新型抗纤维化药物吡非尼酮

吡非尼酮是正在开发中的新型抗纤维化药物,具有广谱的抗肺、肝、肾、心和腹膜纤维化作用,其作用机制包括:抑制脂质过氧化,减少转化生长因子β(TGF-β)、血小板源性的生长因子(PDGF)和肿瘤坏死因子α(TNF-α)的生成,从而减轻炎症反应.和目前常用的抗纤维药物相比,本品不良反应较低.现对其药动学、药理作用、临床试验、作用机制和不良反应进行综述.     

抗肺纤维化新药吡非尼酮

特发性肺纤维化是由不明原因引起的疾病,目前还没有一种药物来有效治疗该疾病.吡非尼酮是一类吡啶类的小分子物质,通过抑制转化生长因子-β,改变胶原合成和累积,抑制细胞外基质增殖和表达,具有抗炎、抗氧化和抗纤维化的作用.在一系列的临床试验中,显示了吡非尼酮是潜在治疗特发性纤维化的药物,具有良好的应用前景.     

吡非尼酮的合成

2-氨基-5-甲基吡啶经重氮化、水解得到5-甲基-2（1H）-吡啶酮,再与碘苯在CuCl催化下进行N-芳基化反应得到吡非尼酮,总收率50%.     

吡非尼酮的药理学及疾病治疗学研究进展

吡非尼酮是近年来上市用于治疗特发性肺纤维化的药物。研究证实该药具有抑制胶原合成、抗炎和抗氧化的作用。吡非尼酮作为一种广谱的抗纤维化药物,在特发性肺纤维化、肝纤维化、肾纤维化、心脏组织纤维化、多发性硬化症、神经纤维瘤、子宫肌瘤、恶性胶质瘤的治疗和器官移植纤维化的预防方面均具有广阔的应用前景。     

吡非尼酮治疗特异性肺纤维化的研究进展

摘要：吡非尼酮（PFD）作为一种新型抗纤维化药物,在临床上已经成为治疗特发性肺纤维化（IPF）的一线用药。前期多项体内外研究中,PFD均表现出明显抗纤维化活性。新型冠状病毒肺炎（COVID-19）的部分患者表现出肺部纤维化特征。本文从IPF的发病机制和PFD的药理作用、药动学、临床研究、安全性等方面进行总结概括,并探讨其用于COVID-19伴肺纤维化患者对症治疗的可能性。     

吡非尼酮联合糖皮质激素对特发性肺间质纤维化患者肺功能的影响

目的:研究吡非尼酮联合糖皮质激素对特发性肺间质纤维化患者肺功能的影响。方法:选择2017年4月～2018年7月某院收治的82例特发性肺间质纤维化患者,根据随机双盲法分为对照组和观察组各41例。对照组应用糖皮质激素治疗,观察组在对照组基础上应用吡非尼酮治疗,观察治疗后两组临床疗效及治疗前、3个月后肺功能指标。结果:观察组的总有效率(95.12%)明显高于对照组(80.49%),FVC、FEV1水平较对照组高,差异具有统计学意义(P0.05)。结论:应用吡非尼酮联合糖皮质激素明显改善特发性肺间质纤维化患者肺功能,且临床疗效较好,值得应用推广。     

特发性肺纤维化治疗药吡非尼酮

特发性肺纤维化（IPF）为一种预后不良的进行性疾病,至今仍无有效的治疗手段。而新型的抗纤维化药物吡非尼酮（5-甲基-1-苯基吡啶-2[1H]-酮）已被证明可减缓IPF患者的疾病恶化进程。用肺纤维化动物模型进行的体内和体外研究表明：     

吡非尼酮的动物急性毒性

目的:研究一种新的抗纤维化药物吡非尼酮(PFD)的急性毒性。方法:观察一次性ip、igPFD对小鼠的急性毒性反应和死亡情况,一次性igPFD对大鼠和犬的急性毒性反应及死亡情况。结果:PFD的LD50分别为:1112mg/kg(小鼠ig);561mg/kg(小鼠ip);1221mg/kg(大鼠ig);Beagle犬igPFD的最大耐受剂量>1520mg/kg。结论:PFD对动物有一定的急性毒性作用,但属于低毒。     

吡非尼酮对糖尿病肾病小鼠肾纤维化的改善作用及机制研究

目的 探究吡非尼酮对糖尿病肾病小鼠肾纤维化的改善作用及相关机制.方法 将30只雄性小鼠随机分为对照组、模型组、实验组,各10只.模型组与实验组小鼠采用腹腔注射链尿佐菌素的方法建立糖尿病肾病模型,造模成功后,对照组及模型组小鼠灌胃1％ 羧甲基纤维素钠溶液,实验组小鼠给予吡非尼酮溶液灌胃,均连续灌胃7 d.比较三组小鼠肾功...     

