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胍法辛

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胍法辛
临床资料
商品名（英语：Drug nomenclature）Estulic、Intuniv、Tenex及其他。
AHFS/Drugs.comMonograph
MedlinePlusa601059
核准状况
给药途径口服给药
药物类别（英语：Drug class）α-2A肾上腺素受体激动剂（英语：Alpha-adrenergic agonist）
ATC码
法律规范状态
法律规范
识别信息
  • N-(Diaminomethylidene)-2-(2,6-dichlorophenyl)acetamide
CAS号29110-47-2  checkY
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard（英语：CompTox Chemicals Dashboard） (EPA)
ECHA InfoCard100.044.933 编辑维基数据链接
化学信息
化学式C9H9Cl2N3O
摩尔质量246.09 g·mol−1
3D模型（JSmol（英语：JSmol））
  • Clc1cccc(Cl)c1CC(=O)\N=C(/N)N
  • InChI=1S/C9H9Cl2N3O/c10-6-2-1-3-7(11)5(6)4-8(15)14-9(12)13/h1-3H,4H2,(H4,12,13,14,15) checkY
  • Key:INJOMKTZOLKMBF-UHFFFAOYSA-N checkY

胍法辛（英语：Guanfacine）以Tenex（速释剂型（immediate-release dosage）和Intuniv（缓释剂型（英语：modified-release dosage））等品牌销售，是一种口服α-2A肾上腺素受体激动剂（英语：Alpha-adrenergic agonist），用于治疗注意力不足过动症(ADHD) 和高血压。[2][3]胍法辛经美国食品药物管理局（FDA）批准用于ADHD的单一疗法，[2]也可用于增强其他药品（例如兴奋剂）的辅助之用。[3]胍法辛也被作仿单标示外使用，用于治疗抽动障碍、焦虑症和创伤后压力综合征 (PTSD)。[4]

使用后常见的副作用有嗜睡、便秘和口干。[3]其他副作用可能有低血压和泌尿系统问题。[5]FDA将胍法辛归类为妊娠期"B类"，表示于动物生殖研究方面尚未证明个体于怀孕或母乳哺育期间对胎儿或婴儿有风险，或是不良影响。[6][5]此药物似乎透过激活大脑中的α-2A肾上腺素受体，减少交感神经系统活动来发挥作用。[3]

胍法辛于1974年首次于文献中被描述，[7]并于1986年在美国被批准用于医疗用途。[3]市面上有这种药品的通用名药物贩售。[3]它是美国于2020年排名第300的最常用处方药，开立的处方笺数量超过100万张。[8][9]

医疗用途

Red pills
每片为一毫克剂量的胍法辛药片。

胍法辛经FDA批准作为单一疗法，或可联合兴奋剂，用于治疗注意力不足过动症 (ADHD)。[2][10][11]胍法辛被认为无物质滥用潜力（与兴奋剂不同），它甚至可用于降低尼古丁和古柯碱等的滥用问题。[12]此药物也被FDA批准用于治疗高血压。[13]胍法辛可协同增强苯丙胺（安非他命）和哌醋甲酯等兴奋剂在治疗ADHD的作用，且在许多情况下还可帮助控制兴奋剂的副作用。[3]据称胍法辛于治疗ADHD时，可帮助个体更好控制行为、抑制不适当的分心和冲动，并抑制不适当的攻击性冲动。[14]对此药品所做的系统综述和元分析，发现其对于治疗儿童和成人ADHD均有效，在成人治疗中发现效应值适中 (标准化平均差异（Hedges' g） = -0.66)。[15][16][17]有项系统综述和元分析还发现胍法辛可减少患有ADHD的儿童和青少年的对立反抗行为（这些儿童和青少年或者患有，或是不患有对立性反抗症，效应值为小至中等）。[18]但胍法辛和其他α2-肾上腺素受体激动剂被认为在治疗ADHD的有效性方面不如兴奋剂。[18][19][17]

