A Multicenter, Phase 2 Study to Assess the Safety and Efficacy of Epidural Resiniferatoxin for the Treatment of Intractable Pain Associated With Advanced Cancer

This Phase 2 study assesses the safety and efficacy of a single injection of Resiniferatoxin versus placebo for the treatment of intractable advanced cancer pain.

开始日期2025-09-01

申办/合作机构

Sorrento Therapeutics, Inc.

NCT02522611

/ Not yet recruiting临床1/2期IIT

An Open-Label, Phase 1b Safety and Efficacy Trial of Periganglionic Resiniferatoxin for the Treatment of Intractable Pain Due to Cancer-induced Bone Pain

Background:
Cancer-induced bone pain (CIBP) is common in people with cancer. Bone cancer can also lead to anxiety, depression, and reduced mobility and quality of life. Researchers believe a research drug called resiniferatoxin (RTX) may be able to help.
Objective:
To learn whether RTX is safe and can reduce cancer induced bone pain.
Eligibility:
People ages 18 and older with CIBP that is not relieved by standard treatments
Design:
Participants will have up to 6 outpatient visits over about 7 months. These will include:
Medical history
Physical exam
Blood and urine tests.
Thermal testing: a disk placed on the skin to test ability to sense temperature in and around the area of pain
Chest x-ray
EKG: stickers are placed on the chest to measure heart signals
ECG: measures electrical activity of the heart
Participants will have 1 inpatient visit lasting 2-4 days. This will include:
Catheter inserted into a vein in the arm. They are given anesthesia, sedation, and x-ray contrast.
A needle is passed through the skin of the back to inject the RTX.
Participants will keep a log of the pain medications they take after surgery.
Participants will be called 1 week and 2, 3, and 4 months after the injection.
Participants will be mailed surveys and questionnaires to complete 2, 3, and 4 months after the injection.

开始日期2025-06-02

申办/合作机构

National Institute of Neurological Disorders & Stroke

NCT05695339

/ Recruiting临床1期IIT

Phase I Open Label Clinical Trial Using Resiniferatoxin, A Non-Opioid Medication, For the Management of Refractory Morton's Neuroma Pain

Morton s neuroma is an irritation of the nerves that affect the feet. People with this condition may have burning or shooting pain in the balls of their feet. They may also have numbness in adjacent areas. These symptoms may become more frequent and severe over time. The pain may become permanent. Current treatments tend to be short-lived, and they do not work in all people. Better treatments are needed.
Objective:
To test a study drug, resiniferatoxin (RTX), in people with Morton s neuroma.
Eligibility:
Healthy people aged 18 and older who have Morton s neuroma and have tried other standard treatments that did not ease their pain.
Design:
Participants will be involved in the study up to 4 months.
They will be screened. They will have a physical exam with blood tests. They will have a test of their heart function. They will have X-rays of their affected feet. They will have tests to assess their pain and how their feet react to touch and changes in temperature. They will complete questionnaires about their pain.
RTX is injected into the foot at the site of the nerve pain. Participants will receive a shot to numb the area before the RTX is administered. They will be monitored in the clinic for 4 hours after they receive the RTX.
Participants will receive up to 5 follow-up phone calls per week. Each call will take 5 to 10 minutes. They will be asked about their foot pain and whether they have had any side effects from the RTX.
Participants will return to the clinic 4 weeks after the treatment. Previous tests will be repeated.

开始日期2025-03-13

申办/合作机构

National Institutes of Health Clinical Center

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100 项与树胶脂毒素相关的专利（医药）

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项与树胶脂毒素相关的文献（医药）

2025-05-01·AMERICAN JOURNAL OF CARDIOLOGY

Association of Coronary Revascularization Modality and Timing With Outcomes of Acute Coronary Syndrome in Kidney Transplant Recipients

Article

作者: Aguayo, Esteban ; Benharash, Peyman ; Tabibian, Kevin ; Gandjian, Matthew ; Kwon, Oh Jin ; Zinoviev, Radoslav ; Yalzadeh, Dariush ; Sanaiha, Yas ; Hadaya, Joseph

