Review of kappa antagonists
07章 阿片样镇痛药(Opioid Analgesics
葡糖醛酸苷化
HH N+
HO
O
OH
HH N+
HO
O
OH
Normorphine
H3C H N+
O COOH OH
HO
O
O HO
OH
Morphine-6-glucuronide
Morphine的结构修饰
H3C N
3-位羟基 6-位羟基
3-位羟基和 6-位羟基
7，8位双键，6位羟基，14-羟基
HO
O
OH
17位N-烃化
（Morphine and Related Opioid
Agonists）
一、阿片生物碱类
H3C N
HO
O
OH
天然的()-Morphine的结构特点
具有五个环稠合而成的复杂立体结构
B/C环呈顺式；C/D环呈反式；C/E环呈顺 式
含有5个手性中心（5R，6S，9R，13S， 14R）
在质子化状态ine的N-甲基用其它烷基、链烯烃 基或芳烃基取代，其中活性最强的为N-βPhenylethylmorphine（N-β-苯乙基吗 啡），镇痛作用约为Morphine的14倍；
N-甲基若被烯丙基取代，称为烯丙吗啡 （Nalorphine），为受体拮抗剂，
蒂巴因（Thebaine）为原料与甲基乙烯酮进行Diels-Alder 反应,生成化合物，其镇痛活性与Morphine相当.
1806年 阿片中分离出Morphine 1923年Gulland和 Robinson确定了Morphine的 化学结构1952年Gates 和Tschudi完成了化学全 合成工作
小剂量纳洛酮对氯胺酮抗抑郁作用的影响
小剂量纳洛酮对氯胺酮抗抑郁作用的影响摘要】目的：观察小剂量纳洛酮(naloxone，NL)对氯胺酮(ketamine，KT)抗抑郁作用的影响，为临床合理联合用药提供依据。
方法：60只小鼠随机分为5组：空白组（KB组）、模型组（MX组）、30mg?kg-1氯胺酮组（K组）、100ng?kg-1纳洛酮组（N组）、氯胺酮与低剂量纳洛酮合用组(K+N组)。
药物处理前1天除KB组外其余组小鼠强迫游泳(forced swimming test,FST)15min造模；24小时后各组分别腹腔注射给药，30min后，强迫游泳实验并记录其5min内不动的时间，测定后处死，采用高效液相色谱法分析海马谷氨酸（Glu）、γ-氨基丁酸（GABA）含量，计算Glu/GABA比值。
结果：与KB组相比，MX组强迫游泳实验不动的时间延长（P<0.01），海马组织Glu/GABA比值降低（P<0.01）；与MX组相比，K组、N组和K+N组强迫游泳实验不动的时间减少(P<0.05、P<0.05、P<0.01)，海马组织Glu/GABA比值升高（P<0.05、P<0.05、P<0.01）；与K组相比,K+N组强迫游泳实验不动的时间减少(P<0.05)，海马组织Glu/GABA比值升高（P<0.05）。
结论：小剂量纳洛酮(100ng?kg-1)能够增强氯胺酮(30mg?kg-1)的抗抑郁作用，且其机制与Glu/GABA升高有关。
【关键词】氯胺酮；纳洛酮；抑郁；强迫游泳；Glu；GABA【中图分类号】R749.05 【文献标识码】A 【文章编号】1007-8231（2016）22-0089-03抑郁症是一种常见的精神疾病，以出现普遍、持续的情绪低落以及对周围环境失去兴趣等主要症状为临床特征，并伴随睡眠、食欲、能量水平、精神运动功能和认知水平等方面的交替症状[1]。
有研究表明抑郁症的发生与Glu和GABA的变化有关[2]。
MyD88抑制乙型肝炎病毒复制依赖活化NF-κB信号通路
万方数据 万方数据 万方数据丝篁塑量壁鎏！Ｑ堕堡ｉ旦箜！鲞箜！塑』坐虫坐垡丛堡！虫望塑ｉ！些！鱼塑：也堡！塑！！ｙ堂！：盟！：；到显著抑制，而共转染ＲｃＣＭＶ．１ｎＢａ．ＳＲ细胞内ＨＢＶ复制中间体ＤＮＡ的水平得到上调（图２Ａ），检测细胞上清液中的ＨＢｅＡｇ和ＨＢｓＡｇ也得到了相同的结果（结果未在本文显示）。
免疫荧光结果也显示，单独表达ＭｙＤ８８可明显抑制ＨＢＶｃｏｒｅ蛋白的合成；而ｋＢａ—ＳＲ与ＭｙＤ８８共表达后ｃｏｒｅ蛋白在细胞中的表达量可显著增加（图２Ｂ）。
以上结果说明，ＮＦ．ｓ：Ｂ活化被阻断后ＭｙＤ８８抑制ＨＢＶ复制的效应也得到抑制，进一步提示ＭｙＤ８８抑制ＨＢＶ复制中的作用依赖于ＮＦ—ｘＢ信号通路的活化。
Ａ畿∞￡确Ｓ《蠢６。
螂㈨ｊ．芒羞４．００Ｅ＋０３￡８蚕２．００Ｅ＋０３ｐｅｍｖ３Ｊ（ｏａｔｏＭ归∞（ｏ．４ｔ，Ｏ脑轴Ｒ蝴髑堆哼ｗ蝌稍《卜Ｄ螃Ｅ乒毛吐（０．憾ｌｑＯ＋Ｂｏ－０２图２阻断ＮＦ－ｒ。
Ｂ信号通路对ｎｙＩ粥８抑制ＨＢＶ效应的影响ｒｉｇ２．ＢｌｏｃｋａｇｅｏｆＮＦ－ｒ。
ＢａｃｔｉｖａｔｉｏｎａｂｏｌｉｓｈｅｓＭｙＤ６８ｍｅｄｉａｔｅｄｓｕｐｐｒｅｓｓｉｏｎｏｆＨＢＶＡ：ＢｌｏｃｋａｇｅｏｆＮＦ—ＫＢａｃｔｉｖａｔｉｏｎａｂｏｌｉｓｈｅｓＭｙＤ８８ｍｅｄｉａｔｅｄｓｕｐｐｒｅｓｓｉｏｎｏｆｐａｒｔｉｃｌｅ—ａｓｓｏｃｉａｔｅｄＨＢＶｒｅｐｌｉｃａｔｉｖｅｉｎｔｅｒｍｅｄｉａｔｅＤＮＡ．Ｂ：ＢｌｏｃｋａｇｅｏｆＮＦ－·ｃＢａｃｔｉｖａｔｉｏｎａｂｏｌｉｓｈｅｓＭｙＤ８８ｍｅｄｉａｔｅｄｓｕｐｐｒｅｓｓｉｏｎｏｆｐｒｏｔｅｉｎ．３．活化ＮＦ．ｓ：Ｂ信号通路可抑制ＨＢＶ的复制和表达为进一步探讨单独活化ＮＦ．ｔｃＢ信号通路对ＨＢＶ复制的影响，将ＨＢＶ的复制型质粒ｐＨＢＶ３．８与空载或不同剂量的ＮＦ．ｆｃＢ激活剂ｐＲｃ—Ｇ．ａｃｔｉｎ．３ＨＡ．ＩⅪ血／ＩＫ邸共转染Ｈｕｈ７细胞，检测上清液中ＨＢｓＡｇ和ＨＢｅＡｇ的表达水平以及细胞内ＨＢＶ复制中问体ＤＮＡ的水平。
A review of the species of protozoan epibionts on crustaceans-11
A REVIEW OF THE SPECIES OF PROTOZOAN EPIBIONTS ONCRUSTACEANS.I.PERITRICH CILIATESBYGREGORIO FERNANDEZ-LEBORANS and MARIA LUISA TATO-PORTODepartamento de Biologia Animal I(Zoologia),Facultad de Biologia,Pnta9a,Universidad Complutense,E-28040Madrid,SpainABSTRACTAn updated inventory of the peritrich(Protozoa,Ciliophora)epibiont species on crustaceans has been carried out.Data concerning268epibiont species,their taxonomic position,and the various crustacean basibionts were considered.The overview comprised in this study may be of use in further surveys of protozoan-crustacean epibiosis.RESUMENSe ha realizado un inventario actualizado de las especies de peritricos(Protozoa,Ciliophora) epibiontes en crustáceos.Se han considerado los datos concernientes a268especies epibiontes,su posición taxonómica,y los diferentes crustáceos visión general que comprende este estudio puede ser utilizada en futuras investigaciones sobre la epibiosis protozoos-crustáceos.INTRODUCTIONEpibiosis is a facultative association of two organisms:the epibiont and the basibiont(Wahl,1989).The term“epibiont”includes organisms that,during the sessile phase of their life cycle,are attached to the surface of a living substratum, while the basibiont lodges and constitutes a support for the epibiont(Threlkeld et al.,1993).Both concepts describe ecological functions(Wahl,1989).Several crustacean groups,cladocerans,copepods,cirripedes,isopods,amphi-pods,and decapods,include forms that are hosts for macroepibiont invertebrates (Ross,1983),and for protozoan microepibionts of the phylum Ciliophora:apos-tomatids,chonotrichids,suctorians,peritrichs,and heterotrichs(Corliss,1979; Small&Lynn,1985).The study of ciliate epibionts on crustaceans began in the last century.Bütschli(1887-89)made a compilation from former publications.After-wards,other authors(Keiser,1921;Kahl,1934,1935;Precht,1935;Raabe,1947; c®Koninklijke Brill NV,Leiden,2000Crustaceana73(6):643-683644G.FERNANDEZ-LEBORANS&M.L.TATO-PORTONenninger,1948)not only described epibiont species,but proposed explanations for the processes of epibiosis.A review of the protozoan epibionts found on de-capod crustaceans was carried out by Sprague&Couch(1971).Green(1974), in a study of the epibionts living on cladocerans,pays considerable attention to protozoan species.Ho&Perkins(1985)have focused on the epibionts found on copepods.In other contemporary and also earlier works,the following aspects have been taken into account:(1)speci city between ciliates and their crustacean basi-bionts(Evans et al.,1981;Batisse,1986,1992;Clamp,1991);(2)the morpholog-ical and physiological adaptations of the epibionts(D’Eliscu,1975;Batisse,1986, 1994;Fenchel,1987;Clamp,1991;Lom&De Puytorac,1994);(3)the effects pro-duced by the epibionts on the crustaceans(Herman et al.,1971;Turner et al.,1979; Kankaala&Eloranta,1987;Nagasawa,1988);(4)the possible use of epibionts for the assessment of water quality(Antipa,1977;Henebry&Ridgeway,1979;Scott &Thune,1986);(5)the implications of protozoan epibionts on cultures of vari-ous species of crustaceans(Overstreet,1973;Johnson,1977,1978;Lightner,1977, 1988;Couch,1978;Scott&Thune,1986;V ogelbein&Thune,1988;Camacho& Chinchilla,1989);and(6)the organization of the epibiont communities on plank-tonic crustaceans(Threlkeld et al.,1993).Despite the fact that there is a considerable amount of information about the protozoan epibionts on crustaceans,since the works of Sprague&Couch(1971), Green(1974),and Ho&Perkins(1985),which relate to speci c crustacean groups, no further general reviews have appeared.Several new species of protozoan ciliate epibionts have recently been described(Dovgal,1985;Batisse,1992;Fernandez-Leborans&Gomez del Arco,1996;Zhadan&Mikrjukov,1996;Fernandez-Leborans et al.,1996,1997),and some of these are peritrich ciliates(Matthes& Guhl,1973;Bierhof&Roos,1977;Jankowski,1986;Dale&Blom,1987;Clamp, 1990,1991;Threlkeld&Willey,1993;Hudson&Lester,1994;Stoukal&Matis, 1994;Foissner,1996).The purpose of this work is to provide an up-to-date review of the peritrich ciliates living as epibionts on crustaceans:268species have been considered in this compilation,which may contribute data for studies of epibiosis in crustaceans.CRUSTACEAN PROTOZOAN EPIBIONTS,I.PERITRICH CILIATES645RESULTS1)Phylum CILIOPHORA Do ein,1901Class OLIGOHYMENOPHOREA De Puytorac,Batisse,Bohatier,Corliss, Deroux,Didier,Dragesco,Fryd-Versavel,Grain,Grolière,Hovasse,Iftode,Laval,Roque,Savoie&Tuffrau,1974Subclass P ERITRICHIA Calkins,1933Order S ESSILIDA Kahl,1933Family Epistylididae Kahl,1935Genus Rhabdostyla Kent,1880( g.1)R.bosminae Levander,1907.On the cladoceran Bosmina sp.R.conipes Kahl,1935.On the cladoceran Daphnia sp.Fresh water.On the cladocerans Daphnia magna,D.longispina and Scapholeberis mucronata (cf.Green,1957,1974).R.cyclopis Kahl,1935.On the copepod Cyclops sp.Fresh water.R.cylindrica Stiller,1935.On the cladoceran Leptodora ke Balaton (Hungary).On the cladoceran Leptodora kindtii.Denmark(Green,1974).R.hungarica Stiller,1931.On the cladoceran Leptodora ke Balaton (Hungary).R.globularis Stokes,1890.On the cladoceran Bosmina longirostris and on Diaphanosoma brachyurum.Germany(Nenninger,1948).R.invaginata Stokes,1886.On the ostracod Cypris sp.R.sessilis Penard,1922.On the copepod Cyclops sp.Fresh water.R.pyriformis Perty,1852(cf.Kahl,1935;on Entomostraca).On the clado-ceran Daphnia longispina(cf.Nenninger,1948).On the cladoceran Daph-nia hyalina(cf.Sommer,1950).On Daphnia pulex and Ceriodaphnia reticu-lata(cf.Hamman,1952).On Daphnia magna,D.pulex,D.cucullata,Simo-cephalus vetulus,Ceriodaphnia reticulata,and Leptodora kindtii(cf.Green, 1953).On Daphnia magna(cf.Green,1955).On Daphnia magna andD.longispina(cf.Green,1957).On Daphnia atkinsoni,D.hyalina,D.lon-gispina,D.curvirostris,D.obtusa,Ceriodaphnia laticaudata,and C.pulchel-la(cf.Green,1974).R.vernalis Stokes,1887.On the copepod Eucyclops agilis(cf.Henebry& Ridgeway,1979).1)For authors and dates of species of Crustacea mentioned herein,see separate section,below.646G.FERNANDEZ-LEBORANS&M.L.TATO-PORTOFigs.1-2.1,Rhabdostyla(R.pyriformis,after Green,1957);2,Epistylis(E.gammari,after Precht,1935).Rhabdostyla sp.Bierhof&Roos,1977.Between the spines at the end of the telson on Gammarus tigrinus.Germany.Rhabdostyla sp.Weissman et al.,1993.On the copepod Acartia hudsonica. Genus Epistylis Ehrenberg,1832( g.2)E.anastatica(Linnaeus,1767)(cf.Kent,1881).Syn.:Vorticella anastatica L.,1767.On Entomostraca and freshwater plants.On cyclopoid copepods and Daphnia pulex(cf.Green,1974).E.astaci Nenninger,1948.Fresh water.On the gills of the decapod Astacusastacus(as A. uviatilis)(Germany).On A.leptodactylus(cf.Stiller,1971).On the gills of Austropotamobius torrentium(cf.Matthes&Guhl,1973).E.bimarginata Nenninger,1948.Fresh water.On the appendages of Astacusastacus(as A. uviatilis).Germany.E.branchiophila Perty,1852.Syn.:E.formosa Nenninger,1948.On theparasitic copepod Lernaea cyprinacea,in freshwater environments of South Africa(Van As&Viljoen,1984).E.breviramosa Stiller,1931.On the antennal lament of the cladoceran Daph-nia ke Balaton(Hungary).On the copepod Cyclops sp.,Czechoslovakia (Srámek-Husek,1948).On the cladocerans Bosmina longirostris and Alona af nis(cf.Green,1974).E.cambari Kellicott,1885.On the gills of the decapod Cambarus sp.