Traumatic brain injury (TBI) causes acute deficits in cerebral perfusion which may lead to secondary injury and worse outcomes. Inhaled nitric oxide (iNO) is a vasodilator that increases cerebral blood flow and is clinically used for hypoxic respiratory failure in neonates and adults. The investigators will perform a randomized controlled trial of iNO treatment in TBI patients acutely after injury. The investigators will then assess perfusion changes with optic neuromonitoring, blood biomarkers, and 6 month clinical outcomes.

开始日期2024-12-01

申办/合作机构

University of Pennsylvania

NCT04231760 / Not yet recruiting临床1/2期IIT

The Effect of Inhaled Nitric Oxide on Pulmonary Gas-exchange in COPD

Chronic Obstructive Pulmonary Disease (COPD) is a lung disorder commonly caused by smoking, which makes breathing more difficult. When COPD patients exercise, they are not efficient breathers and this leads to serious breathing difficulties, which often causes these patients to stop exercise at low intensities. Even though patients with a mild form of COPD have relatively well preserved lung function, they still have inefficient breathing during exercise. The investigators think that these individuals have problems exchanging fresh gas (i.e., oxygen) into the blood stream because of poor lung blood vessel function. The investigators will test whether inhaled medications, specifically nitric oxide, can improve lung blood vessel function and decrease breathing difficulties during exercise. With this research, the investigators will understand more about breathing efficiency and lung blood vessel function in individuals with mild COPD, and find out whether improving lung blood vessel function helps COPD patients breathe easier and exercise longer. Understanding the reasons behind the feeling of difficult breathing may lead to more effective therapy and improved quality of life in COPD patients.

开始日期2024-12-01

申办/合作机构

University of Alberta

NCT06402565 / Not yet recruiting临床1期

A Randomized, Controlled, Evaluator-Blinded Study to Assess the Safety and Efficacy of NOX1416 in the Treatment of Chronic, Non-Healing, Diabetic Foot Ulcers

The goal of this multi-center, randomized, placebo-controlled, evaluator-blinded study is to assess the safety and efficacy of NOX1416 in the treatment of chronic, non-healing, diabetic foot ulcers (DFUs). Subjects will be randomized to receive treatment with NOX1416 or placebo, as an adjunct to Standard of Care (SOC).
The primary objective of the study is to demonstrate the safety and tolerability of NOX1416 as adjunct to SOC. The secondary objective is to evaluate the clinical benefit of daily NOX1416, as an adjunct to standard of care SOC. Each site will assign a physician (or designee) to serve as the blinded evaluator who is responsible for assessing the study endpoints. The blinded evaluator will not be involved in the clinical care of subjects.

开始日期2024-11-30

申办/合作机构

NOxy Health Products, LLC

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项与一酸化窒素相关的文献（医药）

2025-06-01·Archivos Argentinos de Pediatria

Massive pulmonary thromboembolism in an adolescent with SARS-CoV-2 infection

Article

作者: Castillo Acevedo, Cecilia ; Acuña Aguirre, Carlos ; Chauriye Kuncar, Verónica ; Díaz Espejo, Piaignacia

Thromboembolic events incidence is low in pediatrics; high suspicion and explicit management algorithms are essential. We present a 12-year-old female patient with two weeks of dyspnea, orthopnea, and ankle edema. Tests showed metabolic acidosis, hyperlactatemia, elevated D-dimer, and positive SARS-CoV-2 CRP. The echocardiogram showed severe right ventricular dysfunction and supra-systemic pulmonary hypertension. Chest CT angiography showed extensive bilateral pulmonary thromboembolism. Anticoagulant therapy was started. She presented with hemodynamic instability. Adrenaline, norepinephrine, milrinone, and nitric oxide were started. The clinical picture was extremely severe in the first 24 hours. It was decided to perform systemic thrombolysis with alteplase, which led to an improvement. Cardiorespiratory stabilization and anticoagulation are the mainstays of therapy in massive pulmonary thromboembolism. Fibrinolytic therapy is used in selected high-risk cases. In this patient, systemic reperfusion therapy with alteplase was performed with no significant complications.

2024-12-01·Environmental Pollution

Nitric oxide and ascorbic acid confer cadmium (Cd) tolerance by improving plant terpenoid metabolism and epigenetically modifying DNA methylation

Article

作者: Ardebili, Zahra Oraghi ; Ebadi, Mostafa ; Iranbakhsh, Alireza ; Oraghi Ardebili, Zahra ; Farahani, Fatemeh ; Haghighat, Setareh

This study investigated the efficacy of incorporating nitric oxide (NO; 10 μM) and ascorbic acid (Asc; 10 μM) into the culture medium to confer cadmium (Cd; 5 μM) tolerance in thyme (Zataria multiflora). The phytotoxicity of Cd resulted in a decrease in shoot biomass, which NO or Asc mitigated. Adding Asc and NO to the culture medium was associated with substantial DNA hypomethylation. The NO + Cd and Asc + Cd treatments were accompanied by an increase in the unmethylation percentages, about 3-fold higher than the control. The hemi-methylation percentages in the Asc-supplemented seedlings also displayed an upward trend. The transcriptional upregulation in the γ-terpinene synthase (TPS) gene resulted from the applied elicitors, especially NO. In response to the NO and Asc treatments, the transcription of two cytochrome P450 monooxygenase genes (CYP71D178 and CYP71D180) went up. Incorporating Asc or NO into the culture medium enhanced the concentrations of proline, carvacrol, and thymol metabolites. Employing NO or Asc mitigated the 43% decrease in protein content due to the Cd cytotoxicity. The NO and Asc applications improved the activity of the phenylalanine ammonia-lyase (PAL) enzyme. NO and Asc utilization increased the accumulation of flavonoids. NO and Asc also up-regulated the activities of two enzymatic antioxidants (catalase and peroxidase). Collectively, this study provided novel insight into how Asc or NO confers Cd tolerance by epigenetically remodeling DNA methylation, transcriptionally up-regulating terpenoid and phenylpropanoid metabolism, increasing proline concentration, and improving antioxidants.