Coronary artery disease (CAD) remains a leading cause of morbidity and mortality among renal transplant (RTx) recipients, with non-ST-segment-elevation acute coronary syndrome (NSTE-ACS) representing a disproportionately high burden. However, the optimal revascularization strategy for NSTE-ACS in RTx recipients remains unclear. This retrospective study analyzed the 2016 to 2021 Nationwide Readmissions Database. RTx recipients (≥18 years) undergoing coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI) for NSTE-ACS were included. The primary outcome was in-hospital mortality, while perioperative complications, unplanned 30- and 90-day readmissions, repeat revascularization, and renal allograft failure were also considered. Multivariable logistic regression and Royston-Parmar models were used to identify the risk-adjusted association of revascularization modality, timing, and outcomes. Of an estimated 3,323 patients, 20.5% underwent CABG and 79.5% PCI. Following adjustment, CABG was associated with higher perioperative complications (AOR 3.46, 95% CI 2.31 to 5.19) and demonstrated a trend toward increased mortality risk (AOR 1.79, 95% CI 0.76 to 4.18). Royston-Parmar analysis demonstrated no difference in freedom from readmission or renal allograft failure within 90 days of discharge, but CABG was associated with a lower hazard of repeat revascularization (HR 0.24, 95% CI 0.08 to 0.76). Timing analysis revealed stable mortality rates across intervals for both modalities. While PCI complications increased with longer delays to revascularization, CABG demonstrated a more stable pattern. In conclusion, our findings suggest that PCI appears to be associated with lower risks of mortality and complications compared to CABG in RTx recipients with NSTE-ACS. However, CABG may offer benefits of reduced risk of repeat revascularization and greater flexibility in timing without compromising renal allograft function.

2025-05-01·Respiratory Medicine and Research

Evaluation of efficacy and safety of rituximab in patients with progressive interstitial lung disease (ILD) with inflammatory component (EvER-ILD2): A multicentre double-blind placebo-controlled randomized trial

Article

作者: Marchand-Adam, Sylvain ; Nunes, Hilario ; Montani, David ; Chenivesse, Cécile ; Cottin, Vincent ; Jouneau, Stéphane ; Crestani, Bruno ; Bejan-Angoulvant, Theodora ; Bonniaud, Philippe ; Ferreira, Marion ; Mureau, Elody ; Caille, Agnès ; Cadranel, Jacques ; Mousset, Elodie

INTRODUCTION:

Progressive interstitial lung diseases (ILDs) are rare but severe diseases, with high mortality and morbidity, with no effective pharmacological treatment allowing for long-term remission, and therefore no clear therapeutic recommendations. Several ILDs present inflammatory components (ILDic), which may justify the use of anti-inflammatory and immunosuppressive drugs, as first-step therapy. Except for systemic sclerosis (SSc)-ILD and sarcoidosis, the evidence in favor of this approach is very weak. The EvER-ILD2 study is the first one to prospectively evaluate the efficacy and safety of rituximab (RTX) versus placebo in a broad range of progressive ILD outside sarcoidosis and connective tissue diseases. A pharmacokinetic-pharmacodynamic analysis based on RTX serum concentrations will allow identification of potential factors associated with therapeutic response and/or adverse effects.

METHODS:

EvER-ILD2 study is a French multicentre, prospective, randomized, double blind, placebo-controlled, superiority trial. Patients with progressive ILDic will be randomized into 2 groups of treatment: one course of RTX (RTX group) and one course of placebo (Placebo group). The primary outcome is the change in Forced Vital Capacity (FVC, mL) from baseline to 6 months. Several clinical, biological, and quality of life secondary outcomes will be measured at 3 and 6 months. A sample size of 126 patients (63 patients per group) would allow to show a 100 mL difference between groups in the change of FVC from baseline to 6 months, based on a common standard deviation for FVC change of 200 mL with a power of 80% and a two-sided alpha of 5%.

ETHICS AND DISSEMINATION:

The protocol was approved by the French Research Ethics Committee (CPP Ile de France VI) on September 27, 2022, and by the French competent authority on October 02, 2022. This article refers to protocol V1, dated September 2022. An independent data safety monitoring board will review safety data for the duration of the trial. Results will be disseminated via peer reviewed publication and presentation at international conferences.

TRIAL REGISTRATION NUMBER:

NCT05596786 (clinicaltrials.gov), EU-CT number 2022-500,375-31-00 (European Medicines agency).

2025-04-01·NEUROLOGICAL SCIENCES

Nomogram for the prediction of relapse factors in patients with neuromyelitis optica spectrum disorder during rituximab treatment

Article

作者: Huang, Yanning ; Huang, Dehui ; Sun, Hui ; Zhang, Xi ; Gao, Sai ; Wu, Lei

OBJECTIVES:

Develop a nomogram to analyse the factors influencing the relapse of neuromyelitis optica spectrum disorder (NMOSD) during rituximab (RTX) treatment.

