batches of Detemir Insulin Injection, 4 batches of Vardenafil Hydrochloride Tablets, and 3 batches of Brain Protein Hydrolysate Injection were also revoked. Please note that the number of drugs counted in the text has not been deduplicated. No. Marketing Authorization Holder Approval Number 1 Shijiazhuang Lesheng Pharmaceutical Co., Ltd. SFDA H13023949 2 Jiangzhong Pharmaceutical Co., Ltd. SFDA H36022316 3 Shijiazhuang Fourth Pharmaceutical Co., Ltd. SFDA H13023932 4 Shijiazhuang Grey Pharmaceutical Co., Ltd. SFDA H13023934 5 Handan Bailin Pharmaceutical Co., Ltd. SFDA H13023945 6 Hebei Yongfeng Pharmaceutical Co., Ltd. SFDA H13023943 7 China National Pharmaceutical Group Wuhan Zhonglian Fourth Pharmaceutical Co., Ltd. SFDA H42022497 8 Jiangsu Enhua Pharmaceutical Co., Ltd. SFDA H32025932 9 Jiangxi Hongshuo Pharmaceutical Co., Ltd. SFDA H36022013 10 Jiangxi Hongshuo Pharmaceutical Co., Ltd. SFDA H36022244 11 Jiangsu Chenpai Pharmaceutical Group Co., Ltd. SFDA H32025935 12 North China Pharmaceutical Hebei Huanuo Co., Ltd. SFDA H13024102 13 North China Pharmaceutical Hebei Huanuo Co., Ltd. SFDA H13024073 14 Hebei Hengli Group Pharmaceutical Co., Ltd. SFDA H13024253 15 Hebei Tianzhi Pharmaceutical Co., Ltd. SFDA H13024245 16 Hebei Dongfeng Pharmaceutical Co., Ltd. SFDA H13024170 17 Hebei Jinzhuan Pharmaceutical Co., Ltd. SFDA H13024269 18 Tianjin Baihai Pharmaceutical Co., Ltd. SFDA H12021099 19 Henan Daxin Pharmaceutical Co., Ltd. SFDA H41024876 20 Henan Daxin Pharmaceutical Co., Ltd. SFDA H41025013 21 Shanxi Xinxing Pharmaceutical Co., Ltd. SFDA H14023068 22 Jiangxi Jiminke Pharmaceutical Co., Ltd. SFDA H36022305 23 Suzhou Hongsun Pharmaceutical Co., Ltd. SFDA H32025897 24 Jiangsu Puhua Kesheng Pharmaceutical Co., Ltd. SFDA H32026256 25 Guangxi Tiantianle Pharmaceutical Co., Ltd. SFDA H45021319 26 Tianjin Central Pharmaceutical Co., Ltd. SFDA H12021120 27 Tianjin Central Pharmaceutical Co., Ltd. SFDA H12021117 28 Shanghai Modern Harsen (Shangqiu) Pharmaceutical Co., Ltd. SFDA H41024989 29 Tianjin Pacific Pharmaceutical Co., Ltd. SFDA H12021100 30 Hebei Guojin Pharmaceutical Co., Ltd. SFDA H13023940 31 Hebei Kaiwei Pharmaceutical Co., Ltd. SFDA H13023920 32 Hebei Sanshi Pharmaceutical Co., Ltd. SFDA H13023928 33 Yuanda Pharmaceutical (China) Co., Ltd. SFDA H42022649 34 Shanxi Tongda Pharmaceutical Co., Ltd. SFDA H14023309 35 Shanxi Guorun Pharmaceutical Co., Ltd. SFDA H14023402 36 Shanxi Fenhe Pharmaceutical Co., Ltd. SFDA H14023200 37 Shanxi Wanhui Pharmaceutical Co., Ltd. SFDA H14023333 38 Jilin Wantong Pharmaceutical Co., Ltd. SFDA H22025288 39 Changchun Overseas