2024-10-01·Molecular Neurobiology

Ivermectin Exerts Anticonvulsant Effects Against Status Epilepticus Induced by Lithium-Pilocarpine in Rats via GABAA Receptor and Neuroinflammation Modulation: Possible Interaction of Opioidergic Pathways and KATP Channel with Nitrergic System

Article

作者: Afsahi, Sahar ; Mohammad Jafari, Razieh ; Dehpour, Ahmad Reza ; Ebrahim Soltani, Zahra ; Toutounchian, Samaneh ; Manavi, Mohammad Amin

Status epilepticus (SE) is a critical medical emergency marked by persistent or rapidly repeating seizures, posing a threat to life. Using the lithium-pilocarpine-induced SE model, we decide to evaluate the anti-seizure effects of ivermectin as a positive allosteric modulator of GABA_A receptor and the underlying mechanisms involved. Lithium chloride was injected intraperitoneally at a dose of 127 mg/kg, followed by the administration of pilocarpine at a dose of 60 mg/kg after a 20-h interval in order to induce SE. Subsequently, the rats received varying amounts of ivermectin (0.3, 1, 3, 5, and 10 mg/kg, i.p.) 30 min before the onset of SE. To study the underlying molecular mechanisms, we had pharmacological interventions of diazepam (1 mg/kg), glibenclamide and nicorandil as ATP-sensitive potassium channel blocker and opener (both 1 mg/kg, i.p.), naltrexone and morphine, as opioid receptor antagonist and agonist (1 mg/kg and 0.5 mg/kg, i.p., respectively). In addition, three nitric oxide inhibitors, namely, L-NAME (10 mg/kg, i.p.), 7-NI (30 mg/kg, i.p.), and aminoguanidine (100 mg/kg, i.p.), were administered to the rats in the experiment. Finally, we use ELISA and western blotting, respectively, to examine the amounts of pro-inflammatory cytokines (TNF-α and IL-1β), nitrite, and GABA_A receptors in the rat hippocampal tissue. The study found that ivermectin, at doses of 3, 5, and 10 mg/kg, exerts anti-seizure effects and decrease Racine's scale SE score. Interestingly glibenclamide and naltrexone reduced the anti-seizure effects of ivermectin, and from other hand diazepam, nicorandil, morphine, L-NAME, 7-NI, and aminoguanidine, enhance the effects when co-administrated with subeffective dose of ivermectin. Additionally, the study found that ivermectin decreased the elevated levels of TNF-α and IL-1β following SE, while increased the reduced expression of GABA_A receptors. Overall, these findings suggest that ivermectin has anti-seizure effects in a SE seizure which may be mediated by the modulation of GABAergic, opioidergic, and nitrergic pathways and K_ATP channels.