(NE ofU.S.A.).On the maxillae of the cray sh Astacus leptodactylus(fresh water) (cf.Matthes&Guhl,1973).E.crassicollis Stein,1867.On freshwater Entomostraca and on the pleopodsand gills of cray sh.On the gills of Astacus astacus(as A. uviatilis),andCRUSTACEAN PROTOZOAN EPIBIONTS,I.PERITRICH CILIATES647 the maxillae,maxillipeds,and gills of A.leptodactylus,in Europe(Matthes& Guhl,1973).E.cyprinaceae Van As&Viljoen,1984.On the parasitic copepod Lernaea cyprinacea(fresh water,South Africa).E.daphniae Fauré-Fremiet,1905.On the cladoceran Daphnia sp.On Daphnia magna(cf.Nenninger,1948).On the copepod Boeckella triarticulata(New Zealand)(Xu&Burns,1990).On the cladoceran Moina macrocopa in an urban stream.E.diaptomi Fauré-Fremiet,1905.On the copepod Diaptomus sp.E.digitalis Ehrenberg,1838.On the copepod Cyclops sp.E.epibarnimiana Van As&Viljoen,1984.On the parasitic copepod Lernaea barnimiana(fresh water,South Africa).E.fugitans Kellicott,1887.On the cladoceran Sida crystallina.North America.E.gammari Precht,1935.On the antennae of the gammarid Gammarus sp. (Kiel channel).On the proximal part of the rst antenna and,less commonly, on the second antenna of Gammarus oceanicus and G.salinus.In the Baltic Sea and areas of Norway(Fenchel,1965).On the rst antenna of Gammarus tigrinus(cf.Stiller,1971).E.halophila Stiller,1942.On the cladocerans Daphnia longispina and D.pulex (Lake Cserepeser,Hungary).E.harpacticola Kahl,1933.On harpacticoid copepods in the Kiel channel. E.helenae Green,1957.On the cladocerans Daphnia pulex,D.magna,D.ob-tusa,D.longispina,D.curvirostris,Ceriodaphnia pulchella,C.reticulata, ticaudata,Moina macrocopa,M.micrura,Chydorus sphaericus,Simo-cephalus serrulatus,and S.vetulus(cf.Green,1957,1974).On Daphnia magna(cf.Nenninger,1948).On Ceriodaphnia reticulata and Simocephalus vetulus(cf.Matthes,1950).E.humilis Kellicott,1887.On the gammarid Gammarus sp.and other Ento-mostraca.custris Imhoff,1884.On the pelagic copepod Cyclops sp.On the buccal appendages of the branchiopod Lepidurus apus(freshwater areas near Vienna, Austria)(Foissner,1996).E.magna V an As&Viljoen,1984.On the parasitic copepod Lernaea cypri-nacea(fresh water,South Africa).E.niagarae Kellicott,1883.On the body surface of cray sh(Niagara River, U.S.A.).On the antennae and body of the European cray sh Astacus lep-todactylus,on Austropotamobius torrentium,and on Orconectes limosus(as Cambarus af nis)(cf.Matthes&Guhl,1973).On the surface of the copepod648G.FERNANDEZ-LEBORANS&M.L.TATO-PORTOEucyclops serrulatus,and on the cladocerans Daphnia pulex,D.rosea,Cerio-daphnia reticulata,and Scapholeberis mucronata(lakes of Colorado,U.S.A.) (Willey&Threlkeld,1993).E.nitocrae Precht,1935.On the third pereiopod of Gammarus tigrinus(cf.Bierhof&Roos,1977).E.nympharum Engelman,1862.On cladocerans(Nenninger,1948).On Cy-clops sp.(cf.Foissner&Schiffman,1974).On the branchiuran Dolops ra-narum(cf.Van As&Viljoen,1984).E.ovalis Biegel,1954.On the gnathopods of Gammarus tigrinus.On the thirdpereiopod of the gammarid Gammarus pulex,and on the spines at the end of the third uropod of Gammarus tigrinus(cf.Bierhof&Roos,1977).E.plicatilis Ehrenberg,1838.On the copepods Eucyclops agilis,Cyclopsvernalis,and C.bicuspidatus(Ashmore Lake,Illinois,U.S.A.)(Henebry& Ridgeway,1979).E.salina Stiller,1941.On the rst and second antennae,coxae,and gills of thegammarid Gammarus pulex(cf.Bierhof&Roos,1977).E.thienemanni Sommer,1951.On the gills of Gammarus tigrinus(cf.Bierhof&Roos,1977).E.zschokkei(Keiser,1921).Syn.:Opercularia zschokkei Keiser,1921.On thegnathopods of the gammarid Gammarus tigrinus and on other Entomostraca.On the cladoceran Acantholeberis curvirostris(cf.Nenninger,1948).Epistylis sp.Hutton,1964.On the decapod Penaeus duorarum(Florida,U.S.A.).Between the setae of the rst antenna of Gammarus tigrinus(cf.Bierhof& Roos,1977).Epistylis sp.Hutton,1964.On the decapod Ploeticus robustus(Daytona Beach, Florida,U.S.A.).Epistylis sp.Viljoen&Van As,1983.Two species on the thoracic appendages of a freshwater brachyuran,apparently erroneously identi ed as“Potamon sp.”(South Africa)[the genus Potamon does not occur in southern Africa].Epistylis sp.Pearse,1932.On the gills of the decapods Coenobita clypeatus, Geograpsus lividus,and Pachygrapsus transversus(Florida,U.S.A.).Epistylis sp.Hudson&Lester,1994.On the gills of the decapod Scylla serrata (Moreton Bay,Queensland,Australia).Epistylis sp.Turner et al.,1979.On the estuarine copepods Acartia tonsa andA.clausi(Escambia Bay,Florida,U.S.A.).Epistylis sp.Villarreal&Hutchings,1986.Fresh water.On the maxillipeds, pereiopods,and ventral portion of the abdomen of the decapod Cherax tenuimanus(Australia).CRUSTACEAN PROTOZOAN EPIBIONTS,I.PERITRICH CILIATES649 Family Lagenophryidae Bütschli,1889Genus Lagenophrys Stein,1852( g.3)L.aegleae Mouchet-Bennati,1932.Fresh water.On the branchial laments of the anomurans Aegla sp.,Aegla castro,and Aegla franca.Arroyo Miguelete, (Uruguay)and Parana River(Brazil).L.ampulla Stein,1851.Fresh water.On the gills of species of the genus Gammarus.L.andos(Jankowski,1986)(cf.Clamp,1991).Syn.:Circolagenophrys andos Jankowski,1986.Fresh water.On the decapod Parastacus chilensis(Chile).L.anticthos Clamp,1988.Fresh water.On the branchial laments of the decapods Parastacus pugnax,P.defossus,and P.saffordi(Chile,Brazil, Uruguay).L.aselli Plate,1886.On the branchial surface of the isopod Asellus aquaticus (Hamburg,Germany).L.awerinzewi Abonyi,1928.On the gills of the decapod Potamon uviatilis(as Telphusa uviatilis)(Africa).L.bipartita Stokes,1890.On the cladoceran Daphnia sp.(fresh water,U.S.A.).L.branchiarum Nie&Ho,1943.Fresh water.On the gills of the caridean shrimp Macrobrachium nipponense(as Palaemon nipponense)(Japan).L.callinectes Couch,1967.Marine and in estuaries.On the gills of the decapods Callinectes sapidus,C.bocourti,and C.maracaiboensis(Chesapeake Bay, Maryland,Virginia,and Gulf of Mexico).mensalis Swarczewsky,1930.Fresh water.On gammarids(Lake Baikal).L.darwini Kane,1965.On the branchial laments of the decapod Cherax quadricarinatus(stream near Darwin,Australia).L.dennisi Clamp,1987.Fresh water.On the decapods Orconectes illinoiensis, Cambarus bartonii bartonii,and C.chasmodactylus(North America).L.deserti Kane,1965.Fresh water.On the gills of the decapods Cherax tenuimanus and C.quinquecarinatus(SW rivers,Australia).L.diogenes(Jankowski,1986).Syns.:Circolagenophrys diogenes Jankowski, 1986,Lagenophrys incompta Clamp,1987.Fresh water.On the gills of the decapods Orconectes illinoiensis and Cambarus diogenes(Illinois,U.S.A.).L.discoidea Kellicott,1887(cf.Clamp,1990).Syns.:Lagenophrys labiata Wallengren,1900(a junior homonym of biata Stokes,1887(cf.Clamp, 1990));L.wallengreni Abonyi,1928;Circolagenophrys entocytheris Jankow-ski,1986.Fresh water.On ostracods.On the cray sh Cambarus sp.,C.chas-modactylus,C.bartonii bartonii,and Orconectes illinoiensis(Ontario,Canada and U.S.A.).650G.FERNANDEZ-LEBORANS&M.L.TATO-PORTOFigs.3-7.3,Lagenophrys(L.eupagurus,after Clamp,1989);4,Clistolagenophrys(C.primitiva, after Swarczewsky,1930);5,Setonophrys(munis,after Clamp,1991);6,Operculigera (O.asymmetrica,after Clamp,1991);7,Usconophrys(U.aperta,after Clamp,1991).L.dungogi Kane,1965.On the branchial laments of the decapod Euastacus sp.(stream near Dungog,Australia).L.engaei Kane,1965.On the branchial laments,basal areas of the gills, branchiostegite membrane and,more rarely,on the pleopods of the decapods Engaeus victoriensis and Austroastacus hemicirratulus(Victoria,Tasmania, and Melbourne,Australia).L.eupagurus Kellicott,1893(cf.Clamp,1989).Syns.:Lagenophrys lunatus Imamura,1940;Lagenophrys articularis Nie&Ho,1943.Marine,in estu-arine areas and fresh water.On the decapods Litopenaeus setiferus(as Pe-CRUSTACEAN PROTOZOAN EPIBIONTS,I.PERITRICH CILIATES651 naeus s.)(Penaeidea,Penaeidae),on the surface of the body,Litopenaeus van-namei(as Penaeus v.),on the surface of the body,Macrobrachium nipponense (Caridea,Palaemonidae)on antennae and pleopods,Macrobrachium ohione, on the surface of the middle of the pleura,Macrobrachium rosenbergii,on the gills,Palaemon paucidens(Caridea,Palaemonidae),Palaemonetes inter-medius(Caridea,Palaemonidae),Palaemonetes kadiakensis,Palaemonetes paludosus,Palaemonetes pugio,Palaemonetes varians,on the whole body, except on the gills,Palaemonetes vulgaris,Upogebia af nis(Thalassinidea, Upogebiidae),and Pagurus longicarpus(Anomura,Paguridae),on the gills (U.S.A.,Japan,Venezuela,Thailand).L.foxi Clamp,1987.Fresh water.On the gills of the gammarids Gammarus pseudolimnaeus,G.troglophilus,G.minus,and Gammarus sp.(Missouri, U.S.A.).L.in ata Swarczewsky,1930.On the distal areas of pleopods of the gammarid Gmelinoides fasciata(Lake Baikal).L.jacobi(Kane,1969).Syn.:Stylohedra jacobi Kane,1969.On freshwater decapods in Australia.L.johnsoni Clamp,1990.Syn.:Lagenophrys labiata Stokes,1887(partim). Fresh water.On the appendages and the surface of the carapace of the gammarids Gammarus fasciatus,G.daiberi,G.tigrinus,and Crangonyx gracilis(New Jersey,Michigan,and North Carolina,U.S.A.).biata Stokes,1887(cf.Clamp,1990).Fresh water.On the appendages and on the surface of the carapace of the gammarids Gammarus fasciatus, G.daiberi,G.tigrinus,and Cangronyx gracilis(New Jersey,Michigan,and North Carolina,U.S.A.).L.leniusculus(Jankowski,1986).Syns.:Circolagenophrys leniusculus Jan-kowski,1986;L.oregonensis Clamp,1987.Fresh water.On the carapace, gills,ventral surface of the abdomen,uropods,pereiopods,and pleopods of the decapod Pacifastacus leniusculus leniusculus,and on the gills of P.leniusculus trowbridgii and P.connectens(North America).L.lenticula(Kellicott,1885)(cf.Clamp,1991).Syns.:Stylohedra lenticula Kellicott,1885;S.lenticulata Kahl,1935;Lagenophrys lenticulata(Kahl, 1935)(cf.Thomsen,1945).Fresh water.Setae of the sixth and seventh pereiopods of the gammarids Hyalella azteca and H.curvispina(U.S.A., Canada,Mexico,and Uruguay).L.limnoria Clamp,1988.Syn.:Circolagenophrys circularis Jankowski,1986 (cf.Clamp,1991).On the isopod Limnoria lignorum.L.macrostoma Swarczewsky,1930.Fresh water.On gammarids(Lake Baikal). L.matthesi Schödel,1983.On the maxillipeds of the gammarids Gammarus pulex and Carinogammarus roeselii.652G.FERNANDEZ-LEBORANS&M.L.TATO-PORTOL.metopauliadis Corliss&Brough,1965.Fresh water.On the gills of the brachyuran Metopaulias depressus(endemic on Jamaica).L.monolistrae Stammer,1935.On the pleopods of the isopod Monolistra sp.L.nassa Stein,1852.Fresh water.On the pleopods of the gammarid Gammarus pulex.L.oblonga Swarczewsky,1930.On the antennae of the gammarid Gammarus hyacinthinus(Lake Baikal).L.orchestiae Abonyi,1928.On the amphipod Orchestia cavimana(Lake Balaton,Hungary).L.ornata Swarczewsky,1930.Fresh water.On ke Baikal.L.ovalis Swarczewsky,1930.Fresh water.On the thoracic appendages of ke Baikal.L.parva Swarczewsky,1930.On ke Baikal.L.patina Stokes,1887(cf.Clamp,1990).Syn.:Lagenophrys labiata Stokes, 1887(cf.Shomay,1955).