METHODS:

A retrospective analysis of 214 NMOSD patients identified 181 with AQP4-IgG-seropositive. 32 patients who relapsed during RTX treatment were included, and 122 sets of lymphocyte subset monitoring data were collected. 110 sets of data were finally included and divided into relapse (n = 30) and nonrelapse (n = 80) groups depending on whether a relapse occurred between two adjacent RTX treatments. Logistic and LASSO regressions were used to identify the relevant factors influencing NMOSD relapse, and a nomogram was constructed. Receiver operating characteristic (ROC) curves were generated to evaluate the nomogram's ability to differentiate, and the bootstrap method was utilized for internal validation. Calibration curve and decision curve analysis were also conducted.

RESULTS:

Comparing baseline data revealed differences in the RTX administration interval, CD3^-CD19⁺ B lymphocyte and CD3^-CD56⁺ NK cell levels. The RTX administration interval and the level of CD3^-CD19⁺ B lymphocytes were independent variables influencing relapse. The nomogram had an area under the curve (AUC) of 0.71 and a 95% confidence interval (CI) of 0.58-0.83. The Hosmer-Lemeshow (H-L) goodness-of-fit test yielded a χ² = 11.80 (p = 0.16). Decision curve analysis revealed that the model provided greater net benefits within the threshold probability range of 0.18-0.98.

CONCLUSION:

The nomogram developed in this study showed that the RTX administration interval and CD3^-CD19⁺ B lymphocyte levels independently influence NMOSD relapse, indicating good discriminative ability, consistency, and clinical benefits.

项与树胶脂毒素相关的新闻（医药）

2024-10-22

·PipelineReview

First participants enrolled in first-in-human Phase I clinical trial with nociceptin (NOP) receptor agonist

AACHEN, Germany I October 22, 2024 I Today, Grünenthal announced that the first participants have been enrolled in a first-in-human Phase I clinical trial for a nociceptin (NOP) receptor agonist. The trial will include 90 healthy volunteers and aims to demonstrate a favourable safety and tolerability profile and to confirm the pharmacokinetic characteristics of the compound after single and multiple ascending doses. The results of the trial are expected in Q3 2025. “Grünenthal pioneered the research into NOP receptor agonists to deliver a unique and transformative first-in-class therapy option to millions of patients suffering from chronic pain,” says Gillian Burgess, Head of Research, Grünenthal. “With a unique mechanism of action for treating chronic pain, these molecules have the potential to deliver robust pain relief combined with an improved safety profile compared to the available standard of care.” Pre-clinical data show that NOP receptor agonists have the potential to act as potent analgesics without abuse liability. 1 Leveraging the clinical data Grünenthal obtained during the development of its NOP receptor programme, Grünenthal now brings forward a candidate that shows best-in-class potency and selectivity for the NOP receptor. These properties are predicted to provide robust pain relief in a broad range of chronic pain indications without the serious central nervous system related side effects associated with available opioids. Grünenthal’s R&D pipeline includes multiple programmes across different stages, targets, modalities, and mechanisms of action to deliver innovative treatment options for patients suffering from pain and related diseases. Recently, a Phase I clinical trial with a Glucocorticoid Receptor Modulator (GRM) has been completed. The compound is developed to provide patients with a therapy option for chronic inflammatory diseases. In addition, Grünenthal is running a Phase III clinical trial with Qutenza ® (capsaicin) 8% topical system in post-surgical neuropathic pain, aiming to expand its label in the United States. A global Phase III programme investigating the efficacy, safety and tolerability of Resiniferatoxin in patients with painful osteoarthritis of the knee is currently ongoing. About the NOP Receptor The nociceptin (NOP) receptor is a G protein-coupled receptor whose natural ligand is the 17 amino acid neuropeptide known as nociceptin (N/OFQ). 2 NOP Receptor agonists have been shown to act as potent analgesics without abuse liability in pre-clinical models. 1 Although the NOP Receptor shares some sequence identity (~60%) with the opioid receptors μ-OP (MOP), κ-OP (KOP), and δ-OP (DOP), they possess little or no affinity for opioid peptides or morphine-like compounds. Likewise, opioid receptors possess little affinity towards NOP’s endogenous ligand nociceptin. 3 About Grünenthal Grünenthal is a global leader in pain management and related diseases. As a science-based, fully integrated pharmaceutical company, we have a long track record of bringing innovative treatments and state-of-the-art technologies to patients worldwide. Our purpose is to change lives for the better – and innovation is our passion. We are focusing all our activities and efforts on working towards our vision of a World Free of Pain. Grünenthal is headquartered in Aachen, Germany, and has affiliates in 27 countries across Europe, Latin America, and the U.S. Our products are available in approx. 100 countries. In 2023, Grünenthal employed around 4,400 people and achieved revenues of €1.8 billion. More information: https://www.grunenthal.com Follow us on: LinkedIn: Grunenthal Group Instagram: grunenthal 1 Lin AP, Ko MC. The therapeutic potential of nociceptin/orphanin FQ receptor agonists as analgesics without abuse liability. ACS Chem Neurosci. 2013 Feb 20;4(2):214-24. doi: 10.1021/cn300124f. Epub 2012 Nov 6. PMID: 23421672; PMCID: PMC3582300. 2 Henderson G, McKnight AT (August 1997). “The orphan opioid receptor and its endogenous ligand– nociceptin/orphanin FQ”. Trends in Pharmacological Sciences. 18 (8): 293–300. doi:10.1016/S0165- 6147(97)90645-3. PMID 9277133. 3 Butour JL, Moisand C, Mazarguil H, Mollereau C, Meunier JC (February 1997). “Recognition and activation of the opioid receptor-like ORL 1 receptor by nociceptin, nociceptin analogs and opioids”. European Journal of Pharmacology. 321 (1): 97–103. doi:10.1016/S0014-2999(96)00919-3. PMID 9083791. SOURCE: Grünenthal Group