项与一酸化窒素相关的新闻（医药）

2024-11-07

·CPHI制药在线

天然产物抗高血压作用研究进展

关注并星标CPHI制药在线高血压是一种常见的慢性疾病，它不仅影响患者的身体健康，还可能对患者的心理和社会生活产生负面影响。随着人们生活节奏的加快和饮食结构的改变，高血压的发病率逐年上升。中药等天然产物自古以来就用于调理机体、增强体质和防治疾病，其中许多是药食同源类植物，可食用也可药用，具有治未病、安全性高、副作用小、商业价值高等优点。近年来，天然产物在高血压疾病的治疗研究应用也不断增多，其降压的机制主要包括：抑制ACE活性；降低REN和AngII 水平；上调 SOD 水平，降低 MDA 表达；提高 NO 表达水平，下调 ET 水平；舒张血管；增强抗氧化应激功能；保护血管内皮功能；减轻炎症反应；抑制血管重构；减轻靶器官损伤；调控相关信号通路等多种作用途径。 01 抑制 ACE 活性血管紧张素转化酶（angiotensin converting enzyme，ACE）可将血管紧张素(angiotensin，Ang)I 转化为AngII，是调节血压重要的靶点。从山楂中分离纯化出的有效成分能有效抑制ACE活性，并使用自发性高血压大鼠（spontaneously hypertensive rat，SHR）进行验证，结果表明，其对血清 ACE 活性有抑制作用，且体内降压作用明显。采用超滤、多色谱结合等方法，从决明子中获得ACE 抑制肽，其对 SHR存在明显的降压作用，并且可减少心室壁厚度。研究发现枸杞多肽可降低 ACE 活性，对 SHR 有降压作用，结果表明其作用可能是通过抑制ACE–AngII–AT1-R（angiotensin type 1 receptor， AT1-R）通路，激活ACE2/Ang(1-7)/Mas受体（Mas-R）通路来实现的。葛根黄酮在体外可剂量依赖性抑制ACE 活性，在体内抑制血浆肾素（Renin，REN）活性，可在短时间内显著降低 SHR血压。当归挥发油可调节ACE2/Ang(1-7)/Mas-R轴，抑制ACE 系统，发挥降压作用。 02 降低 AngII 水平 AngII 能激活血管紧张素受体，收缩血管，增加血管阻力，升高血压。研究表明马齿苋醇提物可降低 REN与AngII 水平，降低胰岛素抵抗大鼠血压。决明子水提物可降低 LNNA（L-N-Nitro-Arginine）诱导所致大鼠高血压，作用机制与降低 REN、 AngII 和醛固酮含量，调节肾素-血管紧张素-醛固酮（renin-angiotensin-aldosterone system，RAAS）系统相关。枸杞蛋白酶解液能抑制ACE 活性，降低 AngII、AT1-R 表达，升高ACE2和Mas-R 水平，进而产生降压作用。葛根注射液可降低AngII、内皮素（endothelin，ET）水平，抑制肾血管重塑，降低SHR血压。研究表明夏枯草提取物能下调 ET、AngII表达，上调一氧化氮（nitirc oxide，NO）表达起到降压作用。银杏降低血压的作用，与其抑制血管紧张素Ⅰ( AngiotensinⅠ，AngⅠ) 转化酶和血管舒张的能力有关，也与其增加内皮细胞 eNOS 的表达有关。体内研究表明，玫瑰茄热提取物可通过降低血浆ACE、AngⅡ和血管紧张素转换酶和醛固酮水平而产生抗高血压作用。同时可升高主动脉和心肌一氧化氮合酶和一氧化氮，降低诱导型一氧化氮合酶，从而降低血管舒张和血压。还可改善 N-硝基-L-精氨酸甲酯引起的心肌细胞坏死、炎症、空泡化等组织学变化。马齿苋、决明子、枸杞、葛根、夏枯草等可通过下调AngII 水平，REN水平，影响 RAAS 系统，从而发挥降血压作用，同时还可改善胰岛素抵抗。 03 降低 MDA 水平丙二醛（malonaldehyde，MDA）是一种脂质过氧化物，血管平滑肌在高血压条件下，会出现炎症反应，产生过多的自由基，引发脂质过氧化物反应，导致大量 MDA 形成。山楂提取物可降低血清中MDA 含量，升高NO 水平，下调 SHR血压。莱菔子水溶性生物碱可降低 SHR 血压，抑制心血压管重构，作用机制与提高超氧化物歧化酶（superoxide dismutase，SOD）活性，降低MDA 水平，增强一氧化氮合酶（nitric oxide synthase，NOS）活性，升高NO 水平，降低 AngII 表达相关。怀菊花浸膏可上调心、脑、肾组织 SOD 表达，下调MDA 水平，降低 SHR血压。葛根素可通过降低 MDA 水平，升高 NO、内皮型 NOS 水平，抑制氧化应激，降低血压。 04 升高 NO、NOS 水平 NO在体内是由 L-精氨酸通过 NOS 催化产生，具有舒张血管、降低外周血管阻力和抑制血小板聚集等作用。小蓟醇提物可通过增加中叶素（intermedin， IMD）的含量，提高 NO、NOS 的表达，降低AngII 表达，对抗肾性高血压。决明子水提物可正向调节内皮型 NOS表达，增强抗氧化与ACE 抑制作用，有效下调血压。莱菔子能负向调节ET，正向调节NO水平，改善血管内皮功能。葛根可通过增强内皮型 NOS、SOD 活性，减少心房钠尿肽（atrialnatriureticpeptide， ANP）分泌，从而降低一氧化氮合成酶抑制剂（Nω-Nitro-L-arginine methyl ester hydrochloride，L-NAME）引起的高血压。葛根素可提高 NO 和环磷酸鸟苷（cyclic guanosine monophosphate，cGMP）水平，增加内皮型 NOS 磷酸化水平，降低 AT1和 Cav1（caveolin-1）水平，诱导降压作用。