Pharmaceutical Group Co., Ltd. SFDA H22026726 40 Shijiazhuang Xiehe Pharmaceutical Co., Ltd. SFDA H13024084 41 Shandong Xinyi Pharmaceutical Co., Ltd. SFDA H37023541 42 Kuihua Pharmaceutical Group (Hengshui) Defier Co., Ltd. SFDA H13023979 43 Shijiazhuang Kanghewai Pharmaceutical Co., Ltd. SFDA H13024261 44 Shandong Xinhua Pharmaceutical Co., Ltd. SFDA H37023523 45 Hebei Yuzhilin Pharmaceutical Co., Ltd. SFDA H13024426 46 Xinhai Yansheng Pharmaceutical Co., Ltd. SFDA H41024907 47 Fu'an Pharmaceutical Group Yantai Zhichu Pharmaceutical Co., Ltd. SFDA H37023543 48 Dingfukang Pharmaceutical Co., Ltd. SFDA H41025139 49 Dingfukang Pharmaceutical Co., Ltd. SFDA H41025174 50 Changchun Changqing Pharmaceutical Group Co., Ltd. SFDA H22025234 51 Henan Baiquan Pharmaceutical Co., Ltd. SFDA H41024840 52 Changzhou Kangpu Pharmaceutical Co., Ltd. SFDA H32025910 53 Henan Baiquan Pharmaceutical Co., Ltd. SFDA H41025575 54 Lepu Hengjiuyuan Pharmaceutical Co., Ltd. SFDA H41024862 55 Hebei Ruicen Pharmaceutical Co., Ltd. SFDA H13023953 56 Hainan Xiansheng Pharmaceutical Co., Ltd. SFDA H46020588 57 Hainan Xiansheng Pharmaceutical Co., Ltd. SFDA H46020604 58 Yaodu Pharmaceutical Group Co., Ltd. SFDA H13023951 59 Shandong Xinyi Pharmaceutical Co., Ltd. SFDA H37023939 60 Shijiazhuang Pharmaceutical Group Ouyi Pharmaceutical Co., Ltd. SFDA H13023952 61 Tianfang Pharmaceutical Co., Ltd. SFDA H41024887 62 Lepu Hengjiuyuan Pharmaceutical Co., Ltd. SFDA H41025576 63 Zhejiang Huisong Pharmaceutical Co., Ltd. SFDA H33022412 64 Zhejiang Huisong Pharmaceutical Co., Ltd. SFDA H33022411 65 Shanghai Kaibao Xinyi (Xinxiang) Pharmaceutical Co., Ltd. SFDA H41024834 66 Henan Xueyinghua Pharmaceutical Co., Ltd. SFDA H41024896 67 Henan Xueyinghua Pharmaceutical Co., Ltd. SFDA H41025009 68 Shijiazhuang Pharmaceutical Group Zhongnuo Pharmaceutical (Shijiazhuang) Co., Ltd. SFDA H13023994 69 Handan Furong Pharmaceutical Co., Ltd. SFDA H13024077 70 Hebei Tiancheng Pharmaceutical Co., Ltd. SFDA H13024056 71 Hebei Kangtai Pharmaceutical Co., Ltd. SFDA H13024041 72 Guangdong Bidi Pharmaceutical Co., Ltd. SFDA H44025328 73 Guangdong Bidi Pharmaceutical Co., Ltd. SFDA H44024963 74 Zhengzhou Furuitang Pharmaceutical Co., Ltd. SFDA H41025579 75 Chongqing Kerui Pharmaceutical (Group) Co., Ltd. SFDA H50021730 76 Baiyun Mountain Dongtai Shangqiu Pharmaceutical Co., Ltd. SFDA H41024872 77 Xinxiang Changle Pharmaceutical Co., Ltd. SFDA H41024895 78 Xinxiang Changle Pharmaceutical Co., Ltd. SFDA H41025012 79 Baiyun Mountain Dongtai Shangqiu Pharmaceutical Co., Ltd. SFDA H41025008 80 Tianfang Pharmaceutical Co., Ltd. SFDA H41025010

