簡介：中文中文8900字出處出處BALATSOSNAA,DIMITRIOSV,PANAGIOTISM,ETALCOMPETITIVEINHIBITIONOFHUMANPOLYASPECIFICRIBONUCLEASEPARNBYSYNTHETICFLUOROPYRANOSYLNUCLEOSIDESJBIOCHEMISTRY,2009,4826604451本科畢業(yè)論文設計外文翻譯譯文譯文通過合成氟通過合成氟代嘧啶代嘧啶核苷競爭性抑制人多聚核苷競爭性抑制人多聚A特異性特異性核糖核酸酶核糖核酸酶PARNCOMPETITIVEINHIBITIONOFHUMANPOLYASPECIFICRIBONUCLEASEPARNBYSYNTHETICFLUOROPYRANOSYLNUCLEOSIDES摘要摘要聚（A）特異性核糖核酸酶（PARN是一種獲得性相互影響的脫腺苷，這個脫腺苷酶是居間的，和其它外切核酸酶類連接在一起，參與真核信使RNA的翻譯表達，因而它能積極參與有規(guī)律的基因的表達。到目前為止，氨基糖苷類和自然核苷酸是唯一報道的人類PARN活動的調節(jié)器。在現在的研究中，我們發(fā)現合成的核苷類似物連接一個氟代嘧啶核苷的糖基和苯甲酰修飾的胞嘧啶或腺嘌呤作為基本官能團能有效地抑制人類PARN。如以前所報道，當對多種腫瘤細胞系進行測試時，這種核苷類似物表現出很大的抑制作用。動力學分析表明，對PARN的抑制是有競爭性的，并不能通過改變外切核糖核酸酶類鎂（Ⅱ）的濃度來釋放。此外，用乙酰和/或糖基三苯甲基來替代糖基上2′，4′或6′的OH是抑制效果的關鍵。要了解核苷如何準確的進入PARN活性部位，通過分子動力學模擬之后我們對分子進行對接。在硅片分析表明，這些化合物能有效地進入PARN活性中心。我們的研究結果支持這一想法即通過起催化作用的氨基酸殘基的相互作用使糖基介導的穩(wěn)定的核苷到達活躍的部位。兩者合計，在體外和硅片的數據表明，我們人類PARN分子之間的目標是通過降低信使RNM的周轉率而使這些化合物可發(fā)揮治療作用，從而解釋其在分子水平上的已知的體內抑制作用。脫腺苷化是鎂（Ⅱ）依賴的外切核糖核酸酶類，它可以不斷裂解多聚（A）的末端，并釋放5′平滑肌磷酸酶1。在所有的脫腺苷，聚（A）特異性核糖核酸酶（PARN）是獨一無二的，因為它可以在脫腺苷化期間與5′帽結構和可以進入活動現場。生化和在硅片的三維模型分析顯示這三個糖羥基在高效抑制作用方面是重要的角色。我們的數據表明，在本研究中所使用的類似物鉛化合物可作為服務于發(fā)展的新可能的PARN抑制劑和其他基本DEADENYLASES與新的治療方法的潛力用。材料與方法材料所有化學品包括嘌呤核苷酸和脫氧核苷酸，亞甲基藍，POLYADENYLIC酸鉀鹽（平均粒徑300腺苷，巴士A300）來自SIGMAALDRICH核苷類似物的合成。氟代嘧啶核苷合成如前所述（31）。簡單地說，凝結1′，2′，4′，6′四O乙?；?′脫氧3′氟葡萄糖胞嘧啶，SILYATEDN4苯甲酰胞嘧啶，或N6苯甲酰腺嘌呤造成的1的生產（2′，4′，6′三O乙酰基3′脫氧3′氟ΒD吡喃葡萄糖N4苯甲酰胞嘧啶（5條）或9（2′，4′，6′三O乙?；?′脫氧3′氟ΒD吡喃葡萄糖）N6苯甲酰（±1）腺嘌呤，分別來說，在場的三甲基硅三氟甲烷磺酸鈉和錫氯化物。脫保護的第5條與氫氧化鈉乙醇吡啶格A1分別產生1（3′，4′脫氧3′氟ΒD吡喃葡萄糖）胞嘧啶（C6）的，1（3′4′脫氧3′氟ΒD吡喃葡萄糖）N4苯甲酰胞嘧啶（A6的），或9（3′，4′脫氧3′氟ΒD吡喃葡萄糖）N6苯甲?；汆堰剩ˋ2）的。A2的治療和干2，2二甲氧基丙烷，N，N二甲基甲酰胺，通過乙酰化后的自由羥基集團在2′位的糖基醋酸酸酐/吡啶，去除異亞丙基，而且，最后，選擇性保護的主要6′羥基組一組取得了三苯甲基化合物A4。氧化的氟乙?；绑wA4與吡啶踵鉻酸鹽/乙酸酐給予9（3′脫氧3′氟6′O型三苯甲基ΒDGLYCEROHEX2′ENOPYRANOSYL4′ULOSE）N6苯甲?；汆堰剩ˋ3）。表達和純化重組PARN。質粒編碼的全尺寸74KDA的人類PARN（VIRTANEN教授提供的，UPPSALAUNIVERSITY，瑞典）（用于N末端HIS6標簽的多肽表達），被傳遞給BL21（DE3）細胞去表達重組蛋白，如前所述33，加入一些修改。簡單地說，菌落生長在37℃過夜的卡那霉素（50UL/ML）。培養(yǎng)物在（1100）稀釋后在相同的37℃被異丙基1硫代Β的D半乳糖苷（IPTG）誘導的一個最終的濃度01MM的培養(yǎng)基中生長。用于PARN表達的培養(yǎng)液被允許在37℃下培養(yǎng)3小時。在4℃下經離心法收集細胞要20分鐘，和顆粒被凍結在70℃。表達了他的標記可溶性蛋白進行純化下列先前描述協(xié)議33。PARN活性測定和動力學分析。如所述前34，酶的活性可以被亞甲藍所測定。作為時間函數脫腺苷酶率被確定用時間進程分析（圖1）。亞甲藍是由12MG的亞甲藍溶解在100ML的3嗎啉基丙磺酸緩沖液中制備而成的（01M的3嗎啉基丙磺酸氫氧化鉀，PH值75和2MMEDTA）。標準反應緩沖液含