(Corliss&Brough,1965;Clamp,1973).Fresh water.On the pereiopods and gills of the gammarids Gammarus sp.and Hyalella azteca.American continent.L.rugosa Kane,1965.Fresh water.On the gills of the decapod Geocharax falcata(Victoria,Australia).L.similis Swarczewsky,1930.On ke Baikal.L.simplex Swarczewsky,1930.On ke Baikal.L.solida Swarczewsky,1930.On ke Baikal.L.stammeri Lust,1950.On ostracods.Germany.(Lust,1950a).L.stokesi Swarczewsky,1930.On ke Baikal.L.stygia Clamp,1990.Syn.:Lagenophrys labiata Stokes,1887(cf.Jakschik, 1967).Subterranean water.On the gills of the cave-dwelling amphipod Bactrurus mucronatus(Illinois,U.S.A.).L.tattersalli Willis,1942.On European copepods.L.turneri Kane,1969.On freshwater decapods in Australia.L.vaginicola Stein,1852.Syn.:Lagenophrys obovata Stokes,1887.On the genital setae and thoracopods of the copepods Cyclops miniatus and Cantho-camptus sp.L.verecunda Felgenhauer,1982.On the decapod Palaemonetes kadiakensis (Illinois,U.S.A.).L.willisi Kane,1965.Fresh water.On the gills of the decapods Cherax destructor,C.albidus,and C.rotundus(Melbourne,New South Wales(e.g., Newcastle),and NW Australia).Genus Clistolagenophrys Clamp,1991( g.4)C.primitiva(Swarczewsky,1930)(cf.Clamp,1991).Syn.:Lagenophrys primi-tiva Swarczewsky,1930.On pereiopods and pleopods of the gammarid Pallasea cancellus(Lake Baikal).Genus Setonophrys Jankowski,1986(cf.Clamp,1991)( g.5)S.bispinosa(Kane,1965)(cf.Clamp,1991).Syn.:Lagenophrys bispinosa Kane,1965.On pereiopods of the decapod Cherax rotundus setosus.Stream near Newcastle(N.S.W.,Australia).munis(Kane,1965)(cf.Clamp,1991).Syn.:Lagenophrys communis Kane,1965.On the body surface(telson,pleopods,pereiopods,carapace...) of the decapod Cherax destructor.On the gills of the decapods C.rotundus,C.albidus,C.quadricarinatus,Euastacus armatus,and Engaeus marmoratus(Victoria,Melbourne,and Tasmania,Australia).S.lingulata(Kane,1965)(cf.Clamp,1991).Syn.:Lagenophrys lingulata Kane,1965.On the branchial laments and branchiostegite membrane of the decapods Cherax destructor, C.albidus,and C.rotundus(Victoria, Melbourne,and coastal and central areas of Australia).S.nivalis(Kane,1969)(cf.Clamp,1991).Syn.:Lagenophrys nivalis Kane, 1969.On freshwater decapods in Australia.S.occlusa(Kane,1965)(cf.Clamp,1991).Syn.:Lagenophrys occlusa Kane, 1965.On the anterior zone of the branchial cavity of the decapods Cherax destructor,C.albidus,and C.rotundus(Victoria and New South Wales, Australia).S.seticola(Kane,1965)(cf.Clamp,1991).Syn.:Lagenophrys seticola Kane, 1965.On the setae of the decapods Engaeus fultoni and Geocharax falcata (Victoria,Melbourne,and Templestowe,Australia).S.spinosa(Kane,1965)(cf.Clamp,1991).Syn.:Lagenophrys spinosa Kane, 1965.On the pleopods,carapace,and telson of the decapod Cherax destructor (Victoria,Melbourne,and Heathcote,Australia).S.tricorniculata Clamp,1991.On the pleopods of the decapod Geocharax falcata(Victoria,Grampian Mountains,and Wannon River,Australia). Genus Operculigera Kane,1969( g.6)O.asymmetrica Clamp,1991.On the base of the gills of the freshwater decapods Parastacus pugnax and Samastacus spinifrons(Concepción and Talcahuano,Chile).O.insolita Clamp,1991.On the base of the gills of the freshwater decapod Parastacus pugnax(Concepción,Talcahuano,Malleco,and Puren,Chile).O.montanea Kane,1969.On the freshwater decapod Colubotelson sp.(Aus-tralia).O.obstipa Clamp,1991.Pleopods of the isopod Metaphreatoicus australis (New South Wales,Australia).O.parastacis Jankowski,1986.On the base of the gills of the decapod Parastacus nicoleti(Isla Teja,Valdivia,Chile).O.seticola Clamp,1991.On the setae at the base of gills of the decapod Parastacus pugnax(Concepción,Chile).O.striata Jankowski,1986.On the decapod Parastacus chilensis.Chile.O.taura Clamp,1991.On the branchial laments of the freshwater decapod Parastacus pugnax(Concepción,Malleco,and Puren,Chile).O.velata Jankowski,1986.On the gills of the anomuran Aegla laevis.Chile.O.zeenahensis Kane,1969.On freshwater decapods in Australia.Family Usconophryidae Clamp,1991Genus Usconophrys Jankowski,1985(cf.Clamp,1991)( g.7)U.aperta(Plate,1889)(cf.Clamp,1991).Syns.:Lagenophrys aperta Plate, 1889;Usconophrys dauricus Jankowski,1986.On the gills and pleopods of the isopod Asellus aquaticus(Marburg and Hessen,Germany;North Carolina, U.S.A.;Brittany,Finisterre,Plougarneau,Pont-Menou,and Douron River, France).U.rotunda(Precht,1935)(cf.Clamp,1991).Syn.:Lagenophrys rotunda Precht,1935.On ostracods.Germany.Family Operculariidae Fauré-Fremiet,1979(in Corliss,1979)Genus Opercularia Stein,1854( g.8)O.allensi Stokes,1887.Syn.:O.ramosa Stokes,1887.On several living and inert substrata.On the body of the cray sh Astacus leptodactylus(cf.Matthes &Guhl,1973).O.asellicola Kahl,1935.On the isopod Asellus sp.Germany.O.coarctata Claparède&Lachmann,1858.On crabs(Buck,1961).O.crustaceorum Biegel,1954.On the gills of the cray sh Astacus astacus(asA. uviatilis).On the maxillae,maxillipeds,and pleopods of Austropotamo-bius torrentium(cf.Matthes&Guhl,1973).O.cylindrata Wrzesniowski,1807.On the copepod Cyclops sp.O.gammari Fauré-Fremiet,1905.Pereiopods of the gammarid amphipod Gammarus sp.O.lichtensteini Stein,1868.On various crabs and molluscs.O.nutans Ehrenberg,1838.Syn.:O.microstoma Stein,1854.On Entomostraca.On the cladoceran Alona af nis(cf.Matthes,1950).On the maxillipeds of the European cray sh Astacus leptodactylus(cf.Matthes&Guhl,1973).O.protecta Penard,1922.On the setae of pereiopods of the gammarid amphi-pod Gammarus pulex.O.reichelei Matthes&Guhl,1973.Found exclusively on the maxillipeds of the cray sh Astacus leptodactylus.O.stenostoma Stein,1868.On the isopod Asellus aquaticus.Genus Orbopercularia Lust,1950(cf.Lust,1950b)( g.9)O.astacicola(Matthes,1950)(cf.Matthes&Guhl,1973).Syn.:Opercularia astacicola Matthes,1950.Maxillipeds and pleopods of the cray sh Aus-tropotamobius torrentium.Genus Propyxidium Corliss,1979( g.10)P.aselli Penard,1922.On the isopod Asellus sp.P.asymmetrica Matthes&Guhl,1973.On the European cray sh Astacus astacus(as A. uviatilis).P.bosminae Kahl,1935.On the cladoceran Bosmina sp.P.canthocampti Penard,1922.On the pereiopods of the harpacticoid copepod Canthocamptus sp.Fresh water.P.cothurnioide Kent,1880.On the ostracod Cypris sp.P.hebes Kellicott,1888.On the pereiopods of the isopod Asellus aquaticus.P.henneguyi(Fauré-Fremiet,1905)(cf.Kahl,1935).Syn.:Opercularia hen-neguyi Fauré-Fremiet,1905.On the rst abdominal segment of the copepod Cyclops sp.Genus Ballodora Dogiel&Furssenko,1921( g.11)B.dimorpha Dogiel&Furssenko,1921.On Porcellio sp.and other terrestrialisopods.Genus Nuechterleinella Matthes,1990( g.12)N.corneliae Matthes,1990.On the ostracod Cypria ophthalmica.Genus Bezedniella Stoukal&Matis,1994( g.13)B.prima Stoukal&Matis,1994.Fresh water.On the ostracod Cypria sp.(Slovakia).Figs.8-14.8,Opercularia(O.nutans,after Foissner et al.,1992);9,Orbopercularia(O.astacicola, after Matthes&Guhl,1973);10,Propyxidium(P.canthocampti,after Penard,1922);11,Ballodora (B.dimorpha,after Dogiel&Furssenko,1921);12,Nuechterleinella(N.corneliae,after Matthes, 1990);13,Bezedniella(B.prima,after Stoukal&Matis,1994);14,Rovinjella(R.spheromae,afterMatthes,1972).Family Rovinjellidae Matthes,1972Genus Rovinjella Matthes,1972( g.14)R.spheromae Matthes,1972.On the marine isopod Sphaeroma serratum. Family Scyphidiidae Kahl,1933Genus Scyphidia Dujardin,1841( g.15)Scyphidia sp.Henebry&Ridgeway,1979.On the cladocerans Scapholeberis kingi,Alona costata,and Pleuroxus denticulatus(Ashmore Lake,Illinois, U.S.A.).Family Vaginicolidae De Fromentel,1874Genus Platycola Kent,1881( g.16)P.baikalica(Swarczewsky,1930).Syn.:Vaginicola baicalica Swarczewsky, 1930.Fresh water.On the gills of the gammarids Brandtia lata,Pallasea grubei,and Echinogammarus fuscus(Lake Baikal).P.callistoma Hadzi,1940.Fresh water.On the cave-dwelling isopod Microlis-tra spinosissima(former Yugoslavia).P.circularis Dons,1940.Marine.On the uropods of the isopod Limnoria sp.P.decumbens(Ehrenberg,1830).Syns.:Vaginicola decumbens Ehrenberg, 1830;Platycola ampulla De Fromentel,1874;P.regularis De Fromentel, 1874;P.striata De Fromentel,1874;P.truncata De Fromentel,1874;P.longicollis Kent,1882;P.intermedia Kahl,1935;P.re exa Kahl,1935;P.amphora Swarcezwsky,1930;P.amphoroides Sommer,1951.Fresh water.On several vegetable and animal substrata.On the gills of the gammarid Brachiuropus sp.(Lake Baikal)(Swarczewsky,1930).geniformis Hadzi,1940.Fresh water.On the cave-dwelling isopod Micro-listra spinosissima(former Yugoslavia).P.pala Swarczewsky,1930.Syn.:Vaginicola pala Swarczewsky,1930.On the gills of the gammarid Palicarinus puzyllii(as Parapallesa pazill)(Lake Baikal).Genus Cothurnia Ehrenberg,1831(cf.Claparède&Lachmann,1858)( g.17)C.angusta Kahl,1933.Brackish or fresh water.On ostracods(Kiel,Germany).C.anomala Stiller,1951.Fresh water.On the amphipod Corophium curvispi-num(Lake Balaton,Hungary).C.antarctica(Daday,1911)(cf.Warren&Paynter,1991).Syn.:Cothurniopsisantarctica Daday,1911.Marine.Epibiont on the ostracod Philomedes lae-vipes(Antarctic areas).C.astaci Stein,1854.Fresh water.On the pleopods and gills of cray sh.On the maxillae,maxillipeds,and pleopods of the cray sh Astacus astacus。
N ENG DA-EPOCH-R