胍法辛也被用于治疗抽动障碍、焦虑症（如广泛性焦虑症）和创伤后压力综合征（PTSD）。[4]胍法辛和其他α2A-肾上腺素受体激动剂具有抗焦虑药般的作用，[20]可减少杏仁核产生的情绪反应，并加强前额叶皮质对情绪、行动和思想的调节。[21]这些作用源自于对心理压力诱导的儿茶酚胺释放的抑制，以及前额叶皮质中受体侧突触的作用。[21]由于其生物半衰期时间较长，也可改善PTSD患者因做噩梦而导致的睡眠中断。[22]所有这些行为都可能有助于缓解与PTSD相关的过度警觉、创伤记忆重现和冲动。[23]胍法辛似乎对治疗遭受心理创伤或受虐待儿童特别有帮助。[21]

不良影响

胍法辛的副作用是有剂量曝露-反应相关性（英语：Dose–response relationship）。[24]

很常见（>10%发生率）的不良反应有嗜睡、疲倦、头痛和腹痛。[25]

常见（发生率1-10%）不良反应有厌食、恶心、口干、尿失禁和皮疹。[25]

根据报告，胍法辛会导致罹患ADHD儿童有很高的嗜睡率，例如在一项试验中，服用胍法辛组的嗜睡率为73%，服用安慰剂组为6%。[26][27]

胍法辛可能会导致罹患ADHD的儿童睡眠恶化，包括减少总睡眠时间。[26][27]

于2020年所做的一项系统综述发现胍法辛产生的副作用有腹痛、镇静和QT间期延长（英语：Drug-induced QT prolongation）。[28]

交互作用

胍法辛的利用率受CYP3A4和CYP3A5（英语：CYP3A5）两种酵素的显著影响。抑制或诱导这些酵素的药物会改变胍法辛于循环中的数量，因而改变其功效和不良反应发生率。由于其对心脏有影响，若与其他循环系统活性药物一起使用时应谨慎。当它与镇静剂一起使用时，也应谨慎。[25]

药理学

药效学

胍法辛[29]
结合位点 亲和力(纳摩尔（nM）) 物种 参考
α-2A肾上腺素受体 50.3 – 93.3 人类 [30][31]
α-2B肾上腺素受体 1,020 – 1,380 人类 [30][31]
α-2C肾上腺素受体 1,120 – 3,890 人类 [30][31]
数值越小，与结合位点亲和力越强。

胍法辛是α-2A肾上腺素受体的高度结合选择性（英语：binding selectivity）激动剂，对其他受体的结合亲和力较低。[29]然而它也是一种5-HT2B受体激动剂。[32][33][34][35]

胍法辛透过活化中枢神经系统内的α2A-肾上腺素受体[36]而发挥作用。导致周围神经系统流出减少，而降低外周交感神经张力，从而降低血管的心脏收缩压和舒张（英语：dystole）压。[37]

胍法辛在治疗ADHD时，被认为是透过加强前额叶皮质对注意力和行为的调节来发挥作用。[38][14]这些对前额叶皮质功能的增强作用被认为是由于药物刺激树突上的受体侧突触α2A-肾上腺素受体，而非依赖释放侧突触α2A-肾上腺素受体的活化。[14]环磷酸鸟苷（cAMP）介导的HCN通道（英语：HCN channel）和KCNQ通道（英语：KCNQ channels）开放受到抑制，而增强前额叶皮质突触连接和神经元动作电位发生。[38][39]在猴子身上的实验结果，发现胍法辛可改善工作记忆、注意力调节和行为抑制，而这些作用与其镇静作用无关。[14]使用胍法辛治疗前额叶疾患是由耶鲁大学医学院阿恩斯滕实验室（Arnsten Lab）所开发。[38][14]