簡介：中文中文9326字出處出處BRITISHJOURNALOFPHARMACOLOGY,2009,1572195206譯文譯文傳病媒介設計與施藥綜述細胞滲透性肽二十年從分子機制到治療THEMEDSECTIONVECTORDESIGNANDDRUGDELIVERYREVIEWTWENTYYEARSOFCELLPENETRATINGPEPTIDESFROMMOLECULARMECHANISMSTOTHERAPEUTICSFREDERICHEITZ,MAYCATHERINEMORRISANDGILLSDIVITACENTREDERECHERCHESDEBIOCHIMIEMACROMOLECULAIRE,UMR5237,CNRS,UM1,UM2,CRBMDEPARTMENTOFMOLECULARBIOPHYSICSANDTHERAPEUTICS,1919ROUTEDEMENDE,MONTPELLIER,FRANCE摘要最近發(fā)現由于滲透功能欠佳以及低效的生物利用率而未用于臨床的新型有效治療分子，已經成為了治療學發(fā)展的關鍵。用于提高治療分子細胞的吸收技術已經設計出來，其中包括細胞滲透性肽（CPPS）。對若干蛋白質進入細胞的能力進行研究中首次發(fā)現了CPPS。迄今為止，大量CPPS已被發(fā)現，并可分為2個主要類別，第一個要求通過細胞內攝作用與藥物進行化學銜接，第二個包括與藥物形成穩(wěn)定的非共價化合物。現今，CPPS成為了用于非攻擊性進入細胞的理想工具，并成功用于不同于小型化學分子，核酸類，蛋白質類，肽類，脂質體與顆粒的治療分子體外與體內的遞送物質。這篇綜述集中于結構/功能以及日常給藥過程中CPPS的細胞攝取機制。我們也會強調用于治療分子遞送的多肽載體運用，并提供最新臨床評價。這篇文章是傳病媒介設計與施藥綜述的一部分，此章節(jié)中出現的所有文章以列于論文最后。關鍵詞細胞滲透性肽；非共價遞藥系統(tǒng)；低分子反意核糖核酸；納米顆粒；施藥；分子機制；治療學縮寫詞CPP細胞滲透性肽；GAG葡糖胺聚糖；NLS核定為系列；PMO磷酸類嗎琳代低聚物；PNA核酸肽；PTD蛋白質轉導域引言施藥的挑戰(zhàn)過去10多年，為了突破小型分子和基因治療的局限性，我們已經證明最新的大型治療分子并沒有遵循利平斯基的規(guī)則，這是一個極大的促進因素，比如蛋白毒液肽相銜接POOGAETAL,1998。自此，設計出許多其他能夠觸發(fā)介質穿透細胞膜進入細胞質的CPPSJ?RVERANDLANGEL,2004JOLIOTANDPROCHIANTZ,2004DESHAYESETAL,2005SNYDERANDDOWDY,2005。CPPS是一種普遍少于30種氨基酸類肽，基于天然和非天然蛋白或者是嵌合序列，并且能夠再細分成2類。第一類要求化學與介質鏈接，第二類則包括穩(wěn)定結構和非共價配合物。CPPS也能與結構的觀點相區(qū)分，例如隨便哪個聚陽離子，本質上存在于基本序列或者兼性的聚精氨酸族。代表性的CPPS在表格1中已列明。雖然這份綜述主要關注于基于天然氨基酸類CPPS，但是現今關于CPPS的新觀念包含非天然的和改良的，為了提高穩(wěn)定性或者運輸效率而被提倡。FARRERASINFREUETAL,2007共價策略基于科學技術上的細胞穿透肽的描述，到目前為止主要包括介質與化學交聯(lián)或是跟在CPP融合蛋白標記物表達式之后的克隆所獲得的對肽載體之間共價結合形成結構NAGAHARAETAL,1998GAIT,2003MOULTONANDMOULTON,2004ZATSEPINETAL,2005。大多數著作報道了TAT上的肽類FAWELLETAL,1994VIVESETAL,1997FRANKELANDPABO,1988,穿膜肽DEROSSIETAL,1994,聚精氨酸肽ARG8序列WENDERETAL,2000FUTAKIETAL,2001和傳輸POOGAETAL,1998其他衍生蛋白肽類，例如來自純單皰疹病毒的VP22蛋白ELLIOTTANDO’HARE,1997,PVECELMQUISTETAL,2001,降鈣素衍生肽SCHMIDTETAL,1998KRAUSSETAL,2004,抗生物肽BUFORINI和SYNBPARKETAL,1998PARKETAL,2000,此外還有聚脯氨酸SAP多肽PUJALSETAL,2006也被成功地用于提高與介質的共價鏈接轉導JOLIOTANDPROCHIANTZ,2004ELANDALOUSSIETAL,2005MURRIELANDDOWDY,2006。