吡非尼酮的合成及结构确证

目的：合成抗纤维化药物吡非尼酮。方法以2-氨基-5-甲基吡啶为原料,经重氮化水解为5-甲基-2（1H）-吡啶酮,再经N-芳基化反应得到吡非尼酮。结果合成的吡非尼酮经高分辨质谱、紫外吸收光谱、红外吸收光谱、核磁共振谱、质谱和热分析确证结构,总收率为49.0%,纯度≥99.9%。结论该合成工艺操作简便,收率高,纯度高,是合成吡非尼酮的较好方法。     

肝纤维化的动物模型及治疗药物研究

肝纤维化是肝损伤后的修复反应 ,涉及复杂的细胞及分子机制。选择与人类相似的肝纤维化动物模型不仅是深入研究肝纤维化发病机制的重要基础 ,也是筛选防治肝纤维化药物的有效手段。随着人们对肝纤维化的认识不断深入 ,有效的防治肝纤维化已成为可能。该文就肝纤维化的动物模型及抗纤维化的药物研究作一综述     

气相色谱法测定吡非尼酮中残留溶剂含量

目的建立了吡非尼酮中6种有机溶剂残留量的分离测定方法。方法采用溶液直接进样气相色谱法,色谱柱为HP-INNOWAX毛细管柱(30 m×0.53 mm×2.65 m),载气为氮气,以N,N-二甲基甲酰胺为溶剂,测定了吡非尼酮原料药中异丙醚、丙酮、二氯甲烷、乙腈、二氧六环与吡啶的残留量。结果 6种有机溶剂完全分离,在所考察的浓度范围内线性关系良好,其中异丙醚、丙酮、二氯甲烷、乙腈、二氧六环与吡啶的线性范围分别为10.16~1 016μg.mL-1(r=0.999 99),9.92~992μg.mL-1(r=0.999 99),1.272~127.2μg.mL-1(r=0.999 8),0.848~84.8μg.mL-1(r=0.999 8),0.785~78.5μg.mL-1(r=0.999 9),0.416~41.6μg.mL-1(r=0.999 9)。各残留溶剂的精密度试验RSD均小于5%,平均回收率在96.22%~99.97%之间。结论本实验所建立的方法简便、灵敏、准确,可用于吡非尼酮中有机溶剂残留量的测定。     

Pirfenidone diminishes cyclophosphamide-induced lung fibrosis in mice

The deposition of excess or abnormal collagen characteristic of pulmonary fibrosis can disrupt gas exchange resulting in severe respiratory impairment. There currently are no effective pharmacologic agents available that inhibit the fibrotic process. Pirfenidone (5-methyl-1-phenyl-2-(1H)-pyridone) is an investigational drug that, when administered at 0.5% (w/w) of the diet, decreases both histologic and biochemical evidence of lung fibrosis in hamsters treated intratracheally with bleomycin. The effectiveness of pirfenidone against lung fibrosis initiated by a systemically administered agent was investigated in mice treated intraperitoneally with 200 mg/kg cyclophosphamide (CP). Control and treated animals were fed a diet containing 0.277% (w/w) pirfenidone beginning 1 day after CP. Despite anorexia in the CP-treated mice the first day after treatment, they ingested a greater average pirfenidone dose over 20 days than saline-treated control mice (717±44 versus 564±30 mg/kg per day, respectively). Total lung hydroxyproline content, an index of fibrosis, was significantly lower 21 days after treatment with CP plus pirfenidone as compared to mice treated with CP alone. Although microscopic lung fibrosis scores were not significantly decreased by pirfenidone in CP-treated mice, the overall incidence of fibrosis was significantly decreased. Histologically, mice treated with CP showed fibrosis while mice treated with CP plus pirfenidone exhibited fewer abnormalities. The rate of hydroxyproline synthesis by lung tissue 9 days after treatment with CP was significantly elevated. This rate was not affected by pirfenidone treatment. Overall, these data support an antifibrotic effect of pirfenidone against CP-induced lung fibrosis in mice. The mechanism of its effect is not known, but appears to be unrelated to an inhibition of collagen synthesis.     