胍法辛对α2A-肾上腺素受体的选择性比可乐定高很多，可乐定不仅能结合及活化α2A肾上腺素受体，还能结合及活化α2B和α2C肾上腺素受体以及咪唑啉受体（英语：Imidazoline receptor）。[14]此药品在降低血压和镇静方面比可乐定为弱，对受体侧突触的α2A肾上腺素受体的作用也比可乐定为弱（降低蓝斑核活性和正肾上腺素释放的效果低10倍），并且在释放侧突触的α2A肾上腺素受体方面可能具有更大的功效（由胍法辛比可乐定更能增强老年猴子的前额皮质相关工作记忆所显示）。[14]

5-HT2B受体被活化后是众人已知的抗标靶，与心脏瓣膜疾病（英语：Valvular heart disease）有关联。[32][33]然而并非所有5-HT2B受体激动剂（例如罗平尼咯）都具有这种作用。[32][33]虽然胍法辛已被使用许久，但并无与心脏瓣膜疾病相关的报导，可能是其对5-HT2B受体有较小的激动效力。[35][40][41]在体外研究中，其对5-HT2B受体的亲和力比对α2A肾上腺素受体的亲和力低100倍，对5-HT2B受体的亲和力比血清素低30倍，而在活化5-HT2B受体的效力比对血清素低1,000倍。[40]结论是在临床性浓度下，胍法辛预计不会表现出与5-HT2B受体的显著结合或激活，因此不太可能是人类的心脏瓣膜疾病的病原体。[40]但仍有不同的研究提出胍法辛在5-HT2B受体激动方面具有不同程度功效的报告，[34][35][40][41]截至2018年，尚无关于胍法辛导致心脏瓣膜疾病风险的临床数据。[42]虽说胍法辛于此的可能性较低，但仍可能存有风险。[40]

药物动力学

口服胍法辛的生物利用度为80%。没明确的证据表明存在任何首过代谢。其生物半衰期为17小时，主要消除途径为肾脏。主要代谢产物是3-羟基化衍生物，具有中等生物转化的证据，关键中间体是环氧化合物。[43]肾功能受损患者的消除过程未受影响。因此对此类患者而言，有经过肝脏代谢的假设，此类患者产生姿位性低血压和镇静等副作用频率增加也证明此点。[44]

历史

胍法辛于1974年首次经文献描述，[7][45][46][47][48]于1986年被FDA核准用于治疗高血压，商品名为Tenex。[49]接着于2010年被FDA批准用于治疗6至17岁族群的ADHD。[10]它于2015年被欧洲药品管理局批准用于治疗ADHD，商品名为Intuniv。[50]此药品于2018年被加入澳大利亚药品福利计划（英语：Pharmaceutical Benefits Scheme）中，用于治疗ADHD。[51]

社会与文化

品牌名称

此药品的品牌名称有Tenex（速释剂型）、Afken、Estulic和Intuniv（缓释剂型）。

药品研究

胍法辛已被研究作为治疗PTSD用。对成人的疗效证据有限，但一项研究发现对同时罹患ADHD的儿童有积极的结果。[52]此药物对于使用选择性5-羟色胺再摄取抑制剂 (SSRI) 治疗无反应的成年PTSD患者也可能有用。[53]

使用胍法辛治疗妥瑞症的研究结果是好坏参半。[54]

胍法辛似乎不能有效改善患有ADHD和行为性失眠的儿童的睡眠。[26]反而是此药品在一项临床试验中会让某些睡眠参数恶化（例如总睡眠时间）。[26][27]

胍法辛已被研究用于治疗类阿片药物、乙醇和尼古丁的戒断，[55]已被证明有助于减少试图戒烟者因压力所引起对尼古丁的渴望，这可能涉及加强前额叶皮质介导的自我控制。[56]

胍法辛已被研究用于治疗影响前额叶皮质功能相关的各种疾病，包括脑外伤、中风、思觉失调和老年人的认知和注意力问题。[14][57]

目前有研究使用胍法辛作治疗COVID19后综合征之用。[58][59][60]

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