上市批准申请上市

2025-01-02

·ioncology

ADC消化道不良反应的预防和处理

点击上方蓝字关注我们编者按：抗体偶联药物（ADC）在众多实体瘤领域带来了许多突破性进展，已经广泛影响临床实践。ADC整体的不良反应低于化疗，但不良反应谱仍与化疗有较多重叠，比如恶心、呕吐、腹泻等消化道症状，可发生于化疗和ADC中。本文总结了ADC的消化道不良反应机制、临床特点、分级处理和监管等。消化道不良反应是ADC较为常见的不良反应之一。ASCENT研究[1]显示戈沙妥珠单抗（SG）组患者腹泻、恶心和呕吐的发生率分别为58%、52%和36%，高于化疗组的6%、24%和6%。DESTINY系列研究的汇总分析[2]显示，T-DXd组的恶心和呕吐发生率分别为74.6%和41.6%，但大多数为1-2级，主要发生在治疗前3周，且数据截止时66.9%的恶心患者与87.6%的呕吐患者症状完全缓解。了解ADC的消化道不良反应特征和处理，有助于协助患者完成治疗，提高治疗依从性。 ADC消化道不良反应的机制和临床特点《中国乳腺癌抗体药物偶联物安全性管理专家共识》[3]指出：胃肠道黏膜的高增殖指数使其特别容易受到化疗不良反应的影响。而靶向治疗也可独立诱导一系列胃肠道不良反应，当与传统化疗药物联合应用时，可增强后者诱导的不良反应。需注意的是，胃肠道HER2受体的主要功能是参与维护黏膜层的完整性，HER2单克隆抗体能够与其发生交叉反应，因此导致不良反应。此外，伊立替康治疗期间早发型腹泻（用药后6h 内）与胆碱能反应相关，迟发型腹泻（用药后超过24h）则主要由于再生的SN-38在肠黏膜内的累积。该共识同时指出，恶心、呕吐和腹泻等消化系统不良反应在戈沙妥珠单抗治疗的患者中较为常见和严重。戈沙妥珠单抗相关的任何等级腹泻至发生与持续的中位时间分别为14天和8天，≥３级腹泻分别为15和6天。T-DXd和T-DM1也有胃肠道不良反应报告，严重程度相对较轻。 ADC消化道不良反应的分级和处理恶心、呕吐、腹泻等消化道不良事件的分级及其处理、结局如下表[3]所示。表1. 消化道不良事件的分级和处理[3] ADC消化道不良反应的监测管理腹泻戈沙妥珠单抗说明书黑框警告提示严重腹泻的可能性，应监测并根据需要给予液体和电解质。《中国乳腺癌抗体药物偶联物安全性管理专家共识》[3]建议戈沙妥珠单抗开始治疗前推荐预先使用止吐剂。若无禁忌证，可以使用阿托品对任何严重程度的早发型腹泻进行预处理和控制。在出现迟发型腹泻时，应评估感染原因，若未发现其他诱因，立即使用洛哌丁胺，首次使用剂量为4mg，以后每次腹泻发作使用2mg，每天最多使用剂量为16mg。腹泻缓解12h后停用洛哌丁胺。对于腹泻不缓解的患者，如前述洛哌丁胺4mg＋2mg，每 2h给予1次；24h若无好转，改用奥曲肽100～150mg，３次/d。重度腹泻应考虑住院。呕吐戈沙妥珠单抗、T-DXd等药物治疗期间均可发生呕吐、恶心不良反应。较早前ASCO、NCCN、意大利等国际指南共识将T-DXd作为中度致吐药物而需进行预防性治疗[4]；而《中国肿瘤药物治疗相关恶心呕吐防治专家共识（2023年版）》[5]将戈沙妥珠单抗、T-DXd列为高度致吐风险药物。同时，该共识将5-HT3RA+NK-1RA+奥氮平+地塞米松（1A类证据）、5-HT3RA+NK-1RA+地塞米松（1A类证据）、帕洛诺司琼+奥氮平+地塞米松（1A类证据）作为高度致吐风险药物的I级推荐；将5-HT3RA+地塞米松（1A类证据）、5-HT3RA+NK-1RA+地塞米松（1A类证据）、帕洛诺司琼+奥氮平+地塞米松（1A类证据）作为中度致吐风险的I级推荐预防用药。表2. 不同程度恶心呕吐的预防策略用药推荐[4] 恶心意大利专家共识[3]指出，恶心的发生存在重要的主观心理因素，且4-5级严重事件极其罕见。对于有过恶心经历的患者，可能会产生治疗偏见，临床需做好沟通。对于这类预期性恶心的治疗主要是从首次用药开始进行有效预防，有效的医患沟通和支持以及针灸等其他辅助治疗可能会有所帮助。 ▌参考文献： [1]Carey, L. A., Loirat, D., Punie, K., et al. (2022). Sacituzumab govitecan as second-line treatment for metastatic triple-negative breast cancer-phase 3 ASCENT study subanalysis. NPJ breast cancer, 8(1), 72. [2]Yeon Hee Park, Javier Cortés, Shanu Modi, et al. Pooled analysis on characteristics of nausea and vomiting in patients receiving trastuzumab deruxtecan (T-DXd) in clinical studies. 2024 ASCO abstract 12118. [3]中国医师协会肿瘤医师分会乳腺癌学组,中国抗癌协会国际医疗交流分会.中国乳腺癌抗体药物偶联物安全性管理专家共识[J].中华肿瘤杂志,2022,44(9):913-927.DOI:10.3760/cma.j.cn112152-20220521-00360. [4]Bianchini G,Arpino G,Biganzoli L,et al.Emetogenicity of Antibody-Drug Conjugates in Solid Tumors with a Focus on Trastuzumab Deruxtecan:Insights from an Italian Expert Panel.Cancers(Basel).2022 Feb 17;14(4):1022. [5]中国抗癌协会癌症康复与姑息治疗专业委员会,中国抗癌协会肿瘤临床化疗专业委员会,中国抗癌协会肿瘤支持治疗专业委员会,中国临床肿瘤学会肿瘤支持与康复治疗专家委员会.中国抗肿瘤治疗相关恶心呕吐预防和治疗指南（2023版）[J].中华肿瘤杂志,2024,46(6):481-501.DOI:10.3760/cma.j.cn112152-20240123-00046. 材料编码 CN-20250102-00003 本资料仅供医疗卫生专业人士参考，请勿向非医疗卫生专业人士发放（来源：《肿瘤瞭望》编辑部）声明凡署名原创的文章版权属《肿瘤瞭望》所有，欢迎分享、转载。本文仅供医疗卫生专业人士了解最新医药资讯参考使用，不代表本平台观点。该等信息不能以任何方式取代专业的医疗指导，也不应被视为诊疗建议，如果该信息被用于资讯以外的目的，本站及作者不承担相关责任。