人参提取物可刺激丝氨酸/苏氨酸蛋白激酶 B（protein kinase B，AKT）介导内皮型NOS 的激活，增加NO 的产生，抑制血管壁增厚，减轻SHR 高血压。动物实验表明，姜黄对ACE 和精氨酸酶活性有抑制作用，并且可以升高NO 水平，发挥降压作用。 05 改善内皮功能血管内皮损伤是高血压发生、发展的关键性早期环节。内皮损伤/修复失衡导致内皮功能障碍，进而引起高血压。血管内皮是心血管系统的连续细胞内衬，也被称为“天然的血液容器”，在维持心血管系统中起着重要作用。内皮细胞被认为是危险因素和血管疾病之间的第一道防线。血管内皮细胞、平滑肌细胞的表型转化受特定因素和信号通路的调节，如磷脂酰肌醇-3-激酶/蛋白激B /内皮型一氧化氮合酶( Phosphatidylinositol-3-kinase /Protein Kinase B /Endothelial Nitric Oxide Synthase，PI3K /AKT /eNOS) 信号通路和促分裂原活化的蛋白激酶( Mitogen-activated Protein Kinase，MAPK) 信号通路。此外，血管内皮损伤与缺乏内皮型一氧化氮的产生和由于过量的内皮素-1 成而导致的血管收缩增加有关，从而导致通透性增强，释放炎症介质。研究发现，半夏白术天麻汤能保护血管内皮细胞，促进内皮细胞增殖，降低活性氧和超敏C 反应蛋白( C-reative Protein，CRP) 水平，通过减少内皮细胞的氧化应激和炎症表达，保护内皮细胞中，从而降低血压。枸杞多糖可促进血管舒张因子的释放，降低血管对于收缩物质的反应，增强内皮依赖性舒张。昆布中的褐藻糖胶可激活内皮型 NOS与 Akt 磷酸化，升高 NO水平，增强内皮非依赖性血管功能，保护血管结构，抑制氧化应激，阻碍血压升高。人参超微粉能抑制交感神经与RAAS 系统，改善内皮功能紊乱，增强抗自由基氧化功能，降低SHR血压。 06 减少氧化应激氧化应激是血压升高的标志。高血压患者氧化应激水平升高导致活性氧产生/累积失衡。活性氧参与平滑肌肉收缩、内皮依赖性舒张、平滑肌生长、增殖和迁移，从而有助于血流量、动脉壁厚度和总外周阻力的微调。氧化应激可以激活核因子κB 通路。核因子κB 激活也被证明可以诱导 TNF-α，IL-6和IL-1β水平。核转录因子红系2相关因子2/血红素加氧酶-1( Nuclear Factor-erythroid 2-related Factor 2 /Heme Oxygenase-1，Nrf2 /HO-1 是细胞内抗氧化应激的主要调控途径，也被认为是减轻内皮细胞损伤的理想靶点。研究表明，积雪草酸可以增加超氧化物歧化酶、活性氧和谷胱氨肽的活性，显著增强 Nrf2 的激活，通过 Nrf2 /HO-1信号通路抑制自发性高血压大鼠心脏纤维化。枸杞提取液能调节血管舒张因子水平，增强抗氧化损伤功能，保护靶器官，改善高血压状态。葛根素能增可抗氧化作用，上调内皮型 NOS 磷酸化水平，抑制血细胞黏附因子 1(vascular cell adhesion molecule-1，VCAM1)和转化生长因子-β（transforming growth factor-β,TGF-β)1 信号传导，保护内皮功能障碍与末端器官损伤，降低血压。褐藻糖胶通过改善氧化应激和恢复主动脉平滑肌中的前列腺素水平，对高脂血症、高血压和主动脉平滑肌高反应性具有保护作用。人参皂苷 Rb1 能调节辅助性 T 细胞17(T helper cell 17，Th17)/调节性T 细胞(Regulatory T cells, Treg)比例，增强抗氧化作用，改善氧化应激状态，产生降压效果。姜黄素可以下调 AT1R 表达，增强抗氧化能力，抑制细胞凋亡，保存线粒体 DNA，改善血压升高和肾功能不全。 07 其他研究报道山楂可以部分恢复肝脏组织形态，通过脂质组学调节特定的脂质分子对抗高血压。山楂水提物、决明子水提物能调节总胆固醇(total cholesterol，TC)、甘油三酯(triglyceride， TG)、低密度脂蛋白胆固醇(low-density lipoprotein cholesterol，LDL-C)含量和高密度脂蛋白胆固醇(high density lipoprotein cholesterol，HDL-C)水平，表现出良好的调脂、控制血压作用。枸杞可通过下调长链非编码 RNA 酮(long noncoding RNA，lncRNA sONE)的表达来降低血压。莱菔子的水煎液降压作用明显，其机制与改变内源性代谢物相关。酸枣仁总皂苷能通过中枢神经系统调节血压，抑制 REN 活性。酸枣仁醇提物可作用于大鼠外周血管，明显降低血压。海带粉可降低 SHR 大鼠牛磺酸含量。人参皂苷 Rg2 可通过抑制基质金属蛋白酶(matrix metalloproteinase，MMP)2 和MMP9 表达量以降低 SHR 血压。夏枯草乙醇提取物可增加钙素基因相关肽(calcium gene related peptide，CGRP)表达，降低 REN、ET含量，发挥降压作用。姜黄素治疗可重塑肠道微生物群的组成，影响肠道稳态，改善肠-脑轴失调。部分天然产物还可通过影响脂质代谢、肠道菌群、神经系统等多种途，直接或者间接调控血压。参考资料 [1]周权，张高传，章家敏，赵益，刘红宁．药食同源类中药抗高血压基础研究进展[J/OL]．世界科学技术-中医药现代化. [2]王立英,李天星,白帆,等.中药防治高血压的现代生物学机制研究进展[J].世界中医药,2023,18(18):2690-2695+2700. END 【智药研习社线上研习会报名】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~

