Phase II study of low-dose interleukin-11 in patients with MDS

当归挥发油对小鼠抑郁行为的影响谢云亮1*，张博2（1.苏州高新区人民医院神经内科，江苏苏州215129）（2.苏州高新区人民医院医联体办公室，江苏苏州215129）摘要：通过建立慢性轻度不可知应激刺激（CUMS）诱导的小鼠抑郁模型，研究当归挥发油对抑郁行为的影响及机制。

小鼠随机分为正常组、模型组、低、中、高剂量当归挥发油组（15、30、60 mg/kg）及盐酸氟西汀组（2.1 mg/kg）。

干预4周后发现，与模型组比较，当归挥发油各剂量组小鼠中央穿越次数、中央区活动时间及糖水偏好度升高（P<0.01），悬尾不动时间下降（P<0.05，P<0.01），海马CA1区病理变化减轻，血清白细胞介素-1β（IL-1β）、IL-6及肿瘤坏死因子-α（TNF-α）含量降低（P<0.01），而IL-10含量增加（P<0.01）；除低剂量当归挥发油组小鼠脑组织多巴胺（DA）含量及神经营养蛋白-3（NT-3）表达无明显变化外（P>0.05），剩余各组小鼠DA、去甲肾上腺素（NE）、5-羟色胺（5-HT）含量及神经生长因子（NGF）、NT-3、脑源性神经营养因子（BDNF）表达均升高（P<0.05，P<0.01）。

上述结果表明，当归挥发油具有改善CUMS诱导的小鼠抑郁行为作用，该作用与抑制神经炎症、上调单胺类神经递质含量及促进神经营养因子表达有关。

关键词：当归挥发油；抑郁；炎症；单胺类神经递质；神经营养因子文章编号：1673-9078(2024)03-9-17 DOI: 10.13982/j.mfst.1673-9078.2024.3.0355Effects of Angelica sinensis Volatile Oil on Depressive Behavior in MiceXIE Yunliang1*, ZHANG Bo2(1.Department of Neurology, Suzhou High-tech Zone People’s Hospital, Suzhou 215129, China)(2.Office of Medical Association, Suzhou High-tech Zone People’s Hospital, Suzhou 215129, China)Abstract: To determine the effects and mechanism of Angelica sinensis volatile oil (ASVO) on depressive behavior, chronic unpredictable mild stress (CUMS)-induced depression mouse models were established. Mice were divided into normal, model, low-dose, medium-dose, and high-dose ASVO (15, 30, and 60 mg/kg, respectively), and fluoxetine hydrochloride (2.1 mg/kg) groups. After four weeks of intervention, the number of central zone crossing, central zone activity duration, and sucrose preference were increased (P<0.01) while the tail suspension time was reduced (P<0.05, P<0.01)in all ASVO groups compared with those in the model group. The pathological changes in the hippocampal CA1 region were alleviated, and the contents of serum interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α) decreased (P<0.01) while that of IL-10 increased (P<0.01). Despite no significant changes in the dopamine (DA) content and neurotrophin-3 (NT-3) expression in the brain tissue of mice in the low-dose ASVO group (P>0.05), the contents of DA, norepinephrine (NE), and 5-hydroxytryptamine (5-HT) and the expression of nerve growth factor (NGF), NT-3, and brain-derived neurotrophic factor (BDNF) increased in the other groups (P<0.05, P<0.01). These results indicate that ASVO can引文格式：谢云亮,张博.当归挥发油对小鼠抑郁行为的影响[J] .现代食品科技,2024,40(3):9-17.XIE Yunliang, ZHANG Bo. Effects of Angelica sinensis volatile oil on depressive behavior in mice [J] . Modern Food Science and Technology, 2024, 40(3): 9-17.收稿日期：2023-03-26基金项目：吉林省教育厅科技项目（JJKH20210059KJ；JJKH20210055KJ）作者简介：谢云亮（1981-），男，博士，副主任医师，主要从事神经系统疾病的营养防治工作，9improve CUMS-induced depressive behavior in mice, which is related to the inhibition of neuroinflammation, upregulation of monoamine neurotransmitter contents, and promotion of neurotrophic factor expression.Key words:Angelica sinensis volatile oil; depression; inflammation; monoamine neurotransmitters; neurotrophic factor抑郁症是一种以长期心境低落、意志消沉为主要特征的慢性情绪障碍疾病，思维迟缓、快感缺乏、情绪低落、睡眠紊乱、食欲减退和认知功能降低是其主要表现，严重者可出现悲观厌世及自杀念头，对患者工作、学习及生活均可造成不利影响[1] 。

氨甲蝶呤对映体获得性耐药A549细胞株二氢叶酸还原酶基因表达分析李道静;何晓东;孙余婕;凡任芝;许维东;孙利;张永娟;张白银;沈佐君【摘要】目的研究氨甲蝶呤(MTX)对映体[L-(+)-MTX和D-(-)-MTX]耐药与二氢叶酸还原酶(DHFR)基因表达的关系.方法用浓度递增结合低剂量持续诱导法获得A549细胞对不同构型及不同浓度的MTX对映体的耐药细胞株,荧光定量PCR检测耐药细胞株中DHFR基因的相对含量.结果对两种不同对映体的获得性耐药存在差异,D型耐药细胞耐药指数高于L型;对映体各浓度耐药细胞间耐药指数也有差异.15 μmol/L L型、D型MTX首次诱导耐药细胞的DHFR相对含量低于亲本细胞,对该浓度对映体耐药的各细胞组间没有差别(P>0.05).35～45 μmol/L浓度耐药细胞的DHFR相对含量增加,45μmol/L D型耐药细胞DHFR相对含量高于对应浓度L型耐药细胞,差异有显著性(P<0.05).结果首次诱导MTX耐药以抑制DHFR基因为主.DHFR基因表达具有手性差异.DHFR基因的检测有望作为肿瘤治疗监测的指标.【期刊名称】《临床检验杂志》【年(卷),期】2011(029)003【总页数】3页(P219-221)【关键词】二氢叶酸还原酶;氨甲蝶呤;对映体;耐药;实时荧光定量PCR【作者】李道静;何晓东;孙余婕;凡任芝;许维东;孙利;张永娟;张白银;沈佐君【作者单位】安徽医科大学附属省立医院临床检验中心,合肥,230001;安徽医科大学附属省立医院临床检验中心,合肥,230001;安徽医科大学附属省立医院临床检验中心,合肥,230001;安徽医科大学附属省立医院临床检验中心,合肥,230001;安徽医科大学附属省立医院临床检验中心,合肥,230001;安徽医科大学附属省立医院临床检验中心,合肥,230001;安徽医科大学附属省立医院临床检验中心,合肥,230001;安徽医科大学附属省立医院临床检验中心,合肥,230001;安徽医科大学附属省立医院临床检验中心,合肥,230001【正文语种】中文【中图分类】R734.2手性对映体形式(D、L构型)是自然界的生命本质属性之一，生物体内生物大分子都具有手性。

科普 |白介素家族—身体里的双刃剑【背景】有许多肿瘤患者经常在治疗和检查单子中会看到白介素，有的时候甚至会使用注射的白介素药物，在和病友以及医生的交谈咨询中，我们又似乎对听到的药物信息有疑惑，有的说白介素可以提高免疫力作用，有的说白介素可以害死人，而且这些话似乎听起来都有道理，就更让很多患者丈二和尚摸不着头脑了，甚至因此可能对我们需要注射白介素药物的患者产生怀疑。

那么，今天就为大家简单介绍一下白介素家族，这个在我们身体里的双刃剑，到底有没有各位病友和医生说的那么神奇。

【白介素到底是什么？】白细胞介素是由多种细胞产生的一类细胞因子。

目前至少发现了38种白细胞介素，是一个大家族，各种白介素细胞因子已被研究用于治疗和用于感染性疾病，一方面是因为它们在免疫缺陷的条件下刺激免疫系统的能力，另一方面是因为它们在暴发性感染的情况下可以抑制过度免疫激活的能力。

这说明白介素有着可以使“免疫力”上升或者下降的作用，正可谓是“利弊相绕”【白介素如何使用？】如此看来，目前临床当中我们可以用到增强免疫力的白介素是白介素IL-2，那么如何使用呢？1.一般可静脉输注或皮下注射每日20～100万IU/m2体表面积，每日一次，四周为一疗程。

2.癌性胸、腹水腔内注射应尽量排出胸、腹水后，每次注射50～100万IU/m2体表面积，每周1～2次，注射2～4周。

3.可与放疗、化疗、手术及其它免疫制剂联合使用。

【白介素使用后注意事项】使用重组白介素IL-2的病友可能会发生一些副作用，例如畏寒、发热，头痛，疲惫等；个别病友可出现恶心、呕吐、少数病人皮下注射后局部可出现轻度红肿、硬节、疼痛如果在治疗中出现身体不适，请及时告知您的医疗保健人员；大多数情况这些药物副作用会随着治疗的进展以及人体逐渐适应药物，症状逐渐消失，不需要特殊处理。

如果症状持续，那么大多数会在停药后好转。

【其他】此外，白介素家族似乎都与感染有关，甚至在某些研究展现出了对感染很好的疗效，但目前还没有投入到临床之中，一旦在后面更新的研究有白介素对于感染的进展，那么在临床上合理使用白介素会对肿瘤患者的生存助力是一份更大的保障。