抗体药物偶联物临床结果

2024-12-24

·医脉通

生命篇章：吡咯替尼温暖照亮曲妥珠单抗耐药患者治愈之路

导读在生命的舞台上，34岁的毛女士，一位慈爱的母亲，面对HR-/HER2+早期乳腺癌的诊断，她选择了勇敢地与之抗衡。治疗的过程并非一帆风顺，病魔最终还是将毛女士推向了晚期乳腺癌的深渊。在本期【“艾”的例量，伴“妮”同行】栏目中，我们将一同走进毛女士的生命旅程，在曲妥珠单抗治疗的希望之光骤然黯淡之时，是吡咯替尼的曙光，再次为她点燃了新的希望，让她得以走向更远的未来。母爱如山，不惧命运的波涛 2019年，一场突如其来的风暴席卷了毛女士的生活。她被诊断为HR-/HER2+乳腺癌，pT2N0M0，ⅡA期。对于一个两岁孩子的母亲来说，这无疑是沉重的打击，但正因为是一名母亲，她不能轻易认输。在医生的指导下，她以乐观和坚强的姿态，开始了与病魔的斗争。毛女士先后接受了EC*4-TH*4化疗、放疗，以及维持1年的曲妥珠单抗靶向治疗。2020年6月4日，随着最后一次的曲妥珠单抗治疗结束，毛女士的治疗之旅终于告一段落。然而，正当毛女士以为生活已逐渐回到正轨时，肝转移的诊断如同晴天霹雳再一次打乱了她的人生。2021年，在复旦大学附属肿瘤医院的进一步检查中，毛女士被确诊为HR+/HER2+乳腺癌肝转移。毛女士的内心经历了剧烈的波动，她感到恐惧、无助，但更多的是对儿子未来的担忧。然而，作为一名母亲，她知道她必须成为儿子的坚强后盾。她告诉自己，无论多么艰难，她都要为了儿子，为了这个家，继续战斗下去。在家人的鼓励和支持下，毛女士开始寻找新的治疗希望。她和家人都坚信，一定会有一线生机。图1 2021年8月，PET-CT提示肝右上叶后段（VII段）转移灶，FDG代谢增高；MRI结果显示:肝S7段结节，约15mm*12mm，T1W1低信号，T2W1稍高信号，增强后强化，另见肝脏微小结节长T1长T2信号，界清，无强化一项研究，重燃生命的希望在曲妥珠单抗治疗结束后的第10个月，肝脏转移成为了毛女士的抗癌新战场。既往研究数据提示，曲妥珠单抗辅助治疗后，大约有15%的患者在8年内出现疾病进展；而在治疗结束后一年内，这一比例大约是5%1。遗憾的是，毛女士成为了那不幸的少数之一。在病魔面前，命运是那么不可预测。在早期曲妥珠单抗经治后进展的群体中，毛女士这类无病间期（DFI）较短的患者，往往表现为更具侵袭性的疾病特征。针对这类曲妥珠单抗原发性耐药患者，目前公布的研究数据较为有限，且结果并不尽如人意。既往两项针对曲妥珠单抗原发性耐药患者的Ⅲ期研究显示，接受阿法替尼联合长春瑞滨治疗的曲妥珠单抗原发性耐药患者中位无进展生存期（mPFS）仅为5.5个月；接受依维莫司联合曲妥珠单抗、长春瑞滨的曲妥珠单抗原发性耐药患者mPFS为7.0个月2,3。这些数据揭示了曲妥珠单抗原发性耐药患者存在显著未被满足的治疗需求，亟需探索最佳治疗策略和药物，以改善这些患者的预后和生活质量。天无绝人之路，一则消息为毛女士的治疗带来了一线生机。PICTURE研究正在招募入组患者。这是由复旦大学附属肿瘤医院胡夕春教授牵头的一项针对曲妥珠单抗原发性耐药患者的单臂、多中心Ⅱ临床研究，纳入早期或晚期治疗期间曲妥珠单抗治疗不敏感的患者，接受吡咯替尼和卡培他滨的治疗。毛女士恰好满足PICTURE研究的入组标准，在医生的建议和鼓励下，她说道：“我愿意尝试，为了能有更多的时间陪伴我的孩子。” 吡咯替尼联合卡培他滨，创造生命的奇迹 2021年9月7日，完善相关检查后的毛女士顺利加入临床试验，正式开始吡咯替尼联合卡培他滨治疗。用药2周期后，毛女士的肝S7段结节从15mm*12mm缩至约7mm*8mm，达到部分缓解（PR）；用药4周期后，肝S7段结节缩至约7.5mm。这一奇迹，不仅记录在检查报告单上，更深深地刻在了毛女士的心中。她看着逐渐好转的复查结果，更加坚定了自己的信念：继续战斗，永不放弃！2022年4月，当地医院复查结果提示，毛女士的肝S7段类结节未见，达到完全缓解（CR）。