最近，CPPS的新世代，提出了結合不同的轉導基序ABESETAL,2007或者是與蛋白或低聚核苷酸結合域串聯(lián)的轉導域MEADEANDDOWDY,2007。不同的化學物質已被涉及，用來穩(wěn)定或裂解主要的二硫鍵或硫代酯聯(lián)在內的共軛體系。根據介質的穩(wěn)定性和效率，有幾個參數需要考慮，包括聯(lián)動化學類型，隔離物的本質GAIT,2003ZATSEPINETAL,2005共價策略，大體上報告了DNA模仿分子或寡核苷酸立體的遞送，其中包括PNAKOPPELHUS

簡介：中文中文6395字出處出處NATUREBIOTECHNOLOGY,2000,181111511155本科畢業(yè)論文設計外文翻譯學院專業(yè)藥學藥學姓名學號指導老師指導老師職稱合作老師合作老師職稱外文題目（原文）外文題目（原文）TRANSGENICTRANSGENICPLANTSPLANTSASASFACTORIESFACTORIESFORFORBIOPHARMACEUTICALSBIOPHARMACEUTICALS譯文譯文轉基因植物轉基因植物生物醫(yī)藥的生產工廠生物醫(yī)藥的生產工廠GLYNISGIDDINGS,GORDONALLISON,DOUGLASBROOKS,ANDADRIANCARTERINSTITUTEOFBIOLOGICALSCIENCES,UNIVERSITYOFWALES,ABERYSTWYTH,CLEDWYNBUILDING,ABERYSTWYTHCEREDIGIONSY233DD,UKCORRESPONDINGAUTHORGDGABERACUKRECEIVED12NOVEMBER1999ACCEPTED11AUGUST2000由于容易轉化且能為蛋白質提供廉價來源，植物在蛋白質和多肽等生物藥物生產中具著巨大潛力。在第一個植物來源的生物藥物正在進行臨床試驗的同時，許多生物技術公司正積極開發(fā)，進行大田試驗，并獲得植物表達系統(tǒng)的專利。水蛭素是一個轉基因植物生物藥品，目前首次在加拿大進行了商業(yè)化生產。但產物的純化是一昂貴的過程，目前開發(fā)了多種方法解決這個問題，包括油體膜蛋白融合技術，使提取油體的方法獲得目的蛋白。在某些情況下，我們可以利用直接消化經修飾的植物來進行生物制藥產品的給藥，這種情況下，就可能消除對純化步驟的需要。這種生物藥品和可食疫苗可以存儲和分布在種子，塊莖，或水果中，使得發(fā)展中國家的管理部分可以更便宜和容易實施免疫計劃。通過轉基因植物生產可以使一些如葡糖腦苷脂酶等有限使用的昂貴生物培養(yǎng)生產的外源蛋白綜述，見（REF14）進行概述。農業(yè)生產系統(tǒng)通常使用兩種轉化方法在植物里生產重組藥品。第一種利用農桿菌穩(wěn)定轉化，基因槍法，或其他標準的轉化技術來生產轉基因植物。煙草被廣泛用作模型表達系統(tǒng)，其他一些植物也已被使用，其中包括煙草，擬南芥，番茄，香蕉，蘿卜，豇豆（黑眼豆），油菜，埃塞俄比亞芥菜，馬鈴薯，水稻，小麥和玉米。第二種是當重組病毒在非轉基因植物宿主中表達和復制時感染非轉基因植物。最常用的主要病毒系統(tǒng)是煙草花葉病毒（TMV）和豇豆花葉病毒（CPMV）。雖然產量類似于轉化植株，但他們產量可以更高。煙草花葉病毒衍生載體已被用于在番茄和煙草生產口服降血壓肽（血管緊張素1轉換酶抑制劑），以及在NBETHAMIANA中生產艾滋病毒抑制劑（Α天花粉蛋白）。嵌合CPMV顆粒，顯性人類鼻病毒14和HIV1，已從轉基因豇豆植物中分離出來。他們被發(fā)現可以在艾滋病毒嵌合體的情況下引起抗體的產生，以消除在體內由HIV1病毒感染的T細胞。第二種方法對于疫苗生產可能是很有用的。疫苗可以防范疾病，保護機體，他們通過刺激胃腸道的相關淋巴組織來促使免疫球蛋白A的產生。進入病毒顆粒、或將其和病毒蛋白鏈接的抗原表位的表達促進這一進程。轉基因植物藥物蛋白的表達主要是由組成型CAMV35S啟動的。然而，可能會導致低產量，例如，人血清白蛋白占可溶性總蛋白的002（TSP）和人類蛋白C為0001％（見13）。種子限制表達可以帶來更高的產量。種子表達的腦啡肽，例如，TSP可以累積到29％。種子的表達已通過外源基因引入谷蛋白（GT3）信號肽序列和GT3啟動子作用下轉錄實現了。