临床1期临床3期临床2期

2024-06-13

·梅斯医学

EULAR 2024 ：生物制剂或靶向合成DMARDs在难治性类风湿关节炎患者中的治疗潜力

对常规治疗反应不佳的类风湿关节炎患者，这些患者即使接受了标准的治疗方案，包括传统的合成DMARDs（如甲氨蝶呤）、生物制剂（如抗肿瘤坏死因子α药物）或靶向合成DMARDs（如JAK抑制剂），疾病仍然活跃，症状持续或加重，未能达到临床缓解或低疾病活动度的状态。这一特定患者群体被欧洲抗风湿联盟(EULAR)定义为“难治性类风湿关节炎”。目前，难治性类风湿关节炎患者治疗策略变得尤为复杂，需要考虑更强烈的免疫调节治疗、生物制剂的转换或联合治疗，以及新型的治疗靶点和药物。为进一步寻找更佳有效的治疗方案，在2024欧洲风湿病学大会（EULAR）上，研究人员报告了一项研究，旨在评估不同的生物制剂或靶向合成DMARDs在难治性类风湿关节炎患者中的临床疗效。在这项研究中，研究人员利用捷克ATTRA生物登记处中接受类风湿关节炎治疗的患者队列，评估符合EULAR定义的难治性类风湿关节炎患者在接受后续生物制剂或靶向合成DMARDs治疗后的疾病进程。比较了简化疾病活动指数(SDAI)和缓解状态/低疾病活动度(LDA)的情况。使用Kaplan-Meier方法评估药物保留率，分别在3个月、6个月和12个月时进行评估。结果以中位数及其对应的95%置信区间(CI)表示。连续变量通过中位数以及第5和第95百分位数来表示。结果显示，在8,493名患者中，有939名（11%）符合EULAR定义的难治性类风湿关节炎标准。从这个队列中，选取了642名资料完整、在2007年10月至2023年1月期间开始后续生物制剂或靶向合成DMARDs治疗的个体进行研究。大多数患者为女性（84.7%），中位年龄为56岁（34至74岁）。64.8%的患者正在接受传统合成DMARDs联合治疗，60.4%的患者正在使用糖皮质激素。很大比例的患者开始接受非TNFi 治疗（n=406），其中147名患者开始使用IL-6受体拮抗剂(IL-6Ri)，133名使用JAK抑制剂(JAKi)，71名使用利妥昔单抗(RTX)，55名使用阿巴西普(ABA)。第6个月时，SDAI/LDA的比率分别为58.9%（JAKi）、57.5%（RTX）、54.9%（IL-6Ri）、54.4%（TNFi）和32.2%（ABA）。第12个月的生物制剂或靶向合成DMARDs药物保留率分别为RTX 90.1（83.5至97.3），IL-6Ri 68.6（61.5至76.6），JAKi 67.5（59.9至76.0），ABA 59.5（47.8至74.2），TNFi 58.8（52.8至65.4）。研究人员进一步观察到RTX的治疗维持时间最长，而TNFi的治疗维持时间最短（中位数（95% CI）为71.6个月（49.8至未达到）vs 18.4个月（14.7至25.2）；p<0.001）。41.1%的患者经历了疗效丧失，23.9%出现初始治疗失败，14.1%因不良事件停止后续治疗。结论：难治性类风湿关节炎患者开始使用JAKi、RTX、IL-6Ri或TNFi治疗后，超过一半在六个月内达到了缓解或低疾病活动状态，并在两年内保持了稳定的药物保留率，其中RTX的维持时间最长。在这项描述性分析中，未对可能影响观察到的有效性结果的基线参数进行调整。参考资料： CHALLENGING THE DIFFICULT-TO-TREAT RHEUMATOID ARTHRITIS: COMPARATIVE ANALYSIS OF CLINICAL EFFICACY AND DRUG RETENTION OF SUBSEQUENT BIOLOGIC AND TARGETED SYNTHETIC DISEASE-MODIFYING ANTI-RHEUMATIC DRUGS 来源 | 梅斯医学官网编辑 | Swagpp ●太重磅！国务院：医务人员薪酬不得与药品、耗材、检查、化验等业务收入挂钩！严禁下达创收指标！回归一类公益，全额拨款能来到吗？ ● 重大颠覆！Nature子刊：睡眠不会促进大脑“排毒”，甚至会降低清除废物的能力！Science研究被推翻？ ●震惊！一盒红霉素软膏药店售价39元，电商平台只要3块6，便宜超10倍！网友：医保买药反而更贵，报销个寂寞，被逼着去网上自费买版权说明：梅斯医学（MedSci）是国内领先的医学科研与学术服务平台，致力于医疗质量的改进，为临床实践提供智慧、精准的决策支持，让医生与患者受益。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。点击下方「阅读原文」立刻下载梅斯医学APP！