经过了8个月的吡咯替尼联合卡培他滨治疗，她成功地扭转了病情，打了一个漂亮的翻身仗。2022年9月，PET-CT复查结果提示，毛女士的肝右上叶后段转移灶消失，疗效CR。2024年10月是毛女士最近的一次复查，影像学检查显示，毛女士各方面情况稳定，并无新病灶。这来之不易的完全缓解，让毛女士喜极而泣。这意味着，在PICTURE研究的帮助下，她从病魔手中抢夺回更多陪伴家人的时间了！她可以继续看着孩子成长了！图2 2022年9月PET-CT显示肝右上后叶段（VII段）转移灶消失不仅如此，吡咯替尼联合卡培他滨的治疗方案整体耐受性良好。治疗初期，毛女士曾出现3级腹泻，但在医生的建议下使用易蒙停与静脉补液后，腹泻得到了有效控制，目前仅偶尔出现腹泻。时至今日，毛女士的PFS已超3年，至今仍在服药。这不仅是她对生命的坚持，更是她对家庭的承诺。吡咯替尼联合卡培他滨的治疗方案，以其良好的耐受性和持久的疗效，为毛女士带来了长期的生存获益。毛女士的主诊医生，PICTURE研究的sub-I曹君医生分享到：“PICTURE研究的完整报告已于2023年8月10日在《BMC Medicine》期刊上发表。研究结果显示，中位随访时间20.1个月时（范围：1.3-38.2），总人群的mPFS达到11.8个月（95%CI，8.4-15.1），达到了主要研究终点。其中，像毛女士一样的曲妥珠单抗辅助治疗后12个月内进展的患者（亚组B）mPFS更是达到17.8个月（95%CI，13.8-NR）之久4。2023年ESMO大会期间，PICTURE研究公布了最新的中位总生存期（mOS）数据。结果显示了吡咯替尼联合卡培他滨在曲妥珠单抗原发性耐药的HER2阳性晚期患者中的长期疗效，其中亚组B的mOS最长，达41.7个月（95%CI，38.5-NR）5。此外，吡咯替尼联合卡培他滨用药安全性良好，未发现新的安全性事件，没有患者因不良事件停用吡咯替尼4。” 图3 PICTURE研究中总人群的mPFS 图4 PICTURE研究中亚组B的mOS “PICTURE研究是目前CSCO指南推荐的主流抗HER2治疗方案中，首个在曲妥珠单抗原发性耐药这一难治人群中开展前瞻性临床研究并取得惊喜结果的方案。其中，亚组B人群在临床试验中通常被归类为曲妥珠原发性耐药患者，其17.8个月的PFS可能并不低于既往报道的HER2阳性乳腺癌晚期一线治疗PFS4。与此同时，亚组B和亚组C的mPFS提示，曲妥珠单抗治疗期间进展的患者和治疗结束后进展的患者可能涉及不同的耐药机制，可进一步探索。综合来看，吡咯替尼满足了曲妥珠原发性耐药患者的临床需求，为其提供了一个安全有效的治疗方案。”曹君医生在采访中说到。坚守治疗，吟唱希望之歌谁无暴风劲雨时，守得云开见月明。3年多的治疗坚守，也让毛女士的生活状态越来越好。如今，她的体力已基本恢复，足以照顾正在上小学的孩子。除了每日需按时服药和定期前往医院检查外，疾病对她的生活影响已微乎其微。她特别感激医生的帮助，让她有机会参与PICTURE临床试验，吡咯替尼联合卡培他滨的治疗方案为她的生命带来了新的光明。同时，她也深感幸运，因为家人的支持和鼓励，让她在面对疾病时能够保持乐观的心态和愉悦的心情。她相信，这也是她治疗效果良好的重要因素之一。针对曲妥珠单抗治疗失败后的HER2阳性晚期乳腺癌解救治疗，最新的《中国临床肿瘤学会（CSCO）乳腺癌指南》推荐了酪氨酸激酶抑制剂（TKI）和抗体-药物偶联物（ADC）等多种治疗选择，但并不是所有治疗方案都公布了原发耐药群体的数据6。对于曲妥珠单抗原发性耐药患者，ADC的治疗有效性有待临床研究进一步验证。而PICTURE研究的疗效充分说明，吡咯替尼联合卡培他滨能够为曲妥珠单抗经治患者带来长期生存获益。该研究结果为曲妥珠单抗经治人群的用药提供了强有力的循证医学证据，并填补了疾病特征更为凶猛的原发耐药这类人群的治疗空白。结语在医学的探索与进步中，吡咯替尼的应用重新为毛女士的家庭带来了温暖与光明。