Pirfenidone: anti-fibrotic agent with a potential therapeutic role in the management of transplantation patients

Pirfenidone has a simple chemical structure, but may have profound implications for transplantation management. One of the leading causes of allograft failure is chronic allograft dysfunction, manifested by chronic inflammation and chronic fibrosis [Estenne, M., Hertz, M.I., 2002. Bronchiolitis obliterans after human lung transplantation. AJRCCM. 166, 440-444.]. This review summarizes the literature to date on Pirfenidone in the setting of transplantation, and those studies pertinent to the mechanisms of organ rejection and possible use of Pirfenidone in transplantation patients.     

柚皮素纳米制剂的药理作用研究进展

药物临床试验是新药研发过程中极其重要的阶段,临床试验完成质量的高低直接关系到人类的生命与健康,因此必须保证药物的安全、有效和质量控制。专职研究护士在现今的药物临床研究试验中扮演着多重角色,对临床试验的质量起到了一定的保障作用。依据临床试验的相关法律法规,结合自身工作经验,浅析临床试验中常见问题发生的原因、处理及预防措施,以期提高专职研究护士的作用,从而提升药物临床试验的质量。     

Pharmacokinetics and metabolism of a novel antifibrotic drug pirfenidone,in mice following intravenous administration

The present study describes the pharmacokinetics and metabolism of pirfenidone (PD), a compound which has been shown to have significant antifibrotic effects in rodent models of pulmonary and cardiac fibrosis. Despite the fact that this compound is currently in phase II clinical trials, little data are available on the metabolism and disposition of this agent in rodents or humans. Radioactive PD [benzene ring (14)C(U)] was administered i.v. to mice at 40 mg PD/kg body weight, and animals were killed at varying times for determination of parent compound and metabolites in various tissues. The disappearance of parent compound from the plasma followed apparent 2-compartment elimination kinetics with a terminal elimination half-life of 8.6 min. Cl (0.10 ml/min/g) and V(d(ss)) (0.67 ml/g) indicated that PD was rapidly distributed in body water. This is consistent with the finding that peak tissue radioactivity occurred within 5 min following the i.v. administration of [(14)C]-PD and that well-perfused tissues, kidney>liver>lung have much higher levels of parent compound and metabolites than did fat. Two peaks isolated from plasma samples by HPLC yielded mass spectra that were consistent with initial oxidation to the alcohol followed by further metabolism to the carboxylic acid. The radioactivity recovered in the 24 h urine samples averaged 97% of the administered dose and none of that was associated with the parent compound. The short plasma half-life of parent compound in mice supports the need for additional studies in humans where the compound has been shown to have clinical benefits.     

基于openFDA对吡非尼酮和尼达尼布药品不良反应的比较分析

目的：通过对特发性肺纤维化（IPF）治疗药物吡非尼酮与尼达尼布不良反应进行对比分析,为临床安全用药提供参考。方法：利用美国食品药品监督管理局公共数据项目（the US Food and Drug Administration Pubic Data Open Project,openFDA）中的不良反应端点的交互式图表板块访问不良反应应用程序接口（API）,检索2004年1月至2021年12月期间吡非尼酮与尼达尼布的不良反应报告,并对数据进行分析。结果与结论：吡非尼酮与尼达尼布的不良反应报告数分别为27753和13621份,男性总体不良反应事件多于女性,两种药物主要适应症为IPF,常见的不良反应为胃肠道反应、疲劳、呼吸困难和体重下降等,其中吡非尼酮以恶心最为常见,尼达尼布以腹泻居多。除皮肤相关的不良事件,吡非尼酮多数常见不良反应发生率和严重不良反应事件发生率均低于尼达尼布,其安全性相对更高。     

HPLC法测定吡菲尼酮片的含量及有关物质

目的:建立HPLC法测定吡菲尼酮片的含量及有关物质。方法:色谱柱为Kromasil C₁₈柱（250 mm×4.6 mm,5μm）;流动相为乙腈-0.1 mol·L^-1磷酸二氢钾缓冲液（34:66）（氢氧化钠调pH至6.8）;流速为1.0 ml·min^-1;检测波长为220 nm;柱温为30℃。结果:吡菲尼酮在36.00～180.00μg·ml^-1浓度范围线性关系良好（r=0.999 9）,最低检测限0.72 ng,平均回收率为98.75%,RSD=0.50%,各杂质峰与主峰分离良好。结论:本方法简单方便,专属性强,准确可靠,可用于测定吡菲尼酮片的含量及有关物质。