在煙草中轉基因免疫球蛋白的轉錄也由種子特異性，發(fā)育調節(jié)，豆素B4的啟動子控制。由于在細胞質中免疫球蛋白經常干擾細胞的功能，最好是將它們分泌到非共質體系，或定位到內質網處，在那里他們積累到更多比例（15％）。定位可通過豆球蛋白B4的信號序列實現。雖然由于上述生產系統(tǒng)易轉化、易于應用它們已被廣泛應用于研究和驗證概念的研究，但并不是用于商業(yè)或其他大鬼魅應用的理想選擇。從這些植物分離純化重組蛋白將是低效和昂貴的，而且需要去除各種代謝物，包括尼古丁。此外，種子只占煙草植物中很一小部分比重，將必須使用營養(yǎng)組織。商業(yè)生產中從含水高的組織中提取蛋白質可能導致蛋白質的損失，而且降低了處理效率

簡介：中文中文38003800字譯文譯文實驗性腎衰竭對頭孢噻利誘導大鼠癲癇發(fā)作的藥效學實驗性腎衰竭對頭孢噻利誘導大鼠癲癇發(fā)作的藥效學影響影響EFFECTOFEXPERIMENTALRENALFAILUREONTHEPHARMACODYNAMICSOFCEFOSELISINDUCEDSEIZURESINRATSMASASHINAGATAANDMASATOYASUHARA我們調查了輸液速度和實驗性腎衰竭對頭孢噻利（CFSL）誘導大鼠癲癇發(fā)作的藥效學影響，作為CFSL誘導癲癇發(fā)作的動物模型，給雄性WISTAR大鼠靜脈注射了來自三個不同國家之一的CFSL（1458G/H/RAT），直到最大癲癇發(fā)作（其發(fā)生在輸液后的80到360分鐘）。當停止滴入CSFL后，腦脊液（CSF），血液（血清）以及腦中均可檢測出其成分。CSFL誘導癲癇發(fā)作的血藥濃度隨著輸液速度的增加而增加，但是腦組織液以及腦脊液中癲癇發(fā)作的血藥濃度將不受輸液速度的影響。給輸尿管結扎（UL）以及對照組大鼠以14G/H/RAT的速度靜脈注射CFSL直到癲癇發(fā)作，然后以相同的步驟來確定輸液速度對CFSL的血藥濃度的影響。腎衰竭對CFSL誘導癲癇發(fā)作的要求在伴隨著一個在規(guī)定的數額顯著下降。輸尿管結扎的大鼠的血清，腦液以及CSF中的血藥濃度明顯比對照組大鼠的低。結果表明，實驗策略和動物模型在這個調查中用來評估疾病的影響還有CFSL誘導大鼠癲癇發(fā)作的其他各種藥效學影響是有用的，而腎功能衰竭是影響CFSL神經毒性最危險的因素之一。關鍵詞關鍵詞頭孢噻利；腎功能衰竭；癲癇；藥效學頭孢噻利（CSFL），第四代頭孢菌素抗生素，已經于1998年9月引入日本市場在同年12月，因中樞神經系統(tǒng)CNS產生的副作用如癲癇發(fā)作和恍惚狀態(tài)被警告列入CSFL的標簽。在很多情況下，這些不良反應已經在老年人和/或者腎功能衰竭患者中被觀察出來。因此，腎功能衰竭被認為是影響CFSL神經毒性最危險的因素之一。CFSL主要經腎臟排泄，腎功能衰竭患者可增加CFSL的血藥濃度。另外，關于腎衰竭能否改變CFSL誘導大鼠癲癇發(fā)作的藥效學還是未知數。的濃度，用BIORAD蛋白分析法NIPPONBIORADLABORATORIES,JAPAN測定CSF中的蛋白濃度，使用牛血清白蛋白作為參照物。CFSLCFSL血藥濃度的分析血藥濃度的分析用HPLC測定CFSL的血藥濃度。測定條件，100ΜL（01M）的血清以及鈉和10ΜL鉀磷酸鹽緩沖液PH70，100MG/ML的硫酸頭孢匹羅和100ΜL乙腈混合，渦旋10S，離心（13000轉/MIN）2MIN后作為內標物取上清液100ΜL（002M）鈉和鉀磷酸鹽緩沖液（PH25）400ΜL，混合，渦旋10S，取5ΜL注入HPLC色譜柱。分析30ΜLCSF，內標物的濃度減少到1MG/ML，以及注射量為50ΜL。測定腦內的CFSL濃度，準確稱量右半球，用生理鹽水勻漿（量為右半球重量的5倍），取勻漿200ΜL（01M），鈉和鉀磷酸鹽緩沖液PH7020ΜL，1MG/ML硫酸頭孢匹羅和200ΜL乙腈混合，渦旋10S，作為內標物，最終混合成50ΜL注入HPLC色譜柱。HPLC色譜儀器為LC9A（SHIMADZU,JAPAN），254NM的SPD6A分光光度計，色譜柱TSKGELODS80TM5MM,46MMID315CM,TOSOH,JAPAN流動相為0065V/V的乙腈溶液，002M的鈉和鉀磷酸鹽緩沖液PH25，流速為10ML/MIN數據分析數據分析所有結果表示平均±SD評價不同的樣品組分意味著在UL和對照組大鼠中使用F試驗判斷平等差異，其次是學生T試驗或者WELCH的T試驗。TUKEY–KRAMER試驗用來分析其他實驗結果。結果結果輸液速度對血液、腦以及輸液速度對血液、腦以及CSF中致最大癲癇發(fā)作的藥物濃度的影響中致最大癲癇發(fā)作的藥物濃度的影響從表1中可看出，根據不同的藥物輸注速率1458G/H/RAT靜脈注射CFSL產生的使大鼠最大癲癇發(fā)作的時間在80607AND360651MIN。全部動物的給藥劑量在29603TO34605G/KG，并隨著輸液速度的增加而減少。在血清中到達最大癲癇發(fā)作的CFSL藥物濃度明顯受到藥物輸液速度的影響，藥物濃度隨著輸液速度的增加而增加；在腦和CSF中到達最大癲癇發(fā)作的CFSL藥物濃度不受藥物輸液速度的影響。