环球中医药2023年7月第16卷第7期　Global Traditional Chinese Medicine,July 2023,Vol.16,No.71317　㊃基础研究㊃基金项目:北京市自然科学基金(7192116);北京中医药大学校级课题-李元文名师工作坊;北京市中医管理局课题-中医药继续教育导航工程-继教专委会建设及精品课程制作;北京中医药大学2020年新教师启动基金(2020⁃JYB⁃XJSJJ⁃044);北京中医药大学横向科研项目(HX202119)作者单位:100078　北京中医药大学东方医院皮肤科[于心荟(硕士研究生)㊁李元文㊁任雪雯(博士研究生)㊁邓宇童(博士研究生)㊁王莹(博士研究生)];北京中医药大学东直门医院皮肤科(冯蕙裳);江阴江天药业有限公司(王化龙㊁刘晓东)作者简介:于心荟(1998-),2021级在读硕士研究生㊂研究方向:中医皮肤性病学㊂E⁃mail:yuxinhui9898@通信作者:冯蕙裳(1992-),硕士,住院医师㊂研究方向:中医皮肤病学㊂E⁃mail:fhs1116@化斑解毒方对咪喹莫特诱导银屑病样皮炎小鼠模型抗炎机制探究于心荟　李元文　任雪雯　邓宇童　王莹　王化龙　刘晓东　冯蕙裳【摘要】　目的　观察化斑解毒方对咪喹莫特诱导银屑病样皮炎小鼠模型的抗炎作用㊂方法　采用咪喹莫特诱导小鼠银屑病样皮炎,以随机数字表法将60只小鼠随机分为空白组㊁模型组㊁化斑解毒方低㊁中㊁高剂量组及甲氨蝶呤组,每组10只㊂观察各组小鼠银屑病皮损严重程度指数(psoriasis area and severity index,PASI)评分,苏木素 伊红染色观察组织病理学变化,酶联免疫吸附法检测肿瘤坏死因子⁃α(tumor necrosis factor⁃α,TNF⁃α)㊁干扰素⁃γ(interferon⁃γ,IFN⁃γ)㊁白细胞介素⁃23(interleukin⁃23,IL⁃23)㊁白细胞介素⁃1β(interleukin⁃1β,IL⁃1β)表达水平,蛋白免疫印迹法测定核转录因子⁃κB(nuclear factor⁃κB,NF⁃κB)水平㊂结果　(1)模型组与空白组PASI 评分具有统计学差异(P <0.05),各药物组PASI 评分较模型组均降低,差异有统计学意义(P <0.05);(2)模型组TNF⁃α㊁IFN⁃γ㊁IL⁃1β㊁IL⁃23表达水平较空白组显著升高(P <0.05);与模型组相比,各药物组TNF⁃α㊁IFN⁃γ㊁IL⁃1β表达水平显著降低(P <0.05),甲氨蝶呤组㊁化斑解毒方中㊁高剂量组IL⁃23水平显著降低(P <0.05);化斑解毒方低剂量组IL⁃23表达水平与模型组无显著差异(P >0.05);(3)与空白组相比,模型组NF⁃кB 表达水平显著升高(P <0.05);各用药组NF⁃κB 表达水平较模型组显著降低(P <0.05);化斑解毒方各剂量组NF⁃кB 表达水平与甲氨蝶呤组相比无显著差异(P >0.05)㊂结论　化斑解毒方可以明显改善银屑病样皮损症状及病理学改变,并通过调节细胞炎性因子表达改善炎症㊂【关键词】　化斑解毒方;　银屑病;　核转录因子⁃κB;　肿瘤坏死因子⁃α;　干扰素⁃γ;　白细胞介素⁃23;　白细胞介素⁃1β【中图分类号】　R285.5　【文献标识码】　A　doi:10.3969/j.issn.1674⁃1749.2023.07.006Study on the anti⁃inflammatory mechanism of Huaban Jiedu Decoction on imiquimod induced psoriasis⁃like dermatitis in miceYU Xinhui ,LI Yuanwen ,REN Xuewen ,DENG Yutong ,WANG Ying ,WANG Hualong ,LIU Xiaodong ,FENG HuichangDongfang Hospital Beijing University of Chinese Medicine ,Beijing 100078,China Corresponding author :FENG Huichang ,E⁃mail :fhs1116@【Abstract 】　Objective To study the anti⁃inflammatory effects of different concentrations of HuabanJiedu Decoction on imiquimod induced psoriasis⁃like dermatitis in mice.Methods Psoriasis⁃likedermatitis was induced by imiquimod.Sixty mice were randomly divided into blank group,model group,low dose group,medium dose group,high dose group and methotrexate group with 10mice in each group.1318　环球中医药2023年7月第16卷第7期　Global Traditional Chinese Medicine,July2023,Vol.16,No.7 To observe the psoriasis area and severity index(PASI)and histopathological changes by HE staining.The expression levels of tumor necrosis factor⁃α(TNF⁃α),interferon⁃γ(IFN⁃γ),interleukin⁃23(IL⁃23)and interleukin⁃1β(IL⁃1β)in mice skin tissue homogenates were detected by ELISA.The expression level ofnuclear factor⁃κB(NF⁃κB)was measured by Western blotting assay.Results　(1)The PASI scores ofthe model group and the blank group were statistically different(P<0.05).Compared with the modelgroup,the PASI score of each drugged group was lower,and the difference was statistically significant(P<0.05).(2)Compared with the blank group,the expression levels of TNF⁃α,IFN⁃γ,IL⁃1β,IL⁃23inthe model group were significantly increased(P<0.05).Compared with the model group,the expressionlevels of TNF⁃α,IFN⁃γand IL⁃1βin each drug group were significantly decreased(P<0.05),and thelevel of IL⁃23in the methotrexate group and the Huaban Jiedu Decoction medium and high dose groups were significantly decreased(P<0.05).There was no significant difference in the expression level of IL⁃23between the Huaban Jiedu Decoction low dose group and the model group(P>0.05).(3)Compared withthe blank group,the expression levels of NF⁃κB in the model group was significantly increased(P<0.05).The expression level of NF⁃κB in each drugged group was significantly lower than that in the model group(P<0.05).There was no significant difference in the expression level of NF⁃кB between every HuabanJiedu Decoction group and the methotrexate group(P>0.05).Conclusion　Huaban Jiedu Decoction can significantly improve the symptoms and pathological changes of psoriasis⁃like skin lesions,and improve in⁃flammation by regulating the expression of inflammatory cytokines.【Key words】　Huaban Jiedu Decoction;　Psoriasis;　Nuclear factor⁃κB;　Tumor necrosis factor⁃α;　Interferon⁃γ;　Interleukin⁃23;　Interleukin⁃1β 银屑病是一种常见的慢性炎症性复发性皮肤疾病,临床表现主要是鳞屑性红斑或斑块,世界范围内发病率约1%~3%[1]㊂免疫异常被视为银屑病发病的重要环节,免疫细胞激活后产生多种炎症细胞因子,促进细胞增殖角化及炎症细胞浸润,导致银屑病的发生发展㊂化斑解毒方是李元文教授通过前期数据挖掘结合多年的临床经验与理论探索总结出的中药方剂[2],临床应用于寻常型银屑病血热证患者具有确切疗效,能够有效减轻患者皮肤炎症反应,但其治疗银屑病的作用机制尚不明确㊂本研究拟通过测定不同浓度的化斑解毒方对咪喹莫特诱导银屑病样皮炎小鼠肿瘤坏死因子⁃α(tumor necrosis factor⁃α,TNF⁃α)㊁干扰素⁃γ(interferon⁃γ, IFN⁃γ)㊁白细胞介素⁃23(interleukin⁃23,IL⁃23)㊁白细胞介素⁃1β(interleukin⁃1β,IL⁃1β)㊁核转录因子⁃κB (nuclear factor⁃κB,NF⁃κB)表达水平的影响,探究其治疗银屑病的抗炎作用,并为化斑解毒方的临床应用提供理论依据㊂1　材料与方法1.1　实验动物SPF级雄性BALB/c小鼠60只,8周龄,体质量约20g,购于斯贝福(北京)生物技术有限公司,动物质量合格证号:110324221101061643;实验动物生产许可证号:SCKX(京)2019⁃0010㊂小鼠于北京中医药大学动物房适应性喂养1周后开始实验㊂1.2　实验药物化斑解毒方组成:白花蛇舌草30g㊁半枝莲15g㊁威灵仙10g㊁苍术10g㊁土茯苓15g㊁生槐花10g㊁玄参20g㊁生地10g㊁香附10g㊁牛蒡子10g㊁知母10g㊁金银花15g㊁猪苓10g㊁白术10g㊁炙甘草6g㊂所用药物为颗粒剂,由江阴天江药业有限公司配制,产品批号2202306㊂甲氨蝶呤片(通化茂祥制药有限公司,产品批号:197220504,规格:2.5mg);咪喹莫特乳膏(四川明欣药业有限责任公司,产品批号40220501,规格: 250mg∶12.5mg)㊂1.3　主要实验试剂与仪器凡士林(德新康,批号:Q/371426DXK027);4%多聚甲醛(Solarbio,批号:P1110);苏木素 伊红(hematoxylin⁃eosin,HE)染色试剂盒(北京中科万邦生物科技有限公司,批号:RY⁃0002);中性树胶封片剂(北京中科万邦生物科技有限公司,批号:FP⁃0001);TNF⁃α㊁IFN⁃γ㊁IL⁃1β㊁IL⁃23酶联免疫吸附试验试剂盒(北京百奥思科生物医学技术有限公司,批号分别为:MD7125㊁MD16214㊁MD124889㊁MD53662);NF⁃κBp65抗体(Abcam,批号: AB32536);辣根过氧化物酶标记山羊抗兔IgG环球中医药2023年7月第16卷第7期　Global Traditional Chinese Medicine,July2023,Vol.16,No.71319(Affinity,批号:T0021)㊂数码相机(Leica);JT⁃12S脱水机㊁JB⁃P7包埋机(武汉俊杰电子有限公司);电泳仪(美国Bio⁃Rad); Spectramac M3多功能酶标仪(美国MD);紫外分光光度计(美国赛默飞世尔科技公司);ST16R高速冷冻离心机(美国Thermo Sorvall);THZ⁃312台式恒温振荡器(上海精宏实验设备有限公司);化学发光成像系统(美国ChemiDoc MP)㊂1.4　实验方法1.4.1　动物分组与造模　将60只小鼠适应性喂养1周后,全部予背部去毛,面积约2cm×3cm㊂以随机数字表法将60只小鼠随机分为空白组㊁模型组㊁化斑解毒方低㊁中㊁高剂量组及甲氨蝶呤组,每组10只㊂脱毛后24小时确认小鼠脱毛处无损伤后开始造模,空白组小鼠于备皮区每日涂抹凡士林62.5mg,其余各组涂抹等质量5%咪喹莫特乳膏,连续7天㊂1.4.2　给药方法　造模后,各组均以标准饲料喂养并自由饮水,每3天更换垫料㊂造模开始第二日予以干预,每组小鼠以0.1mL/(10g㊃d)灌胃1次,空白组与模型组小鼠予以蒸馏水,化斑解毒方低㊁中㊁高剂量组分别予中药1/2倍㊁1倍及2倍量,甲氨蝶呤组予甲氨蝶呤片混悬液㊂小鼠灌胃药物剂量根据体表法进行计算,根据标准成年人体质量70kg,则对应小鼠药物剂量约为成人的9.1倍,折算出化斑解毒方中剂量组小鼠每日给药剂量为24.83g/kg,甲氨蝶呤组每日给药剂量为1mg/kg㊂1.4.3　取材方法　在实验第7天进行标本制备,对小鼠予4%水合氯醛(0.1mL/10g)腹腔注射进行麻醉㊂取小鼠背部银屑病皮损集中皮肤(全层创面),面积为2cm×2cm的正方形,空白组取相同部位,所得皮肤组织以90°为范围平均分为4份,3份置于无菌无酶冻存管,置于液氮冷冻后,放于-80℃超低温冰箱保存用于做蛋白检测;1份放于4%多聚甲醛中固定,用于切片染色㊂1.5　观察指标1.5.1　各组小鼠皮损变化情况评价　于模型建立及治疗期间,每日观察各组小鼠皮损变化,并采用数码相机对同一部位拍照记录㊂观察期间无小鼠死亡情况,重复数量为1㊂根据校正后的银屑病样皮损面积和疾病严重程度(psoriasis area and severity index,PASI)评分作为标准,对鳞屑㊁浸润㊁红斑的严重程度进行评分,由轻到重分为5个等级,从0到4进行赋分㊂计算三项评分之和表示皮损严重程度;取每日各组总分平均值绘制趋势线,从而反映小鼠皮损的变化情况㊂1.5.2　皮肤组织HE染色及观察　取固定于4%多聚甲醛中的皮肤组织,修剪至合适大小,二甲苯脱蜡后,用从高到低浓度酒精及蒸馏水洗脱,苏木素水溶液染色10分钟,0.7%盐酸乙醇分化30秒,置于酒精中脱水,酒精伊红染色2分钟,冲洗后先后酒精脱水㊁二甲苯透明㊁中性树胶封片,放置于显微镜下观察并摄片㊂1.5.3　皮肤组织炎症因子水平检测　采用酶联免疫吸附(ELISA)法检测各组小鼠皮肤组织匀浆中TNF⁃α㊁IFN⁃γ㊁IL⁃1β㊁IL⁃23水平㊂将试剂盒取出平衡至室温,取出冰箱中冻存的皮肤样本研碎㊂实验操作步骤以ELISA检测试剂盒为准㊂显色后立即用酶标仪在450nm波长测量各孔的光密度值(OD值),绘制浓度标准曲线计算样品中相应检测目标的浓度㊂以蛋白免疫印迹法检测皮肤标本中NF⁃κB水平㊂取出冻存标本加入裂解液,超声破碎细胞取上清,按照BCA试剂盒说明书对蛋白定量,对蛋白样品进行电泳及转膜㊂将转移膜置于封闭液中封闭1小时,加入用封闭液稀释的一抗工作液4℃孵育过夜,洗净后加入二抗工作液室温孵育60分钟,洗膜后使用显色剂显影,利用化学发光成像系统成像并通过测定主带的光密度值计算上述蛋白在皮肤组织中的表达水平㊂1.6　统计学方法实验所得数据为计量资料,采用SPSS20.0软件对所得数据进行统计分析,数据以均数±标准差(x±s)表示㊂其中,IFN⁃γ㊁IL⁃1β㊁NF⁃кB各组数据符合正态分布且满足方差齐性,采用单因素方差分析(One⁃way ANOVA),组间比较应用LSD法;其余结果指标数据不符合正态分布或不满足方差齐性,故采用Kruskal⁃Wallis检验,组间比较应用Wilcoxon Mann⁃Whitney U秩和检验(Bonferronni法)㊂检验水准a=0.05,P<0.05表示差异有统计学意义㊂2　结果2.1　皮损变化及评分比较空白组小鼠未见皮损,模型组小鼠皮肤存在不同程度红斑㊁浸润㊁鳞屑等皮肤损害㊂与模型组相比,化斑解毒方各剂量组及甲氨蝶呤组小鼠皮肤红斑色泽㊁浸润程度㊁出现鳞屑皮肤面积大小㊁鳞屑厚度均较轻㊂第7天时,化斑解毒方低㊁中㊁高剂量组㊁1320　环球中医药2023年7月第16卷第7期　Global Traditional Chinese Medicine,July 2023,Vol.16,No.7甲氨蝶呤组小鼠皮损相比于模型组,红斑面积较小㊁颜色浅,皮肤浸润程度较轻,鳞屑较少㊂见图1㊂注:A 空白组;B 模型组;C 化斑解毒方低剂量组;D 化斑解毒方中剂量组;E 化斑解毒方高剂量组;F 甲氨蝶呤组㊂图1　各组银屑病样皮炎小鼠皮肤表现 皮损评分结果显示,空白组与模型组之间PASI评分存在统计学差异(P <0.05);与模型组相比,化斑解毒方各剂量组及甲氨蝶呤组PASI 评分降低,皮损症状改善(P <0.05)㊂依据PASI 评分绘制化斑解毒方各剂量组与模型组㊁甲氨蝶呤组的7日曲线可观察评分变化㊂见图2,表1㊂图2　各组银屑病样皮炎小鼠PASI 评分变化曲线2.2　皮肤组织学变化HE 染色显示:空白组角质层细胞未见明显异常,基底层细胞连续,血管周围及真皮浅层未见炎症细胞浸润;模型组表现为表皮角化过度伴角化不全,棘细胞数量增加,棘层肥厚,表皮突向下延伸呈棒槌状,真皮内可见毛细血管扩张,血管周围淋巴细胞浸润,类似银屑病的皮损病理表现;与模型组相比,化斑解毒方各剂量组和甲氨蝶呤组小鼠病理损害程度较低,表皮角化不全减轻,棘层厚度变薄,淋巴细胞浸润减少㊂见图3㊂表1　各组银屑病样皮炎小鼠PASI 评分比较(x ±s )组别鼠只PASI 评分(分)第1天第2天第3天第4天第5天第6天第7天模型组100.5±0.53 2.3±0.48 2.3±0.59 3.2±1.48 4.8±0.42 6.6±0.707.6±0.70化斑解毒方低剂量组100.5±0.53 1.2±0.79a 1.7±0.68a 2.6±0.97 3.4±1.17a 4.4±0.84a 4.4±0.84a 化斑解毒方中剂量组100.2±0.420.8±0.62a 1.4±0.84a 1.9±0.94a3.0±1.16a 3.5±1.08a4.3±0.95a 化斑解毒方高剂量组100.6±0.27 2.0±0.67 2.4±0.70 2.8±0.79 3.8±0.79a 4.6±0.70a 5.0±0.67a 甲氨蝶呤组100.2±0.421.7±0.48a2.3±0.682.9±0.573.7±1.06a4.4±1.08a4.2±1.03a注:与模型组相比,a P <0.05㊂注:A 空白组;B 模型组;C 化斑解毒方低剂量组;D 化斑解毒方中剂量组;E 化斑解毒方高剂量组;F 甲氨蝶呤组㊂图3　各组银屑病样皮炎小鼠皮肤病理变化比较(HE 染色,×400)环球中医药2023年7月第16卷第7期　Global Traditional Chinese Medicine,July 2023,Vol.16,No.71321　表2　各组银屑病样皮炎小鼠皮肤组织中TNF⁃α㊁IFN⁃γ㊁IL⁃1β㊁IL⁃23表达水比较(x ±s ,pg /mL)组别鼠只TNF⁃αINF⁃γIL⁃1βIL⁃23空白组1042.47±3.2218.42±1.2322.53±2.1710.52±1.04模型组10107.35±6.03a 50.64±3.61a 79.86±2.62a 22.96±2.98a 化斑解毒方低剂量组1072.69±2.57ab 31.40±2.49ab 60.55±1.66ab 20.73±3.50a 化斑解毒方中剂量组1055.18±2.55ab 27.64±1.32ab 54.25±1.52ab 13.64±1.04ab 化斑解毒方高剂量组1051.35±1.60abc 24.81±1.49ab 49.31±1.56ab 12.85±1.02abc甲氨蝶呤组1051.72±1.89ab19.26±2.32b45.63±2.54ab11.20±0.66b注:与空白组相比,a P <0.05;与模型组相比,b P <0.05;与甲氨蝶呤组相比,c P >0.05㊂2.3　皮肤组织中TNF⁃α㊁IFN⁃γ㊁IL⁃1β㊁IL⁃23表达情况与空白组相比,模型组小鼠皮肤组织中TNF⁃α㊁IFN⁃γ㊁IL⁃23㊁IL⁃1β表达水平显著升高(P <0.05);与模型组相比,各用药组炎症因子水平均有不同程度降低,其中以甲氨蝶呤组及化斑解毒方高剂量组最为显著;另外,化斑解毒方低剂量组与模型组IL⁃23表达水平无明显差异(P >0.05)㊂见表2㊂2.4　皮肤组织中NF⁃кB 表达水平与空白组相比,模型组NF⁃кB 表达水平显著升高(P <0.05);与模型组相比,各用药组NF⁃кB 表达水平显著降低(P <0.05);化斑解毒方各剂量组NF⁃кB 表达水平较甲氨蝶呤组无显著差异(P >0.05)㊂因空白组中两个数据离散度过大,考虑误差,在统计过程中主动剔除㊂结果见表3及图4㊂表3　各组银屑病样皮炎小鼠皮肤组织中NF⁃кB 表达水平比较(x ±s )组别鼠只NF⁃кB 相对表达量空白组80.53±0.47模型组100.96±0.09a 化斑解毒方低剂量组100.73±0.12abc 化斑解毒方中剂量组100.73±0.08abc化斑解毒方高剂量组100.70±0.12abc 甲氨蝶呤组100.67±0.09ab注:与空白组相比,a P <0.05;与模型组相比,b P <0.05;与甲氨蝶呤组相比,c P >0.05㊂注:A 空白组;B 模型组;C 化斑解毒方低剂量组D 化斑解毒方中剂量组;E 化斑解毒方高剂量组;F 甲氨蝶呤组㊂图4　各组银屑病样皮炎小鼠皮肤组织中NF⁃кB 蛋白表达情况3　讨论银屑病是皮肤科常见且重大的疾病,其发病机制复杂且尚不明确[3]㊂目前普遍认为银屑病的发病主要由免疫细胞介导的炎症反应㊁多种细胞因子失衡及细胞间信号转导通路异常等导致[4]㊂现代医学对轻度银屑病治疗以外用药为主,中㊁重度常联合甲氨蝶呤㊁阿维A 酸㊁环孢素等系统治疗,近年来生物制剂也日益广泛应用于银屑病的治疗[5]㊂中药治疗相对安全且价格适中,探索更为稳定有效的中药方剂有助于解除银屑病患者的困扰,并为银屑病的临床治疗提供更多选择㊂中医学普遍认为,银屑病发生与 血”与 风”两个因素密切相关,病机多为营血亏虚或外邪入里以致血热内蕴,生风化燥,肌肤失养,发为白疕[6]㊂李元文教授认为寻常型银屑病的病因病机在血热瘀阻㊁化燥生风的基础之上,兼有湿邪为患,且多与毒邪相关[7]㊂化斑解毒方在目前常用清热凉血解毒药如生地㊁玄参㊁知母㊁金银花㊁生槐花㊁白花蛇舌草㊁半枝莲㊁土茯苓之外[8],加用健脾化湿之苍术㊁白术㊁猪苓,佐以威灵仙通络,香附理气,旨在宣通中焦之气,气行则血行,气机通畅则瘀血得通㊁风邪自灭,故红斑鳞屑得以消减㊂化斑解毒方临床治疗寻常型银屑病疗效确切,但其治疗的分子层面的机制仍不明确,故本实验通过对不同浓度化斑解毒方的抗炎方面机制进行探究㊂作为由免疫介导的炎症性皮肤病,银屑病的发生发展过程由多种免疫细胞和炎症因子共同作用㊂TNF⁃α是重要的促炎因子,可影响角质细胞的再生㊁诱导表皮中性粒细胞浸润,并可诱导免疫细胞增殖产生不同的趋化因子的细胞因子,加重炎症反应㊂IFN⁃γ能够增强抗原加工和呈递㊁诱导免疫反应,在银屑病患者血清中显著升高,并且可能与银屑病的活动有关[9]㊂IL⁃1β是在早起皮肤1322　环球中医药2023年7月第16卷第7期　Global Traditional Chinese Medicine,July2023,Vol.16,No.7损伤中占主导地位的细胞因子,其增多导致早期银屑病炎症加重[10]㊂IL⁃23是银屑病免疫反应机制的上游炎症因子之一,可诱导Thl7细胞分化产生细胞因子,进一步促进角质形成细胞增殖及炎症级联反应[11]㊂本研究中,甲氨蝶呤组㊁化斑解毒方各剂量组TNF⁃α㊁IFN⁃γ㊁IL⁃1β表达水平较模型组显著降低,提示经治疗后细胞炎症因子水平下降,组织炎症缓解,同理甲氨蝶呤组与化斑解毒方中㊁高剂量组的IL⁃23表达水平降低亦提示炎症减轻㊂化斑解毒方高剂量组与甲氨蝶呤组TNF⁃α㊁IL⁃23表达水平无显著差异,提示二者在影响TNF⁃α㊁IL⁃23的作用上效果趋于相同㊂化斑解毒方低剂量组IL⁃23表达水平与模型组无显著差异,提示对此炎症因子作用效果不明显,考虑血药浓度可能未达到起效水平,或与造模用药时间较短等因素有关,具体原因需进一步探究㊂NF⁃кB被认为是免疫及炎症反应的中心枢纽,激活后可诱导下游炎症因子和趋化因子表达,促进组织炎症发生[12]㊂NF⁃кB在银屑病过程中表达水平升高[13],并可调控细胞凋亡,影响银屑病炎症进展[14]㊂本研究结果显示,与空白组相比,模型组NF⁃кB表达水平显著升高,提示在咪喹莫特诱导银屑病样皮炎小鼠中NF⁃кB过度激活;与模型组相比,各用药组NF⁃кB显著下调,提示化斑解毒方的抗炎作用可能与抑制NF⁃кB表达有关,且下调情况在化斑解毒方各组间呈现一定的量效差异㊂化斑解毒方各剂量组NF⁃кB表达水平与甲氨蝶呤组无统计学差异,提示化斑解毒方可有效抑制银屑病皮损中的NF⁃кB表达,从而改善炎症反应㊂综上所述,化斑解毒方在改善银屑病皮损症状及组织病理学表现上有确切治疗作用;同时在分子层面上,化斑解毒方能够通过降低TNF⁃α㊁IFN⁃γ㊁IL⁃1β㊁IL⁃23的表达水平㊁抑制NF⁃кB在组织细胞中的表达减轻炎症反应,起到抗炎作用,且化斑解毒方的抑制炎症作用与使用剂量呈正相关㊂但是,本研究所检测的只是银屑病炎症反应相关的部分细胞因子,没有涉及细胞通路及其他治疗机制方面的研究;且咪喹莫特诱导的小鼠模型不能完全代表人类银屑病的发展及转归过程㊂因此,探究化斑解毒方的作用机制仍需经过其他分子水平研究及临床实验进一步验证㊂参考文献[1]　郑佳媛,陈显侠,骆志成.银屑病瘙痒发病机制的研究现况[J].中国医学科学院学报,2022,44(3):529⁃534. [2]　李雪,杭小涵,邓宇童,等.银屑病中医治疗 枢机”之窥见[J].北京中医药,2021,40(8):826⁃829.[3]　中华医学会皮肤性病学分会银屑病专业委员会.中国银屑病诊疗指南(2018完整版)[J].中华皮肤科杂志,2019,52(10):667⁃710.[4]　Griffiths C E M,Armstrong A W,Gudjonsson J E,et al.Psoriasis[J].Lancet,2021,397(10281):1301⁃1315. [5]　Armstrong A W,Read C.Pathophysiology,clinical presentation,and treatment of psoriasis:A review[J].JAMA,2020,323(19):1945⁃1960.[6]　王晓瑾,张建英,张守亮,等.中医药防治银屑病的机制研究进展[J].中国实验方剂学杂志,2022,28(21):243⁃253. [7]　钱冬冬,张怀亮.银屑病的 毒邪”现代理论探析[J].环球中医药,2015,8(8):950⁃952.[8]　成雪,刘朝圣,刘芳榕,等.基于国家专利的中药复方调治银屑病用药规律研究[J].中国中医药信息杂志,2023,30(2):62⁃67.[9]　Grän F,Kerstan A,Serfling E,et al.Current developments inthe immunology of psoriasis[J].Yale J Biol Med,2020,93(1):97⁃110.[10]　Orsmond A,Bereza⁃Malcolm L,Lynch T,et al.Skin barrierdysregulation in psoriasis[J].Int J Mol Sci,2021,22(19):10841.[11]　薛潇春,原源,沈闻文,等.IL⁃23p19抗体古塞奇尤在银屑病治疗中的应用研究进展[J].山东医药,2020,60(18):106⁃109.[12]　王生,刘洋,张晶.川芎嗪调控NF⁃κB信号通路对银屑病HaCaT细胞模型趋化因子和炎症因子表达影响[J].中国免疫学杂志,2022,38(8):952⁃957.[13]　Rendon A,Schäkel K.Psoriasis pathogenesis and treatment[J].Int J Mol Sci,2019,20(6):1475.[14]　王胜珊.银屑病发病诊断及治疗中的MPAK/NF⁃κB信号通路作用[J].解剖学研究,2017,39(6):468⁃471,486.(收稿日期:2022⁃09⁃25)(本文编辑:张楠)。