临床结果

2024-10-10

·PRNewswire

Mallinckrodt Announces an Expanded Rollout of the INOmax® EVOLVE™ DS Delivery System in U.S. Hospitals

– The INOmax EVOLVE DS is our next-generation nitric oxide delivery system that combines mini-cylinder technology, automation, integration, and interaction into one device1 – – The INOmax EVOLVE DS is now available for contracting and distribution for use in U.S. hospitals – DUBLIN, Oct. 10, 2024 /PRNewswire/ -- Mallinckrodt plc, a global specialty pharmaceutical company, today announced the rollout of the U.S. Food and Drug Administration (FDA) cleared INOmax® EVOLVE™ DS delivery system for the delivery of INOmax® (nitric oxide) gas, for inhalation. This nationwide rollout follows the successful introduction of the INOmax EVOLVE DS Pilot program. The INOmax EVOLVE DS is our next-generation inhaled nitric oxide delivery system with a fully integrated design and includes a primary delivery system, a monitoring system, an electronic blender, automated backup delivery, mini-cylinders, and more.1 The INOmax EVOLVE DS is intended to help meet the needs of neonatal intensive care unit (NICU) patients and healthcare professionals by offering improved automation, which enhances safety features, and a streamlined design that elevates the user experience.1 Please see Applications and Device Warnings below. INOmax is an FDA-approved treatment that is indicated to improve oxygenation and reduce the need for extracorporeal membrane oxygenation in term and near-term (>34 weeks gestation) neonates with hypoxic respiratory failure associated with clinical or echocardiographic evidence of pulmonary hypertension in conjunction with ventilatory support and other appropriate agents.2 INOmax is contraindicated in the treatment of neonates dependent on right-to-left shunting of blood.2 Please see additional Important Safety Information for INOmax below. "We are excited to enter the nationwide rollout phase of our next-generation INOmax delivery system for NICU patients and the hospital staff responsible for their care," said Lisa French, Executive Vice President & Chief Commercial Officer. "This innovation milestone reflects our long-standing commitment to providing delivery system options with comprehensive safety features.1 We will continue to work closely with our customers to support availability of the INOmax EVOLVE DS delivery system." A few of the many INOmax EVOLVE DS features include1: 1.4-lb mini-cylinders Automated pre-use checkout Pre-high-calibrated NO/NO2 gas sensor modules and automatic low calibration Automatic cylinder switching when empty Electronic blender with automatic activation when a minimum amount of oxygen flow has been detected Electronic medical record connectivity that transfers over 100 data parameters3 Touchscreen display with an easy-to-use interface The comprehensive INOmax EVOLVE DS Pilot program provided users the opportunity for an extensive review of our next-generation delivery system. We appreciate each hospital's feedback including one Respiratory Therapist's (RT) statement that, "After using the INOmax EVOLVE DS during the pilot introduction, and in current use, it is evident that Mallinckrodt took the input from bedside RTs into account. The smaller cylinders and streamlined design make it easier to move the device around the hospital and store supplies."1 INOmax has a well-established efficacy and safety profile with more than 20 years on the market and over 875,000 patients treated globally.2,4 In 2023, the INOmax EVOLVE DS was awarded the Human Factors and Ergonomics Society Stanley Caplan User-Centered Product Design Award, presented to teams that have demonstrated outstanding innovation and design for products, software, and systems. Mallinckrodt accepted the award on February 15, 2024. If a customer is interested in learning more about the INOmax EVOLVE DS, they can reach out to their local representative or visit INOmax.com for the latest updates. APPLICATIONS The INOmax EVOLVE DS delivery system delivers INOmax (nitric oxide) gas, for inhalation. The EVOLVE DS must only be used in accordance with the indications, usage, contraindications, and warnings and precautions described in the INOmax package insert and labeling and is indicated for use in term and near term (>34 weeks gestation) neonates with hypoxic respiratory failure (HRF) associated with clinical or echocardiographic evidence of pulmonary hypertension. The EVOLVE DS is indicated for a maximum of 14 days of use. DEVICE WARNINGS Abrupt discontinuation of INOmax can lead to worsening oxygenation and increasing pulmonary artery pressure (rebound pulmonary hypertension syndrome). To avoid abrupt discontinuation, use the eINOblender as a backup immediately to reinstate INOmax therapy and refer to the INOmax package insert. Do not discontinue INOmax delivery if the high NO2 alarm activates. Assess the delivery system for proper setup while maintaining INOmax delivery and verify INOmax and/or FiO2 are appropriate. Do not use equipment that is not specified as part of the system or that is not designed for INOmax mixtures. Using equipment that is not specified can cause the system to malfunction. If an alarm occurs, safeguard the patient first before performing troubleshooting procedures. Use only INOmax, pharmaceutical grade NO. Rx Only For technical assistance or for information on the INOmax EVOLVE DS delivery system, call (877) 566-9466. IMPORTANT SAFETY INFORMATION (Cont'd) Abrupt discontinuation of INOmax may lead to increasing pulmonary artery pressure and worsening oxygenation. Methemoglobinemia and NO2 levels are dose dependent. Nitric oxide donor compounds may have an additive effect with INOmax on the risk of developing methemoglobinemia. Nitrogen dioxide may cause airway inflammation and damage to lung tissues. In patients with pre-existing left ventricular dysfunction, INOmax may increase pulmonary capillary wedge pressure leading to pulmonary edema. Monitor for PaO2, inspired NO2, and methemoglobin during INOmax administration. INOmax must be administered using a calibrated FDA-cleared Nitric Oxide delivery system. Please see Full Prescribing Information . ABOUT MALLINCKRODT Mallinckrodt is a global business consisting of multiple wholly owned subsidiaries that develop, manufacture, market, and distribute specialty pharmaceutical products and therapies. The company's Specialty Brands reportable segment's areas of focus include autoimmune and rare diseases in specialty areas like neurology, rheumatology, hepatology, nephrology, pulmonology, ophthalmology, and oncology; immunotherapy and neonatal respiratory critical care therapies; analgesics; and gastrointestinal products. Its Specialty Generics reportable segment includes specialty generic drugs and active pharmaceutical ingredients. To learn more about Mallinckrodt, visit . CAUTIONARY STATEMENTS RELATED TO FORWARD-LOOKING STATEMENTS This release contains forward-looking statements, including with regard to INOmax (nitric oxide) gas, the INOmax EVOLVE™ DS delivery system, the potential of these products to improve health and treatment outcomes, their potential impact on patients and the availability of the INOmax EVOLVE™ DS delivery system in U.S. hospitals in the future. The statements are based on assumptions about many important factors, including the following, which could cause actual results to differ materially from those in the forward-looking statements: the effects of Mallinckrodt's recent emergence from bankruptcy; satisfaction of, and compliance with, regulatory and other requirements, including the clinical guidelines and protocols, and hospital policies and practices; actions of regulatory bodies and other governmental authorities; changes in laws and regulations; changes in market demand; issues with product quality, manufacturing or supply, or patient safety issues or adverse side effects or adverse reactions associated with INOmax (nitric oxide) gas and the INOmax EVOLVE™ DS delivery system; and other risks identified and described in more detail in the "Risk Factors" section and "Management's Discussion and Analysis of Financial Condition and Results of Operations" sections of Mallinckrodt's most recent Annual Report on Form 10-K , Quarterly Reports on Form 10-Q, and other filings with the SEC, all of which are available on its website. The forward-looking statements made herein speak only as of the date hereof and Mallinckrodt does not assume any obligation to update or revise any forward-looking statement, whether as a result of new information, future events and developments or otherwise, except as required by law. CONTACT Media Inquiries Green Room Communications 908-577-4531 [email protected] Investor Relations Derek Belz Vice President, Investor Relations 314-654-3950 [email protected] Mallinckrodt, the "M" brand mark and the Mallinckrodt Pharmaceuticals logo are trademarks of a Mallinckrodt company. Other brands are trademarks of a Mallinckrodt company or their respective owners. ©2024 Mallinckrodt. US-2400582 10/24 References 1 INOmax EVOLVETM DS Operation Manual. Mallinckrodt Pharmaceuticals. 2 INOmax. Package insert. INO Therapeutics LLC; 2023. 3 EVOLVE DS. Serial Data Protocol for versions 01.04.09 and later. Technical Bulletin. TB-23001. Mallinckrodt Pharmaceuticals. 2023. 4 Data on File – Ref-01753. Mallinckrodt Pharmaceuticals. SOURCE Mallinckrodt plc WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