簡介：中文中文18萬字萬字出處出處BEENKENA,MOHAMMADIMTHEFGFFAMILYBIOLOGY,PATHOPHYSIOLOGYANDTHERAPYJNATUREREVIEWSDRUGDISCOVERY,2009,83235253本科畢業(yè)論文設計外文翻譯譯文譯文FGF家族生物學，病理生理學和治療學簡述家族生物學，病理生理學和治療學簡述THEFGFFAMILYBIOLOGY,PATHOPHYSIOLOGYANDTHERAPY摘要摘要成纖維細胞生長因子家族（FGFS）中的各個因子調控著一系列的發(fā)育過程，包括腦的發(fā)育、肢體的分化和軀干的形成。研究者已經對FGFS在促有絲分裂、細胞的保護和促血管生成方面的作用進行了探索。最近，學者們發(fā)現了在膽汁酸、葡萄糖和磷酸鹽平衡過程中起內分泌調節(jié)作用的FGF19亞家族所具有的重要功能，這一發(fā)現引起了人們對該家族在藥理學方面應用潛力的巨大興趣。本綜述探討了使用重組FGFS和小分子成纖維細胞生長因子受體激酶抑制劑治療癌癥和心血管疾病等傳統(tǒng)的應用方法和新發(fā)現的FGFS在治療代謝綜合征及堿性磷酸酶過少癥等疾病方面所具有的潛力。前言前言根據不同的序列同源性和系統(tǒng)發(fā)育的規(guī)律可將哺乳動物的18種成纖維細胞生長因子（FGF1FGF10和FGF16，FGF23）分為6亞家族FGF1和FGF2；FGF3，FGF7，FGF10，FGF22；FGF4，FGF5和FGF6；FGF8，FGF17和FGF18；FGF9，FGF16和FGF20和FGF19，FGF21和FGF231。部分已編號的“FGFS”并未被分配到任意亞家族中，其中包括成纖維細胞生長因子同源因子（以往被稱為FGF11－FGF14）。這些因子具有和FGF家族很高的序列同源性，但沒有激活成纖維細胞生長因子受體（FGFRS）的能力，因此不被規(guī)類為成纖維細胞生長因子家族中的成員2（纖維細胞生長因子同源因子的詳細介紹請參見方框1）；FGF15是小鼠體內的人類FGF19的同源蛋白（即人類FGF19＝小鼠FGF15）。FGFS被公認為一種旁泌因子，在胚胎發(fā)育過程種的組織和器官形成中起重要作用前5各亞家族的FGF生長因子屬于這一類。與此相對的，最近人們證明了FGF19，FGF21和FGF23亞家族起內分泌激素的功能，如對膽汁酸，膽固醇，葡萄糖，維生素D和磷酸鹽內穩(wěn)調節(jié)器的作用，這種作用的發(fā)生主要依賴于靶向組織中KLOTHO蛋白質的存在。與成纖維細胞生長因子信號異常相關的人類疾病早有報道。發(fā)揮異常調控作了連續(xù)的正電性表面區(qū)域。相對的，FGF19、FGF21和FGF23亞家族的HBS包含由Β1Β2折疊和Β10Β12區(qū)域形成的隆起，使HSGAG和FGFS核心骨干的親和力降低，并導致這個亞家族的獨特的內分泌特點。FGFRSFGFRSFGF配體通過結合和激活酪氨酸激酶受體家族發(fā)揮作用，這一過程需要HSGAG的參與。FGFR家族有四種受體基因（FGFR1FGFR4）編碼受體，所編碼受體由三個免疫球蛋白樣區(qū)域（D1、D2和D3區(qū)）、單通過（SINGLEPASS）跨膜區(qū)和細胞內的酪氨酸激酶域構成。FGFRS存在一段富含酸性氨基酸和絲氨酸的序列，位于D1區(qū)和D2區(qū)之間，成為酸盒（ACIDBOX）。FGFRS細胞外功能區(qū)的D2區(qū)和D3區(qū)是FGF的結合區(qū)域，而D1區(qū)和酸盒可以發(fā)揮自動抑制FGF和FGFR結合的作用（圖2A）。通過外顯子跳躍刪除FGFR1、FGFR3中的D1域和（或）酸盒，使FGFR形成不同的異構體。在FGFR1–3的D3區(qū)后半部分的選擇性剪接產生B型（FGFR1B–3B）和C型（FGFR1C–3C）異構體,這些異構體具有特殊的FGF結合性質，主要存在于上皮細胞和間充質細胞。上皮細胞和間充質細胞含有不用的FGFR異構體。