骨髓增生异样综合征的医治进展【关键词】骨髓增生异样骨髓增生异样综合征（MDS）是一种取得性干细胞疾病，可致使无效造血和外周血细胞减少，有进展为急性髓细胞性白血病（AML）的趋势。

其病因不明，男女都可发病，男性多于女性，多见于60岁以上老年人［1］，儿童中见于婴儿到青春期的任何年龄。

MDS多表现为贫血、出血、发烧、感染和肝脾肿大，血象常为全血细胞减少，亦可为一个或两个系列血细胞减少，呈病态造血表现，骨髓多增生活跃或明显活跃，少数病例可增生减低［25］。

诊断要紧依托临床表现和血象骨髓象，必要时能够做骨髓细胞培育和细胞遗传学检查。

1 分型法美英协作组（FAB）依照血象和骨髓象改变将MDS分为五个类型：难治性贫血（RA）、伴有环形铁粒幼细胞的难治性贫血（RAS）、伴原始细胞增多的难治性贫血（RAEB）、转变中的伴原始细胞增多的难治性贫血（RAEB T）、慢性粒单核细胞白血病（CMML）。

在小儿，MDS 也常见于患原发性恶性肿瘤并同意多种医治的病人。

从MDS转化为AML 约占小儿AML的15%，可是AML并非是MDS的必然结局，专门是RA、RAS、CMML。

转化为AML的MDS以RAEB和RAEB T多见［23］。

2 医治目前对不同类型的MDS，采纳不同的医治计谋。

RA、RAS以贫血为主症，采纳药物刺激骨髓造血为主，可兼以诱导分化剂医治；RAEB 以小剂量化疗加诱导分化剂医治；RAEB T应采纳类似急性白血病的常规联合化疗为主医治。

对MDS应采纳个体化的医治方法，现分述如下［6］：支持医治至今除骨髓移植外，尚没有任何方式能够根治MDS，故支持医治仍然是重要的医治手腕，其目的是减轻病情和降低病亡率，同时也改善生活质量。

输血及抗生素的利用严峻贫血者输红细胞悬液。

对因血小板减少而有出血偏向或血小板低于20×109/L者可输浓集血小板。

粒细胞减少伴感染的病人，利用强有力的广谱抗生素［3］。

关于反复大量输血的患者，有研究指出铁螯合剂的应用能够明显减少各类疾病中因为输血引发的铁负荷过重［7］。

靶向生物制剂治疗银屑病的免疫学机制和应用陈永锋【期刊名称】《皮肤性病诊疗学杂志》【年(卷),期】2015(000)004【总页数】3页(P271-273)【关键词】银屑病;生物制剂,靶向【作者】陈永锋【作者单位】广东省皮肤病医院，广东广州 510091【正文语种】中文【中图分类】R758.63银屑病是多基因遗传背景下的自身免疫紊乱性疾病，其发病主要与T细胞介导的免疫有关。

目前已知参与银屑病发病的T细胞亚群主要有CD4+Th1细胞、Th17细胞和Th22细胞[1]。

近年来，随着对银屑病免疫学机制和易感基因研究的不断深入，根据作用机制的不同，越来越多的靶向生物制剂被研发出来用于治疗银屑病，为银屑病的系统治疗开创新纪元。

银屑病发病的免疫学机制包括固有免疫和适应性免疫两方面，角质形成细胞和树突细胞是固有免疫系统中的主要细胞，也是介导银屑病发病的起始环节；T淋巴细胞介导的适应性免疫系统，在银屑病的发病机制中起着重要的作用[2]。

银屑病患者的皮损中有多种免疫细胞和免疫分子相互作用，影响细胞内信号传导系统的功能，刺激角质形成细胞及真皮乳头层血管的异常增生形成鳞屑性红斑。

应用靶向性的生物制剂可阻断淋巴细胞的炎症效应，在一定程度上有效的控制银屑病的发生。

银屑病的免疫致病过程包括树突状细胞呈递抗原激活T细胞， T细胞被激活后迁移至病变皮肤，活化的T细胞释放细胞因子发挥多种功能，皮损中T细胞活化是银屑病表皮过度增殖的关键。

皮肤中的T淋巴细胞和抗原呈递细胞被外界的刺激因素激活，分泌包括TNF、IL- 23等在内的多种细胞因子。

在这些细胞因子的刺激下，幼稚CD4淋巴细胞分化成5种亚型的细胞，包括Th1、Th2、Th17、Th22和Treg细胞。

其中Th1作用于细胞内对病原菌的清除；Th2激发产生针对细胞外病原菌的防御反应；Th17和Th22辅助Th1和Th2产生炎症反应[3- 4]；Treg细胞分泌具有免疫抑制功能的细胞因子来限制免疫反应的发展[5]。

甲状腺癌的发生能够导致患者病死率和致残率的显著上升,手术治疗仍然是目前临床上甲状腺癌的主要治疗方式,其能够在改善患者生存质量、延长患者生存时间方面发挥作用[1-3]。

但甲状腺癌患者术后的规范化治疗,仍然是目前临床上需要解决的问题。

甲状腺癌术后口服甲状腺素片,能够稳定术后甲状腺激素水平、降低手术并发症,但并不能进一步延长患者的生存时间,患者体内免疫功能抑制导致的肿瘤复发转移风险仍然较高[4-5]。

树突细胞-细胞因子诱导的杀伤细胞(dendritic cell-cy ⁃tokine-induced killer cells ,DC-CIK )作为免疫治疗方式,近年来在乳腺癌、卵巢癌或甲状腺癌的辅助治疗过程中发挥了重要作用[6-8]。

DC-CIK 能够通过诱导患者体内自然杀伤性T 淋巴细胞、树突状T 淋巴细胞及肿瘤浸润性T 淋巴细胞的激活,进而提高机体免疫应答水平,促进残留肿瘤细胞的杀伤和清除。

为了指导临床上甲状腺癌术后的辅助治疗,本研究选取110例甲状腺癌术后患者,探讨DC-CIK 治疗的临床效果,报道如下。

1资料与方法1.1一般资料选取2016年1月—2019年1月湖北省天门市中医医院110例甲状腺癌术后患者作为研究对象,采用随机数字表法分为观察组和对照组各55例。

纳入标准:(1)单侧甲状腺病灶,术前经颈部超声、CT 检查初步确诊,术后经病理学检查证实;(2)年龄23~65岁;(3)未发生淋巴结转移,实施甲状腺全切手术;(4)术后KPS 评分≥70分;(5)本研究经医学伦理委员会审核通过,获得患者本人及[作者简介]张华安(1975-11-29),男,湖北天门人,副主任医师,研究方向:普通外科。

E-mail:*******************DC-CIK 生物免疫疗法对甲状腺癌术后免疫调节的作用张华安周晓芳蒋易君张淏嘉湖北省天门市中医医院普外科（湖北天门431700）·技术交流·Technique Communication ·898家属的知情同意。

不同剂量丙种球蛋白冲击治疗重症寻常型天疱疮对免疫功能的影响及临床意义布瓦杰尔·亚克亚;梁俊琴;康晓静【摘要】目的探讨不同剂量丙种球蛋白冲击治疗重症寻常型天疱疮对免疫功能的影响及临床意义.方法将新疆维吾尔自治区人民医院80例重症寻常型天疱疮患者按随机数表法分为观察组与对照组,各40例,所有患者均经病理学及荧光免疫法确诊.2组均采取给予激素治疗(甲泼尼龙80 mg/d静脉滴注,1次/w,治疗2w);之后观察组给予大剂量丙种球蛋白20 g/d静脉滴注,连续治疗5d,对照组给予小剂量丙种球蛋白10 g/d静脉滴注,连续治疗7d.比较2组临床疗效、血清细胞因子[白细胞介素-6(IL-6)、白细胞介素-17(IL-10)、白细胞介素-23(IL-23)、γ-干扰素(IFN-γ)]、免疫功能指标变化.结果 2组总有效率比较差异均无统计学意义(P＞0.05).2组治疗后IL-6、IL-17、IL-23低于治疗前,IFN-γ高于治疗前,差异有统计学意义(P＜0.05).观察组IL-6、IL-17、IL-23低于对照组,IFN-γ高于对照组,差异有统计学意义(P＜0.05).观察组治疗后CD3+、CD4+、CD8+、CD4+/CD8+均高于治疗前,且观察组高于对照组,差异有统计学意义(P＜0.05).2组不良反应发生率比较差异无统计学意义(P＞0.05).结论大剂量与小剂量丙种球蛋白冲击治疗重症寻常型疗效相当,但前者可更好地维持血清细胞因子平衡,改善机体免疫功能,且不良反应并未显著增加,值得在临床推广使用.%Objective To investigate the effect of different dosesof gamma globulin on immune function in patients with severe pemphigus vulgaris and its clinical significance.Methods 80 patients diagnosed as severe pemphigus vulgaris by pathology and immunofluorescence assay in the hospital were randomly divided into observation group and control group (40 cases for each).Both groups were treated with hormonetherapy:80 mg/d methylprednisolone intravenously once a week for 2 weeks,then the observation group were treated with high-dose gamma globulin (20 g/d) intravenously for 5 d,whereas the control group were treated with low-dose gamma globulin 10 g/d intravenousy for 7d.The clinical efficacy,serum cytokines including interleukin-6 (IL-6),interleukin-17 (IL-10),interleukin-23 (IL-23),interferon gamma (IFN-γ)and immune function indexes were compared between the two groups.Results The total effective rates of the two groups were not statistically significant.The IL-6,IL-17 and IL-23 of the two groups were lower than those before treatment,and IFN-γ was higher than that before treatment,which the differences were statistically significant.IL-6,IL-17 and IL-23 in the observation group were lower than that in the control group,and IFN-γ was higher than the control group,which the differences were statistically significant.After the treatment,CD3+,CD4+ and CD8+,and CD4/CD8 in the observation group was higher than that before treatment (P ＜0.05).The incidence of adverse reactions in the two groups was not statistically significant (P ＞0.05).Conclusion The curative effects of high dose and low dose gamma globulin shock treatment on severe ordinary pemphigus vulgaris are equivalent,but the former could maintain serum cytokine balance well,improve immune function,and adverse reactions were not increased significantly,which is worth in clinical use.【期刊名称】《新疆医科大学学报》【年(卷),期】2017(040)012【总页数】4页(P1522-1525)【关键词】丙种球蛋白;重症寻常型天疱疮;免疫功能【作者】布瓦杰尔·亚克亚;梁俊琴;康晓静【作者单位】新疆维吾尔自治区人民医院皮肤科,乌鲁木齐830000;新疆维吾尔自治区人民医院皮肤科,乌鲁木齐830000;新疆维吾尔自治区人民医院皮肤科,乌鲁木齐830000【正文语种】中文【中图分类】R4天疱疮是一种自身免疫性大疱性皮肤病，发病率为(0.5～3.2)/10万[1]。

肿瘤免疫治疗中细胞因子应用近年来，肿瘤免疫治疗取得了巨大的进步，极大地改善了患者的预后状态并提高了患者的生存率。

目前，癌症免疫治疗主要集中在T细胞表面受体TCR以及共刺激分子（如：CD28）等。

针对于第三信使细胞因子的癌症治疗应用还处于研究阶段，且还没有大量的应用到临床试验中。

但其实，早在1986年，美国食品和药物管理局（FDA）就批准了重组IFN-α用于治疗毛细胞白血病。

细胞因子是由多种免疫细胞或非免疫细胞（如：内皮细胞、表皮细胞、成纤维细胞等）合成和分泌的一类具有多种生物功能小分子蛋白，其分子量通常小于30kDa。

细胞因子在体内可通过旁分泌、自分泌或内分泌等方式介导细胞间相互作用，从而调节细胞的增殖、分化、生存以及免疫应答等。

基于功能不同，细胞因子又可分为白细胞介素（interleukin/ILs）、干扰素（interferons/IFNs）、肿瘤坏死因子（tumor necrosis factors/TNFs）、集落刺激因子（colony-stimulating factors/CSFs）以及趋化因子（chemokines）。

细胞因子药物细胞因子在免疫应答中具有十分重要的作用。

基于一些临床前和临床研究，多种细胞因子已被视为抗癌候选药物。

迄今为止，FDA已批准了两种重组细胞因子用于癌症免疫治疗，分别为甘乐能（干扰素α-2b）和普留净（阿地白介素）（表1）。

甘乐能可用于治疗毛细胞白血病、恶性黑色素瘤、滤泡性淋巴瘤和艾滋病相关的卡波西肉瘤[1]，而普留净则具有治疗转移性肾细胞癌(RCC) 和转移性黑色素瘤的功效[2]。

表 1 FDA批准的细胞因子药物此外，其他细胞因子类药物也在开发中，包括临床试验中研究最广泛的集落刺激因子（G-CSF、GM-CSF）、血管内皮生长因子（VEGF）、IL-2和IFN-γ等（图1）[3]。