临床结果

2023-11-20

·CPHI制药在线

系统性红斑狼疮药物治疗研究进展

关注并星标CPHI制药在线系统性红斑狼疮（SLE）是一种以局部或全身炎性反应为特征的自身免疫性疾病，发病隐匿，潜在发病率和病死率高，SLE 患者有不同的症状和体征，临床诊断SLE的重要依据是自身抗体的产生。目前SLE 的临床治疗多以激素和免疫抑制剂为主，由于这些药物特异性差，长期使用会伴随严重甚至危及生命的不良反应。近年来，新型靶向药物的出现为SLE的临床治疗提供了新的选择，这些靶向药物具有服用方便、不良反应小、效果明显、代谢快、特异性高等特点。 SLE的抗炎治疗糖皮质激素（GC）是 SLE 患者的临床治疗一线药物，能够有效抑制结缔组织水平的提升，并且能够调控组胺物质水平，抗炎和抑制毛细血管的扩张，使得患者的病态症状得到有效改善。GC还存在稳定溶酶体膜，改善休克等作用，提升临床治疗效果，但该类药物往往会引起一系列不良反应，如骨质疏松、消化系统并发症、库欣综合征以及高血压等心血管疾病。在SLE的治疗上，通常根据疾病是否初发、病情轻重、是否合并感染、肾脏病理类型以及是否合并肾功能损害或血液系统危象等因素，来调整GC的剂量、种类和使用疗程。激素治疗可分为诱导缓解期、维持期及复发治疗3个阶段。大量的GC联合免疫抑制剂治疗在诱导缓解期使用，维持期则逐渐减量直至最小治疗剂量，一旦病情复发，依患者情况增加到合适剂量，待病情稳定后再缓慢减量。GC的合理使用大大提高了SLE患者的存活率。 SLE 免疫抑制治疗免疫抑制剂是风湿疾病治疗的一类常用药物，其通过抑制机体异常免疫表达来控制体内细胞及体液免疫应答，减轻组织免疫损伤，从而达到降低患者免疫力的作用，常采用联合用药的方式来提高疗效。该类药物治疗机制包括：清除致敏淋巴细胞、清除机体异常免疫反应中的淋巴细胞、清除非特异炎症中的非淋巴样细胞和抑制残存的淋巴样细胞的功能。常用的免疫抑制剂有环磷酰胺（CTX）、硫唑嘌呤（AZA）、霉酸酚酯（MMF）、甲氨蝶呤（MTX）、钙调磷酸酶抑制剂、羟氯喹（HCQ）和中药雷公藤多苷等。 ①环磷酰胺（CTX）。CTX是双功能烷化剂及细胞周期非特异性药物，可影响DNA和RNA的功能，对S期作用显著，从而干扰 DNA 合成而产生细胞毒作用。CTX 通过抑制淋巴细胞增殖，强力作用于B细胞，也对T 细胞有毒性作用，同时有抑制体液免疫与细胞免疫的功能。其对SLE的治疗特别是LN有良好疗效，但烷化剂存在骨髓抑制、感染、性腺抑制或增加肿瘤风险等不良反应。长期大剂量的 CTX 治疗正在逐步被 GC和 CTX 联合使用或序贯使用免疫抑制剂所替代。 ②硫唑嘌呤（AZA）。AZA 是嘌呤类似物，其代谢产物巯嘌呤能干扰嘌呤合成，并有细胞毒作用，可以抑制细胞和抗体介导的免疫应答，通过多种途径抑制核酸的生物合成，从而阻止参与免疫识别和免疫放大的细胞的增生；其次向DNA 链内掺入硫代嘌呤类似物可导致 DNA 破坏。临床上 AZA 大多用于轻中型SLE患者，以减少GC的使用剂量，也用于LN中CTX 的替代治疗。AZA 对 LN 患者在临床缓解，巩固疗效、减少复发的疗效显著。 ③霉酸酚酯（MMF）。MMF可抑制嘌呤从头合成途径，但不影响补救途径的嘌呤合成，从而抑制淋巴细胞活化，抑制生成 T 细胞、B 细胞及抗体，减少血小板破坏，其独特的免疫抑制作用使其不发生骨髓和性腺抑制，有较高安全性。MMF 还针对糖蛋白的转化起到抑制作用，能使 T 细胞与内皮细胞间的黏附力下降，还有减少巨噬细胞的和抑制血管平滑肌增生等作用。研究认为 MMF 可减少沉积于肾脏的免疫复合物，对减轻肾脏损害有一定缓解作用。 ④甲氨蝶呤（MTX）。