每種FGF都要結合上皮或間充質細胞的FGFRS，而FGF1比較特殊，可同時作用兩種剪切異構體。HSGAGS和受體配體二聚體結合后，激活FGFR的胞內酪氨酸激酶區(qū)域，通過轉磷酸作用激活酪氨酸環(huán)路，環(huán)路的磷酸化在酪氨酸C末端磷酸化后形成，然后激酶插入到近膜區(qū)。主要的FGFR胞內作用底物是磷脂酶C（PLA）FRS1和FRS2（FGFR作用底物2）。FGFR的C末端的固有酪氨酸（在FGFR1中，該酪氨酸為Y766）磷酸化，產生一個PLCΓ的SH2區(qū)結合位點，這一過程需要PLCΓ的磷酸化和激活。相對的，FRS2由FGFR的近膜區(qū)組成。FRS2的磷酸化是MAPK通路（RAS–MITOGENACTIVATEDPROTEINKINASE）和PHOSPHOINOSITIDE3KINASE–AKT通路激活必需的。FGFS也可通過FGFFGFR復合物激活的胞吞作用在細胞核和細胞液中，作為內源性配體發(fā)揮作用。FGFFGFRFGFFGFR特異性特異性FGFFGFR結合的特殊性在于其受到18種FGFS和7種主要FGFRS（FGFR1B、FGFR1C、FGFR2B、FGFR2C,、FGFR3B、FGFR3C和FGFR4）基本序列的差異性的影響，FGFS、FGFRS和HSGAGS三者的復合物的空間關系只是短暫存在。FGFRS的剪切異構體具有組織特異性FGFRB異構體在上皮組織中表達，FGFRC異構體在間充質細胞組織中表達。FGF即可在上皮組織中表達也可在間充質細胞組織中表達，通常選擇與之相反的組織的受體作用。一般來說，上皮組織中表達的FGFS會激活間充質細胞中的FGFR，反之亦然。FGF1比較特殊，與同一種FGFR的B、C異構體都可結合。FGFS過量表達會引起結合特性的異常，從而產生生理學病癥，如在癌癥中FGFS過量表達。FGF1、FGF2、FGF8和FGF10及其同家族FGFRS的研究發(fā)現了FGF的N末端和Β1折疊長度的差異（FIG1B），FGFR的D3區(qū)有兩種異構體形

簡介：中文中文2700字出處出處BIOLOGIAPLANTARUM,2004,481129132八種野生郁金物種的體外植株再生和遺傳保護八種野生郁金物種的體外植株再生和遺傳保護INVITROPLANTREGENERATIONANDGENOTYPECONSERVATIONOFEIGHTWILDSPECIESOFCURCUMA組織培養(yǎng)和凍存組，國家局植物遺傳資源，新德里110012，印度ALBERTKATZCENTERFORDESERTAGROBIOLOGY,BENGURIONUNIVERSITYOFTHENEGEV,SEDEBOQUERCAMPUS,ISRAEL摘要摘要對八種郁金野生物種的體外植株再生和中期基因保存方法進行了優(yōu)化。這兩種現象都存在基因型依賴性，所使用細胞分裂素的種類和濃度對其有著顯著的影響。在一般情況下，發(fā)現芐基腺嘌呤（BA）比測試的其他細胞分裂素有利于植株再生和異戊烯基腺嘌呤（2IP）則有利于基因型保護。每個發(fā)芽數介于13至72和貯存期由264至379天。在30天的培養(yǎng)后，CMALABARICA在MS114ΜMZEATIN（72個芽）中芽的再生頻率最高。郁金（未知的野生種）在MS246ΜM的2IP中可能存儲期最長，最長期限（379天）。其次是CAROMATICA在MS228ΜMZEATIN中（363天）。組織培養(yǎng)的植株同他們的母本形態(tài)相似。在體外培養(yǎng)保存的植物的組織可以快速繁殖及轉移到溫室土壤中產生正常的根莖。關鍵詞關鍵詞種質資源，遺傳資源，微體繁殖，組織培養(yǎng)姜黃屬植物（姜科）由80余種根莖型多年生草本植物組成，廣泛分布于亞洲熱帶地區(qū)，亦分布于非洲和澳洲。體外技術可用于郁金種質資源保護，馬鈴薯，木薯和山藥種質資源的情況可以證明。在我們的實驗室組織培養(yǎng)已成為無性繁殖和各種作物品種保護的有效方法。直接組織培養(yǎng)再生植株（不通過愈傷組織）是體外保存計劃成功的先決條件因為通過愈傷組織誘導再生植株可能導致體細胞無性系變異。NADGAUDA等（1978）和BALACHANDRAN等（1990年）報道了以CLONGA根莖上的芽作為外植體進行體外增殖和通過葉片誘導的愈傷組織進行增殖。然而，除了CAERUGINOSA，CCAESIA（BALACHANDRAN1990年）和CAROMATICANAYAK2000，這些關于野生物種的快繁報告是無法現成利用的。迄今用于野生郁金物種的保護的體外技術還沒有系統(tǒng)工作的報告。目前的研究對野生郁金的直接植株再生和有效保護的體外方法進行了優(yōu)化。