对于重组细胞因子及其受体来讲，高纯度以及高活性对于其功能研究实验是十分必要的，比如细胞毒性检测、因子药物筛选阳性对照等。

∗基金项目:海南省自然科学基金资助项目(编号: 2021GJ03101)作者单位:572000海南省三亚市海南医学院附属三亚市中心医院/海南省第三人民医院麻醉手术科第一作者:解飞,男,37岁,大学本科,主治医师㊂E-mail: 125956593@通讯作者:徐夏,E-mail:932855832@ ㊃胆石症㊃环泊酚与小剂量右美托咪定复合镇痛腹腔镜胆囊切除术治疗胆囊结石患者麻醉效果研究∗解飞,胡艳丽,周海,徐夏㊀㊀ʌ摘要ɔ㊀目的㊀观察环泊酚与小剂量右美托咪定复合镇痛腹腔镜胆囊切除术(LC)治疗的胆囊结石患者的麻醉效果㊂方法㊀2023年2月~2023年6月我院收治的69例胆囊结石患者被随机分为对照组34例和观察组35例,两组均接受LC治疗㊂在手术时,给予对照组环泊酚麻醉镇痛,给予观察组环泊酚复合小剂量右美托咪定麻醉镇痛㊂此后,均采用吸入麻醉㊂在插管前(T0)和拔管后10min(T2)采用疼痛视觉模拟(VAS)法和Ramsay镇静量表评估麻醉效果㊂在T0㊁插管后10min(T1)和T2时,监测收缩压(SBP)㊁舒张压(DBP)和心率(HR)㊂采用ELISA法检测血清白细胞介素-1β(IL-1β)㊁IL-6和肿瘤坏死因子-α(TNF-α)水平㊂结果㊀在T2时,观察组VAS和Ramsay评分分别为(3.5ʃ0.3)分和(2.7ʃ0.5)分,显著低于对照组ʌ分别为(3.9ʃ0.4)分和(3.3ʃ0.5)分,P<0.05ɔ;观察组苏醒时间和拔管时间分别为(12.4ʃ2.7)min和(16.2ʃ2.9)min,显著短于对照组ʌ(16.8ʃ3.3)min和(19.7ʃ3.8)min,P<0.05ɔ;在T1时,观察组SBP㊁DBP和HR分别为(118.7ʃ8.6)mmHg㊁(71.0ʃ6.3)mmHg和(78.8ʃ7.4)次/min,显著低于或慢于对照组ʌ分别为(124.1ʃ9.3) mmHg㊁(74.6ʃ6.5)mmHg和(82.6ʃ6.7)次/min,P<0.05ɔ;在T2时,观察组SBP㊁DBP和HR分别为(121.4ʃ10.5)mmHg㊁(76.6ʃ5.9)mmHg和(76.2ʃ6.7)次/min,显著低于或慢于对照组ʌ分别为(127.6ʃ10.2)mmHg㊁(81.6ʃ6.1)mmHg和(80.8ʃ8.6)次/min,P<0.05ɔ;在术后3d,观察组血清IL-1β㊁IL-6和TNF-α水平分别为(41.3ʃ7.1)pg/mL㊁(108.9ʃ20.5)pg/mL和(14.7ʃ2.7)pg/mL,显著低于对照组ʌ分别为(46.9ʃ8.4)pg/mL㊁(122.8ʃ24.7)pg/mL和(19.2ʃ3.9)pg/mL,P<0.05ɔ㊂结论㊀应用环泊酚与小剂量右美托咪定复合镇痛能够减轻接受LC手术患者疼痛,为手术展开提供稳定的血流动力学条件,可能与抑制了机体应激反应有关㊂㊀㊀ʌ关键词ɔ㊀胆囊结石;腹腔镜胆囊切除术;环泊酚;右美托咪定;细胞因子;镇痛㊀㊀DOI:10.3969/j.issn.1672-5069.2024.03.036㊀㊀Analgesia with ciprofol and dexmedetomidine combination in patients with cholecystolithiasis undergoing laparoscopic cholecystectomy㊀Xie Fei,Hu Yanli,Zhou Hai,et al.Department of Anesthesi,Hainan Third Provincial People s Hospital/ Central Hospital,Affiliated to Hainan Medical College,Sanya572000,Hainan Province,China㊀㊀ʌAbstractɔ㊀Objective㊀The aim of this study was to investigate the analgesia with ciprofol and dexmedetomidine combination in patients with cholecystolithiasis undergoing laparoscopic cholecystectomy(LC).Methods㊀69patients with cholecystolithiasis were enrolled in our hospital between February2023and June2023,and were randomly divided into control(n= 34)and observation group(n=35),and all patients in the two groups received LC.For analgesia,the ciprofol was given in patients in the control,and the ciprofol and low-dose of dexmedetomidine combination were given in patients in the observation during perioperative period.Thereafter,the aspiration anaesthesia was carried out.The visual analogue scale(VAS)and Ramsay sedation scale were applied to evaluate the anesthetic effect before intubation(T0)and10min after extubation(T2).The systolic blood pressure(SBP),diastolic blood pressure(DBP)and heart rate(HR)were measured by multifunctional monitor at T0,10 min after intubation(T1)and T2.Serum interleukin-1β(IL-1β),IL-6and tumor necrosis factor-α(TNF-α)levels were measured by ELISA.Results㊀At T2,the VAS and Ramsay scores in the observation group were(3.5ʃ0.3)and(2.7ʃ0.5),both significantly lower than[(3.9ʃ0.4)and(3.3ʃ0.5),respectively,P<0.05]in the control;the wakening time andextubation time in the observation group were(12.4ʃ2.7)minand(16.2ʃ2.9)min,both significantly shorter than[(16.8ʃ3.3)min and(19.7ʃ3.8)min,P<0.05]in the control;at T1,the SBP,DBP and HR were(118.7ʃ8.6)mmHg,(71.0ʃ6.3)mmHg and(78.8ʃ7.4)beats/min,all significantly lower orslower than[(124.1ʃ9.3)mmHg,(74.6ʃ6.5)mmHg and(82.6ʃ6.7)beats/min,P<0.05]in the control;at T2,the SBP,DBP and HR were(121.4ʃ10.5)mmHg,(76.6ʃ5.9)mmHg and(76.2ʃ6.7)beats/min,significantly lower or slower than[(127.6ʃ10.2)mmHg,(81.6ʃ6.1)mmHg and(80.8ʃ8.6) beats/min,P<0.05]in the control;3days after operation,serum IL-1β,IL-6and TNF-αlevels were(41.3ʃ7.1)pg/mL, (108.9ʃ20.5)pg/mL and(14.7ʃ2.7)pg/mL,all significantly lower than[(46.9ʃ8.4)pg/mL,(122.8ʃ24.7)pg/mL and (19.2ʃ3.9)pg/mL,respectively,P<0.05]in the control group.Conclusion㊀The anesthesia with cyclopofol and low-dose of dexmedetomidine combination could relieve pain and provide stable hemodynamic conditions in patients with cholecystolithiasis underwent LC,which might be related to the mild stress of body reactions.㊀㊀ʌKey wordsɔ㊀Cholecystolithiasis;Laparoscopic cholecystectomy;Ciprofol;Dexmedetomidine;Cytokines;Analgesia㊀㊀胆囊结石(cholecystolithiasis)往往伴有胆囊炎的存在[1]㊂传统开腹手术行胆囊切除术存在创伤大㊁恢复慢㊁术后疼痛明显等问题[2]㊂近年来,腹腔镜技术的引入为胆囊切除提供了更为先进的手术方法选择,腹腔镜胆囊切除术(laparoscopic cholecystectomy, LC)采取在腹部打开几个小切口,插入腹腔镜和其他手术器械进行手术,实现了胆囊的微创切除,与传统手术相比,LC具有创伤小㊁恢复快㊁术后疼痛轻等优势,患者术后痛苦减轻,恢复时间大大缩短[3]㊂此外,随着手术器械和技术的不断改进,LC的安全性和效果也得到了进一步提高,医生可以通过腹腔镜摄像头清晰地观察胆囊及其周围组织,准确地进行手术操作,最大程度地保障腹腔脏器的安全[4]㊂环泊酚和右美托咪定是一种复合镇痛方案,常用于全身麻醉手术,它们的复合使用可以提供良好的麻醉效果,相较于单一麻醉药物的使用,具有减少麻醉药物用量㊁快速恢复清醒㊁减少术后恶心和呕吐等并发症的优点㊂本研究应用环泊酚与小剂量右美托咪定复合镇痛LC治疗的胆囊结石患者,观察了麻醉效果,现报道如下㊂1㊀资料与方法1.1病例来源㊀2023年2月~2023年6月我院收治的胆囊结石患者69例,男36例,女33例;年龄为35~65岁,平均年龄为(47.1ʃ53.3)岁㊂体质指数(body mass index,BMI)为22~27kg/m2,平均为(24.6ʃ1.7)kg/m3㊂符合‘中国慢性胆囊炎和胆囊结石内科诊疗共识意见(2018年)“[5]的诊断标准㊂美国麻醉医师协会(ASA)I级24例,Ⅱ级28例,Ⅲ级17例㊂排除标准:①合并肝细胞癌或肝硬化;②存在活动性肝炎;③存在心㊁肺㊁肾等重要器官功能障碍;④具有麻醉药物过敏史㊂采取随机投掷硬币法将患者分为对照组34例和观察组35例,两组年龄㊁性别㊁BMI和病情比较差异均无统计学意义(P> 0.05),具有可比性㊂本研究符合‘赫尔辛基宣言“及其附录准则,患者签署知情同意书㊂1.2手术和麻醉方法㊀所有患者接受LC手术㊂患者进入手术室后均常规予以心电监护㊁桡动脉穿刺置管和脑电双频指数(BIS)监测㊂在观察组,麻醉诱导:给予环泊酚(辽宁海思科制药有限公司,国药准字H20210007)0.4mg㊃kg-1和右美托咪定(江苏恒瑞医药股份有限公司,国药准字H20090248)0.5μg ㊃kg-1静脉注射;在对照组,只应用环泊酚,用量用法同观察组,不给予右美托咪定㊂术中维持麻醉:术中持续吸入0.75~1.25倍肺泡最低有效浓度七氟烷(上海恒瑞医药有限公司,国药准字H20070172),每间隔1h,追加瑞芬太尼(宜昌人福药业有限责任公司,国药准字H20030197)和苯磺顺阿曲库铵(江苏恒瑞医药股份有限公司,国药准字H20174008)各0.2μg㊃kg-1,控制在中等麻醉,BIS维持在40~60间㊂在缝合腹壁完毕后停止药物输注㊂1.3麻醉效果评估㊀记录两组停止药物输注后苏醒时间和拔管时间,并在插管前(T0)和拔管后10min (T2)采用视觉模拟评分法(visual analog scale,VAS)和Ramsay镇静量表评估麻醉效果㊂1.4监测与检测㊀使用深圳迈瑞生物医疗电子股份有限公司提供的BeneView T9型多功能监护仪检测T0㊁插管后10min(T1)和T2时收缩压(systolic blood pressure,SBP)㊁舒张压(diastolic blood pressure, DBP)和心率(heart rate,HR);采用ELISA法[6]检测血清白细胞介素-1β(interleukin-1β,IL-1β)㊁IL-6和肿瘤坏死因子-α(tumor necrosis factor-alpha,TNF -α)水平(北京安捷伦科技有限公司)㊂1.5统计学方法㊀应用SPSS Statistics24.0软件行统计学分析,应用Shapiro-Wilk进行正态性检验,对正态分布的计量资料以(xʃs)表示,采用独立t检验㊂计数资料以(%)表示,采用x2检验或Fisher精确概率计算㊂以P<0.05为差异有统计学意义㊂2㊀结果2.1两组麻醉效果比较㊀在T0时,两组VAS评分和Ramsay评分无统计学差异(P>0.05);在T2时,观察组VAS评分和Ramsay评分均显著低于对照组(P< 0.05);观察组苏醒时间和拔管时间均显著短于对照组(P<0.05,表1)㊂2.2两组血流动力学指标比较㊀在T0时,两组SBP㊁DBP和HR比较无统计学差异(P>0.05);在T1和T2时,观察组SBP㊁DBP和HR均显著低于或慢于对照组,差异有统计学意义(P<0.05,表2)㊂2.3两组血清细胞因子水平比较㊀术前,两组IL-1β㊁IL-6和TNF-α水平无显著性差异(P>0.05);在术后3d,观察组IL-1β㊁IL-6和TNF-α水平均显著低于对照组(P<0.05,表3)㊂表1㊀两组麻醉效果(xʃs)比较例数VAS评分T0T2Ramsay评分T0T2苏醒时间(min)拔管时间(min)对照组34 5.6ʃ1.1 3.9ʃ0.4 3.8ʃ0.8 3.3ʃ0.516.8ʃ3.319.7ʃ3.8观察组35 5.4ʃ0.9 3.5ʃ0.3① 3.7ʃ0.6 2.7ʃ0.5①12.4ʃ2.7①16.2ʃ2.9①㊀㊀与对照组比,①P<0.05表2㊀两组血流动力学指标(xʃs)比较例数SBP(mmHg)DBP(mmHg)HR(次/min)对照组T03491.3ʃ11.675.2ʃ7.176.5ʃ7.9 T134124.1ʃ9.374.6ʃ6.582.6ʃ6.7T234127.6ʃ10.281.6ʃ6.180.8ʃ8.6观察组T03590.9ʃ11.176.1ʃ7.475.9ʃ8.0 T135118.7ʃ8.6①71.0ʃ6.3①78.8ʃ7.4①T235121.4ʃ10.5①76.6ʃ5.9①76.2ʃ6.7①与对照组比,①P<0.05表3㊀两组血清细胞因子水平(pg/mL,xʃs)比较例数IL-1βIL-6TNF-α对照组术前3439.7ʃ7.355.7ʃ12.38.2ʃ1.93d3446.9ʃ8.4122.8ʃ24.719.2ʃ3.9观察组术前3539.5ʃ6.955.2ʃ12.18.4ʃ2.13d3541.3ʃ7.1①108.9ʃ20.5①14.7ʃ2.7①㊀㊀与对照组比,①P<0.053㊀讨论LC是一种通过腹腔镜技术切除胆囊的手术[6,7]㊂相比传统的开腹手术,LC具有创伤小㊁恢复快㊁术后疼痛轻等优点[8]㊂麻醉是手术中重要的一环,贯穿手术始终,而麻醉药物和方法的选择也日益更新㊂环泊酚是一种静脉麻醉药物,具有快速起效和短效的特点,可通过静脉注射进入体内,使患者迅速进入无意识状态[9]㊂小剂量右美托咪定是一种超短效麻醉镇痛药物,属于阿片类药物,通过静脉输注,能够迅速减轻疼痛感,并提供镇静和镇痛效果,其特点是作用持续时间短,停药后迅速消失,减少了术后镇痛的需要[10]㊂相关研究报道,环泊酚和小剂量右美托咪定可以在手术过程中同时使用,以达到麻醉和镇痛的效果㊂环泊酚作用于中枢神经系统,主要通过靶向γ-氨基丁酸(GABA)受体来产生药理效应,其主要作用是增强GABA受体的抑制性效应,从而抑制神经元的兴奋性,导致全身麻醉状态,而小剂量右美托咪定作用于中枢神经系统,主要通过靶向α2-肾上腺素受体产生药理效应,用于控制术中和术后疼痛,这种复合镇痛方案可以提供良好的麻醉效果[11,12]㊂本研究结果显示,在T2时,观察组VAS和Ramsay评分显著低于对照组,且观察组苏醒时间和拔管时间均显著短于对照组(P<0.05),表明应用环泊酚与小剂量右美托咪定复合镇痛的观察组比单独使用环泊酚有更好的止痛效果㊂环泊酚可通过静脉注射诱导麻醉状态,右美托咪定是一种强效镇痛药物,与单独使用环泊酚相比,环泊酚和小剂量右美托咪定协同作用,可以迅速减轻术中和术后疼痛感[13-15]㊂通过对比两组血流动力学指标发现,在T1和T2时,观察组SBP㊁DBP和HR显著低于或慢于对照组(P<0.05),表明使用环泊酚与小剂量右美托咪定复合镇痛所引起的应激反应小于单独使用环泊酚㊂同时,在术后3d,观察组血清IL-1β㊁IL-6和TNF-α水平显著低于对照组(P<0.05)㊂环泊酚作为一种麻醉药物,使用剂量过大可能会导致机体的应激反应,如血压升高㊁心率增快等,而复合使用小剂量右美托咪定可以减少环泊酚的使用剂量,从而减少了潜在的应激反应发生风险㊂也有研究指出,小剂量右美托咪定具有调节麻醉深度的作用,可使麻醉状态更加稳定,通过复合使用小剂量右美托咪定,可以更好地调控麻醉深度,减少患者的应激反应[16-18]㊂另外,环泊酚和小剂量右美托咪定都具有快速起效和短效的特点,复合使用可以使患者在手术结束后更快地清醒和恢复神志,减少术后的应激反应㊂研究认为,使用环泊酚与小剂量右美托咪定复合镇痛的安全性相对较高㊂环泊酚单独使用时可能会引起术后恶心和呕吐等副作用㊂然而,复合使用小剂量右美托咪定可以减少环泊酚的使用剂量,从而减少了术后恶心和呕吐发生率[17]㊂右美托咪定可以通过激活α2-肾上腺素能受体抑制交感神经系统和中枢神经系统的活性,减少交感神经冲动的传递和呼吸中枢的抑制作用,从而降低低血压和呼吸抑制的发生㊂同时,右美托咪定还可以减少环泊酚对中枢神经系统的抑制作用,从而也减少了环泊酚引起的低血压的发生[19,20]㊂ʌ参考文献ɔ[1]Schuld J,Glanemann M.Acutecholecystitis.Viszeralmedizin,2015,31(3):163-165.[2]Rex DK.Endoscopist-directed propofol.Gastrointest Endosc ClinN Am,2016,26(3):485-492.[3]Nishizawa T,Suzuki H.Propofol for gastrointestinal endoscopy.U-nited Eur Gastroenterol J,2018,6(6):801-805.[4]赵闯,梁超,董宝剑,等.原发性肝癌患者接受TACE术时行右美托咪定联合吗啡麻醉临床应用价值分析.实用肝脏病杂志,2021,24(2):260-263.[5]中华消化杂志编辑委员会,中华医学会消化病学分会肝胆疾病协作组.中国慢性胆囊炎㊁胆囊结石内科诊疗共识意见(2018年).临床肝胆病杂志,2019,35(6):1231-1236. [6]Mondardini MC,Amigoni A,Cortellazzi P,et al.Intranasaldexmedetomidine in pediatrics:update of current knowledge.Mi-nerva Anestesiol,2019,85(12):1334-1345.[7]Hu Y,Zhou H,Zhang H,et al.The neuroprotective effect ofdexmedetomidine and its mechanism.Front Pharmacol,2022,13(9):965-971.[8]Tasbihgou SR,Barends C,Absalom AR.The role of dexmedetomi-dine in neurosurgery.Best Pract Res Clin Anaesthesiol,2021,35(2):221-229.[9]Mashour GA,Sanders RD,Lee U.Propofolanesthesia:A leap intothe void.Anesthesiology,2022,136(3):405-407. [10]Abbasian N,Terreblanche B,Ok M,et al.Propofol vial coring.Can J Anaesth,2022,69(9):1167-1168.[11]Manning AN,Bezzo LK,Hobson JK,et al.Dexmedetomidinedosing to prevent pediatric emergence delirium.AANA J,2020,88(5):359-364.[12]陈启全,李晓婷,杨勋祎,等.超声造影㊁剪切波弹性成像和增强CT检查诊断肝细胞癌价值分析.实用肝脏病杂志,2023,26(3):408-411.[13]罗登,赖习华,刘首记.腹腔镜胆囊切除术治疗胆囊结石伴慢性胆囊炎患者治疗效果分析.实用肝脏病杂志,2021,24(2): 276-279.[14]陈俊光,邓晓妃,林树俊,等.急性化脓性胆囊炎患者超声影像学特点及其诊断价值.实用肝脏病杂志,2022,25(1):116 -119.[15]Persson N,Uusalo P,Nedergaard M,et al.Coulddexmedetomidine be repurposed as a glymphatic enhancer?Trends Pharmacol Sci,2022,43(12):1030-1040.[16]Yuki K.The immunomodulatory mechanism of dexmedetomidine.Int Immunopharmacol,2021,97(9):1077-1086. [17]Doherty SE,Doyle LA,McCullough SJ,et parison of reti-noscopy results with and without1%cyclopentolate in school-aged children.Ophthalmic Physiol Opt,2019,39(4):272-281. [18]Imai T,Hasebe S,Furuse T,et al.Adverse reactions to1%cyclo-pentolate eye drops in children:an analysis using logistic regression models.Ophthalmic Physiol Opt,2021,41(2):424-430. [19]da Costa AC,Santa-Cruz F,Sena BF,et al.Dedifferentiated lipo-sarcoma of the gallbladder:first reported case.World J Surg Oncol, 2018,16(1):221.[20]Tylicka M,Matuszczak E,Karpińska M,et al.Proteasome activityand C-reactive protein concentration in the course of inflammatory reaction in relation to the type of abdominal operation and the surgi-cal technique used.Mediators Inflamm,2018,2018:2469098.(收稿:2023-09-08)(本文编辑:张骏飞)。