MTX作为二氢叶酸还原酶抑制剂，可阻碍嘌呤正常合成，从而影响胸腺嘧啶合成，其作用于细胞分裂的 S 期，抑制 DNA 的生物合成，并发挥一定的抗炎作用。但临床研究发现，MTX还有免疫介导的药敏反应及其他不良反应，主要表现为皮肤发红瘙痒、胃肠道反应和肝肾功能损害等，严重者发生骨髓抑制，可并发感染甚至死亡，患者用药安全性较差。 ⑤钙调磷酸酶抑制剂(CNI)。CNI包括环孢素和他克莫司。CNI 主要抑制T淋巴细胞钙调磷酸酶，通过抑制活化T细胞核因子与 DNA 结合从而抑制白细胞介素 IL-2 的表达。IL-2 对 T细胞存活和分化起关键作用，CNI 通过降低 IL-2 表达而抑制 T 细胞功能。因对淋巴细胞的作用具有选择性，故CNI 并无骨髓和性腺抑制作用。他克莫司对LN的疗效不劣于MMF，而联合小剂量激素和MMF 治疗 LN 疗效优于环磷酰胺脉冲方案。欧洲SLE 治疗指南推荐对严重肾病综合征或疗效不佳的LN，可加用小剂量CNI。 ⑥羟氯喹（HCQ）。HCQ是临床治疗常用的抗疟药，常与免疫抑制剂联合用药，它的药理机制包括抗炎和免疫调节。多伦多SLE 研究团队的一项研究表明，在疾病的前5年，超过60%的时间使用抗疟药治疗可减少SLE发病次数，降低损伤累积范围和GC累积用量。HCQ 引起的碱化可导致溶酶体的膨胀和空泡化，进而抑制了溶酶体功能，包括酶的释放、受体再循环、质膜修复、细胞信号传导和能量代谢。这类药物的免疫调节作用是由免疫抑制、抗炎、抗凝、光保护等机制介导的，通过免疫调节有助于维持代谢平衡、保护脏器、改善SLE 活动性及降低病死率和感染等并发症的出现。《2020中国系统性红斑狼疮诊疗指南》建议GC联合 HCQ治疗效果不佳或无法将激素剂量调整至相对安全剂量以下的患者应联合使用免疫抑制剂。 ⑦雷公藤多苷。雷公藤多苷是抗炎免疫调节的中药提取物，可阻断5-羟色胺、组胺、前列腺素 E2产生，从而抑制炎性反应，阻断炎性介质的级联反应，还可抑制 IL-2 产生及其受体效应，诱导已活化淋巴细胞凋亡，对 SLE 炎性反应早期血管通透性增高、渗出水肿有明显抑制作用。在免疫调节方面，雷公藤多苷还能直接抑制亢进的 B 细胞功能，达到辅助治疗 SLE，明显改善患者免疫功能的作用。靶向药物近年来，随着医药研究突飞猛进，各种靶向药物相继出现，主要包含两大类，分别为生物制剂和小分子靶向药物，其主要机制包括抑制B和T淋巴细胞的活化，阻断免疫细胞间的相互作用，以及抑制细胞因子的产生等。靶向药物可以作用于特定的病变部位，通过增加目标局部的药物浓度来减轻药物对正常组织和细胞的毒性作用，也提高了治疗的特异性。 ①靶向B淋巴细胞贝利木单抗已于2011年获得 FDA 和欧洲药品监管局（EMA）正式批准，成为首个获批用于SLE 治疗的靶向药物。B淋巴细胞激活因子（BAFF）是一种肿瘤坏死因子（TNF）样细胞因子，支持 B细胞在不同发育阶段的生存和分化。贝利木单抗的作用靶点是与其有较高亲和力的BAFF，药物的结合将影响BAFF作用于B细胞表面上的受体，抑制B细胞的增殖、分化及血清中自身抗体的生成。研究表明，贝利木单抗可明显减缓 SLE 的疾病活动度，减少泼尼松和GC的用量，但长期服用此药有增加抑郁症的风险。利妥昔单抗（RTX）是一种选择性靶向B细胞特异性表面分子CD20的人鼠嵌合型单克隆抗体，CD20是一种局限于B细胞谱系的细胞表面蛋白，它首先在骨髓中的早期前B细胞阶段表达，并在B细胞发育过程中持续存在，直到最终分化为浆细胞RTX治疗SLE 可以通过抗体依赖细胞介导和补体介导的细胞毒作用来诱导细胞凋亡，B细胞的不断消耗，自身免疫对机体的损伤不断减弱。