布地奈德药学特性解析专家讲座.pptx

,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,Prof.Bian RuLian,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,Klicka hr fr att ndra format p bakgrundstexten,Niv tv,Niv tre,Niv fyra,Niv fem,Klicka hr fr att ndra format p bakgrundsrubriken,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Klicka hr fr att ndra format p bakgrundsrubriken,Klicka hr fr att ndra format p bakgrundstexten,Niv tv,Niv tre,Niv fyra,Niv fem,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,SRD-2010-O-08-0283(A),单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,Prof.Bian RuLian,*,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,*,Prof.Bian RuLian,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,Prof.Bian RuLian,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,Prof.Bian RuLian,*,布地奈德药学特征解析,布地奈德药学特性解析,第1页,F,O,HO,C=O,SCH,2,F,OCOC,2,H,5,CH,3,F,丙酸氟替卡松,(,FP),布地奈德,(,BUD),糠酸莫米他松,(,MF),CL,O,HO,C=O,cl,O,CH,3,C,O,CL,O,HO,C=O,CH,2,OCOC,2,H,5,OCOC,2,H,5,CH,3,H,二丙酸倍氯米松,(,BDP),O,HO,C=O,CH,2,OCOC,2,H,5,OCOC,2,H,5,CH,3,几个吸入性糖皮质激素化学结构,C21,位,游离羟基,O,HO,C=O,CH,2,OH,O,O,H,C,H,C,3,H,7,布地奈德药学特性解析,第2页,常见,ICS,药学特征比较,特征 莫米他松,BUD FP DEX,受体亲和力 高,(18),中,(9.4),高,(18)1,气道滞留率 高,最高 高 低,水溶性(,mg/L),极,低,(8h ND,Hgger and Rohdewald,Rev Contemp Pharm 1998 and Miller-Larsson,布地奈德药学特性解析,第3页,ICS,起效速度,布地奈德药学特性解析,第4页,水溶性对,ICS,起效影响,布地奈德药学特性解析,第5页,COPD:Sputum Clearance of Budesonide and Fluticasone,fluticasone,budesonide,Harrison,布地奈德药学特性解析,第6页,Engel T,et al(1991),A single dose of budesonide causes a rapid improvement in FEV,1,55,60,65,70,75,0,1,2,3,4,5,6,7,8,9,Budesonide 1600,g,Placebo,Time(hours),p=0.001 for area under the curve,FEV,1,(%predicted normal),P0.05,布地奈德药学特性解析,第7页,ICS,起效时间比较,布地奈德3小时,丙酸氟替卡松12小时,二丙酸倍氯米松3天内,莫米他松7小时,Reichmuth D Drugs Today;37:300,布地奈德药学特性解析,第8页,糖皮质激素二种作用机制,经典机制,基因组机制,(,genomic mechanism),胞内受体,intracellular glucocorticoid receptor,iGR,非经典机制,非基因组机制,(,non-genomic mechanism),膜受体介导特异性作用(,mGR),布地奈德药学特性解析,第9页,两种,GR,受体比较,Powell,et al.1999 Endocrine,iGR mGR,定 位,胞浆 细胞膜,分子量,70-97,kD 97-150 kD,数 量,75-90%,10-25%,解离常数,*19.5,nM 239 nM,*,Scatchard,分析,地塞米松,分 布,成熟细胞 未成熟细胞,布地奈德药学特性解析,第10页,ICS,快速收缩气道血管作用机制,Sympathetic neuronal cell,Vascular smooth muscle cell,Norepinephrine,Extraneuronal uptake(metabolism),EMT,1,-adrenoreceptor,Corticosteroids,Neuronal uptake(re-use),布地奈德药学特性解析,第11页,提醒,加大剂量,有利于,ICS,经过非经典路径快速起效,布地奈德药学特性解析,第12页,Volovitz B,et al,Effectiveness and safety