她的故事，是无数乳腺癌患者抗争的缩影，也是医学研究不断前行的动力。毛女士的坚持和乐观，让我们相信，即使在最黑暗的时刻，希望之光也从未远离。专家简介曹君教授复旦大学附属肿瘤医院肿瘤内科副主任医师上海市抗癌协会乳腺癌专业委员会青年委员上海市抗癌协会癌症康复与姑息治疗专业委员会委员上海市女医师协会乳腺专委会委员上海市抗癌协会疑难肿瘤专委会委员中国医药教育协会医学国际交流促进工作委员会常委中国生物工程学会肿瘤药物基因组学专业委员会委员上海市中西医结合学会甲乳外科专委会委员中国医药教育协会肿瘤转移专业委员会委员中国女医师协会乳腺专委会委员长江学术带乳腺联盟（YBCSG）委员《中国癌症杂志》审稿专家参与编写《肿瘤科常见诊疗问题问答》、《乳腺肿瘤治疗学》、《肿瘤内科治疗手册》、《肿瘤内科化疗方案手册》等多部书籍参考资料： 1. Eight-year data from APHINITY study show Roche’s Perjeta-based regimen continues to reduce the risk of disease returning for people with HER2-positive early breast cancer. News release. Roche. July 14, 2022. Accessed July 14, 2022. bit.ly/3uOrzSj 2. Harbeck N, Huang C-S, Hurvitz S, et al. Afatinib plus vinorelbine versus trastuzumab plus vinorelbine in patients with HER2-overexpressing metastatic breast cancer who had progressed on one previous trastuzumab treatment (LUX-Breast 1): an open-label, randomised, phase 3 trial. Lancet Oncol. 2016;17(3):357–66. 3. André F, O’Regan R, Ozguroglu M, et al. Everolimus for women with trastuzumabresistant, HER2-positive, advanced breast cancer (BOLERO-3): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Oncol. 2014;15(6):580–91. 4. Cao J, Teng Y, Li H, et al. Pyrotinib plus capecitabine for trastuzumab-resistant, HER2-positive advanced breast cancer (PICTURE): a single-arm, multicenter phase 2 trial. BMC Med. 2023 Aug 9;21(1):300. doi: 10.1186/s12916-023-02999-0. 5. Xichun Hu, et al. Pyrotinib plus capecitabine for trastuzumab-resistant, HER2-positive advanced breast cancer:updated survival results from the phase 2 PICTURE tria. 2023 ESMO FPN: 424P. 6. 2024 CSCO乳腺癌指南. END 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。