Dose-Adjusted EPOCH-Rituximab Therapy in Primary Mediastinal B-Cell LymphomaKieron Dunleavy, M.D., Stefania Pittaluga, M.D., Ph.D., Lauren S. Maeda, M.D., Ranjana Advani, M.D., Clara C. Chen, M.D., Julie Hessler, R.N., Seth M. Steinberg, Ph.D., Cliona Grant, M.D., George Wright, Ph.D., Gaurav Varma,M.S.P.H., Louis M. Staudt, M.D., Ph.D., Elaine S. Jaffe, M.D., and Wyndham H. Wilson, M.D., Ph.D.N Engl J Med 2013; 368:1408-1416April 11, 2013DOI: 10.1056/NEJMoa1214561Share:AbstractArticleReferencesCiting Articles (26)LettersKaplan–Meier Estimates of Event-free and Overall Survival of Patients with Primary Mediastinal B-CellLymphoma Receiving DA-EPOCH-R, According to Study Group.Cardiac Ejection Fraction after Treatment with DA-EPOCH-R in 42 Patients in the Prospective NCI Cohort.Primary mediastinal B-cell lymphoma is adistinct pathogenetic subtype of diffuse large-B-cell lymphoma that arises in the thymus.1,2Although it comprises only 10% of cases of diffuse large-B-cell lymphoma, primary mediastinal B-cell lymphoma, which predominantly affects young women,3 is aggressive and typically ismanifested by a localized, bulky mediastinal mass, often with pleural and pericardial effusions.Less commonly, the disease involves extranodal sites, including the lung, kidneys, gastrointestinal organs, or brain.4,5 This disease is clinically and biologically related to nodular sclerosingHodgkin's lymphoma; the putative cell of origin for both conditions is a thymic B cell.1,2The molecular features of primary mediastinal B-cell lymphoma, and its relationship to Hodgkin'slymphoma and other types of diffuse large-B-cell lymphoma, have been studied.1,2,6-8 Mostpatients with primary mediastinal B-cell lymphoma have mutations in the B-cell lymphoma 6 gene (BCL6), usually along with somatic mutations in the immunoglobulin heavy-chain gene, suggesting late-stage germinal-center differentiation.6,7 Unlike other types of diffuse large-B-cell lymphoma,primary mediastinal B-cell lymphoma involves defective immunoglobulin production despite theexpression of the B-cell transcription factors OCT-2, BOB.1, and PU.1. More than half of patients with the disease also have amplification of the REL proto-oncogene and the JAK2 tyrosine kinase gene, which frequently are found in patients with Hodgkin's lymphoma, suggesting that thesediseases are related.9,10 Furthermore, genes that are more highly expressed in primarymediastinal B-cell lymphoma than in other types of diffuse large-B-cell lymphoma arecharacteristically overexpressed in Hodgkin's lymphoma.2Prospective studies in primary mediastinal B-cell lymphoma are few, which has led to conflictingfindings and a lack of treatment standards.11-14 Nonetheless, several observations have emerged from the literature. First, in most patients, adequate tumor control is not achieved with standardimmunochemotherapy, necessitating routine mediastinal radiotherapy.13-15 Second, even withradiotherapy, which is associated with serious late side effects, 20% of patients have diseaseprogression.11,13 Third, more aggressive chemotherapy is associated with an improvedoutcome.12,13 Consistent with this observation, we found that the dose-intense chemotherapy regimen consisting of dose-adjusted etoposide, doxorubicin, and cyclophosphamide with vincristine and prednisone (DA-EPOCH) had a favorable overall survival rate (79%) without consolidation radiotherapy in patients with primary mediastinal B-cell lymphoma.16 On the basis of the hypothesis that rituximab may improve treatment, we undertook a phase 2, prospective study of DA-EPOCH plus rituximab (DA-EPOCH-R) to determine whether it would improve outcomes and obviate the need for radiotherapy.METHODSStudy ConductThe study was designed and the manuscript was written by the last author. All authors reviewed and approved the draft of the manuscript submitted for publication. All the authors vouch for the adherence of the study to the protocol (available with the full text of this article at ) and for the completeness and accuracy of the data and analysis. The prospective study was approved by the institutional review board of the National Cancer Institute (NCI). All patients provided written informed consent. The retrospective analysis was approved by the institutional review board at Stanford University.Filgrastim was provided to the NCI through an agreement with Amgen, which played no role in the study design, analysis, or data collection. No other commercial support was provided for the prospective study.Prospective NCI StudyPatientsFrom November 1999 through August 2012, we prospectively enrolled 51 patients with untreated primary mediastinal B-cell lymphoma in an uncontrolled phase 2 study of DA-EPOCH-R. The primary study objectives were the rate of complete response, the rate of progression-free survival, and the toxicity of DA-EPOCH-R.All eligible patients had not received any previous systemic chemotherapy, had adequate organ function, and had negative results on testing for the human immunodeficiency virus; among women with childbearing potential, a negative test for pregnancy was required. Any localized mediastinal masses (stage I) had to measure at least 5 cm in the greatest dimension. Evaluations included standard blood tests, whole-body computed tomography (CT), and bone marrow biopsy. Assessment of cardiac function, by means of echocardiography, and of central nervous system disease, with the use of CT or magnetic resonance imaging (MRI) and flow cytometry or cytologic analysis of cerebral spinal fluid, were performed if clinically indicated.Study TherapyPatients received chemotherapy consisting of DA-EPOCH-R with filgrastim for 6 to 8 cycles.17,18 Disease sites were evaluated after cycles 4 and 6. Patients with a reduction of more than 20% inthe greatest diameter of their tumor masses between cycles 4 and 6 received 8 cycles of treatment. Patients with a reduction of 20% or less between cycles 4 and 6 discontinued therapy after 6 cycles. The method of administering the DA-EPOCH-R is summarized in the Supplementary Appendix (available at ).We used standard criteria for tumor response to assess the study end points.19,20 We used 18F-fluorodeoxyglucose–positron-emission tomography–CT (FDG-PET-CT) after therapy to evaluate residual masses. Patients who had a maximum standardized uptake value greater than that of the mediastinal blood pool in the residual mediastinal mass underwent repeat scans at approximately 6-week intervals until normalization or stabilization. Mediastinal blood pool activity was defined as the maximum standardized uptake value over the great vessels and ranged from 1.5 to 2.5 in the study population. Tumor biopsy was performed as clinically indicated. Patients with evidence of thymic rebound underwent repeat CT at 6-week intervals until stabilization. All FDG-PET-CT scans were reviewed and scored by the same nuclear-medicine physician. No patients received radiation treatment during this prospective study.Independent, Retrospective Stanford StudyTo provide an independent assessment of DA-EPOCH-R, we collaborated with investigators at Stanford University Medical Center who had begun to use DA-EPOCH-R in 2007 to treat primary mediastinal B-cell lymphoma.21 They reviewed all charts from 2007 through 2012 and found 16 previously untreated patients who had been consecutively treated with DA-EPOCH-R; none required radiotherapy. NCI investigators confirmed the presence of primary mediastinal B-cell lymphoma in all 16 patients, according to the WHO [World Health Organization] Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th edition.3 Standard immunohistochemical studies were performed as indicated.3,18Other Comparative DataTo provide a long-term assessment of the DA-EPOCH platform, we reviewed the pathological data for all patients from our phase 2 study of DA-EPOCH in patients with diffuse large-B-cell lymphoma, which also did not permit radiotherapy, and identified 18 patients with primary mediastinal B-cell lymphoma.16Statistical AnalysisWe calculated the duration of overall survival from the date of enrollment until the time of death or last follow-up. The duration of event-free survival was calculated from the date of enrollment until the date of progression, radiotherapy, discovery of a second mass, or time of last follow-up. We used the Kaplan–Meier method to determine the probability of overall or event-free survival.22 Patients' characteristics were compared by means of Fisher's exact test for dichotomous variables and by means of the Wilcoxon rank-sum test for continuous variables. All P values are two-tailed.The median follow-up was calculated from the date of enrollment through November 2012, the date of the most recent update.RESULTSBaseline Characteristics and Clinical OutcomesThe 51 patients enrolled in the NCI phase 2 prospective study had a median age of 30 years (range, 19 to 52) and a median tumor diameter of 11 cm; 59% were women (Table 1TABLE 1Baseline Characteristics of the Study Patients.). Indicators of advanced disease included bulky tumor with a greatest diameter of 10 cm or more (in 65% of patients), an elevated lactate dehydrogenase level (in 78%), and stage IV disease (in 29%).The 16 patients identified in the retrospective Stanford study had baseline characteristics similar to those of our 51 patients (Table 1) except for a significantly lower frequency of extranodal disease and significantly older age; 56% of patients had bulky disease, and 44% of patients had stage IV disease.At a median follow-up of 63 months (range, 3 to 156), the event-free survival rate in the prospective NCI study was 93% (95% confidence interval [CI], 81 to 98), and the overall survivalrate was 97% (95% CI, 81 to 99) (Figure 1A and 1B FIGURE 1Kaplan–Meier Estimates of Event-free and Overall Survival of Patients with Primary Mediastinal B-Cell Lymphoma Receiving DA-EPOCH-R, According to Study Group.). Three patients had evidence of disease after DA-EPOCH-R treatment; two had persistent focal disease, as detected on FDG-PET-CT, and one had disease progression. Two of these patients underwent mediastinal radiotherapy, and one was observed after excisional biopsy. All three patients became disease-free. One later died from acute myeloid leukemia, while still in remission from his primary mediastinal B-cell lymphoma.In the retrospective Stanford cohort, over a median follow-up of 37 months (range, 5 to 53), 100% of patients (95% CI, 79 to 100) were alive and event-free (Figure 1C and 1D).Finally, we assessed the outcome for 18 patients with primary mediastinal B-cell lymphoma who were enrolled in our phase 2 study of DA-EPOCH.16 These patients had baseline characteristics similar to those in the prospective DA-EPOCH-R study (data not