氢吗啡酮与舒芬太尼用于高龄全髋关节置换术后静脉自控镇痛的疗效比较杨福明【摘要】目的：探讨氢吗啡酮用于高龄全髋置换术后静脉自控镇痛的临床疗效。

方法选取2011年5月-2013年5月在我院骨科实施全髋置换术的80例高龄患者，按照随机原则分成两组各40例，观察组术后使用氢吗啡酮10mg＋托烷司琼10mg＋生理盐水配置成100ml泵入静脉自控镇痛；对照组术后使用舒芬太尼100μg＋托烷司琼10mg＋生理盐水配置成100ml泵入静脉自控镇痛，比较两组术后6h、12h、24h的疼痛视觉模拟评分(VAS)、Ramsay镇静评分及不良反应。

结果观察组不良反应发生率明显低于对照组(P<0.01）；观察组患者术后6h、12h、24h VAS评分和Ramsay镇静评分均低于对照组(P<0.05）。

结论氢吗啡酮应用于高龄全髋置换术后静脉自控镇痛，其临床疗效确切，且不良反应发生率低，值得临床推广使用。

【期刊名称】《江西医药》【年(卷),期】2016(051)006【总页数】3页(P582-584)【关键词】氢吗啡酮;舒芬太尼;全髋关节置换术;疼痛;临床疗效【作者】杨福明【作者单位】南昌大学第一附属医院麻醉科，南昌 330006【正文语种】中文【中图分类】R614老年全髋关节置换术患者常由于疼痛剧烈，限制患肢的术后早期功能锻炼，加上老年患者多合并基础疾病，术后疼痛对其影响更为显著，有效的术后静脉镇痛可缓解患者疼痛，有利于患者功能锻炼、减少并发症发生率，同时可通过减少炎性因子的表达而减缓炎性应激反应［1，2］。

有研究发现，通过静脉镇痛对患者术后的功能活动基本无影响，可有效地维持人体循环系统的稳定，对于减少术后肺部感染、泌尿系感染及心脑血管并发症等有一定的临床价值［3］。

目前已有多项研究显示对于进行全髋置换术患者行静脉自控镇痛可取得比较满意的疗效［4］。

但对于高龄患者而言，目前仍存在争议。

本文比较氢吗啡酮与舒芬太尼应用于高龄全髋关节置换术后静脉自控镇痛的临床疗效差异，现报告如下。

云南医药２０１２年第３３卷第６期难治性特发性血小板减少性紫癜是临床常见的问题，本文就２２例的患者进行了观察，报告如下。

临床资料新发病例１５例，复发及难治性病例７例，诊断符合张之南、沈悌主编的《血液病诊断及疗效标准》。

１．新发病例→激素治疗２周→评价疗效→进步、无效的病例→随机进入对照组（继续给予激素及免疫抑制剂治疗）及治疗组（在原治疗的基础上加用白介素１１，２５μｇ·ｋｇ－１·ｄ－１，≥３ｄ或≤２周。

２．复发及难治病例→随机进入对照组（继续给予激素及免疫抑制剂治疗）及治疗组（在原治疗的基础上加用白介素１１，２５μｇ·ｋｇ－１·ｄ－１，≥３ｄ或≤２周）。

３．连续观察血常规每周３次，观察血小板的最低值，血小板减少持续时间，血小板恢复至正常时间及出院随访６个月血小板数值是否保持稳定，同时注意观察治疗前后骨髓巨核细胞变化的情况，每２周复查一次骨髓细胞学检查；治疗期间注意有无出血及输注血小板情况，注意记录白介素１１使用期间的药物不良反应。

４．疗效判定标准：按照第２届全国血液学学术会议的标准进行判定。

显效：血小板恢复正常，无出血症状。

良效：血小板升至５０×１０９／Ｌ以上或较原水平上升３０×１０９／Ｌ以上，无或基本无出血症状。

进步：血小板有所上升，出血症状有所改善．持续２周以上。

无效：血小板计数及出血症状无改善或恶化。

５．不良反应评价：采用ＷＨＯ药物不良反应项目及分级来评价，包括：局部注射部位反应、肌肉关节疼痛、水肿、发热、心悸、感冒样症状、皮疹、血栓栓塞等。

结果１．临床出血情况：２２例接受治疗的患者，１周１６例出血情况均得到改善，未再次出现新鲜部位出血。

５例无明显改善。

２．血小板计数：２２倒患者中显效：７例（３１．８２％）；良效：６例（２７．２７％）；进步：３例（１３．６４％）。

无效：６例（２７．２７％）。

讨论特发性血小板减少性紫癜（ＩＴＰ）发病率约为５～１０／１０万人口，６５岁以上老年人发病率有升高趋势，其确切病因尚不清楚，与发病相关的因素有：①持续抗原暴露；②抗体产生中某些重链基因的选择；③自身免症原因不明：ＳＬＥ、伊文综合征等；④异常抗原表达：淋巴增生性疾病，慢性淋巴细胞性白血病；⑤持续感染：ＨＩＶ感染、丙型肝炎、幽门螺杆菌感染等。

- 129 -*基金项目：萍乡市科技计划项目（2020PY010）①萍乡市人民医院呼吸科　江西　萍乡　337000通信作者：刘平香氟替美维吸入粉雾剂联合小剂量阿奇霉素用于老年AECOPD患者肺康复治疗中的临床观察*刘平香①　董利民①　沈湘波①【摘要】　目的：探究氟替美维吸入粉雾剂联合小剂量阿奇霉素对老年慢性阻塞性肺疾病急性加重期（acute exacerbation chronic obstructive pulmonary disease，AECOPD）患者肺康复治疗的临床效果。

方法：于2021年1月—2023年6月萍乡市人民医院呼吸科收治的老年AECOPD 患者中选取80例为研究对象，并按随机数字表法分成对照组（40例）和研究组（40例）。

两组均于病情稳定后给予治疗，对照组给予氟替美维吸入粉雾剂治疗，研究组加用小剂量阿奇霉素治疗，均治疗1个月。

比较两组炎症指标[C 反应蛋白（C reactive protein，CRP）、白细胞介素-6（interleukin-6，IL-6）、肿瘤坏死因子-α（tumor necrosis factor-alpha，TNF-α）]、肺功能情况[第1秒用力呼气容积（forced exhalation volume for 1 second，FEV 1）、用力肺活量（forced vital capacity，FVC）、FEV 1/FVC%]、慢阻肺自我评估测试（COPD assessment test，CAT）评分、圣乔治呼吸问卷（St.George's respiratory questionnaire，SGRQ）评分和不良反应发生率的差异。

结果：治疗后，两组的CRP、IL-6、TNF-α水平均低于治疗前，FEV 1、FVC、FEV 1/FVC%水平均高于治疗前，且研究组炎症指标和肺功能情况的改善程度均优于对照组，差异均有统计学意义（P <0.05）。