临床3期临床结果

100 项与盐酸洛哌丁胺相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D00729	盐酸洛哌丁胺	A07DA53	DB00836

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
急性腹泻	日本	Janssen Pharmaceutical KK	1981-06-04
腹泻	美国	Johnson & Johnson Holdco (NA), Inc.	1976-12-28

未上市

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适应症	最高研发状态	国家/地区	公司	日期
非小细胞肺癌	临床3期	美国	Boehringer Ingelheim GmbH	2013-04-01
输卵管癌	临床2期	美国	Novartis Pharma AG	2001-09-01
输卵管癌	临床2期	加拿大	Novartis Pharma AG	2001-09-01
输卵管癌	临床2期	荷兰	Novartis Pharma AG	2001-09-01
输卵管癌	临床2期	斯洛伐克	Novartis Pharma AG	2001-09-01
输卵管癌	临床2期	英国	Novartis Pharma AG	2001-09-01
卵巢癌	临床2期	美国	Novartis Pharma AG	2001-09-01
卵巢癌	临床2期	加拿大	Novartis Pharma AG	2001-09-01
卵巢癌	临床2期	荷兰	Novartis Pharma AG	2001-09-01
卵巢癌	临床2期	斯洛伐克	Novartis Pharma AG	2001-09-01

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临床结果

适应症

分期

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT02711891 (Loperamide, CTgov)	早期临床1期	疼痛	34	Loperamide (5% Loperamide Gel)	顧蓋繭鏇鏇繭鏇築淵窪(窪廠憲夢膚醖憲繭鏇壓) = 簾齋餘簾顧觸餘網膚鏇顧蓋鑰遞範夢積構餘膚 (顧夢衊簾製遞簾鏇築醖, 鏇觸餘膚鹹獵窪糧艱窪 ~ 憲遞構願齋鹹鹹獵製選) 更多	-	2024-09-19
				Drug, placebo gel (Placebo Gel)	顧蓋繭鏇鏇繭鏇築淵窪(窪廠憲夢膚醖憲繭鏇壓) = 壓簾壓獵築願築網衊積顧蓋鑰遞範夢積構餘膚 (顧夢衊簾製遞簾鏇築醖, 選蓋鑰構壓蓋繭夢築積 ~ 鑰製鏇鹽觸鏇選鹽衊鏇) 更多
NCT02008565 (CAPABLe, CTgov)	临床3期	大便失禁	300	Anal exercises+Loperamide (Loperamide - Exercise Plus Biofeedback)	艱鏇遞憲壓鹹衊顧獵襯(襯壓鬱蓋窪膚構夢簾壓) = 觸鹹製壓衊網製淵構網襯鏇鏇夢蓋選選簾齋衊 (鏇夢獵鹽糧鏇積窪憲膚, 繭襯積構廠鹽遞鹹鹹襯 ~ 廠遞衊範願蓋製遞蓋鏇) 更多	-	2018-11-20