shown). Over a median follow-up of 16 years, the event-free and overall survival rates were 67% (95% CI, 44 to 84) and 78% (95% CI, 55 to 91), respectively. No cardiac failure or second tumors were observed.The event-free and overall survival rates were greater with the addition of rituximab in the NCI prospective cohort than in the cohort of 18 patients who received DA-EPOCH alone (P=0.007 andP=0.01, respectively). This finding suggests that the addition of rituximab may account for the improvement and is consistent with other reports.11FDG-PET-CT FindingsTo identify DA-EPOCH-R treatment failures early, the 36 patients who were found to have residual mediastinal masses in the prospective study underwent FDG-PET-CT in order to optimize curative radiotherapy. Half the patients had a maximum standardized uptake value that was no more than the value in the mediastinal blood pool, which represents the upper limit of the normal range ofuptake (Table 2TABLE 2FDG-PET-CT Findings after DA-EPOCH-R Therapy in the Prospective NCI Cohort.). The other half had a maximum standardized uptake value that was more than the value in the mediastinal blood pool. Although diffuse or focal uptake within the residual tumor mass that is higher than that in the mediastinal blood pool has been considered indicative of lymphoma,20 among these 18 patients, only 3 (with maximum standardized uptake values of 5.9, 10.2, and 14.5) were found to have residual lymphoma. Thus, FDG-PET-CT had a positive predictive value of 17% and a negative predictive value of 100%.Among the 15 patients with a maximum standardized uptake value greater than that in the mediastinal blood pool who did not have disease, 10 underwent repeat FDG-PET-CT; the other 5 did not undergo additional screening, because their initial FDG-PET-CT scans were interpreted as unlikely to represent disease. The 10 patients underwent 1 to 6 additional FDG-PET-CT scans (total, 26); all the findings were interpreted as false positive results on the basis of stabilization or improvement of the maximum standardized uptake value. None of the 10 patients had a recurrence of lymphoma during follow-up.Three patients underwent post-treatment biopsy. One, with a maximum standardized uptake value of 5.9, had a viable tumor of less than 1 cm in area. Owing to the uncertain importance of this finding, the patient was followed for 7 years without treatment, and the tumor did not recur during follow-up. Two patients, with maximum standardized uptake values of 4.6 and 6.4, had negative biopsy results and no tumor recurrence during 6 years of follow-up.In two patients, treatment failed but repeat biopsy was not performed. One patient had disease progression on CT during treatment, and the other had a post-treatment maximum standardized uptake value that increased from 10.2 to 19, consistent with disease progression.Dose and Toxicity of DA-EPOCH-R in the NCI StudyIn the NCI study, 90% of patients received six cycles, and 10% received eight cycles, of DA-EPOCH-R. More than half the 51 patients had an escalation to at least dose level 4, representing a 73% increase over dose level 1; 6% of patients did not have a dose escalation. More than half thepatients received 69 mg of doxorubicin per square meter of body-surface area for at least one cycle and cumulative doses of 345 to 507 mg per square meter. To assess cardiac toxic effects, ejection fractions were measured in 42 patients. All had normal ejection fractions up to 10 yearsafter treatment (Figure 2FIGURE 2Cardiac Ejection Fraction after Treatment with DA-EPOCH-R in 42 Patients in the Prospective NCI Cohort.). There was no significant relationship between the ejection fraction and the length of time since treatment (P=0.30) or between the ejection fraction and the cumulative doxorubicin dose (P=0.20), and no significant interaction between the dose and time interval (P=0.40).Toxicity was assessed during the administration of all 294 cycles of DA-EPOCH-R. The targeted absolute neutrophil count of less than 500 cells per cubic milliliter occurred during 50% of cycles. Thrombocytopenia (<25,000 platelets per cubic millimeter) occurred during 6% of cycles, and hospitalization for fever and neutropenia occurred during 13% of cycles. Nonhematopoietic toxic effects were similar to those that have been reported previously.17,18 One patient died from acute myeloid leukemia while in remission from his primary mediastinal B-cell lymphoma, 49 months after treatment. Owing to the unexpected severe neutropenia during treatment in this patient, we looked for a germline telomerase mutation, which is associated with chemotherapy intolerance and myeloid leukemia.23 Telomere shortening (length, 2.5 SD below the mean) and a heterozygous mutation for the telomerase reverse transcriptase gene (TERT) codon Ala1062Thr were identified.DISCUSSIONThe use of DA-EPOCH-R obviated the need for radiotherapy in all but 2 of 51 patients (4%) with primary mediastinal B-cell lymphoma in a prospective cohort, and no patients had recurring disease over a median follow-up of more than 5 years (maximum, >13). Furthermore, in an independent retrospective cohort, treatment with DA-EPOCH-R in patients with primary mediastinal B-cell lymphoma resulted in an event-free survival rate of 100%. Despite the limitations of the phase 2 study and the retrospective study, these findings suggest that DA-EPOCH-R is a therapeutic advance for this type of lymphoma. Our results suggest that rituximab significantly improves the outcome of chemotherapy in patients with primary mediastinal B-cell lymphoma.The toxicity of DA-EPOCH-R was similar to that reported previously.16 The use of neutrophil-based dose adjustment maximized the delivered dose and limited the incidence of fever and neutropenia to 13% of the cycles. The infusional schedule of doxorubicin allowed for the delivery of high maximal and cumulative doses of doxorubicin without clinically significant cardiac toxic effects.24,25We used post-treatment FDG-PET-CT to identify patients who had persistent disease and a possible need for radiotherapy. Unlike the high clinical accuracy of FDG-PET-CT in other aggressive lymphomas,20 we found the technique to have a poor positive predictive value in primary mediastinal B-cell lymphoma. We frequently observed residual mediastinal masses that continued to shrink for 6 months, suggesting that inflammatory cells might account for the FDG uptake. These findings indicate that FDG-PET-CT uptake alone is not accurate for determining the presence of disease in these patients.There is no established standard treatment for primary mediastinal B-cell lymphoma. Although R-CHOP chemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) has become a de facto standard, it is not universally accepted.11,12 Most strategies also incorporate consolidation radiotherapy to overcome the inadequacy of immunochemotherapy, although some observers have questioned its routine use.12,26 The most accurate assessment of R-CHOP and radiotherapy is a subgroup analysis of patients with primary mediastinal B-cell lymphoma in the Mabthera International Trial Group study of R-CHOP–based treatment.11 Among 44 patients, 73% received radiotherapy, with an event-free survival rate of 78% at 34 months.11 These results indicate that patients who receive R-CHOP–based treatment, most of whom are young women, may have serious long-term consequences of radiotherapy, including second tumors and the acceleration of atherosclerosis and anthracycline-mediated cardiac damage.27Current standard therapy is also inadequate for children with primary mediastinal B-cell lymphoma. In a recent subgroup analysis in the FAB/LMB96 international study, the event-free and overall survival rates were 66% and 73%, respectively, among children receiving a multiagent pediatric regimen.28Retrospective studies have long suggested that patients with primary mediastinal B-cell lymphoma have improved outcomes with the receipt of regimens of increased dose intensity.13 Dose intensity appears to be important in treating Hodgkin's lymphoma, a closely related disease.29 Indeed, outcomes associated with the use of DA-EPOCH-R may well be related to dose intensity as well as the continuous infusion schedule.30 DA-EPOCH therapy involves the administration of pharmacodynamic doses to normalize drug exposure among patients and maximizes the rate of administration. DA-EPOCH may also more effectively modulate the expression of BCL6,7 which encodes a key germinal-center B-cell transcription factor that suppresses genes involved in lymphocyte activation, differentiation, cell-cycle arrest (p21 and p27Kip1), and response to DNA damage (p53 and ATR) and that is expressed by most primary mediastinal B-cell lymphomas (Table 1).31 The inhibition of topoisomerase II also leads to down-regulation of BCL6 expression, suggesting that regimens directed against topoisomerase II may have increased efficacy in treating primary mediastinal B-cell lymphoma. In this regard, DA-EPOCH-R was designed to inhibit topoisomerase II by including two topoisomerase II inhibitors, etoposide and doxorubicin, and maximizing topoisomerase II inhibition by way of extended drug exposure.16In conclusion, our results indicate that DA-EPOCH-R had a high cure rate and obviated the need for radiotherapy in patients with primary mediastinal B-cell lymphoma. To provide confirmatory evidence, an international trial of DA-EPOCH-R in children with primary mediastinal B-cell lymphoma has been initiated ( number, NCT01516567).。
第八章镇痛药
其他部位的修饰
H3C N 16
9
1
14
13 15
RO 3
O
6O
氢吗啡酮：R = H，镇痛作用为吗啡8~10倍； 氢可酮: R = Me；
其他部位的修饰
H3C
N 16
9
1
H O 14
RO 3
13 15
O
6O
羟吗啡酮, R = H, 镇痛作用强于吗啡，但副作用也 增大；
羟考酮, R = Me
吗啡的N-CH3
吗啡的N-CH3去除后活性丧失； 将吗啡的叔胺改成季铵盐后，活性显著降低； 用其它烷基，链烯烃或芳烃基取代活性降低，
只有N-β-苯乙基去甲吗啡（N-βPhenylethylnormorphine）镇痛作用约为吗啡 的14倍。 用烯丙基、环丙甲基、环丁甲基等不饱和基团 或小环的基团取代后，由激动剂转成为拮抗剂。
have shorter duration Piperidines retain side-effects such as
addiction and depression of the respiratory centre
盐酸哌替啶,Pethidine
度冷丁
HCI
O
4
1
O
N
白色结晶，mp.186-190
Anesthetics: inhibiting pain transmission by nonreceptor-mediated actions on nerve cell memberanes.