作者简介:刘建军,男,主管药师,主要从事药理学研究㊂ ә 通信作者,E -m a i l :w a n g h o n g ji e d m@126.c o m ㊂㊃论 著㊃D O I :10.3969/j.i s s n .1672-9455.2023.19.023小剂量替格瑞洛联合阿托伐他汀钙片治疗冠心病不稳定型心绞痛的疗效及安全性分析刘建军1,王洪杰2ә1.陕西省神木市医院药剂科,陕西榆林719300;2.陕西省汉中市南郑区人民医院心血管内科,陕西汉中723100摘 要:目的 探讨小剂量替格瑞洛联合阿托伐他汀钙片用于冠心病不稳定型心绞痛的疗效及安全性㊂方法 选取冠心病不稳定型心绞痛患者90例,根据随机数字表法分为小剂量组与常规剂量组,每组45例㊂常规治疗基础上,小剂量组口服替格瑞洛首剂量120m g,之后调整至60毫克/次,2次/天;口服阿托伐他汀钙片20毫克/次,1次/天㊂常规治疗基础上,常规剂量组口服替格瑞洛首剂量180m g ,之后调整至90毫克/次,2次/天,阿托伐他汀钙片用法㊁用量同小剂量组㊂两组均持续治疗12周㊂比较两组治疗前及治疗12周后血清炎症因子[高敏C 反应蛋白(h s -C R P )㊁白细胞介素(I L )-6和肿瘤坏死因子-α(T N F -α)]㊁心功能指标[左心室射血分数(L V E F )㊁左心室舒张末期内径(L V E D D )和舒张末期室间隔厚度(I V S T )]㊁心肌酶谱和心肌损伤指标[基质金属蛋白酶-9(MM P -9)㊁1型组织纤溶酶原激活物抑制剂(t P A I -1)㊁可溶性细胞间黏附因子-1(s I C AM -1)㊁心肌肌钙蛋白I (c T n I )㊁N 末端脑钠肽前体(N T -pr o B N P )]及临床疗效和不良反应发生率㊂结果 治疗12周后,两组h s -C R P ㊁I L -6㊁T N F -α水平较治疗前降低(P <0.05),组间比较,差异无统计学意义(P >0.05)㊂治疗12周后,两组L V E F 较治疗前升高(P <0.05),L V E D D ㊁I V S T 较治疗前降低(P <0.05),组间比较,差异无统计学意义(P >0.05)㊂治疗12周后,两组MM P -9㊁t P A I -1㊁s I C AM -1㊁c T n I ㊁N T -p r o B N P 水平较治疗前降低(P <0.05),组间比较差异无统计学意义(P >0.05)㊂治疗12周后,小剂量组总有效率与常规剂量组比较,差异无统计学意义(P >0.05),不良反应发生率低于常规剂量组(P <0.05)㊂结论 小剂量替格瑞洛联合阿托伐他汀钙片治疗冠心病不稳定型心绞痛与常规剂量疗效基本相当,但安全性较好,值得临床推广㊂关键词:小剂量; 替格瑞洛; 阿托伐他汀钙片; 冠心病; 不稳定型心绞痛中图法分类号:R 541.4文献标志码:A文章编号:1672-9455(2023)19-2876-05E f f i c a c y a n d s a f e t y a n a l y s i s o f l o w d o s e t i c a gr e l o r c o m b i n e d w i t h a t o r v a s t a t i n c a l c i u m t a b l e t i n t r e a t i n g c o r o n a r y h e a r t d i s e a s e u n s t a b l e a n gi n a p e c t o r i s L I U J i a n j u n 1,WA N G H o n g ji e 2ә1.D e p a r t m e n t o f P h a r m a c y ,S h e n m u M u n i c i p a l H o s pi t a l ,Y u l i n ,S h a a n x i 719300,C h i n a ;2.D e p a r t m e n t o f C a r d i o v a s c u l a r M e d i c i n e ,N a n z h e n g D i s t r i c t P e o p l e 's H o s pi t a l ,H a n z h o n g ,S h a a n x i 723100,C h i n a A b s t r a c t :O b je c t i v e T o i n v e s t i g a t e t h e ef f i c a c y a n d s a f e t y o f l o w d o s e t i c ag r e l o r c o m b i n e d w i th a t o r v a s t a -ti n c a l c i u m t a b l e t i n t h e t r e a t m e n t o f c o r o n a r y h e a r t d i s e a s e u n s t a b l e a n g i n a p e c t o r i s .M e t h o d s N i n e t y pa -t i e n t s w i t h c o r o n a r y h e a r t d i s e a s e u n s t ab l e a n g i n a p ec t o r i s w e r e s e l e c t ed a n d d i v i de d i n t o t h e l o w d o s e g r o u pa n d c o n v e n t i o n a l d o s e g r o u p a c c o r d i n g t o t h e r a n d o m n u mb e r t a b l e m e t h o d ,45c a s e s i n e a c h g r o u p.O n t h e b a -s i s o f c o n v e n t i o n a l t r e a t m e n t ,t h e l o w d o s e g r o u p o r a l l y t o o k t h e i n i t i a l d o s e o f 120m g t i c a g r e l o r ,t h e n a d ju s -t e d t o 60m g e a c h t i m e ,t w i c e a d a y ;o r a l a t o r v a s t a t i n c a l c i u m t a b l e t 20m g e a c h t i m e ,o n c e a d a y.O n t h e b a s i s o f c o n v e n t i o n a l t r e a t m e n t ,t h e i n i t i a l d o s e o f t i c a g r e l o r i n t h e c o n v e n t i o n a l d o s e g r o u p w a s 180m g,t h e n t h e d o s e w a s a d j u s t e d t o 90m g e a c h t i m e ,t w i c e a d a y ;t h e u s a g e a n d d o s a ge of a t o r v a s t a t i n c a l c i u m t a b l e t s w a s t h e s a m e a s t h a t o f t h e l o w d o s eg r o u p .B o th g r o u p s w e r e c o n ti n u o u s l y tr e a t e d f o r 12w e e k s .T h e s e r u m i n -f l a mm a t o r y f a c t o r s [h i g h s e n s i t i v i t y C-r e a c t i v e p r o t e i n (h s -C R P ),i n t e r l e u k i n (I L )-6a n d t u m o r n e c r o s i s f a c -t o r -α(T N F -α)],c a r d i a c f u n c t i o n i n d e x e s [l e f t v e n t r i c u l a r e je c t i o nf r a c t i o n (L V E F ),l e f t v e n t r i c u l a r e n d d i a s -t o l i c d i a m e t e r (L V E D D )a n d i n t e r v e n t r i c u l a r s e p t u m t h i c k n e s s a t t h e d i a s t o l i c e n d (I V S T )],m yo c a r d i a l e n -z y m e p r o f i l e a n d m y o c a r d i a l i n j u r y i n d e x e s [m a t r i x m e t a l l o p r o t e i n a s e -9(MM P -9),t i s s u e p l a s m i n o ge n a c t i v a -t o r i n h i b i t o r -1(t P A I -1),s o l u b l e i n t e r c e l l u l a r a d h e s i o n m o l e c u l a r -1(s I C AM -1),c a r d i a c t r o po n i n I (c T n I )a n d N -t e r m i n a l p r o -b r a i n n a t r i u r e t i c p e p t i d e (N T -p r o B N P )],c l i n i c a l e f f i c a c y an d o c c u r r e n c e r a t e o f a d v e r s e r e a c -t i o n s b e f o r e t r e a t m e n t a n d i n 12w e e k s a f t e r t r e a t m e n t w e r e c o m p a r e d b e t w e e n t h e t w o g r o u ps .R e s u l t s A f t e r ㊃6782㊃检验医学与临床2023年10月第20卷第19期 L a b M e d C l i n ,O c t o b e r 2023,V o l .20,N o .19Copyright ©博看网. All Rights Reserved.12-w e e k t r e a t m e n t,h s-C R P,I L-6a n d T N F-αl e v e l s i n2g r o u p s w e r e d e c r e a s e d c o m p a r e d w i t h t h o s e b e f o r e t r e a t m e n t(P<0.05),b u t t h e r e w a s n o s t a t i s t i c a l l y s i g n i f i c a n t d i f f e r e n c e b e t w e e n t h e g r o u p s(P>0.05).A f-t e r12w e e k s o f t r e a t m e n t,L V E F i n t h e t w o g r o u p s w a s i n c r e a s e d c o m p a r e d w i t h t h a t b e f o r e t r e a t m e n t,w h i l e L V E D D a n d I V S T w e r e d e c r e a s e d c o m p a r e d w i t h t h o s e b e f o r e t r e a t m e n t(P<0.05),b u t t h e r e w a s n o s t a t i s-t i c a l d i f f e r e n c e b e t w e e n t h e t w o g r o u p s(P>0.05).A f t e r12-w e e k t r e a t m e n t,t h e l e v e l s o f MM P-9,t P A I-1,s I-C AM-1,c T n I a n d N T-p r o B N P i n t h e t w o g r o u p s w e r e d e c r e a s e d c o m p a r e d w i t h t h o s e b e f o r e t r e a t m e n t(P<0.05),b u t t h e r e w a s n o s t a t i s t i c a l l y s i g n i f i c a n t d i f f e r e n c e b e t w e e n g r o u p s(P>0.05).A f t e r12-w e e k t r e a t-m e n t,t h e t o t a l e f f e c t i v e r a t e h a d n o s t a t i s t i c a l d i f f e r e n c e b e t w e e n t h e l o w d o s e g r o u p a n d c o n v e n t i o n a l d o s e g r o u p(P>0.05),b u t t h e i n c i d e n c e r a t e o f a d v e r s e r e a c t i o n s i n t h e l o w d o s e g r o u p w a s l o w e r t h a n t h a t i n t h e c o n v e n t i o n a l d o s e g r o u p(P<0.05).C o n c l u s i o n T h e e f f i c a c y o f l o w d o s e t i c a g r e l o r c o m b i n e d w i t h a t o r v a s t a-t i n c a l c i u m t a b l e t s i n t h e t r e a t m e n t o f c o r o n a r y h e a r t d i s e a s e u n s t a b l e a n g i n a p e c t o r i s i s b a s i c a l l y t h e s a m e a s t h a t o f c o n v e n t i o n a l d o s e,b u t t h e s a f e t y i s g o o d,a n d i t i s w o r t h y o f c l i n i c a l p r o m o t i o n.K e y w o r d s:l o w d o s e;t i c a g r e l o r;a t o r v a s t a t i n c a l c i u m t a b l e t s;c o r o n a r y h e a r t d i s e a s e;u n s t a b l e a n-g i n a p e c t o r i s数据显示,近10年来冠心病患病率及病死率一直处于较高水平且呈持续上升趋势,该病是造成全球范围内成人死亡和疾病负担的主要原因,其发病机制较为复杂,与血管内皮功能损伤㊁炎症因子㊁氧化应激失衡等密切相关[1-2]㊂目前冠心病的治疗主要以调脂㊁控制心血管危险因素㊁血运重建为主,其中阿托伐他汀钙片是治疗该病的基础用药,不仅具有调脂作用,还具有抗血小板聚集㊁抗炎等作用,可保护患者血管内皮功能,诱导新生血管形成,在抑制冠状动脉斑块硬化进程中发挥着重要作用[3]㊂替格瑞洛作为临床较为常用的一种P2Y12受体抑制剂,具有抗炎㊁抗血小板凝聚等多重作用,尽管其已被临床证实可使冠心病患者获益,但关于应用剂量仍是临床关注的重点[4]㊂虽然国内外指南均推荐替格瑞洛常规剂量为90m g,但近年来有研究显示,西方欧美人群对该药物的生物利用度低于亚洲人群,因此推测亚洲人群小剂量给药即可满足临床治疗需求,但确切使用剂量仍无定论[5]㊂此外,有研究显示,小剂量替格瑞洛治疗不稳定型心绞痛具有良好的抗凝效果,对血小板的抑制作用较好,可有效降低出血风险[6]㊂本研究旨在探究小剂量替格瑞洛联合阿托伐他汀钙片治疗冠心病不稳定型心绞痛的疗效及安全性,以期为该病治疗提供参考依据㊂1资料与方法1.1一般资料选取2021年1月 2022年7月神木市医院(以下简称本院)收治的冠心病不稳定型心绞痛患者90例㊂纳入标准:(1)符合冠心病不稳定型心绞痛诊断标准[7],以长时间静息性心绞痛(时间超过20m i n)㊁新发心绞痛㊁恶化性心绞痛㊁心肌梗死后心绞痛为主要临床表现,安静状态下常规心电图至少2个导联S T段下移不低于1mm,近期心电图提示新出现的胸导联T波倒置(或胸导联T波倒置较之前的心电图加深),动态心电图S T段抬高(胸导联㊁肢体导联分别不低于2㊁1mm)或S T段压低(下斜型或水平型)不低于1mm,心绞痛发作时心电图可见S T段压低0.5~<1.0mm;(2)患者入组年龄不低于18岁;(3)临床资料记录完整㊂排除标准:(1)肾㊁肝㊁肺等器官严重功能障碍;(2)血液系统疾病㊁风湿免疫性疾病㊁慢性结缔组织疾病及恶性肿瘤;(3)伴有出血倾向或出血性疾病;(4)严重心力衰竭㊁心律失常㊁心脏瓣膜病㊁心肌病;(5)对本研究使用药物过敏;(6)伴有滥用药物史或精神病病史;(7)入组前1个月内已进行冠状动脉支架植入术㊁冠状动脉旁路搭桥术等血运重建治疗;(8)入组前3个月内发生急性感染㊁受重大创伤;(9)入组前3个月内服用过替格瑞洛㊁阿托伐他汀钙片㊂根据随机数字表法将90例冠心病不稳定型心绞痛患者分为小剂量组与常规剂量组,每组45例㊂两组患者在体质量指数㊁合并症等方面比较,差异无统计学意义(P>0.05),具有可比性㊂见表1㊂本研究经本院医学伦理委员会审批通过,患者及家属均签署知情同意书㊂1.2方法1.2.1治疗方法两组患者均进行调脂㊁抗心肌缺血㊁控制心律等常规治疗㊂常规治疗基础上,小剂量组口服替格瑞洛(国药准字H20203435,浙江海正药业股份有限公司)首剂量120m g,之后调整至60毫克/次,2次/天;口服阿托伐他汀钙片(国药准字H20051408,辉瑞制药有限公司)20毫克/次, 1次/天㊂常规治疗基础上,常规剂量组口服替格瑞洛首剂量180m g,之后调整至90毫克/次,2次/天,阿托伐他汀钙片用法㊁用量同小剂量组㊂两组均持续治疗12周㊂1.2.2检测方法(1)炎症因子:于治疗前㊁治疗12周后空腹采集晨起肘静脉血5m L,离心机(T D Z4A-W S型,金坛市恒丰仪器制造有限公司)离心处理(离心时间15m i n,离心半径6.5c m,转速2500r/m i n),之后取上清液于-80ħ冷冻保存㊂检测仪器为全自动生化分析仪(N S A-400P型,沈阳东软医疗系统有限㊃7782㊃检验医学与临床2023年10月第20卷第19期 L a b M e d C l i n,O c t o b e r2023,V o l.20,N o.19Copyright©博看网. All Rights Reserved.公司),其中高敏C 反应蛋白(h s -C R P )以免疫增强比浊法(四川新健康成生物股份有限公司试剂盒)检测,白细胞介素(I L )-6㊁肿瘤坏死因子-α(T N F -α)以酶联免疫吸附试验(上海研伴实业有限公司试剂盒)检测㊂(2)心功能指标:于治疗前㊁治疗12周后采用彩色多普勒超声诊断仪(西门子A C U S O N S C 2000型,S i e -m e n s A G ,G e r m a n y)检测左心室射血分数(L V E F )㊁左心室舒张末期内径(L V E D D )和舒张末期室间隔厚度(I V S T )㊂(3)心肌酶谱和心肌损伤指标:分别于治疗前和治疗12周后测定,基质金属蛋白酶-9(MM P -9)㊁1型组织纤溶酶原激活物抑制剂(t P A I -1)㊁可溶性细胞间黏附因子-1(s I C AM -1)㊁心肌肌钙蛋白I (c T -n I )㊁N 末端脑钠肽前体(N T -pr o B N P )均以酶联免疫吸附试验(上海继和生物科技有限公司试剂盒)检测㊂表1 两组一般资料比较组别n性别[n (%)]男女年龄(x ʃs ,岁)体质量指数(x ʃs ,k g/m 2)病程(x ʃs ,年)合并症[n (%)]糖尿病高血压高脂血症小剂量组4526(57.78)19(42.22)61.75ʃ11.0523.62ʃ2.413.39ʃ1.0213(28.89)15(33.33)8(17.78)常规剂量组4525(55.56)20(44.44)60.96ʃ11.2323.70ʃ2.593.42ʃ1.0311(24.44)16(35.56)10(22.22)χ2/t0.0450.3360.1520.1390.2270.0490.278P0.8320.7370.8800.8900.6340.8240.5981.3 疗效判断 治疗12周后记录两组临床疗效㊂心绞痛症状基本消失且心电图基本恢复正常为显效;心绞痛症状改善且心电图检查S T 段升幅ȡ0.05m V为有效;上述情况均未出现或恶化视为无效[7]㊂总有效=显效+有效㊂1.4 观察指标 比较两组治疗前后的炎症因子㊁心功能指标㊁心肌酶谱和心肌损伤指标,以及疗效㊁不良反应(治疗期间呼吸困难㊁恶心呕吐㊁出血等)发生率㊂1.5 统计学处理 采用S P S S 25.0统计软件分析数据㊂计数资料以例数或百分率表示,组间比较采用χ2检验;呈正态分布的计量资料以x ʃs 表示,组间比较采用独立样本t 检验或配对样本t 检验㊂以P <0.05为差异有统计学意义㊂2 结 果2.1 两组血清炎症因子水平比较 治疗12周后,两组h s -C R P ㊁I L -6㊁T N F -α水平较治疗前降低(P <0.05),但组间比较,差异无统计学意义(P >0.05)㊂见表2㊂2.2 两组心功能指标比较 治疗12周后,两组L V E F 较治疗前升高(P <0.05),L V E D D ㊁I V S T 较治疗前降低(P <0.05),组间比较,差异无统计学意义(P >0.05)㊂见表3㊂2.3 两组心肌酶谱和心肌损伤指标比较 治疗12周后,两组MM P -9㊁t P A I -1㊁s I C AM -1㊁c T n I ㊁N T -pr o B N P 水平较治疗前降低(P <0.05),组间比较,差异无统计学意义(P >0.05)㊂见表4㊂表2 两组血清炎症因子水平比较(x ʃs )组别nh s -C R P (m g /L )治疗前治疗12周后I L -6(p g /m L )治疗前治疗12周后T N F -α(μg /L )治疗前治疗12周后小剂量组457.95ʃ1.043.81ʃ0.62*7.45ʃ1.242.86ʃ0.41*431.20ʃ35.60183.12ʃ28.82*常规剂量组457.76ʃ1.213.85ʃ0.64*7.39ʃ1.202.98ʃ0.50*434.60ʃ34.07181.00ʃ27.74*t0.7990.3010.2331.2450.4630.356P0.4270.7640.8160.2170.6450.723注:与治疗前比较,*P <0.05㊂表3 两组心功能指标比较(x ʃs )组别nL V E F (%)治疗前治疗12周后L V E D D (mm )治疗前治疗12周后I V S T (mm )治疗前治疗12周后小剂量组4545.60ʃ7.6062.07ʃ8.23*55.30ʃ5.7151.60ʃ3.81*14.74ʃ2.339.00ʃ1.12*常规剂量组4544.87ʃ7.4265.45ʃ8.69*54.82ʃ5.3350.61ʃ4.20*15.12ʃ2.499.07ʃ1.56*t0.4611.1530.4121.1710.7480.245P0.6460.0340.6810.2450.4570.807注:与治疗前比较,*P <0.05㊂㊃8782㊃检验医学与临床2023年10月第20卷第19期 L a b M e d C l i n ,O c t o b e r 2023,V o l .20,N o .19Copyright ©博看网. All Rights Reserved.表4 两组心肌酶谱和心肌损伤指标比较(x ʃs )组别nMM P -9(μg /L )治疗前治疗12周后t P A I -1(n g /m L )治疗前治疗12周后s I C AM -1(n g /m L )治疗前治疗12周后小剂量组45145.89ʃ16.9591.60ʃ10.10*69.08ʃ7.2055.68ʃ5.58*276.85ʃ28.49190.55ʃ21.27*常规剂量组45143.29ʃ15.0990.01ʃ11.32*68.74ʃ7.1154.24ʃ6.41*270.68ʃ28.20191.07ʃ23.60*t0.7690.7030.2251.1371.0330.110P0.4440.4840.8220.2590.3050.913组别nc T n I (μg /L )治疗前治疗12周后N T -p r o B N P (m g/L )治疗前治疗12周后小剂量组4589.20ʃ10.0754.96ʃ7.14*712.60ʃ94.85274.40ʃ51.24*常规剂量组4588.80ʃ10.4555.76ʃ8.37*710.63ʃ92.31289.00ʃ48.14*t0.1850.4880.1001.393P0.8540.6270.9210.167注:与治疗前比较,*P <0.05㊂2.4 两组临床疗效比较 治疗12周后,小剂量组总有效率与常规剂量组比较,差异无统计学意义(χ2=0.212,P >0.05)㊂见表5㊂2.5 两组不良反应发生率比较 小剂量组不良反应发生率低于常规剂量组,差异有统计学意义(χ2=3.920,P <0.05)㊂见表6㊂表5 两组临床疗效比较[n (%)]组别n显效有效无效总有效小剂量组4526(57.78)17(37.78)2(4.44)43(95.56)常规剂量组4527(60.00)15(33.33)3(6.67)42(93.33)表6 两组不良反应发生率比较[n (%)]组别n呼吸困难头晕头痛恶心呕吐出血合计小剂量组450(0.00)1(2.22)2(4.44)1(2.22)4(8.89)常规剂量组452(4.44)2(4.44)4(8.89)3(6.67)11(24.44)3 讨 论尽管多个大规模临床试验已证实替格瑞洛联合阿托伐他汀钙片能使冠心病不稳定型心绞痛患者获益,但关于替格瑞洛的使用剂量仍存在争议,而小剂量替格瑞洛联合阿托伐他汀钙片治疗冠心病不稳定型心绞痛的疗效和安全性,以及对患者血清炎症因子㊁心肌损伤标志物㊁心功能的影响也尚未明确[8]㊂因此,本研究针对此方面开展初步探究㊂本研究显示,治疗12周后两组h s -C R P ㊁I L -6㊁T N F -α水平均降低(P <0.05),且组间比较,差异无统计学意义(P >0.05),提示与大剂量替格瑞洛联合阿托伐他汀钙片治疗相比,小剂量替格瑞洛联合阿托伐他汀钙片在抗炎方面作用基本相当㊂炎症反应是冠心病发生及发展过程中的关键性因素之一,其不仅参与粥样硬化斑块的形成,还可诱导斑块侵蚀㊁破裂及血栓形成,是引发急性心血管事件的独立影响因素,故抗感染治疗有望成为冠心病药物治疗的关键手段[9]㊂王栋等[10]研究显示,60m g 替格瑞洛与90m g替格瑞洛在治疗不稳定型心绞痛时近期效果相当,两者在减轻炎症反应方面也并无明显差异,与本研究结论相符,可能与中国人对替格瑞洛利用度较高有关,因此降低剂量并不会直接影响药效㊂阿托伐他汀钙片具有抗炎㊁调脂㊁调节血管内皮功能㊁促使血管平滑肌增殖受抑㊁抑制血栓形成等作用,可阻碍或抑制冠状动脉斑块的硬化进程㊂而对于冠心病不稳定型心绞痛患者而言,阿托伐他汀钙片的抗炎机制可能与诱导过氧化物酶体增殖物激活受体-γ表达有关[11]㊂替格瑞洛是环戊基三唑嘧啶类口服抗血小板药物,能够直接作用或可逆结合P 2Y 12受体,诱导信号传导及血小板活化受阻,无须通过肝代谢转化,抗血小板作用显著,具有起效迅速㊁药理作用稳定等特点[12]㊂与大剂量替格瑞洛相比,小剂量替格瑞洛在一定程度上可降低药物依赖程度,经济效益可能更佳,可减轻患者负担㊂本研究显示,小剂量组与常规剂量组心功能㊁心肌酶谱和心肌损伤指标在治疗后均得到改善(P <0.05),组间比较,差异无统计学意义(P >0.05),提示与大剂量替格瑞洛联合阿托伐他汀钙片治疗相比,小剂量替格瑞洛联合阿托伐他汀钙片仍可有效发挥抑制心肌损伤㊁改善心功能的作用㊂MM P -9㊁t P A I -1㊁㊃9782㊃检验医学与临床2023年10月第20卷第19期 L a b M e d C l i n ,O c t o b e r 2023,V o l .20,N o .19Copyright ©博看网. All Rights Reserved.s I C AM-1均参与动脉粥样硬化进展,并介导血栓形成,与冠心病不稳定型心绞痛的发生及发展密切相关[13]㊂推测原因:替格瑞洛联合阿托伐他汀钙片可有效抑制冠心病不稳定型心绞痛患者血小板聚集,维持血管血流动力学稳定,保护血管内皮功能,抑制机体炎症反应,改善纤溶系统功能,缓解心肌损伤,调节心功能㊂本研究显示,治疗12周后两组疗效基本相当,进一步证实小剂量替格瑞洛应用的可行性㊂此外,本研究显示,小剂量组不良反应发生率低于常规剂量组(P<0.05),提示小剂量替格瑞洛联合阿托伐他汀钙片治疗冠心病不稳定型心绞痛安全性较好,这与既往报道[14]相似㊂王悦等[15]研究显示,与90m g的替格瑞洛相比,不稳定型心绞痛患者经皮冠状动脉介入术后长期应用45m g的替格瑞洛对血小板的抑制作用更为显著,更具稳定性和高效性,并可降低出血风险,支持本研究结论㊂药代动力学研究表明,健康成人替格瑞洛药代动力参数与服药剂量呈线性相关,相较于西方欧美人群,亚洲人群对替格瑞洛及其活性代谢物的平均暴露量通常高出约40%,致使其血小板抑制水平更高;而亚洲人群血小板反应活性最佳治疗窗口也与西方欧美人群不同,采用相同的治疗窗口可能会导致出血风险增加[16]㊂综上所述,与大剂量替格瑞洛联合阿托伐他汀钙片治疗相比,小剂量替格瑞洛联合阿托伐他汀钙片治疗冠心病不稳定型心绞痛疗效仍较为满意,可有效减轻炎症反应㊁缓解心肌损伤㊁改善心功能,且安全性较好㊂参考文献[1]韩雅玲,李洋.中国冠心病介入治疗开创及发展史[J].中华心血管病杂志,2021,49(7):645-649.[2]L I A N G F,WA N G Y.C o r o n a r y h e a r t d i s e a s e a n d a t r i a l f i-b r i l l a t i o n:a v ic i o u s c y c l e[J].A m J P h y s i o l H e a r t C i r cP h y s i o l,2021,320(1):H1-H12.[3]S HA R MA R,K UMA R P,P R A S HA N T H S P,e t a l.D u a la n t i p l a t e l e t t h e r a p y i n c o r o n a r y a r t e r y d i s e a s e[J].C a r d i o lT h e r,2020,9(2):349-361.[4]A K K A I F M A,S HA'A B A N A,D A U D N A A,e t a l.C o r-o n a r y h e a r t d i s e a s e(C H D)i n e l d e r l y p a t i e n t s:w h i c h d r u g t o c h o o s e,t i c a g r e l o r a n d c l o p i d o g r e l?A s y s t e m a t i c r e v i e wa n d m e t a-a n a l y s i s o f r a n d o m i z e d c o n t r o l l e d t r i a l s[J].JC a r d i o v a s cD e v D i s,2021,8(10):123-134.[5]L O G A N A T H K,A D AM S O N P D,MO S S A J.T i c a g r e l o ri n t h e m a n a g e m e n t o f c o r o n a r y a r t e r y d i s e a s e[J].F u t u r eC a r d i o l,2021,17(4):561-571.[6]陈芳,张胜高,周瑞红,等.不同剂量替格瑞洛联合低分子肝素钠对ȡ80岁不稳定型心绞痛病人的疗效及血管内皮功能的影响[J].实用老年医学,2022,36(11):1129-1132.[7]中华医学会心血管病学分会,中华心血管病杂志编辑委员会.非S T段抬高型急性冠状动脉综合征诊断和治疗指南(2016)[J].中华心血管病杂志,2017,45(5):359-376.[8]Z HA N G Y R,X U E Z K,C H E N K Y,e t a l.L o a d i n g d o s e s o f t i c a g r e l o r v e r s u s c l o p i d o g r e l i n p r e v e n t i n g p e r i p r o c e-d u r a l m y o c a r d i a l i n f a r c t i o n i n A s i a n p a t i e n t s w i t h a c u t ec o r o n a r y s y nd r o m e[J].Pe rf u s i o n,2021,36(2):122-129.[9]刘牧吟,戴春峰,陈章炜,等.秋水仙碱防治冠心病的研究进展[J].中华心血管病杂志,2022,50(6):606-610. [10]王栋,崔晓冉,李汭傧,等.不同剂量的替格瑞洛治疗不稳定型心绞痛的疗效和安全性比较[J].临床心血管病杂志,2020,36(6):549-553.[11]鲁琦,李论.阿托伐他汀钙对冠心病患者外周血炎症因子及单核细胞极化的影响[J].中国老年学杂志,2020,40(16):3373-3376.[12]HU A N G B,Q I A N Y,X I E S,e t a l.T i c a g r e l o r i n h i b i t s t h eN L R P3i n f l a mm a s o m e t o p r o t e c t a g a i n s t i n f l a mm a t o r yd i se a s e i n d e p e n d e n t of t h e P2Y12s ig n a l i n g p a th w a y[J].C e l l M o l I mm u n o l,2021,18(5):1278-1289.[13]邓瑞,马珍珍,卢小伟.替格瑞洛对不稳定型心绞痛择期P C I患者血清炎性因子及MM P-9㊁s I C AM-1㊁t P A I-1的影响[J].中国循证心血管医学杂志,2019,11(12):1508-1511.[14]A D AM S K I P,O S T R OW S K A M,N A V A R E S E E P,e ta l.P h a r m a c o d y n a m i c a n d c l i n i c a l e f f i c a c y o f r e d u c e d t i-c a g r e l o r m a i n t e n a n c ed o se s i n p a t i e n t s w i t h c o r o n a r y a r-t e r y d i s e a s e[J].C u r r M e d R e s O p i n,2021,37(2):195-206.[15]王悦,王志强,刘倍倍,等.不稳定型心绞痛患者经皮冠状动脉介入术后长期应用小剂量替格瑞洛的抗凝疗效分析[J].心肺血管病杂志,2021,40(1):6-11.[16]S A N D E R S O N N C,P A R K E R W A E,S T O R E Y R F.T i-c a g r e l o r:c l i n i c a lde v e l o p m e n t a n df u t u r e p o t e n t i a l[J].R e v C a r d i o v a s c M e d,2021,22(2):373-394.(收稿日期:2022-12-22修回日期:2023-05-20)㊃0882㊃检验医学与临床2023年10月第20卷第19期 L a b M e d C l i n,O c t o b e r2023,V o l.20,N o.19Copyright©博看网. All Rights Reserved.。