2024-09-29

·医药地理

【掇菁撷华】可控的响应性一氧化氮纳米递送系统在肿瘤治疗中的研究进展

引用本文引用：柳超, 唐小慧, 李莎莎, 等．可控的响应性一氧化氮纳米递送系统在肿瘤治疗中的研究进展[J]．中国医药工业杂志, 2024, 55(9): 1171-1178．DOI：10.16522/j.cnki.cjph.2024.09.001 Research Progress of Controllable and Responsive Nitric Oxide Nanodelivery Systems in Tumor Therapy 可控的响应性一氧化氮纳米递送系统在肿瘤治疗中的研究进展柳超1，唐小慧2，李莎莎3，陈建军1* (1. 新疆医科大学医学工程技术学院，新疆乌鲁木齐 830017；2. 新疆医科大学中心实验室，新疆乌鲁木齐 830017；3. 新疆医科大学药学院，新疆乌鲁木齐 830017) 摘要一氧化氮作为一种内源性信使分子，在肿瘤治疗中具有多重功效，不仅能够引起肿瘤细胞凋亡，还能与其他治疗方式实现较好的协同作用。为提高其治疗效率，研究工作者们设计、制备了各种类型的一氧化氮纳米递送系统并用于肿瘤治疗研究。其中，可控的响应性一氧化氮纳米递送系统以其出色的按需释放能力和优异的疗效受到了广泛关注。本文主要综述了基于不同纳米材料的可控、响应性一氧化氮纳米递送系统，并分别从内源性和外源性刺激响应功能讨论其在肿瘤治疗中的应用，以期为一氧化氮纳米递送系统的进一步发展提供参考。关键词一氧化氮；纳米递送系统；响应性；肿瘤治疗；研究进展文章节选一氧化氮(nitric oxide，NO) 作为一种内源性气体信使分子，在血管舒张、抗血管生成、免疫治疗等过程中扮演着重要的角色。近年有研究显示，高浓度NO可通过多种途径直接引起肿瘤细胞凋亡，有望用于肿瘤治疗。 NO 能改变肿瘤微环境并调节部分恶性肿瘤相关蛋白的表达，进而与其他治疗方式实现良好的协同。例如，在传统化疗(chemotherapy) 中，NO 不仅可以抑制P- 糖蛋白和多药耐药蛋白的表达，还可与化疗药物产生的超氧阴离子反应生成氧化能力更强的活性氮(reactive nitrogen species，RNS)，增强化疗效果。不仅如此，NO 还能加速肿瘤内重要的还原性物质谷胱甘肽(glutathione，GSH) 的转化，减少GSH 与化疗药物加合物的形成，进一步实现化疗增敏。此外，由于NO 能与活性氧(reactive oxygen species，ROS) 反应生成氧化能力和硝化能力更强的RNS，因此可显著提高化疗和ROS 依赖性治疗方式[ 如，光动力治疗(photodynamic therapy，PDT) 及化学动力治疗(chemodynamic therapy，CDT) 等] 的疗效。在肿瘤治疗中，乏氧不仅会促进肿瘤的转移和复发，还会影响众多治疗方式的效果。NO 可使肿瘤微环境中的血管正常化，进而增加血流灌注，促进氧气供给。NO 还可凭借其与氧气相似的分子结构，竞争性地与线粒体结合，降低氧消耗，有效缓解肿瘤部位的乏氧状况，从而增强化疗、放疗(radiotherapy)、PDT、CDT 等方案的效果。研究显示，NO 可作为一种重要的免疫调节物质在肿瘤治疗中发挥作用。例如，NO 可引发肿瘤细胞免疫原性死亡(immunogenic cell death，ICD)，还能促进肿瘤免疫微环境由“冷”向“热”的转变，实现免疫系统的激活和启动。虽然NO 在肿瘤治疗领域具有显著效用及出色的协同能力，但却面临NO 供体水溶性不好、生理条件下稳定性不佳、缺乏靶向性、时空可控的释放能力不足及半衰期短等问题，阻碍了NO 的进一步临床应用。纳米技术的快速发展使各类纳米诊疗系统的应用成为可能。为提高NO 的治疗效率，并加速其向临床转化，研究者们设计、制备了多种负载NO供体的纳米递送系统，可在内源性(GSH、pH 值、酶等) 或外源性( 光、超声、X 射线等) 刺激作用下响应性地释放NO。表1 汇总了刺激响应性载NO 供体的纳米递送系统的相关研究。其中，脂质体(liposomes)、介孔二氧化硅纳米粒(mesoporous silica nanoparticles，MSNs) 、金属有机框架(metal organic framework，MOF)、自组装纳米颗粒、水凝胶等纳米系统，凭借其出色的纳米结构特性和载药性质，被广泛应用于肿瘤治疗领域。本文聚焦于NO 在肿瘤治疗领域的相关研究，主要介绍NO 纳米递送系统及各种NO 供体的发展现状，并分别介绍各类响应性纳米系统在肿瘤治疗研究中的应用。扫描二维码阅读原文/登录官网查看了解更多文章信息基金项目：新疆维吾尔自治区自然科学基金(2021D01C279) 作者简介：柳超(1989—)，男，博士研究生，讲师，专业方向：生物材料。通信作者：陈建军(1977—)，男，教授，博士生导师，从事生物材料及药物检测的研究。 E-mail：cjjliyan@163.com 关于转载：原创内容未经允许，不得转载 END 欢迎订阅《中国医药工业杂志》《中国医药工业杂志》是我国医药工业领域中办刊历史最长的医药期刊，是由上海医药工业研究院主管，上海医药工业研究院、中国药学会和中国化学制药工业协会主办的全国性综合医药学术刊物，国内外公开发行。自1970年11月创刊以来，《中国医药工业杂志》始终以报道我国医药工业和科研中的成果和经验为宗旨，刊载了大量反映中国医药工业发展水平的论文和论著，积累了丰富的第一手原始资料；同时密切关注国际上制药技术的发展新动向，刊登有指导意义的综述和专论。期刊订阅详情请登录《中国医药工业杂志》官网（http://www.cjph.com.cn）了解。《中国医药工业杂志》编辑部