阿斯利康公司瑞舒伐他汀新增适应证
2010 V ol.31 No.3 2010年第31卷第3期159研究论文3 讨论纳洛酮为阿片受体特异性阻断剂，给予小鼠常规试验剂量(0.4～4 mg/kg )能够拮抗阿片类药物的镇痛作用。
本研究使用的纳洛酮剂量为1～100 ng/kg ，研究结果表明，低剂量纳洛酮能够增强曲马多的镇痛效应。
低剂量纳洛酮与曲马多配伍可能通过以下几方面的机制达到协同镇痛作用： ①低剂量阿片受体拮抗剂可以促进阿片肽释放或把阿片肽从与镇痛无关的位点置换出来。
阿片肽的释放是通过突触前自身负反馈抑制通路调控的，低剂量纳洛酮可能作用于突触前阿片受体，从而阻断阿片肽的负反馈环路，促进阿片肽的释放而产生镇痛作用[2]；②Crain 等[5]认为，阿片受体具有双向作用模式，兴奋性模式产生抗镇痛作用，抑制性模式则产生镇痛作用。
低剂量纳洛酮可阻断兴奋性阿片受体的抗镇痛作用，而不影响抑制性阿片受体的镇痛作用；③低剂量纳洛酮可阻止中枢神经细胞释放兴奋性递质——谷氨酸[6]；④疼痛过敏和阿片类药物的耐受作用密切相关，并且都基于共同的神经机制及细胞内机制，低剂量纳洛酮可能使阿片μ受体部位磷酸化，进而影响机体对阿片类药物的耐受性[7]；⑤低剂量纳洛酮增强曲马多的镇痛效应还可能与其使阿片受体密度上调、活度增加有关[8]；⑥有研究[9]提出，低剂量纳洛酮增强阿片类药物镇痛效应的作用可能是通过增加钙离子通道的转导并进而影响细胞内钙离子水平实现的。
本研究结果提示，若在麻醉前给予适量低剂量纳洛酮可望增强曲马多的镇痛作用。
纳洛酮与曲马多配伍用于镇痛或复合麻醉可能是合理的，值得临床试用。
但是纳洛酮配伍曲马多的安全性、最佳配比、不良反应及其机制尚未明确，有待进一步研究以确定。
4 结论低剂量纳洛酮(10～100 ng/mg )能够增强曲马多对小鼠的镇痛效应。
参考文献：[1] 戴体俊. 麻醉药理学[M ]. 第2 版. 北京: 人民卫生出版社, 2005: 48-49.[2] 姚 鹏, 孟凌新, 崔健君. 阿片受体激动药伍用小剂量拮抗药用于镇痛的研究进展[J ]. 国外医学: 麻醉学与复苏分册,2004, 25(2): 80-83.[3] 刘志强, 杨立群, 俞卫锋. 曲马多对小鼠镇痛作用的药物代谢动力学研究[J ]. 中国药物与临床, 2003, 3(3): 237-239.[4] 徐叔云, 陈 修, 卞如濂, 等. 药理实验方法学[M ]. 北京:人民卫生出版社, 1982: 882-886.[5] Crain SM, Shen KF. Antagonists of excitatory opioid receptorfunctions enhance morphine ′s analgesic potency and attenuate opioid tolerance /dependence liability [J ]. Pain, 2000, 84 (2-3): 121-131.[6] 范德义, 方思羽. 纳络酮对脂多糖诱导原代培养星形胶质细胞释放谷氨酸的抑制效应[J ]. 中风与神经疾病杂志, 2004, 21(6): 515-517.[7] 崔凤侠, 王利江, 王宏伟, 等. μ阿片受体的研究进展[J ]. 承德医学院学报, 2005, 22 (4): 346 - 348.[8] 李照庆,周升民,赵念峰. 小剂量纳洛酮在术后芬太尼静脉自控镇痛中的应用[J ]. 食品与药品, 2006, 8 (7): 44-46.[9] Nakae Y , Fujita S, Namiki A. Modulation of myo fi lament Ca 2+sensitivity by delta - and kappa - opioid agonists in intactguinea pig hearts [J ]. Anesth Analg, 2003, 96 (3): 733-739.(责任编辑：华雪蔚)IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII 阿斯利康公司瑞舒伐他汀新增适应证阿斯利康公司的瑞舒伐他汀钙(Crestor )获FDA 批准，用于降低患者脑卒中、心房纤颤(房颤)和动脉血管再生的风险。
糖皮质激素受体与重型精神病性抑郁症的治疗_英文_
・综述与述评・Glucocorti coi d receptor and treat ment of psychoti c major depressi onHU I Xin,ZHOU Cai 2hong,WANG M ing 2wei3(The N ational Center for D rug Screening,Institute of M ateria M edica,Shanghai Institutes for B iological Sciences,Chinese A cade m y of Sciences ;Graduate School of the Chinese A cade m y of Sciences,Shanghai 201203,China )Key words:p sychotic maj or dep ressi on;hypercortis ole m ia;hypothala m ic 2p ituitary 2adrenal axis;glucocorticoid recep t or;antagonistCLC nu m ber:R749.42;R971.43 D ocu m en t code:A Arti cle I D :0513-4870(2005)11-0961-06Received date:2005201228.Foundati on ite m:The M inistry of Science and Technol ogy of China(2002AA2Z343A );Chinese Acade my of Sciences (KS CX12S W 21122);Shanghai Munici pality Science and Technol ogy Devel opment Fund (03dz19224).3Corres ponding author Tel:86-21-50800598,Fax:86-21-50800721,E 2mail:mwwang@sini w est .com糖皮质激素受体与重型精神病性抑郁症的治疗惠 昕,周彩红,王明伟3(中国科学院上海生命科学研究院药物研究所国家新药筛选中心;中国科学院研究生院,上海201203)关键词:重型精神病性抑郁症;肾上腺皮质醇增多症;下丘脑2垂体2肾上腺轴;糖皮质激素受体;拮抗剂1 I n troducti onPsychotic maj or dep ressi on (P MD ),which res ponds poorly t o tricyclic anti 2dep ressants,is a distinct syndr ome of dep ressi on .Hypercortis ole m ia (cortis one hy persecreti on ),a bi ol ogical abnor mality existing in many patients with P MD ,has led t o vari ous theoretical and e mp irical rati onales f or the potential therapeutic use of anti 2glucocorticoid agents in the treat m ent of dep ressi on .Most available anti 2dep ressant medicati ons t oday increase brain levels of glucocorticoid recep t or (GR ),rendering individuals more sensitive t o corticoster oid negative feedback regulated by hypothala m ic 2p ituitary 2adrenal (HP A )axis .Recently,several studies have assessed the behavi oral effects of direct phar macol ogical l owering of cortis ol levels in patients with P MD using GR antagonists,such as RU486(m ifep rist one ).Random ized and contr olled studies have shown that GRantagonists are capable of significantly i m p r ovingp sychosis and dep ressi on sy mp t om s of P MD patients,and thus pointing t o a p r om ising potential of devel op ing GR antagonist as a novel anti 2dep ressant agent t o revoluti onize the treat m ent of dep ressi on .2 Pa thophysi ology of P MDP MD is a mental dis order with considerable morbidity and mortality .Numer ous studies,relative t o its clinical characteristics,bi ol ogical measures,treat m ent course and outcome,and fa m ilial hist ory,suggest that P MD is a distinct subtype of dep ressi on [1].T wenty 2five percent of the patients hos p italized for maj or dep ressi on met the diagnostic criteria forP MD [2],and 1417%of the out patients had a hist ory ofp sychotic characteristics [3,4].Patients with P MD exhibit p r onounced paranoid sy mp t om s,cognitive i m pair ment,hopelessness,hypochondriasis,anxiety,ins omnia,absence of diurnal variati on,andconsti pati on [2,5].Sy mp t om relap se or recurrence is a common feature and suicidal risks are much higherthan non 2p sychotic dep ressi on patients [6].The p revalence is higher (45%)in elderly patients with maj or dep ressi on,but P MD can occur in all ages .P MD is hard t o diagnose,because p sychosis may be subtle,inter m ittent,or concealed,and anti 2dep ressanttherapy al one often results in poor efficacy [3,4,7].・169・药学学报Acta Phar maceutica Sinica 2005,40(11):961-966A lthough P MD patients do res pond t o co mbinati ons of currently available anti2p sychotic and anti2dep ressant medicati ons,and electr oconvulsive therapy(ECT), these therap ies act very sl owly,which lead t o an interi m peri od of high morbidity.ECT re mains the therapy of choice t oday.An ass ociati on of HP A axis activity and mental disturbances was first reported about50years ago[8].It was f ound that dep ressed patients with suicidal behavi or in their past and recent disease hist ory showed a differentially regulated HP A syste m compared with dep ressed patients without suicidal behavi or[9].I n the case of P MD,a series of studies revealed that:(1)a maj ority of P MD patients tested abnor mally f or dexa methas one supp ressi on while patients with non2 affective p sychoses(eg,schiz ophrenia)did not show this feature;(2)both peri pheral cortis ol and adrenocorticotr op in hor mone(ACTH)levels were elevated in patientswith P MD;(3)ECT could cause a perturbati on of the HP A axis[10].Latest experi m ental data de monstrated that selective re moval of f orebrain GR uncovered a substantial l oss in negative feedback, causing sustained increases in circulating stress hor mones.This increase could then elicit sequelae that rese mble the effects of dep ressi on[11].These findings support the neur oendocrine hypothesis that dysregulati on in the HP A axis p lays an i m portant r ole in the pathogenesis and devel opment of P MD,and can exp lain why P MD is often ass ociated with cognitive i m pair ment[2].Hypercortis ole m ia may activate ser ot onergic, dopa m inergic and noradrenergic neur ons in the brain ste m thereby increasing the sensitivity of li m bic2 forebrain areas t o a m inergic inputs[12].Dopa m inergic syste m activati on and higher levels of cerebr os p inal fluid52hydr oxyindoleacetic acid were reported in P MD patients[3].I n additi on,P MD patients have l ower seru m dopa m ine2β2hydr oxylase(DBH)activity(the enzy me that converts dopa m ine t o norep inephrine)[13] leading t o an enhance ment of dopa m ine activity and p sychotic behavi or[14].Besides neur oendocrine changes in P MD patients, larger ventricle2t o2brain rati os and greater atr ophy in parietal regi ons were de monstrated by Rothschild and colleagues[15].Diencephalic atr ophy,reticular activating syste m lesi ons,brain ste m atr ophy,and left2sided fr ont ote mporal atr ophy were als o noted[16].These structural alterati ons were correlated with i m pair ment in mot or functi on,attenti on,me mory,and visual2s patial skills.3 I nvolve m en t of GRFoll owing sti m ulati on,the HP A axis secretes cortis ol fr om the adrenal glands,which in turn inhibits both corticotr ophin2releasing hor mone(CRH)and ACTH release fr om the hypothala mus or p ituitary gland.This feedback mechanis m involves t w o types of adrenal ster oid recep t ors,na mely,m ineral ocorticoid recep t or(MR,type I)and glucocorticoid recep t or (GR,type II).MR mediates the circadian thr ough basal level of corticoster oids,whereas GR ensures a high level of glucocorticoid during circadian peak and stress[17].GR is a hor mone2activated transcri p ti on fact or consisting of t w o subtypes,GRαand GRβ.They have different carboxy ter m ini and only GRαbinds t o cortis ol[18].“I nactivated”GR resides p ri m arily in the cyt op las m ass ociated with a multi m eric comp lex of chaper one p r oteins including heat shock p r oteins (HSPs).Upon ster oid binding,GR undergoes a conf or mati onal change(“activati on”),diss ociates itself fr om the chaper one comp lex,and transl ocates t o the nucleus,where it either binds t o glucocorticoid res ponse ele ments(GREs)on DNA or interacts with other transcri p ti onal fact ors[19].GR is most abundant in hypothala m ic CRH neur ons and p ituitary corticotr opes[12].I n the human brain,the abundance of GRβis far less than that of GRα[18],and GR s are very res ponsive t o changes of cortis ol concentrati ons[12]. Survivors of GR knockout rats dis p layed hypertr ophy and hyper p lasia of the adrenal glands,with corticoster2 one p r oducti on enhanced32fold,and ACTH levels increased102fold[20].GR appears t o“s witch off”cortis ol p r oducti on upon stress and thus maintains homeostasis,the balance bet w een sti m ulative and inhibit ory influences.A set of studies have suggested that high levels of GR in the brain can make the ani m al behave in a more anxi ous or dep ressive manner and that,conversely, bl ocking the recep t ors with an antagonist or knocking it down in brain can make the ani m al appear less anxi ous.For exa mp le,GR2disrup ted m ice not only exhibited aberrant me mories,but als o adop ted a differential search strategy,as tested in a Morris water maze[21].I n GR2di m/di m mutants,a selective i m pair ment of s patial me mory was observed[22]. Transgenic m ice exp ressing anti2sense RNA against GR had a di m inished,but not absent,GR functi on, accompanied by a reducti on in CRH neur ons of the hypothala mus with no effect on corticoster one・269・药学学报Acta Phar maceutica Sinica2005,40(11):961-966levels[23].I