因CD20不在造血干细胞、正常浆细胞和其他正常的组织中出现，所以RTX可有效避免广泛的免疫抑制，提高了用药的安全性。尽管缺乏试验证据，但许多观察性研究显示了RTX在治疗难治性LN和严重非肾性SLE方面的疗效。 Anifrolumab是一种在研的针对 Ⅰ 型干扰素（IFN）受体亚基1的人单克隆抗体，SLE 患者体内 Ⅰ 型IFN基因标志升高明显，而Ⅰ 型IFN是参与炎性反应的细胞因子。因此，Anifrolumab可通过阻断所有Ⅰ型IFN的活性，用于SLE 的治疗。目前，该单抗药物处于治疗SLE关键Ⅲ期临床试验，结果显示 Anifrolumab组患者的不良事件包括呼吸道感染、鼻咽炎、输液相关反应，不良事件的发病例数低于安慰组，还有GC减量情况和皮肤病的严重程度均优于服用安慰剂。 ②靶向T淋巴细胞阿巴西普是一种用于治疗类风湿性关节炎等自身免疫性疾病的药物，它是由一种白细胞分化抗原CTLA-4和细胞外结构融合的免疫球蛋白IgG1的Fc区组成的融合蛋白，可通过中断 CD80/CD86与CD28的相互作用来调节T细胞共刺激分子。阿巴西普可阻断信号通路，使得T细胞不能被激活。虽然阿巴西普对 SLE 治疗的临床试验并未得到阳性结果，抗 CD40L单克隆抗体在 SLE 的Ⅱ期临床试验中也显示无效，但从阿巴西普治疗SLE患者的安全性来看，在难治性病例中，此药可视为一种备用选择。 ③靶向细胞因子西伐木单抗（Sifalimumab）是一种人源性抗IFN-α抗体，最近一项Ⅱb期临床试验表明，Sifalimumab在中度至重度活动性SLE 患者中具有抑制IFN基因表达的作用，患者的疾病活动度和关节损伤得以缓解。除干扰素α外，其他细胞因子也在SLE 的发病机制中发挥重要作用。近年来，研究发现IL-12可促进T细胞向辅助性T细胞 1 ( helper T cell-1 Th1) 分化，而IL-23 则促进Th17分化，针对IL-12/IL-23的乌司奴单克隆抗体在SLE的Ⅱ期临床研究取得了阳性结果。另有研究发现，不阻断细胞因子而直接给予细胞因子也可用于治疗 SLE，如最近报道小剂量 IL-2 能提高调节性 T 细胞比例而治疗SLE。 ④靶向细胞内信号通路 Ⅰ型干扰素在SLE 发病机制中具有重要作用，而JAK /STAT 信号传导通路是Ⅰ型干扰素的主要信号通路，所以阻断 JAK /STAT 通路即可阻断Ⅰ型干扰素的作用。最近研究发现，JAK /STAT 通路在LN 驻留肾脏 T 细胞的维持中发挥重要作用，JAK抑制剂托法替布能抑制此类 T 细胞功能，减轻蛋白尿和肾损害。目前已有多种JAK 抑制剂在临床上用于治疗类风湿关节炎等自身免疫性疾病，但其能否用于治疗 SLE 的证据尚不足。巴瑞替尼在SLE 的Ⅱ期临床研究中也取得了较好疗效，而Ⅲ期临床试验仍在进行中。小规模观察性研究发现托法替布对SLE 患者的皮疹和关节炎具有一定疗效。脾脏酪氨酸激酶抑制剂等能显著减轻狼疮小鼠皮肤和肾脏病变。参考资料 [1]郭佳,李祥,张理涛.系统性红斑狼疮的用药进展[J].中国中西医结合皮肤性病学杂志,2021,20(05):525-528. [2]柴富,王春芳.系统性红斑狼疮相关药物治疗的研究进展[J].检验医学与临床,2022,19(10):1423-1427. [3]杨念生.系统性红斑狼疮药物治疗发展趋势[J].协和医学杂志,2020,11(03):247-251. 金笔奖征文开启，速来投稿参与！来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com▼更多制药资讯，请关注CPHI制药在线▼点击阅读原文，进入智药研习社~