免疫疗法

100 项与一酸化窒素相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	一酸化窒素	R07AX01	DB00435

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
低氧性呼吸衰竭	中国	INO Therapeutics LLC	2022-03-08
新型冠状病毒感染	印度	SaNOtize Research & Development Corp.初创企业	2022-02-09
肺动脉高压	日本	AIR WATER MEDICAL INC	2008-07-16
肺性高血压	冰岛	Linde Healthcare AB	2001-08-01
肺性高血压	欧盟	Linde Healthcare AB	2001-08-01
肺性高血压	列支敦士登	Linde Healthcare AB	2001-08-01
肺性高血压	挪威	Linde Healthcare AB	2001-08-01
新生儿呼吸衰竭	冰岛	Linde Healthcare AB	2001-08-01
新生儿呼吸衰竭	列支敦士登	Linde Healthcare AB	2001-08-01
新生儿呼吸衰竭	挪威	Linde Healthcare AB	2001-08-01
新生儿呼吸衰竭	欧盟	Linde Healthcare AB	2001-08-01
呼吸功能不全	美国	MALLINCKRODT HOSP PRODUCTS IP LTD	1999-12-23

未上市

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
新型冠状病毒感染	临床3期	斯里兰卡	SaNOtize Research & Development Corp.初创企业	2021-11-20
新生儿持续肺动脉高压	临床2期	美国	Mallinckrodt Plc	1998-08-01
吸入性肺炎	临床2期	美国	Mallinckrodt Plc	1998-08-01
新生儿呼吸窘迫综合征	临床2期	美国	Mallinckrodt Plc	1998-08-01
呼吸衰竭	临床2期	美国	Mallinckrodt Plc	1998-08-01
呼吸功能不全	临床2期	美国	Mallinckrodt Plc	1998-08-01
血小板疾病	临床前	美国	Mallinckrodt Plc	2018-04-25
炎症	临床前	美国	Mallinckrodt Plc	2018-04-25
急性胸部综合征	临床前	法国	Mallinckrodt Plc	2008-12-01
成人呼吸窘迫综合征	临床前	美国	Mallinckrodt Plc	2000-09-01

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临床结果

适应症

分期

评价

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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