根莖的芽采自八種野生郁金物種的根狀莖的新芽，分別為CAERUGINOSAROXB表2四種細胞分裂素（在兩個濃度）對體外保存郁金野生物種（天數）的影響。在所有的物種測試中所有細胞分裂素都使用兩個濃度，外植體100來自于莖基部。然而，芽的形成量在各種不同的物種是不同的（表1）。培養(yǎng)3周后，新芽形成小芽（12CM）。在45個星期的培養(yǎng)中觀察芽數，沒有進一步增加。芽的再生遵照每個物種的獨特模式。測試物種種類和細胞分裂素對芽的再生有著顯著的差異。所有的物種合計，每個培養(yǎng)管芽數平均為13至72（見表1）。CMALABARICA在MS114ΜMZEATIN中產生最多數目的芽（每個72個芽）。CAROMATICA，CBROG，CCAESIA，CRAKTAKANTA和CSP在MS111ΜMBA中能產生較多芽。BA有利于CLONGA和CAROMATICA（NAYAK2000年）快速繁殖已經有文獻報導。2IP對CLONGA再生芽作用見于SALVI等的報道中，但在我們的研究中沒有發(fā)現野生物種芽數在2IP培養(yǎng)基中高于其他細胞分裂素的培養(yǎng)基。沒有數據表明在有各種分裂素的培養(yǎng)基中培養(yǎng)物發(fā)現較長的芽。然而，CBROG在MS116ΜMKINETIN中有最高長度的芽（56厘米），其次是CAROMATICA在MS111ΜMBA中的芽48CM。生根不影響芽發(fā)育成植株。觀察發(fā)現培養(yǎng)4周后在所有培養(yǎng)基上生根。不用嘗試去收集每個芽的根的確切個數，根是否來源于單獨的芽在培養(yǎng)中難以區(qū)別。然而，觀察轉移到土壤中的植物，每個芽有24個主根。。每個物種移植到泥土中存活的強壯的植物高達96100％的存活率跟SALVI的等人的意見一致。組織培養(yǎng)的植株同母本的形態(tài)相似。對再生植株的遺傳穩(wěn)定性進行了研究使用8種同工酶和RAPD分析，并沒有發(fā)現體外保存植發(fā)生變異?；谶z傳穩(wěn)定性研究的詳細結果將進行單獨的報告。

簡介：中文中文4465字出處出處INTENSIVECAREMEDICINE,2007,33711621167譯文譯文亞胺培南與多粘菌素相比在治療呼吸機相關性肺炎的安全性和有效性一個匹配的病例對照研究HKALLEL,LHERGA,MBAHLOUL,AHAKIM,HDAMMAK,HCHELLY,CBENHAMIDA,,ACHAARINREKIK,MBOUAZIZ摘要要目的本研究的目的是為了確定多粘菌素在治療由泛耐藥性銅綠假單胞菌或鮑曼不動桿菌引起的呼吸機相關性肺炎的有效性和安全性。設計兩兩匹配一對一的研究。背景結合HABIBBOURGUIBAUNIVERSITYHOSPITAL（SFAX,TUNISIA）醫(yī)藥，外科重癥監(jiān)護病房的要求。患者六十例由泛耐藥性的鮑曼不動桿菌引起的VAP患者與肺炎克雷伯氏菌進行匹配,用60控管與由鮑曼不動桿菌引起的VAP對銅綠假單胞菌敏感的藥物亞胺培南進行匹配。在抗生素的治療中，所有患者的腎功能正常。干預措施案例患者通過多粘菌素靜脈注射治療，控制患者通過亞胺培南靜脈注射治療。測量及結果多粘菌素和亞胺培南群體之間的基準線相似。抗生素治療的平均持續(xù)時間多粘菌素為95±38天（范圍58天），亞胺培南89±28天（范圍520天）（P值032）?？股刂委烿AP中較好的臨床方案，多粘菌素占45（75），亞胺培南占43（717）。在治療抗生素的起始階段，兩組傳染病的時間分辨率參數無統(tǒng)計學差異。在抗生素的治療過程中，沒有一組的患者發(fā)展成腎功能衰竭。結論我們認為，多粘菌素在治療VAP引起的耐銅綠假單胞菌和鮑曼不動桿菌是一種安全的有效的選擇。關鍵字關鍵字呼吸機相關性的肺炎；腎毒性；亞胺培南說明革蘭陰性菌的耐藥性（PDR）是一個全球性的重要問題，特別是在重癥監(jiān)護室（ICU）1，2中。多重耐藥性使經驗性選擇抗菌藥物出現困難，同時延遲了合適的抗菌藥物治療3。在近日出版的文獻中，抵抗抗菌藥物使用的兩個最廣泛的微生物是銅綠假單胞菌和鮑曼不動桿菌4。由于這個原因，最近多粘菌素已被看作是治療這些微生物的最后選擇4。/FIO2，血清尿素氮和肌酐濃度。當天使用多粘菌素或者亞胺培南，記錄一下數據，發(fā)熱，白細胞計數，胸部X光檢查，PAO2/FIO2，血清尿素氮和肌酐濃度。每天記錄患者的情況，直至治療結束。結果有利或不利的情況（發(fā)燒的程度，白細胞計數和胸部透視）。不良反應，主要是急性腎衰竭（基于每日血清尿素氮和肌酐采樣）和肌無力。