n contrast,comp lete inactivati on of the GR gene in the mouse central nervous syste m led t o increases in hypothala m ic CRH p r oducti on and p las ma corticoster one concentrati ons[24].It is note worthy that both strains of m ice dis p layed a phenotype characterized by reduced anxiety,suggesting a r ole of GR in regulating e moti onal behavi or[25].Further studies indicate that GR is not only a regulat or of stress res ponsiveness but als o a key contr oller of e moti onal lability[26].The above observati ons were confir med recently in a line of m ice with ti m e2dependent,f orebrain2s pecific disrup ti on of GR(F BGRK O)[27]using the Cre2l oxP syste m[28].These m ice devel oped a nu mber of both physi ol ogical and behavi oral abnor malities that m i m icked maj or dep ressive dis order in hu mans, including hyperactivity of the HP A axis,i m paired negative feedback regulati on of the HP A axis,and increased dep ressi on2like behavi or.I m portantly,a nu mber of these abnor malities are nor malized by chr onic treat m ent with the tricyclic anti2dep ressant, i m i p ra m ine[27].A s far as recep t or pathol ogy is concerned, cu mulative evidence suggests that neither cyt os olic GR levels nor its binding affinity t o glucocorticoid were altered in patients with P MD[29].A decreased GR mRNA level was detected in the fr ontal cortex and hi ppoca mpus of certain p sychiatric subjects by one gr oup[29],but the result could not be verified by others[30].I ndividuals with fa m ilial glucocorticoid resistance had i m paired HP A feedback and deficient GR functi on leading t o hypercorticoidis m[12],for which an altered GRα/GRβrati o may be res ponsible[31]. Further more,results of several hu man GR poly mor phis m studies could not establish a clear linkage bet w een a m ino acid substituti ons or nucleotide changes in a nu mber of p sychiatric dis orders[20].These investigati ons i m p ly that excessive HP A axis activity found in P MD patients is most likely a phenotyp ic or functi onal deviati on on the part of GR.4 Trea t m en t w ith GR an t agon istsA coup le of anti2glucocorticoid strategies have been e mp l oyed in P MD therapy:(1)cortis ol synthesis inhibit ors,such as metyrapone,a m inoglutethi m ide and ket oconaz ole;and(2)dehydr oep iandr oster one (DHE A)———a ster oid compound with anti2 glucocorticoid p r operties[32].I n additi on,a CRH recep t or antagonist———R121919,that reduces the release of ACTH and hence,the peri pheral corticoster one level,was shown t o i m p r ove affective sy mp t om s in patients with maj or dep ressi on[33]. However,the efficacy of these treat m ents in hypercortis ole m ia p sychotic and non2p sychotic dep ressed patients were less than ideal[3].A maj or concern of using these medicati ons relates t o significant side2effects,including the potential f or adrenal insufficiency and hepatic da mage.Another app r oach is the use of GR antagonists, such as RU486(m ifep rist one),that does not inhibit ster oid bi osynthesis but bl ock GR acti ons at higher doses.RU486is a potent anti2p r ogester one and anti2 glucocorticoid agent in humans,and its phar macol ogical effects are realized via supp ressi on of the interacti on bet w een native ligands and their res pective recep t ors.The mechanis m,by which RU486exerts its antagonistic acti on,has been shown t o be an active p r ocess(recruit m ent of co2rep ress ors during transcri p ti on)[34],in additi on t o recep t or bl ockade,as revealed by the three2di m ensi onal crystal structures of hGR[35].Foll owing RU486 ad m inistrati on,endocrine functi on is perturbed initially but a ne w balance within the HP A axis would s oon be established t o adequately manage circulating levels of RU486and endogenous cortis ol[36].RU486was successfully app lied t o the treat m ent of Cushing’s disease[37].The efficacy was validated in another gr oup of patients who si m ultaneously devel oped p sychosis/dep ressi on and Cushing’s syndr ome[37,38].A p reli m inary study involving8patients with chr onic, non2p sychotic dep ressi on was conducted in1993. RU486(200mg・d-1),given orally f or8weeks, only achieved modest i m p r ove ment in3of the4 subjects[39].This was foll o wed by a s mall,double2 blind,p lacebo2contr olled,cr oss over study(600mg・d-1×4)in5patients with P MD[40].A ll patients showed substantial i m p r ove ment in their HAM2D (Ha m ilt on Rating Scale f or Dep ressi on)scores while receiving RU486,and4of the5patients dis p layed marked i m p r ove ment in their BPRS(B rief Psychotic Rating Scale)scores.Thereafter,Belanoff and his colleagues carried out an open2label trial in30P MD patients with HAM2D scores of18or greater.The subjects were random ly assigned t o receive50,600,or 1200mg of RU486once daily f or7days,and all of the m comp leted the p r ot ocol.W hile side2effects were m ild and s poradic,patients in the t w o high dose gr oup s showed significant reducti on in their sy mp t om s within7 days or less:40%had a greater than50%decrease in・369・HU I Xin,et al:Glucocorticoid recep t or and treat m ent of p sychotic maj or dep ressi ontheir HAM2D scores and over60%de monstrated at least a30%reducti on in BPRS scores.This app r oach p r oduced more rap id effects than atyp ical anti2 p sychotic/anti2dep ressant combinati on therapy,and was well accep ted compared t o ECT.These encouraging efficacy data led t o t w o separate, random ized,double2blind,p lacebo2contr olled clinical trials(600mg of RU486daily×7p lus282day foll ow2 up)enr olling app r oxi m ately400in2patients.Patients in the first trial were stabilized on existing medicati on regi m ens p ri or t o RU486therapy while concom itant treat m ent was not all o wed in the second trial.I nteri m data suggest that RU486is markedly more likely than p lacebo t o effect a rap id and sustained re m issi on in P MD patients[41].Meanwhile,another ster oidal GR antagonist,ORG34517,was studied side2by2side with RU486.It was found that both compounds were superi or t o p lacebo or certain anti2dep ressants in treating P MD in ter m s of onset of acti on and clinical efficacies[42].Latest investigati ons with20P MD subjects taking no p sychotr op ic medicati ons de monstrate that62day course of RU486(f or8weeks)significantly i m p r oved HAM2D and CGI(clinical gl obal i m p ressi ons)scores after1week and bet w een weeks1and4,and BPRS scores after4.A lthough this study was not blinded and without p lacebo contr ol,the outcome points t o the clinical usefulness of relatively l onger ti m e RU486interventi on in the absence of concom itant anti2 dep ressant ad m inistrati on[43].Short2ter m supp ressi on of GR by RU486hel p s t o reset a putative dysfuncti onal glucocorticoid negative feedback mechanis m in dep ressed patients[7].H igh levels of glucocorticoids activate GR and inhibit neur onal excitability as GR activati on may favor l ong2 ter m dep ressi on via potentiati on supp ressi on.It is possible that RU486antagonizes these acti ons and, under conditi ons of high cortis ol,can i m p r ove cogniti on in patients with P MD,schiz ophrenia, uni polar or bi polar dis order[44].This m ight be the molecular basis by which GR antag onists exert their therapeutic effects on P MD.Cy m i p rist one(Figure1)was synthesized based on the structure of RU486.It has a different metabolic p r ofile as oppose t o that of RU486when used in hu mans,with a comparable GR antagonistic activity[45].A lthough multi2center clinical trials f or a rep r oductive indicati on are still ongoing,it is expected that this ne w che m ical entity will s oon be evaluated f or P MD therapy.F i gure1 Structure of cy m i p rist one5 Perspecti veThere is a str ong evidence t o support the hy pothesis that P MD is a distinct syndr ome.Statistically significant differences exist bet w een patients with P MD,s pecifically exhibiting abnor malities in the HP A axis activity and markedly elevated cortis ol levels,and those with non2p sychotic maj or dep ressi on.Regardless of vari ous fact ors that lead t o suscep tibility t o dep ressi on,it is likely that the disease p r ocess s ooner or later engages the stress syste m.Stress in turn can contribute t o the deteri orating course of the illness. Both overactivati on and underactivati on of the stress res ponse are da maging t o humans,and effective treat m ent of dep ressi on requires the“resetting”of the contr olling mechanis m(s).This can often be achieved thr ough classical anti2dep ressants,but s ometi m es may need direct interventi on by altering s pecific molecular components of the regulat ory syste m t o rest ore its balance[11].P MD patients have a very l ow p lacebo res ponse rate,as well as poor res ponse t o anti2dep ressant therapy al one.Hypercortis ole m ia,a clinical manifestati on repeatedly de monstrated in many patients with P MD,has led t o the use of anti2glucocorticoid agents for dep ressi on therapy.Some degree of efficacy has been seen with these drugs,but not without seri ous side2effects,such as hypoadrenalis m and hepat ot oxicity.The intr oducti on of anti2dep ressants with novel mechanis m s of acti on could potentially revoluti onize the treat m ent of dep ressi on,and the rati onale of treating P MD patients with GR antagonists is well2supported by both laborat ory and clinical experiences.Type II GR antagonists are much more s pecific than ECT.One such agent,RU486,is being studied for the treat m ent of patients with P MD and has been reported t o i m p r ove p sychosis and dep ressi on sy mp t om s in random ized,contr olled studies.Since GR bl ockage or dep rivati on is als o efficaci ous in maj or dep ressi on[33],schiz ophrenia[44]and bi polar dis order[46],the dysfuncti on of the HP A axis may・469・药学学报Acta Phar maceutica Sinica2005,40(11):961-966p r ove t o be a common feature in mentally ill patients with diverse clinical manifestati ons.I nterventi onal targets will include a variety of as pects al ong the regulat ory path way of the HP A axis.Ne w therapeutic agents are currently being s ought with the hope of finding a more selective,efficaci ous and safe drug that will i m p r ove the sy mp t o m s of p sychosis that often leads t o suicide in this patient populati on.Acknowledge m en t:W e are indebted t o D r. D.E.Mais for critical revie w of the manuscri p t.References[1]Schatzberg AF,Rothschild AJ.Psychotic(delusi onal)maj or dep ressi on:should it be included as a distinctsyndr ome in DS M2I V?