NCT00515281 (NOVA2, CTgov)	临床2/3期	支气管肺发育不良 \| 脑室周围白质软化 \| 脑室内出血 \| 早产	273	inhaled nitric oxide (INO Control (Short iNO))	窪憲範糧衊壓範膚鑰蓋(網鏇製廠膚襯網壓艱獵) = 觸鹹夢齋壓鏇構淵築積遞願鏇顧繭餘範獵衊範 (蓋壓憲製築蓋夢選簾廠, 壓鹽襯築齋觸鬱積鬱蓋 ~ 鏇繭糧繭艱築願顧鏇夢) 更多	-	2024-10-17
				oxygen+inhaled nitric oxide (INO Treatment (Long iNO))	窪憲範糧衊壓範膚鑰蓋(網鏇製廠膚襯網壓艱獵) = 夢遞糧網範網衊選觸顧遞願鏇顧繭餘範獵衊範 (蓋壓憲製築蓋夢選簾廠, 壓餘齋觸膚鹹願窪獵鏇 ~ 繭願餘夢蓋鏇蓋壓膚餘) 更多
ATS2024	N/A	气道病变	-	Inhaled Nitric Oxide (Bilateral lung injury)	獵積艱繭築糧夢網繭獵(觸淵簾網壓餘憲繭壓衊) = 築糧築餘糧餘顧鏇廠膚願壓鏇壓淵願廠壓積鑰 (夢膚簾願築積構鏇選簾, 2 ~ 8) 更多	-	2024-05-19
				Inhaled Nitric Oxide (Asymmetrical lung injury)	獵積艱繭築糧夢網繭獵(觸淵簾網壓餘憲繭壓衊) = 淵膚獵選憲積壓簾蓋選願壓鏇壓淵願廠壓積鑰 (夢膚簾願築積構鏇選簾, 1 ~ 2) 更多
ATS2024	N/A	新型冠状病毒感染	-	High flow nasal oxygen (HFNO)	糧鹹遞鹹餘壓襯製醖簾(憲齋觸顧衊鏇築範窪淵) = 齋窪衊鑰鹽襯襯襯艱壓鹽醖衊醖鬱餘顧網製觸 (夢網齋醖糧壓積範壓鏇, 1.47% ~ 2.1%)	-	2024-05-19
				High flow nasal oxygen (HFNO) + inhaled nitric oxide (iNO)	鏇鬱壓築齋齋齋網簾選(醖觸簾夢壓餘壓鬱醖遞) = 憲築鹹齋鬱廠齋築糧構醖獵積鬱廠鑰製鹹鏇製 (觸膚顧遞顧範鑰願積願 ) 更多
NCT03873298 (Pubmed) 人工标引	临床2期	间质性肺疾病 pulmonary hypertension	44	nitric oxide	(顧齋積襯範襯顧糧鏇鬱) = 鏇衊積簾鏇顧鏇構壓願膚衊鹹窪鑰壓糧淵糧繭 (獵鏇壓製襯淵網糧醖膚, 265 ~ 409)	积极	2024-05-10
				Placebo	(顧齋積襯範襯顧糧鏇鬱) = 醖遞淵醖壓鏇鏇壓膚鬱膚衊鹹窪鑰壓糧淵糧繭 (獵鏇壓製襯淵網糧醖膚, 250 ~ 407)
NCT03044314 (OVATION, CTgov)	临床4期	肺性高血压	27	nitric oxide administration+Iloprost	蓋遞鏇積網蓋簾構醖蓋(膚糧艱壓齋構網願窪鹹) = 糧醖壓範壓鬱鹹餘醖壓窪獵鏇窪窪廠範醖簾夢 (積顧構廠憲觸選夢觸糧, 襯餘蓋鏇願廠蓋觸夢築 ~ 襯觸廠鏇鹽衊網顧廠壓) 更多	-	2024-04-02
NCT03081052 (Pubmed)	临床4期	-	231	Inhaled Epoprostenol	夢鬱艱積窪糧築憲鏇糧(築遞淵鑰鏇衊艱繭繭鏇) = 鹹糧窪鏇齋製願鹽積簾鬱構蓋淵觸顧鹽鑰鬱範 (糧蓋鏇鏇願築製遞網壓 )	-	2023-07-04
				Nitric Oxide	夢鬱艱積窪糧築憲鏇糧(築遞淵鑰鏇衊艱繭繭鏇) = 醖簾顧壓顧鬱遞廠壓淵鬱構蓋淵觸顧鹽鑰鬱範 (糧蓋鏇鏇願築製遞網壓 )
EHA2023	临床2期	复发难治性急性淋巴细胞白血病巩固	110	mini-HCVD + InO	襯淵觸鏇構構鑰夢繭鑰(構顧壓衊艱餘繭膚衊鏇) = 餘獵遞壓製衊遞憲鏇糧網壓窪衊簾淵淵餘鑰願 (築廠簾顧範範簾襯壓鹹 ) 更多	-	2023-06-08
				mini-HCVD + InO + blina	襯淵觸鏇構構鑰夢繭鑰(構顧壓衊艱餘繭膚衊鏇) = 範襯鹽憲獵糧鏇簾鏇糧網壓窪衊簾淵淵餘鑰願 (築廠簾顧範範簾襯壓鹹 ) 更多
ATS2023	N/A	肺性高血压	-	Inhaled Iloprost	積遞遞膚齋鑰遞窪廠觸(淵構鹽廠遞膚網構築築) = 窪窪網糧醖糧顧淵襯構壓膚襯鑰鹹淵鑰獵簾構 (襯鏇壓鏇鹽網廠襯蓋鹹, 12.2)	-	2023-05-21
				Inhaled Nitric Oxide	積遞遞膚齋鑰遞窪廠觸(淵構鹽廠遞膚網構築築) = 鹽襯鹽網鬱壓願繭觸艱壓膚襯鑰鹹淵鑰獵簾構 (襯鏇壓鏇鹽網廠襯蓋鹹, 12.2)
ATS2023	N/A	新型冠状病毒感染	-	Inhaled Nitric Oxide	鹽糧鏇願窪繭築顧範齋(選淵淵蓋鬱鹹顧窪選簾) = 鹽鏇選觸遞壓構蓋觸齋繭膚艱壓顧憲夢構顧糧 (糧鬱鏇鬱遞鏇餘鹽廠觸 ) 更多	-	2023-05-21
O131 (EBMT2023)	N/A	前体B细胞急性淋巴细胞白血病	51	Blina	(艱廠積觸衊淵壓鏇醖壓) = 衊繭膚壓壓築範製憲艱鏇遞廠夢積蓋獵艱網獵 (蓋糧觸範願遞衊製繭蓋 ) 更多	积极	2023-04-23
				Ino	(艱廠積觸衊淵壓鏇醖壓) = 積簾鬱製餘製淵窪積網鏇遞廠夢積蓋獵艱網獵 (蓋糧觸範願遞衊製繭蓋 ) 更多