PostoperativePain Management –Good Clinical PracticeGeneral recommendationsand principles forsuccessful pain managementProduced in consultation with theEuropean Society of Regional Anaesthesiaand Pain TherapyPostoperativePain Management –Good Clinical PracticeGeneral recommendationsand principles forsuccessful pain managementProduced in consultation with theEuropean Society of Regional Anaesthesiaand Pain TherapyContents ContentsContents11. Introduction and objectives1 Although the choice of drugs shown here is indicative, adjustments will be required to take account ofindividual patient variation and are the responsibility of the prescribing physician.Effective postoperative pain management has a humanitarian role, but there are additional medical and economic benefits for rapid recovery and discharge from hospital. A number of factors contribute to effective postoperative pain management including a structured acute pain management team, patient education, regular staff training, use of balanced analgesia, regular pain assessment using specificassessment tools and adjustment of strategies to meet the needs of special patient groups, such as children and the elderly.Recent advances in pain control provide greater potential for effective postoperative management. This document reflects the opinions of a panel of European anaesthesiologists. Its aims are to raise awareness of recent advances in pain control and to provide advice on how toachieve effective postoperative analgesia. The recommendations and advice are general principles of pain management and do not provide detailed advice for specific surgical procedures.1Effective pain management is now an integral part of modern surgical practice. Postoperative pain management not only minimises patient suffering but also can reduce morbidity and facilitate rapid recovery and early discharge from hospital (see section 8, page 33), which can reduce hospital costs.23Pain is a personal, subjective experience that involves sensory,emotional and behavioural factors associated with actual or potentialtissue injury. What patients tell us about their pain can be very revealing,and an understanding of how the nervous system responds and adaptsto pain in the short and long term is essential if we are to make sense ofpatients’ experiences. The wide area of discomfort surrounding awound, or even a wound that has healed long ago, such as anamputation stump, is a natural consequence of the plasticity of thenervous system. An understanding of the physiological basis of pain ishelpful to the sufferer, and the professionals who have to provideappropriate treatment.According to the International Association for the Study of Pain (IASP),pain is defined as"An unpleasant sensory and emotional experience associated withactual or potential tissue damage, or described in terms of suchdamage."(IASP 1979)There is individual variation in response to pain, which is influenced bygenetic makeup, cultural background, age and gender. Certain patientpopulations are at risk of inadequate pain control and require specialattention. These include:G Paediatric patientsG Geriatric patientsG Patients with difficulty in communicating (due to critical illness,cognitive impairment or language barriers)Postoperative pain can be divided into acute pain and chronic pain:G Acute pain is experienced immediately after surgery (up to 7 days)G Pain which lasts more than 3 months after the injury is considered tobe chronic pain3. Physiology of pain 2. Goals of pain treatmentAcute and chronic pain can arise from cutaneous, deep somatic orvisceral structures. Surgery is typically followed by acute pain and correct identification of the type of pain enables selection of appropriate effective treatment. The type of pain may be somatic (arising from skin, muscle, bone), visceral (arising from organs within the chest and abdomen), or neuropathic (caused by damage or dysfunction in the nervous system). Patients often experience more than one type of pain.3.a. Positive role of painAcute pain plays a useful "positive" physiological role by:G Providing a warning of tissue damageG Inducing immobilisation to allow appropriate healing3.b. Negative effects of painShort term negative effects of acute pain include:G Emotional and physical suffering for the patientG Sleep disturbance(with negative impact on mood and mobilisation)G Cardiovascular side effects(such as hypertension and tachycardia)G Increased oxygen consumption(with negative impact in the case of coronary artery disease)G Impaired bowel movement(while opioids induce constipation or nausea, untreated pain mayalso be an important cause of impaired bowel movement or PONV*)G Negative effects on respiratory function(leading to atelectasis, retention of secretions and pneumonia)G Delays mobilisation and promotes thromboembolism(postoperative pain on mobilisation is one of the major causes fordelayed mobilisation)Long term negative effects of acute pain:G Severe acute pain is a risk factor for the development of chronicpain1G There is a risk of behavioural changes in children for a prolongedperiod (up to 1 year) after surgical painThere are two major mechanisms in the physiology of pain:G Nociceptive (sensory):Inflammatory pain due to chemical,mechanical and thermal stimuli at the nociceptors (nerves thatrespond to painful stimuli).G Neuropathic:Pain due to neural damage in peripheral nervesor within the central nervous system.During normal physiology, pain sensations are elicited by activity in unmyelinated (C-) and thinly myelinated (Ad-) primary afferent neurons that synapse with neurons is the dorsal horn of the spinal cord. Sensory information is then relayed to the thalamus and brainstem.Repetitive activation of C- nociceptive receptors produces alterations in central as well as peripheral nervous systems.3.c. The mechanism of peripheral pain sensitisationNormally, C- fibres (slow-conducting fibres that transmit dull aching pain) are silent in the absence of stimulation, but following acute tissue injury in the presence of ongoing pathophysiology, these nociceptors become sensitised and release a complex mix of pain and inflammatory mediators leading to pain sensations (Figure 1, page 6).1Several investigations into chronic pain have concluded that 20% to 50% of all patients with chronic pain syndromes started with acute pain following trauma or surgery, but the role of effective pain treatment in preventing this risk is not clear.* PONV = Postoperative Nausea and Vomiting.Figure 1.Mechanism of peripheral sensitisation3.d. The mechanism of central sensitisationThe responses in the CNS are primarily physiological. Centralsensitisation is a physiological process and, only if there is continual firing of C-nociceptors over time, will these processes leads to more chronic pain syndromes.Sustained or repetitive C-nociceptor activity produces alterations in the response of the central nervous system to inputs from the periphery.When identical noxious stimuli are repeatedly applied to the skin at a certain rate, there is a progressive build-up in the response of spinalcord dorsal horn neurons (known as ‘wind up’). This allows the size of the dorsal horn neuron’s receptive field to grow (Figure 2). This process,called central sensitisation, occurs with any tissue damage. As with sensitisation of primary afferent nociceptors, this sensitisation of central pain transmission is a normal physiological response of the undamaged nervous system.Figure 2.Pain mediatorsGUnexpected intense pain, particularly if associated with altered vital signs, (hypotension, tachycardia, or fever), is immediately evaluated. New diagnoses, such as wound dehiscence, infection, or deep venous thrombosis, should be considered.GImmediate pain relief without asking for a pain rating is given to patients in obvious pain who are not sufficiently focused to use a pain rating scale.GFamily members are involved when appropriate.4.a. Specific tools for pain assessmentSpecific pain assessment scales are used to quantify pain. The use of one scale within a hospital ensures that everyone in the team "speaks the same language"regarding the intensity of pain. The patient's own report is the most useful tool. The intensity of pain should therefore be assessed as far as possible by the patient as long as he/she is able tocommunicate and express what pain feels like. Always listen to and believe what the patient says.A number of different patient self-assessment scales are available (Figure 3, page 12):A. Facial expressions: a pictogram of six faces with differentexpressions from smiling or happy through to tearful. This scale is suitable for patients where communication is a problem, such as children, elderly patients, confused patients or patients who do not speak the local language.B. Verbal rating scale (VRS): the patient is asked to rate their pain on a five-point scale as "none, mild, moderate, severe or very severe".Assessment of pain is a vital element in effective postoperative pain management. The principles of successful pain assessment are shown in Table 1.44. Assessment of pain4G The treatment strategy to be continued is discussed by the physician responsible for the patient in conjunction with the ward nurses.GThe physician and nurses pay attention to the effects and side effects of the pain treatment.C. Numerical rating scale (NRS): This consists of a simple 0 to 5 or 0 to 10 scale which correlates to no pain at zero and worst possible pain at 5 (or 10). The patient is asked to rate his/her pain intensity as a number.D. Visual analogue scale (VAS): This consists of an ungraduated,straight 100 mm line marked at one end with the term " no pain" and at the other end "the worst possible pain". The patient makes a cross on the line at the point that best approximates to their pain intensity.The VRS and NRS are the most frequently used assessment tools in the clinical setting while the VAS scale is primarily used as a research tool.4.b. Selection of suitable assessment tool (Figure 3, page 12):When selecting a pain assessment tool ensure that:GIt is appropriate for the patient's developmental, physical, emotional, and cognitive statusGIt meets the needs of both the patient and the pain management team4.c. DocumentationDocument pain regularly, take appropriate action and monitor efficacy and side effects of treatment. Record the information in a well-defined place in the patient record, such as the vital sign sheet or a purpose-designed acute pain chart.GThe nurse responsible for the patient reports the intensity of pain and treats the pain within the defined rules of the local guidelines. GThe physician responsible for the patient may need to modify theintervention if evaluation shows that the patient still has significant pain.44Faces painassessmentscale(Fig A) Patientable to communicatewell ?VRS painassessmentscale(Fig B)NRSassessmentscale(Fig C)VASassessmentscale(Fig D) NoYesChoice of assessment tool12Fig A. Alternatecoding Fig B.Fig C. Fig D.G Select a pain assessment tool, and teach the patient to use it.Determine the level of pain above which adjustment of analgesia or other interventions will be considered.G Provide the patient with education and information about pain control.GEmphasise the importance of a factual report of pain, avoiding stoicism or exaggeration.The "Patient Information Project" is a useful source of information for patients who require information about anaesthesia and postoperative pain management. This is a joint project between the Royal College of Anaesthetists and the Association of Anaesthetists of Great Britain and Ireland, together with patient representative groups. The website is:Patients are unlikely to be aware of postoperative pain treatment techniques and as the success of pain relief is influenced by theirknowledge and beliefs, it is helpful to give patients (and parents in case of children) detailed information about postoperative pain and pain treatment. Adequate information gives the patient realistic expectations of the care that can be provided (pain relief, not a "pain free status"). This information can include:G The importance of treating postoperative pain G Available methods of pain treatment G Pain assessment routinesG Goals (optimum pain scoring) (see section 2, page 2)GThe patient's participation in the treatment of painInformation for the patient can be given in different ways (in combination):G Verbal informationGWritten and/or audiovisual information -Brochures -Wall posters -Video films -Web pagesA preoperative discussion with the patient and relatives can include the following:GDiscuss the patient's previous experiences with pain and preferences for pain assessment and management.GGive the patient information about pain management therapies that are available and the rationale underlying their use.GDevelop with the patient a plan for pain assessment and management.141555. Patient education51716Effective treatment of postoperative pain includes a number of factors,including good nursing, non-pharmacological techniques, such as distraction, and balanced (multimodal) analgesia to provide adequate pain relief with optimal drug combinations used at the lowest effective doses.6.a. Pharmacological methods of pain treatment 1Postoperative pain management should be step-wise and balanced (Figure 4, page 18). The four main groups of analgesic drugs used for postoperative pain management are shown in Table 2 opposite, with examples of drugs listed in each group.6.a.i. Balanced (multimodal) analgesiaBalanced (multimodal) analgesia uses two or more analgesic agents that act by different mechanisms to achieve a superior analgesic effect without increasing adverse events compared with increased doses of single agents. For example, epidural opioids can be administered in combination with epidural local anaesthetics; intravenous opioids can be administered in combination with NSAIDs, which have a dose sparing effect for systemically administered opioids.Balanced analgesia is therefore the method of choice wherever possible,based on paracetamol and NSAIDs for low intensity pain with opioid analgesics and/or local analgesia techniques being used for moderate and high intensity pain as indicated (Figure 4, page 18).66. Treatment optionsTable 2Pharmacological options of pain managementNon-opioid analgesicsParacetamolNSAIDs, including COX-2 inhibitors*Gabapentin, pregabalin 2Weak opioidsCodeine TramadolParacetamol combined with codeine or tramadol Strong opioidsMorphine Diamorphine Pethidine Piritramide Oxycodone Adjuvants**Ketamine Clonidine* At the time of writing, COX-2 inhibitor drugs are subject to scrutiny by international regulatory bodies with regard to adverse outcomes when used for long-term oralprescription or for pain relief in patients with cardiovascular problems such as myocardial infarction, angina pectoris, hypertension. Rofecoxib has been withdrawn fromsales and prescription of valdecoxib has been suspended pending further research into its adverse events profile for cardiovascular morbidity and the occurrence of severemuco-cutaneous side effects. The injectable COX-2 inhibitor, parecoxib remains available for short-term use in treating postoperative pain. All NSAIDs should be used with care in patients with cardiovascular disease.** These adjuvants are not recommended for routine use in acute pain management because of their adverse side effects. Their use should be restricted to specialists in managing pain problems.62Gabapentin and pregabalin are approved for pain management but at the time of writing there is little published data to recommend the use of these drugs for acute pain management.1The example doses given are indicative and do not take account of individual patient variation.196.a.ii. Opioids 1Severeintensity painFor example:ThoracotomyUpper abdominal surgery Aortic surgery Knee replacementModerateintensity painFor example:Hip replacement Hysterectomy Jaw surgeryMildintensity painFor example:Inguinal hernia VaricesLaparoscopy(i) Paracetamol and wound infiltration with local anaesthetic (ii) NSAIDs (unless contraindicated) and(iii) Regional block analgesiaAdd weak opioid or rescue analgesia with small increments of intravenous strong opioid if necessary(i) Paracetamol and wound infiltration withlocal anaesthetic (ii) NSAIDs (unless contraindicated) and (iii) Peripheral nerve block(single shot or continuous infusion) or opioid injection (IV PCA)(i) Paracetamol and woundinfiltration with local anaesthetic (ii) NSAIDs (unlesscontraindicated) and (iii) Epidural local analgesia ormajor peripheral nerve or plexus block or opioid injection (IV PCA)1 The examples given here represent levels of pain commonly experienced and are subject to individual variation and contra-indications may apply.Figure 4Treatment options in relation to magnitude of postoperative pain expected following different types of surgery 1Table 3Morphine and weak opioidsMorphine Administration(i) Intravenous.(ii) Subcutaneous by continuous infusion or intermittent boluses via indwelling cannula.(iii) Intramuscular (not recommended due to incidence of pain. 5-10 mg 3-4 hourly).Dosage:IV PCABolus: 1-2 mg, lockout: 5-15 min (usually 7-8 min),no background infusion.Subcutaneous0.1-0.15 mg/kg 4-6 hourly, adapted in relation to pain score, sedation and respiratory rate.Monitoring Pain score, sedation, respiratory rate, side mentsSide effects such as nausea, vomiting, sedation and apnoea.No other opioid or sedative drug should be administered.18continued overleaf1 The doses and routes of administration of drugs described above are general examples and each patient should beassessed individually before prescribing.2120 6.a.iii. Non-opioids 1Table 5Combination of codeine + paracetamolAdministration Oral.DosageParacetamol 500 mg + codeine 30 mg. 4 x 1 g paracetamol/day.Monitoring Pain score, sedation, side effects.CommentsAnalgesic action is likely to be due to conversion to morphine. A small number of patients derive no benefit due to absence of the converting enzyme.NV = nausea and vomitingTramadol Administration(i) Intravenous: inject slowly (risk of high incidence of NV).(ii) Intramuscular.(iii) Oral administration as soon as possible.Dosage 50-100 mg 6 hourly.Monitoring Pain score, sedation, respiratory rate, side mentsTramadol reduces serotonin and norepinephrine reuptake and is a weak opioid agonist.In analgesic efficiency, 100 mg tramadol is equivalent to 5-15 mg morphine.Sedative drugs can have an additive effect.Table 4ParacetamolAdministration(i) Intravenous: Start 30 min before the end of surgery.(ii) Oral administration as soon as possible.Duration: as long as required.Dosage4 x 1 g paracetamol/day (2 g propacetamol/day).Dose to be reduced (e.g. 3 x 1 g/day) in case of hepatic insufficiency.Monitoring Pain scores.CommentsShould be combined with NSAID and/or opioids or loco-regional analgesia for moderate to severe pain.1 The doses and routes of administration of drugs described above are general examples and each patient should beassessed individually before prescribing.1 The doses and routes of administration of drugs described above are generally examples and each patient should be assessed individually before prescribing.Table 3 (continued)Codeine Administration OralDosage3 mg/kg/day combined with paracetamol.A minimum of 30 mg codeine/tablet is required.Monitoring Pain score, sedation, side effects.CommentsAnalgesic action is likely to be due to conversion to morphine. A small number of patients derive no benefit due to absence of the converting enzyme.6.a.iv. AdjuvantsIn addition to systemic administration of NSAIDs or paracetamol, weak opioids and non-opioid analgesic drugs may be administered "on request" for moderate or severe pain. These include ketamine and clonidine. Clonidine can be administered orally, intravenously orperineurally in combination with local anaesthetics. However, the side effects could be significant. The most important ones are hypotension and sedation. Ketamine can be administered via oral, intramuscular or intravenous routes. It has also significant side effects.6.a.v. Regional analgesiaContinuous Central Neuraxis Blockade (CCNB)CCNB is one of the most effective forms of postoperative analgesia, but it is also one of the most invasive. However, CCNB remains the first choice for a number of indications, such as abdominal, thoracic, and major orthopaedic surgery, where adequate pain relief cannot be achieved with other analgesia techniques NB can be achieved via two routes:G Continuous epidural analgesia - the recommended first choice GContinuous spinal analgesia - should be limited to selected cases only, as there is less experience with this techniquePostoperative epidural analgesia is usually accomplished with acombination of a long-acting local anaesthetic and an opioid, in dilute concentrations. Long-acting local anaesthetics are preferred because they are associated with less tachyphylaxis. Maintenance techniques in epidural analgesia include:GContinuous Infusion (CI): An easy technique that requires littleintervention. The cumulative dose of local anaesthetic is likely to be higher and side effects are more likely than with the other two techniques.2322Table 6NSAIDs 1Administration(i) Intravenous: administration should start at least 30-60 min before end of surgery.(ii) Oral administration should start as soon as possible.Duration: 3-5 days.Dosage examples(i) Conventional NSAIDs include:ketorolac: 3 x 30-40 mg/day (only IV form)diclofenac: 2 x 75 mg/day ketoprofen: 4 x 50 mg/day (ii) Selective NSAIDs include:meloxicam 15 mg once dailyCOX-2 inhibitors are now licensed for postoperative pain management. They are as efficient as ketorolac but reduce GI side effects. Examples include: parecoxib: 40 mg followed by 1-2 x 40 mg/day (IV form) or celecoxib: 200 mg/day. However, there is some debate due to cardiovascular risks in patients witharteriosclerosis. *See note below Table 2, page 17MonitoringPain scores.Renal function in patients with renal or cardiac disease, elderly patients, or patients with episodes of severe hypotension. Gastrointestinal side effects. Non-selective NSAIDs would be combined with proton inhibitors (i.e. omeprasol) in patients at risk of gastrointestinal side effects.CommentsCan be added to the pre-medication.Can be used in association with paracetamol and/or opioids or local regional analgesia for moderate to severe pain.1 The doses and routes of administration of drugs described above are general examples and each patient should beassessed individually before prescribing.2524Continuous Peripheral Nerve Blockade (CPNB)Continuous peripheral nerve blocks are being increasingly used since they may provide more selective but still excellent postoperative analgesia with reduced need for opioids over an extended period.Peripheral nerve blocks (PNBs) avoid the side effects associated with central neuraxial blockade, such as hypotension and wide motorblockade with reduced mobility and proprioception, and complications such as epidural haematoma, epidural abscess and paraparesis.After major orthopaedic lower limb surgery, clinical studies showperipheral nerve blocks are as effective as epidural and that both are better than IV opioids. Examples of drugs and dosages for use in continuous peripheral analgesia are shown in Table 8.Table 8Examples of local anaesthetics and doses in continuous peripheral nerve analgesiaG Intermittent Top-up: Results in benefits due to frequent patient/staff contact but can produce a high staff workload and patients may have to wait for treatment.GPatient-Controlled Epidural Analgesia (PCEA): This technique produces high patient satisfaction and reduced dose requirements compared with CI. However, sophisticated pumps are required and accurate catheter position is important for optimal efficacy.Examples of drugs and dosages for use in continuous epidural analgesia are shown in Table 7.Table 7Examples of local anaesthetics and opioids and doses in epidural analgesia 1LocalRopivacaineSufentanil 0.5-1 µg/ml anaesthetics/opioids0.2% (2 mg/ml) or orFentanyl 2-4 µg/mlLevobupivacaine or Bupivacaine0.1-0.2% (1-2 mg/ml)Dosage for continuous 6-12 ml/hinfusion (thoracic or lumbar level)Dosage for patient Background: 4-6 ml/h controlled infusion Bolus dose: 2 ml (2-4 ml)(lumbar or thoracic)2Minimum lockout interval 10 min (10-30 min)Recommended maximum hourly dose (bolus + background): 12 ml1 The tip of the catheter should be placed as close as possible to the surgical dermatomes: T6-T10 for majorintra-abdominal surgery, and L2-L4 for lower limb surgery.2 There are many possible variations in local anaesthetic/opioid concentration yielding good results, the examples givenhere should be taken as a guideline; higher concentrations than the ones mentioned here are sometimes required but cannot be recommended as a routine for postoperative pain relief.Site of catheterLocal anaesthetics and dosage*Ropivacaine 0.2%Bupivacaine 0.1-0.125%Levobupivacaine 0.1-0.2%Interscalene5-9 ml/h Infraclavicular 5-9 ml/h Axillary 5-10 ml/h Femoral 7-10 ml/h Popliteal3-7 ml/h*Sometimes, higher concentrations are required in individual patients. As a standard, starting with a low concentration/dose is recommended to avoid sensory loss or motor block.2726Patient Controlled Regional Analgesia (PCRA) can be used to maintain peripheral nerve block. A low basal infusion rate (e.g. 3-5 ml/h)associated with small PCA boluses (e.g. 2.5-5 ml - lockout: 30-60 min) is the preferred technique.Infiltration blocksPain relief may be achieved by infiltration of the wound with localanaesthetic. The technique is easy to perform by the surgeon at the time of surgery. The efficacy and duration of analgesia depend on the length of the wound and the type of local anaesthetic used (Table 9).The advantages and disadvantages of various techniques of regional analgesia are shown in Table 10.Table 9Local anaesthetic infiltrationLocal anaestheticVolumeAdditivesIntraarticular instillation Knee arthroscopy0.75% Ropivacaine 20 ml Morphine 1-2 mg 0.5% Bupivacaine20 ml Morphine 1-2 mgShoulder arthroscopy 0.75% Ropivacaine10-20 mlIntraperitoneal instillation Gynaecological 0.75% Ropivacaine 20 ml Cholecystectomy 0.25% Ropivacaine40-60 mlWound infiltration Inguinal hernia0.25-0.5% Ropivacaine 30-40 ml 0.25-0.5% Levobupi*30-40 ml0.25-0.5% Bupivacaine Up to 30 mlTable 10Advantages of different techniques of regional analgesiaAdvantagesDisadvantagesContinuous Very effective.Motor block and urinary Epiduralretention may develop Analgesia (CEA)Much experience.or persist depending on the concentrations used.Differential block withDrugs used must have motor sparing is possible.low risk of systemic toxicity and produce as little motor Excellent postoperative block as possible.pain control over an extended period.Requires regular clinical monitoring on surgical Useful for rehabilitation wards or ICU.and physiotherapy.There are no universal Reduces the quantity of guidelines for monitoring.opioid analgesics needed.May mask a haematoma or abscess resulting in damage to spinal nerves.continued overleafThyroid surgery0.25-0.5% Ropivacaine 10-20 ml 0.25-0.5% Levobupi*10-20 ml0.25-0.5% Bupivacaine Up to 20 mlPerianal surgery0.25-0.5% Ropivacaine 30-40 ml 0.25-0.5% Levobupi*30-40 ml0.25-0.5% Bupivacaine Up to 30 mlcontinued opposite* Levobupi = Levobupivacaine.* Levobupi = Levobupivacaine.Please consult the manufacturer’s full prescribing information before use.。