[J].Am J Psychiatry,1992,149(6):733-745.[2]Fle ming SK,B lasey C,Schatzberg AF.Neur opsychol ogicalcorrelates of p sychotic features in maj or dep ressivedis orders:a review and meta2analysis[J].J PsychiatrRes,2004,38(1):27-35.[3]Rothschild AJ.Challenges in the treat m ent of dep ressi onwith p sychotic features[J].B iol Psychiatry,2003,53(8):680-690.[4]Schatzberg AF.New app r oaches t o managing p sychoticdep ressi on[J].J C lin Psychiatry,2003,64(Supp l1):19-23.[5]Nels on E B,Sax K W,Strakowski S M.A ttenti onalperf or mance in patients with p sychotic and nonp sychoticmaj or dep ressi on and schizophrenia[J].Am JPsychiatry,1998,155(1):137-139.[6]Vythilinga m M,Chen J,B re mner JD,et al.Psychoticdep ressi on and mortality[J].Am J Psychiatry,2003,160(3):574-576.[7]Gold P W,D revets WC,Charney DS.Ne w insights int othe r ole of cortis ol and the glucocorticoid recep t or insevere dep ressi on[J].B iol Psychiatry,2002,52(5):381-385.[8]Quart on GC,Clark LD,Cobb S,et al.Mentaldisturbances ass ociated with ACTH and cortis one:arevie w of exp lanat ory hypotheses[J].M edicine(B alti m ore),1955,34(1):13-50.[9]Pfennig A,Kunzel HE,Kern N,et al.Hypothala mus2p ituitary2adrenal syste m regulati on and suicidal behavi orin dep ressi on[J].B iol Psychiatry,2005,57(4):336-342.[10]Posener JA,De Battista C,W illia m s GH,et al.242Hourmonit oring of cortis ol and corticotr op in secreti on inp sychotic and nonp sychotic maj or dep ressi on[J].A rchGen Psychiatry,2000,57(8):755-760.[11]Akil H.Stressed and dep ressed[J].N atM ed,2005,11(2):116-118.[12]de Kl oet ER,V reugdenhil E,O itzl MS,et al.B raincorticoster oid recep t or balance in health and disease[J].Endocrine Rev,1998,19(3):269-301.[13]Mod L,R ih mer Z,Magyar I,et al.Seru m DBH activityin p sychotic vs.nonp sychotic uni polar and bi polardep ressi on[J].Psychiatry Res,1986,19(4):331-333.[14]Nels on JC,Davis J M.DST studies in p sychoticdep ressi on:a meta2analysis[J].Am J Psychiatry,1997,154(11):1497-1503.[15]Rothschild AJ,Benes F,Hebben N,et al.Relati onshi p sbet w een brain CT scan findings and cortis ol in p sychoticand nonp sychotic dep ressed patients[J].B iolPsychiatry,1989,26(6):26565-26575.[16]Si m p s on S,Bald win RC,Jacks on A,et al.Thedifferentiati on of DS M2III2R p sychotic dep ressi on in laterlife fr om nonp sychotic dep ressi on:comparis ons of brainchanges measured by multis pectral analysis of magneticres onance brain i m ages,neur op sychol ogical findings,andclinical features[J].B iol Psychiatry,1999,45(2):193-204.[17]Bach mann CG,L inthorst AC,Holsboer F,et al.Effectof chr onic ad m inistrati on of selective glucocorticoidrecep t or antagonists on the rat hypothala m ic2p ituitary2adrenocortical axis[J].N europsychophar m acology,2003,28(6):1056-1067.[18]Oakley RH,Sar M,Cidl owski JA.The hu manglucocorticoid recep t or beta is of or m[J].J B iol Che m,1996,271(16):9550-9559.[19]PrattWB.The r ole of heat shock p r oteins in regulatingthe functi on,f olding,and trafficking of the glucocorticoidrecep t or[J].J B iol Che m,1993,268(29):21455-21458.[20]DeR ijk RH,Schaaf M,de Kl oet ER.Glucocorticoidrecep t or variants:clinical i m p licati ons[J].J S teroidB ioche m M ol B iol,2002,81(2):103-122.[21]O itzlMS,de Kl oet ER,Joels M,et al.Spatial learningdeficits in m ice with a targeted glucocorticoid recep t orgene disrup ti on[J].Eur J N eurosci,1997,9(11):2284-2296.[22]O itzlMS,Reichardt HM,JoelsM,et al.Point mutati onin the mouse glucocorticoid recep t or p reventing DNAbinding i m pairs s patial memory[J].Proc N atl A cad SciUSA,2001,98(22):12790-12795.[23]D ijkstra I,Tilders FJ,Aguilera G,et al.Reducedactivity of hypothala m ic corticotr op in2releasing hor moneneur ons in transgenic m ice with i m paired glucocorticoidrecep t or functi on[J].J N eurosci,1998,18(10):3909-3918.[24]Tr onche F,Kellendonk C,Kretz O,et al.D isrup ti on ofthe glucocorticoid recep t or gene in the nervous syste mresults in reduced anxiety[J].N at Genet,1999,23(1):99-103.[25]Gass P,Reichardt H M,Strekal ova T,et al.M ice withtargeted mutati ons of glucocorticoid and m ineral ocorticoidrecep t ors:models for dep ressi on and anxiety?[J].Physiol B ehav,2001,73(5):811-825.[26]W ei Q,Lu XY,L iu L,et al.Glucocorticoid recep t or・569・HU I Xin,et al:Glucocorticoid recep t or and treat m ent of p sychotic maj or dep ressi onoverexp ressi on in forebrain:a mouse model of increasede moti onal lability[J].Proc N atl A cad Sci USA,2004,101(32):11851-11856.[27]Boyle MP,B rewer JA,Funatsu M,et al.Acquireddeficit of f orebrain glucocorticoid recep t or p r oducesdep ressi on2like changes in adrenal axis regulati on andbehavi or[J].Proc N atl A cad Sci USA,2005,102(2):473-478.[28]W inter mantel T M,Berger S,Greiner EF,et al.Evaluati on of ster oid recep t or functi on by gene targeting inm ice[J].J S teroid B ioche m M ol B iol,2005,93:107-112.[29]Pariante C M,M iller AH.Glucocorticoid recep t ors inmaj or dep ressi on:relevance t o pathophysi ol ogy andtreat m ent[J].B iol Psychiatry,2001,49(5):391-404.[30]Lopez JF,Chal m ers DT,L ittle KI,et al.Regulati on ofser ot onin1A,glucocorticoid and m ineral ocorticoidrecep t or in rat and hu man hi ppoca mpus[J].B iolPsychiatry,1998,43(8):547-573.[31]Juruena MF,Cleare AJ,Bauer ME,et al.Molecularmechanis m s of glucocorticoid recep t or sensitivity andrelevance t o affective dis orders[J].A ctaN europsychiatrica,2003,15(6):354-367.[32]Reus V I,Wolkowitz OM,Frederick S.Antiglucocorticoidtreat m ents in p sychiatry[J].Psychoneuroendocrinology,1997,22(Supp l):S121-S124.[33]Zobel AW,N ickel T,Künzel HE,et al.Effects of thehigh2affinity corticotr op in2releasing hor mone recep t or1antagonist in maj or dep ressi on:the first20patients treated[J].J Psychiatr R es,2000,34(3):171-181.[34]Schulz M,Eggert M,Baniah mad A,et al.RU4862induced glucocorticoid recep t or agonis m is contr olled bythe recep t or N ter m inus and by corep ress or binding[J].J B iol Che m,2002,277(29):26238-26243.[35]Kaupp i B,Jakob C,Farnegardh M,et al.The three2di m ensi onal structures of antagonistic and agonistic f or m sof the glucocorticoid recep t or ligand2binding domain:RU2 486induces a transconfor mati on that leads t o activeantagonis m[J].J B iol Che m,2003,278(25):22748-22754.[36]Bertagna X,Escour olle H,Pinquier JL,et al.Ad m inistrati on of RU486f or8days in nor mal volunteers:antiglucocorticoid effect with no evidence of peri pheralcortis ol dep rivati on[J].J C lin EndocrinolM etab,1994,78(2):375-380.[37]van der Lely AJ,Foeken K,van der Mast RC,et al.Rap id reversal of acute p sychosis in the Cushing syndr omewith the cortis ol2recep t or antagonist m ifep rist one(RU486)[J].A nn Intern M ed,1991,114(2):143-144. [38]Chu J W,Matthias DF,Belanoff J,et al.Successful l ong2ter m treat m ent of refract ory Cushing’s disease with high2dose m ifep rist one(RU486)[J].J C lin Endocrinol M etab,2001,86(8):3568-3573.[39]Mur phy BE,Fili p ini D,Ghadirian AM.Possible use ofglucocorticoid recep t or antagonists in the treat m ent ofmaj or dep ressi on:p reli m inary results using RU486[J].J Psychiatry N eurosci,1993,18(5):209-213.[40]Belanoff JK,Fl ores BH,Kalezhan M,et al.Rap idreversal of p sychotic dep ressi on using m ifep rist one[J].JC lin Psychophar m acol,2001,21(5):516-521.[41]Belanoff JK,De Battista C.M ifep rist one in p sychoticmaj or dep ressi on[J].B iol Psychiatry,2004,55:1S-242S.[42]Pinder R M.Glucocorticoid antagonists in dep ressi on[J].B iol Psychiatry,2004,55:1S-242S.[43]Si m p s on G M,El Sheshai A,Loza N,et al.An82weekopen2label trial of a62day course of m ifep rist one for thetreat m ent of p sychotic dep ressi on[J].J C lin Psychiatry,2005,66(5):598-602.[44]Gallagher P,W ats on S,S m ith M S,et al.Effects ofadjunctive m ifep rist one(RU2486)ad m inistrati on onneur ocognitive functi on and sy mp t om s in schizophrenia[J].B iol Psychiatry,2005,57(2):155-161.[45]Chen LZ,Zuo L,W ang MW,et al.Ster oids,theirp reparati on,phar maceutical compositi ons thereof and usesof the compounds[P].US Pat:6514956B1,2003202204.[46]Young AH,Gallagher P,W ats on S,et al.I m p r ovementsin neur ocognitive functi on and mood f oll owing adjunctivetreat m ent with m ifep rist one(RU2486)in bi polar dis order[J].N europsychophar m acology,2004,29:1538-1545.・669・药学学报Acta Phar maceutica Sinica2005,40(11):961-966。
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当叔氮上有环丙甲基、甲基烯丙基、环丁甲基等大 基团取代，可以明显提高配基对κ 受体的结合能力， 且大部分表现出κ激动活性。但是，亚型选择性很 低。
Ronsisvalle
2、吗啡结构类型及衍生物
1、吗啡是典型的μ激动剂，对κ活性很低。 2、17 位氮原子上取代有烯丙基或环丙甲基 等疏水性大基团时，可以表现出对κ 受体较 好的活性 3、6位改造可分为以下几种
2.3 6 位羰基及其衍生物
激动
1吗啡的C 环主要采取 扭船式构象，但是6 位 酮基结构C环却是采用 了椅式构象 2)而吗啡环的6位羟基
和氨基既可以作为形
成氢键给体又可以作
拮抗
为氢键的供体，但是
作为酮基只能作为氢
键的受体
2.4 6,7併环衍生物
GLu297 Portoghese
2.4 6,7併环衍生物
高选择性的κ激动剂
阿片受体各亚型的活性均有明显降低
奥维醇类化合物的构效关系
3、吗啡烃类
1、吗喃类结构的10位引入羰基结构，会导 致对阿片受体各亚型的结合能力下降。主要 表现出μ/κ的混合选择性 2、氮上环丙甲基及环丁甲基取代是强效的κ 激动剂。 3、吗啡结构中的酚羟基对于阿片样作用虽 然不是关键的，却可以增强对受体的活性。
μ、δ 和κ 的结合 能力之比为1:4:25，
4、奥维醇及其类似物
2.1 6位巯酯衍生物
强效μ拮抗剂
激动κ 受体
明显提高了κ 激动活性
2.2 6位羟基及6位氨基衍生物
生物电子等排
Nagase 6 位氨基延伸部分对活性是保 守的 1、酰胺氮上无甲基取代比 TRK-820 活性下降300 多倍； 2、呋喃乙烯基被其它基团取 代也会引起配基κ 活性丌同程 度的下降
镇痛活性比吗啡 强85-140 倍，比 芳香乙酰胺类的 U50488强85-350 倍。 ki=3.5nM, ki(κ/μ) ratio=15
4、奥维醇及其类似物
57激动κ受体来发挥镇痛作用；58在体内却表现出纯拮抗活性 因此Wood认为20位羟基的构型并不影响配基的受体结合能力，但 却影响配基对κ受体的激动-拮抗活性
奥维醇酸催化重排衍生物
• 烯键的反式构型对活性和 选择性非常重要的 • 顺反式构型的配基之间在 药理性质上差异主要也是 由于苯环的空间伸展方向 丌一致引起的
吗啡生物碱类非肽类κ配基
阿片受体
阿片受体是视紫红质蛋白家族成员，属于G蛋白偶联受体，目 前已知的阿片受体主要分为以下四种亚型：μ、δ、κ和ORL1 （阿片孤儿受体）
κ受体研究发展史
spiradoline 临床II期被终止
enadoline
κ受体研究新方向
• Neuroprotective against hypoxia/ischemia (cardiovascular protection)
20世纪60年代 Bently提出设想
thebaine
4、奥维醇及其类似物
活性是吗啡 的100012000倍
17-18位烯键还原
阿片受体非选择性激动剂
Rapoport 提出吗啡环上C6Lewis
与抑制 位点作 用
C7-C8三个原子所 构象限制 构成平面以下存 在一个κ受体关键 激动区域 μ的部分激动剂和δ、κ的拮抗剂
J. Cereb. Blood Flow Metab. 26 (3): 414
• Suppression of tumour growth
• British Journal of Cancer (2012) 106, 1148
• Treatment of drug addiction (proven indication) • Anti-depression effects of κ antagonists (current research highlights)
非肽类κ配基
非肽类κ 配基结构繁杂多样，从结构上可以分成吗啡生物碱及其结构类似 物、芳香乙酰胺类、芳基哌啶类和其他结构类型 吗啡生物碱及其类似物 芳香乙酰胺类
芳基哌啶类
其他类
吗啡生物碱及其类似物
• 1、苯併吗喃类
• Байду номын сангаас、吗啡结构类型衍生物
• 3、吗喃类(吗啡烃类)
• 4、奥维醇类及其相关类似物
1、苯併吗喃类