				Placebo (Placebo - Exercise Plus Biofeedback)	艱鏇遞憲壓鹹衊顧獵襯(襯壓鬱蓋窪膚構夢簾壓) = 獵觸觸願網鬱遞製淵築襯鏇鏇夢蓋選選簾齋衊 (鏇夢獵鹽糧鏇積窪憲膚, 蓋鏇膚簾繭繭壓觸觸窪 ~ 鏇廠鬱齋壓簾鏇艱憲鏇) 更多
NCT01618591 (Pubmed \| Clin Infect Dis)	N/A	旅行者腹泻	384	Azithromycin	糧餘繭遞襯壓齋獵願願(餘餘鬱願網醖夢範築夢) = 鏇壓構築蓋憲蓋積製艱獵憲鹽積憲齋範鏇遞夢 (顧壓簾窪顧憲衊餘鹹築 ) 更多	-	2017-11-29
				Levofloxacin	糧餘繭遞襯壓齋獵願願(餘餘鬱願網醖夢範築夢) = 衊簾選觸蓋獵鑰鬱憲遞獵憲鹽積憲齋範鏇遞夢 (顧壓簾窪顧憲衊餘鹹築 ) 更多
NCT02217982 (IIT9, CTgov)	临床4期	复发-缓解型多发性硬化	5	Peanut Butter+Simethicone+Loperamide	簾遞獵鹹壓鹽顧淵積網(壓繭築簾簾憲遞衊選構) = 遞獵廠夢醖獵夢選糧簾觸獵網鹽顧鹹顧齋齋網 (襯鹽鹽鹹獵鹹廠餘鹽遞, 願齋糧顧齋繭鏇壓鹽範 ~ 壓觸繭願願選糧襯鑰鹹) 更多	-	2017-01-06
UEGW2016	N/A	-	-	Loperamide	蓋襯鏇窪餘鑰顧範醖築(鹹夢醖膚選選鬱衊積窪) = Main side effects involve constipation for loperamide and headache for racecadotril 簾簾淵艱鏇獵壓壓鬱醖 (繭淵遞膚簾廠觸鏇觸鏇 )	-	2016-10-01
				Saccharomyces boulardii CNCM I-745
NCT02099006 (Topicals, CTgov)	临床2/3期	疼痛 \| 妇科疾病	9	Baclofen+Amitriptyline+ketoprofen+Loperamide+Ketamine+Gabapentin (Medications)	遞憲觸積蓋壓繭艱壓顧(壓築襯餘淵選鹹積廠獵) = 構顧蓋襯廠膚選衊衊壓選廠糧窪鏇遞觸蓋鹽鑰 (鹹窪願糧繭醖鬱網築願, 選蓋夢遞製衊蓋製築鏇 ~ 醖構衊觸夢製淵膚衊夢) 更多	-	2016-07-15
				placebo (Placebo)	遞憲觸積蓋壓繭艱壓顧(壓築襯餘淵選鹹積廠獵) = 遞衊獵糧遞築簾鑰醖鏇選廠糧窪鏇遞觸蓋鹽鑰 (鹹窪願糧繭醖鬱網築願, 艱糧觸網鬱觸繭齋築鑰 ~ 壓醖淵憲製範膚蓋窪鏇) 更多
NCT00727649 (FIRM, CTgov)	临床2/3期	大便失禁	80	P1L2+Loperamide (P1L2 (Psyllium First, Then Loperamide))	鹹醖糧築淵簾網醖鏇艱(廠鹹鏇製餘鏇窪壓襯淵) = 餘網顧顧艱鬱觸顧餘夢憲窪壓鹹餘觸蓋齋積壓 (遞選鏇積築襯醖鬱鹽鹽, 觸顧夢淵範繭廠壓衊鹹 ~ 獵艱構夢製簾艱鏇範獵) 更多	-	2015-04-01
				L1P2+Pysllium+Loperamide (L1P2 (Loperamide First, Then Pysllium))	鹹醖糧築淵簾網醖鏇艱(廠鹹鏇製餘鏇窪壓襯淵) = 獵鏇鑰鑰遞艱鏇遞範顧憲窪壓鹹餘觸蓋齋積壓 (遞選鏇積築襯醖鬱鹽鹽, 窪窪艱衊製襯範構膚淵 ~ 選憲製襯構醖製鑰範鹽) 更多