of inhaled corticosteroids in controlling acute,asthma attacks in children who were treated in the emergency department:A controlled,comparative study with oral prednisolone.J Allergy Clin Immunol 1998,102:605-9,0,3,1,时间,(,小时,),总体肺指数,6,9,12,3,2,4,5,强松,2 mg/kg,布地奈德,1600 g,布地奈德吸入在急性哮喘患者快速起效,一项纳入,22,例中重度哮喘儿童意在观察给予布地奈德和强松后其最大呼气流速和非指数改变来了解二者有效性和安全性双盲、对照研究：,pulmonary index,All children received SABA,布地奈德药学特性解析,第13页,ICS,作用强度,布地奈德药学特性解析,第14页,各种,ICS,内在活性（,Emax,）,相同，实际作用,强度,取决于：,与糖皮质激素受体亲和力,靶组织,药品暴露量,肺沉积率,滞留时间,一个事实：,布地奈德药学特性解析,第15页,不一样装置不一样微粒输出量,0,10,20,30,40,50,60,设定剂量%,细微粒量(400,g,400,g,1000,g,500,g,GINA,布地奈德药学特性解析,第17页,100,80,60,40,20,0,-20,大鼠气管以同位素标识药品表面灌流后滞留时间比较,0 1 2 3 4 5 6 7 8,占原始水平,BUD,FP,BDP,氢化可松,灌流后时间,(,小时,),(Miller-Larsson et al.1994),布地奈德在气道粘膜滞留时间长,布地奈德药学特性解析,第18页,布地奈德独特酯化作用,脂酶,微粒体,ATP,辅酶,A,布地奈德-21脂肪酸酯 (无活性,),布地奈德,C=O,O,HO,O,CH,2,OH,O,C,H,C,3,H,7,=,C=O,O,HO,O,O,C,H,C,3,H,7,=,CH,2,O-C-(CH,2,),n,CH,3,=,O,Tunek,et al,.1997,布地奈德药学特性解析,第19页,气道,（%）,0,12,20,40,60,80,100,0,保留酯化反应,抑制酯化反应,24,时间（小时）,体循环,（%）,0,12,20,40,60,80,100,0,24,布地奈德在气道和体循环中滞留时间比较,T1/2 18h,T1/2=2.8h,布地奈德药学特性解析,第20页,布地奈德在体内不一样部位酯化差异,总药量,原型药品,酯化药品,3.1,0.7(23%),0.9(30%),4.7,2.1(45%),18,12(68%),2(12%),1.6,1.1(70%),1.6(33%),390,27(7%),315(81%),26,4(16%),18(72%),1.1,0.7(70%),1.1,肌肉注射 1,nmol/rat(250g),气管内滴注 1,nmol/rat(250g),气管,血浆,总药量,原型药品,酯化药品,布地奈德药学特性解析,第21页,布地奈德及其酯化物大鼠气道浓度时间过程,Magnus Jendbro,et al.Pharmacokinetics Of Budesonide And Its Major Ester Metabolite After,Inhalation And Intravenous Administration Of Budesonide In The Rat.Drug Metabolism And Disposition.29:769776,气道,BUD,酯,气道,BUD,肺,BUD,肺,BUD,酯,血浆,BUD,布地奈德药学特性解析,第22页,2,6,24,1,10,100,1000,10 000,Time(hours),气道粘膜浓度(,pmol/g),*,Petersen H,et al,(,),布地奈德,布地奈德酯,氟替卡松,个体测量值,*p0.001,布地奈德在人气道粘膜上滞留时间更长,布地奈德药学特性解析,第23页,10,-1,20,分钟,2,小时,6,小时,吸入后时间,10,组织内平均放射活性,(pmol/g/nmol),25.1%,7.1%,5.0%,I,布地奈德在气道中滞留时间更长,布地奈德,丙酸氟替卡松,倍氯米松,Ralph Brattsand,et al.Clin Thev:;25Suppl C:C28-C41.,布地奈德,vs.,丙酸氟替卡松和倍氯米松,：,P=0.002,布地奈德药学特性解析,第24页,哮喘患儿维持期气道炎症连续存在,哮喘急性发作,气道慢性炎症连续存在,布地奈德药学特性解析,第25页,影响,ICS,治疗作用和,ADR,原因,治疗作用,(,局部,),ADR(,吸收,),激素受体亲协力,(F),激素受体亲协力,(F),肺部沉积率,(B),首过代谢率,(F),气道滞留率,(B),血浆半衰期,(F),布地奈德药学特性解析,第26页,水 溶 性 去除率 表观分布 血浆 生物利用度,药品,(,m,g/ml,)(L/h),容积(,L),半衰期,*,(h),口服 吸入,BDP/BMP 0.1NN0.1/6.530,BUD14,841832.8,1128,氟替卡松 0.04,6981814.4,6,个月对患儿,HPAA,功效无显著影响,1.Zhan JY et al.Influence of Nebulized Corticosteroid on Hypothalamic-Pituitary-Adrenal Axis in Children with Asthma J Appl Clin Pediatr;24:1244-6,血清皮质醇（,nmol/L,）,24h,尿游离皮质醇与尿肌酐比值（,nmol/mmoL,）,各组间,P=,NS,各组间,P=,NS,一项回顾性研究，选取既往未使用过,ICS,治疗哮喘患儿，年纪为,3.710.20,岁,30,例作为对照组，选择已规律雾化吸入布地奈德超出,6,个月，起始剂量,1000g/d,逐步减量至,250g/d,或,500g/d,并维持该剂量最少,3,个月患儿,60,例，分为,BUD250,组（吸入,BUD250g,）年纪为,3.720.19,岁、,BUD500,组（吸入,BUD500g,）年纪为,3.960.18,岁，测定血清皮质醇和,24h,尿游离皮质醇与尿肌酐比值。