小剂量替罗非班联合双抗血小板治疗进展性脑梗死的临床效果作者：陈淦吴卫娟严梓乐李桂岚陈义敏来源：《中国当代医药》2020年第15期[摘要]目的分析小劑量替罗非班联合双抗血小板治疗进展性脑梗死的临床效果。

方法选取我院2018年1～12月收治的46例进展性脑梗死患者作为研究对象，按照随机数字表法分为对照组（23例）与观察组（23例）。

对照组采用双抗血小板方案，观察组采用小剂量替罗非班联合双抗血小板方案。

比较两组的治疗效果、美国国立卫生研究院卒中量表（NIHSS）评分、Barthel指数、超敏C反应蛋白（hs-CRP）、白介素-6（IL-6）、改良Rankin量表（mRS）评分、不良反应发生率。

结果观察组的治疗总有效率高于对照组，差异有统计学意义（P0.05）。

结论采用小剂量替罗非班联合双抗血小板方案治疗进展性脑梗死能够获得良好的治疗效果。

[关键词]小剂量替罗非班;双抗血小板治疗;进展性脑梗死;临床效果[中图分类号] R743.3 [文献标识码] A [文章编号] 1674-4721（2020）5（c）-0083-04Clinical effect of low-dose Tirofiban combined with dual antiplatelet therapy in the treatment of progressive cerebral infarctionCHEN Gan WU Wei-Juan YAN Zi-le LI Gui-lan CHEN Yi-minDepartment of Neurology，People′s Hospital of Sanshui District of Foshan City in Guangdong Province， Foshan 528100， China[Abstract] Objective To analyze the clinical effect of low dose Tirofiban combined with dual antiplatelet therapy in the treatment of progressive cerebral infarction. Methods A total of 46 patients with progressive cerebral infarction admitted to our hospital from January to December in 2018 were selected as the research objects， and they were divided into the control group （23 cases） and the observation group （23 cases） according to the random digital table method. The control group was treated with dual antiplatelet program， and the observation group was treated with low-dose Tirofiban combined with dual antiplatelet program. The scores of national institutes of health stroke scale （NIHSS）， Barthel index， hypersensitivity C-reactive protein （hs-CRP）， interleukin-6 （IL-6）， modified Rankin scale （mRS） and the incidence of adverse reactions were compared between the two groups. Results The total effective rate of the observation group was higher than that of the control group， the difference was statistically significant （P0.05）. Conclusion Low doseTirofiban combined with dual antiplatelet regimen can achieve good therapeutic effect in the treatment of progressive cerebral infarction.[Key words] Low dose Tirofiban; Dual antiplatelet therapy; Progressive cerebral infarction; Clinical effect脑梗死属于神经内科中发病率较高的疾病，其患者数量占脑血管疾病的70%左右，而进展性脑梗死则在脑梗死中并不少见，其是指在一定时间内呈进行性加重状态的脑组织缺血性病变，治疗难度较大[1-2]，致残及致死风险在脑梗死类疾病中位居前列，严重威胁患者的生命安全。

·药物与临床·糖尿病新世界2022年10月糖尿病新世界DIABETES NEW WORLD不同剂量卡格列净联合二甲双胍治疗2型糖尿病临床效果及炎症因子分析黄艳霞临清市中医院药剂科，山东聊城252600[摘要]目的2型糖尿病应用二甲双胍联合不同剂量卡格列净治疗效果分析。

方法选取临清市中医院2020年1月—2022年1月收治的90例2型糖尿病患者为研究对象，按随机数表法分为两组，对照组给予二甲双胍联合高剂量（300mg ）卡格列净，研究组给予二甲双胍联合低剂量（100mg ）卡格列净，分析两组血糖、炎症因子及安全性。

结果治疗后，两组血糖指标均显著降低，差异有统计学意义（P <0.05）；研究组空腹血糖（5.37±0.86）mmol/L 、餐后2h 血糖（7.28±0.78）mmol/L 及糖化血红蛋白（6.97±0.82）%与对照组比较，差异无统计学意义（P >0.05）。

两组炎症因子均显著降低，差异有统计学意义（P <0.05）。

研究组IL-6（6.13±1.25）pg/mL 、CRP （3.98±0.56）mg/L 等炎症因子与对照组（6.06±1.31）pg/mL 、（4.05±0.62）mg/L 比较，差异无统计学意义（P >0.05）。

研究组发生胃肠道反应、低血糖等不良反应发生率4.44%低于对照组的17.78%，差异有统计学意义（P <0.05）。

结论2型糖尿病应用二甲双胍联合不同剂量卡格列净治疗，均能有效改善血糖指标，降低炎症因子，且低剂量卡格列净更具用药安全性。

[关键词]2型糖尿病；二甲双胍；卡格列净；血糖；炎症因子；安全性[中图分类号]R714[文献标识码]A[文章编号]1672-4062（2022）10（a ）-0082-04Clinical Effect and Inflammatory Factors Analysis of Different Doses of Cana⁃gliflozin Combined with Metformin in the Treatment of Type 2Diabetes Mel⁃litusHUANG YanxiaDepartment of Pharmacy,Linqing Hospital of Traditional Chinese Medicine,Liaocheng,Shandong Province,252600China[Abstract ]Objective To analyze the effect of metformin combined with different doses canagliflozin in the treatment of type 2diabetes mellitus.Methods The data of 90patients with type 2diabetes admitted to Linqing Hospital of Tra‐ditional Chinese Medicine from January 2020to January 2022were selected.as the research subjets According to the random number table,the patients were divided into two groups,the control group was given metformin combined withhigh-dose (300mg)canagliflozin,and the study group was given metformin combined with low-dose (100mg)cana‐gliflozin.The blood glucose,inflammatory factors and safety of the two groups were analyzed.Results After treatment,blood glucose indexes in both groups were significantly decreased,and the difference was statistically significant (P <0.05).Compared with the control group,the fasting blood glucose (5.37±0.86)mmol/L,the 2h postprandial blood glucose (7.28±0.78)mmol/L and the glycosylated hemoglobin (6.97±0.82)%of the study group had no statistical significance(P >0.05).Inflammatory factors were significantly decreased in both groups,and the difference was statistically signifi‐cant (P <0.05).Compared with the control group (6.06±1.31)pg/mL and (4.05±0.62)mg/L,the inflammatory factors such as IL-6(6.13±1.25)pg/mL and CRP (3.98±0.56)mg/L of the study group were no significal difference (P >0.05).The incidence of adverse reactions such as gastrointestinal reactions and hypoglycemia in the study group was 4.44%lower than 17.78%in the control group,and the difference was statistically significant (P <0.05).Conclusion Metfor‐DOI ：10.16658/ki.1672-4062.2022.19.082[作者简介]黄艳霞（1976-），女，本科，副主任药师，研究方向为药学。