临床研究免疫疗法

100 项与树胶脂毒素相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	树胶脂毒素	-	DB06515

研发状态

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适应症	最高研发状态	国家/地区	公司	日期
疼痛	临床3期	日本	Grünenthal GmbH	2022-08-26
疼痛	临床3期	加拿大	Grünenthal GmbH	2022-08-26
疼痛	临床3期	捷克	Grünenthal GmbH	2022-08-26
疼痛	临床3期	法国	Grünenthal GmbH	2022-08-26
疼痛	临床3期	德国	Grünenthal GmbH	2022-08-26
疼痛	临床3期	意大利	Grünenthal GmbH	2022-08-26
疼痛	临床3期	墨西哥	Grünenthal GmbH	2022-08-26
疼痛	临床3期	荷兰	Grünenthal GmbH	2022-08-26
疼痛	临床3期	波兰	Grünenthal GmbH	2022-08-26
关节炎疼痛	临床3期	美国	NovaQuest Capital Management LLC	2022-01-30

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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


NCT04885972 (EULAR 12024 \| EULAR 22024) 人工标引	临床2期	膝关节炎	67	RTX-GRT7039 0.5 mg	遞壓鬱遞蓋鹽鏇顧製簾(齋願糧繭襯襯遞築膚壓) = 鏇膚繭顧積願繭艱糧醖糧範蓋繭糧艱淵齋襯壓 (範襯顧選蓋廠壓淵窪選, 19.79) 更多	积极	2024-06-14
				RTX-GRT7039 2 mg	遞壓鬱遞蓋鹽鏇顧製簾(齋願糧繭襯襯遞築膚壓) = 鑰齋選獵鹹遞範構築鏇糧範蓋繭糧艱淵齋襯壓 (範襯顧選蓋廠壓淵窪選, 34.16) 更多
ASN2021	N/A	抗中性粒细胞胞质抗体相关性血管炎维持 ANCA level	62	Rituximab (RTX)	簾壓顧窪鏇獵觸淵獵構(夢顧鏇齋獵艱積顧蓋簾) = 願壓淵選齋觸鏇鬱顧鬱獵醖夢積積蓋繭憲鏇網 (繭築壓鏇鏇憲鹹壓壓醖 )	积极	2021-10-27
				Rituximab-Cyclophosphamide (RTX-CYC)	簾壓顧窪鏇獵觸淵獵構(夢顧鏇齋獵艱積顧蓋簾) = 廠築範糧鹽膚廠淵簾齋獵醖夢積積蓋繭憲鏇網 (繭築壓鏇鏇憲鹹壓壓醖 )
ERA2019	N/A	肾病综合征 IgG level	107	Rituximab (RTX)	鹹鹽構顧觸鹹蓋夢齋構(顧窪淵鬱顧選糧構選遞) = Hypogammaglobulinemia is a frequent complication of RTX treatment in younger children treated for SDNS. The use of RTX in children younger than 8 years has to be carefully evaluated and their clinical and biological follow up should be adapted to the increased risk profil for hypogammaglobulinemia 構積範顧窪積範繭顧範 (構艱繭顧鹽襯壓繭廠餘 )	不佳	2019-06-13
SFN2004	N/A	心痛	-	Resiniferatoxin (RTX)	簾淵範願獵齋製淵齋範(顧築獵夢衊衊壓獵觸蓋) = 鏇齋壓遞艱蓋遞餘簾齋廠夢襯醖廠願構鑰壓餘 (網鬱淵鏇窪壓廠衊窪網 )	-	2004-10-24
				Vehicle	簾淵範願獵齋製淵齋範(顧築獵夢衊衊壓獵觸蓋) = 鏇窪衊淵淵觸願夢積獵廠夢襯醖廠願構鑰壓餘 (網鬱淵鏇窪壓廠衊窪網 )