,雾化吸入布地奈德对下丘脑,-,垂体,-,肾上腺轴,(HPAA),功效无显著影响,1,布地奈德药学特性解析,第29页,雾化吸入布地奈德,6,个月对患儿骨代谢无显著影响,一项为期,6,个月随机、双盲、平行研究，,96,例新诊疗哮喘患儿（平均年纪,11.53.3,岁）随机分为,4,组，布地奈德,400,组,(n=24),：,400ug/d,，布地奈德,800,组,(n=24),：,800ug/d,，布地奈德,800,联合,VitD,组,(n=24),：布地奈德,800ug/d+,维生素,D 500IU,，对照组,(n=24),：孟鲁司特依据年纪,5mg,或,10mg,口服，研究吸入糖皮质激素对骨代谢影响。,雾化吸入布地奈德对患儿骨生成指标：骨钙素,(OC),、碱性磷酸酶,(ALP),，骨吸收指标,:,型胶原交联,C,端肽,(sCTx),均无显著影响,1,1.Stelmach I,et al.Inhaled corticosteroids may have a beneficial effect on bone metabolism,in newly diagnosed asthmatic children.Pulmonary Pharmacology&Therapeutics 24()414-420,分组,骨代谢指标,平均差值,P,值,对照组,(n=24),vs,ICS400,组,(n=24),OC (ng/mL),2,P,0.05,ALP(U/L),3.9,P,0.05,sCTx(ng/mL),0.33,P,0.05,对照组,(n=24),Vs,ICS800,组,(n=24),OC (ng/mL),0.3,P,0.05,ALP(U/L),2,P,0.05,sCTx(ng/mL),0.11,P,0.05,对照组,(n=24),Vs,ICS800,联合,VitD,组,(n=24),OC (ng/mL),8,P,0.05,ALP(U/L),17,P,0.05,sCTx(ng/mL),0.067,P,0.05,布地奈德药学特性解析,第30页,Ensio Norjavaara,et al.,J Allergy Clin Immunol;111:736-42.,Normal pregnancy outcomes in apopulation-based study including 2968pregnant women exposed to budesonide,基于人群研究,2,968,名孕妇使用布地奈德未产生不良影响,布地奈德药学特性解析,第31页,怀孕早期使用布地奈德,1995-1998,年总新生儿,100000,10000,1000,10,1,20,30,35,40,45,50,55,60,男孩,100,65,发生率,出生身长,(cm),25,发生率,100000,10000,1000,100,10,女孩,30,1,出生身长,(cm),35,40,45,50,25,20,65,55,60,Ensio Norjavaara,et al.,J Allergy Clin Immunol;111:736-42.,怀孕早期服用布地奈德，不影响新生儿身长,数据来自瑞典医学出生登记中心：,1995-1998,年,293,948,名新生儿，其中,2,968,名母亲在妊娠早期服用布地奈德,50.8cm,50.2cm,布地奈德药学特性解析,第32页,100000,10000,1000,100,10,1,0,3000,出生体重,(g),1000,6000,4000,5000,7000,发生率,女孩,100000,10000,1000,100,10,1,出生体重,(g),0,5000,4000,3000,1000,6000,男孩,发生率,7000,Ensio Norjavaara,et al.,J Allergy Clin Immunol;111:736-42.,怀孕早期使用布地奈德，不影响新生儿体重,怀孕早期使用布地奈德,1995-1998,年总新生儿,3630g,3500g,布地奈德药学特性解析,第33页,妊娠期哮喘控制不佳会增加各种不良事件，包含早产、宫内发育迟缓、低体重、围产儿死亡和先兆子痫等；,指南强调了妊娠期哮喘控制主要性，并推荐,吸入性激素作为中重度哮喘孕妇一线治疗,；,布地奈德是唯一被,FDA,同意妊娠药品分级为,B,级吸入性激素,Ensio Norjavaara,et al.,J Allergy Clin Immunol;111:736-42.,研究背景,布地奈德药学特性解析,第34页,小 结,BUD,具,有,亲水性,，易在粘液水样层溶解，快速与粘膜接触，起效更快速,ICS,能够经过,非基因路径,产生快速有益作用,这种作用呈剂量依赖性,BUD,独特,酯化作用,，气道粘膜滞留时间长,BUD,分布容积小,半衰期短,长久用药安全性很好,布地奈德药学特性解析,第35页,谢,谢!,布地奈德药学特性解析,第36页,