當患者出院，記錄以下變量日期記錄，從醫(yī)院ICU到出院。肺炎的診斷是基于（1）溫度≤36℃或≥385℃，（2）白細胞計數≤1500或≥1000萬，（3）新的或者漸進滲透的胸部X光片，（4）是否存在或者至少有一種微生物的濃度存在于106個/毫升的進樣管23。急性腎衰竭（ARF）是血清超過150摩爾/升肌酐濃度，且血液尿毒氮濃度超過10毫摩爾/升。每日進行VAP評估。VAP中被認為具有良好的成果，如能很好的緩解敗血癥的相關癥狀（發(fā)熱，白細胞增多），PAO2/FIO2大于187（25KPA）24和放射性分辨率（減少或消失呈現胸部透視X線表現）。VAP中被認為是不利的結果，如果沒有減免敗血癥有關的癥狀和無放射性的分辨率。微生物測試所有病原微生物的檢測使用常規(guī)微生物檢測辦法。藥敏試驗采用紙片擴散法（斷點是由全國衛(wèi)生委員會確定的臨床實驗室標準2526）。多粘菌素的藥敏性是使用10G多粘菌素紙片法。如果抑菌區(qū)域≥11毫米，菌株被認為是敏感的。中間的隔離格蘭陰性菌對抗生素的敏感性被認為是抵抗的。阻礙耐藥性的定義為分離到抗假單胞菌青霉素類，頭孢菌素類，碳氫霉烯了類，喹諾酮類和氨基糖苷類的程度。一個隔離的定義是，如果它抵抗所有的抗假單胞菌青霉素類除了多粘菌素。治療方案在多粘菌素組中，患者采用多粘菌素SULFOMETHATE鈉靜脈注射治療。劑量為600萬單位（≈10萬/公斤），每天分為三劑。在亞胺培南的患者組，采用亞胺培南（亞胺培南/西斯他丁；MSD）靜脈注射治療。劑量為每日2G，分為四個劑量。在這項研究中，初始使用抗菌素治療的所有情況下，在實驗的基礎上使用多粘菌素或者亞胺培南。統(tǒng)計分析確定變量百分率和連續(xù)變量均值（SD）。百分率比較采用卡方檢驗和T檢驗手段。WILCOXON配對試驗是用來比較匹配標準（年齡，SAPSII，與PAO2/FIO2）。應用KAPLANMEIER曲線被用來評估多粘菌素和亞胺培南組之間的差異（1）抗生素治療后的感染參數（2）28天后多粘菌素或亞胺培南治療VAP的

簡介：中文中文47254725字出處出處BIOCHEMICALPHARMACOLOGY,2008,761115901611譯文譯文姜黃素及其天然、合成的類似物的生物活性研究進展姜黃素及其天然、合成的類似物的生物活性研究進展ANANDP,THOMASSG,KUNNUMAKKARAAB摘要摘要姜黃素是存在于印度調味品姜黃中的一種黃色色素，研究發(fā)現它有抗炎、止血、抗腫瘤、治療糖尿病以及心血管、肺、神經系統(tǒng)、皮膚和肝等疾病，同時也能緩解骨骼和肌肉的損傷、抑郁癥、長期的疲勞和神經性疼痛。但姜黃素的顏色、水溶性差、以及體內生物利用度低限制了它的應用?；诮S素多種治療活性，因此人們急于尋求沒有上述問題的“性能好的姜黃素”。人們探索了多種方法來克服這些局限性，包括從姜黃植物中尋找天然的姜黃素類似物，在自然界中尋找天然的姜黃素類似物，合成姜黃素類似物以及用各種油脂和新陳代謝的禁制因素來改造姜黃素，研制姜黃素的脂質體和微粒體劑型，姜黃素前藥的研究，以及聚乙二醇化姜黃素的修飾。姜黃素是一個同型二聚體包含一個甲氧基和一個羥基，一個含有兩個邁克爾受體的庚二烯以及一Α，Β二酮基。眾多研究小組修飾其同系物的結構時已將這些集團都考慮在內。本文重點介紹用這些途徑產生活性更高的姜黃素類及其生物活性研究進展。11介紹介紹姜黃素是一種從姜科植物姜黃的根莖中得到的不溶于水的多酚。由于其廣譜的藥理學活性，姜黃很早就被用于治療多種疾病，姜黃素是姜黃的主要活性成分。從化學的角度，姜黃素含有一個Α，Β不飽和基團的Β二酮基，具有酮式烯酮式互變異構現象。姜黃素已經表現出抗氧化、抗炎、殺菌以及抗癌活性。它還能保肝、腎，抗凝血，預防心肌梗塞以及降血糖，抗風濕的作用。而且已經在很多動物模型和人身上的試驗表明姜黃素即使在很高的劑量下也是非常安全的。雖然姜黃素具有如此優(yōu)越功效和安全性，但迄今為止它并沒有被做為臨床藥物制劑。主要是因為它的水溶性差，生物利用度低，以及強的染色能力，這些問題已成了限制姜黃素臨床用藥的焦點，因此尋找活性相同或更高的姜黃素類似物成為國內外科學家的研究熱點。本文介紹當前在尋找活性更高的姜黃素類方面所做的素抗氧化活性的機制方面已被詳細系統(tǒng)研究，最近WRIGHT，SUNETAL，PRIYADARSINIETAL，LIGERETETAL，SUZUKIETAL，ANDCHENETAL的研究顯示酚羥基基團對抗氧化活性非常重要，正如BARCLAYETAL早期所預測的那樣。SUGIYAMA在使用二甲基四氫化姜黃素探索了Β二酮基在抗氧化過程中潛在的作用，JOVANOVICETAL的工作進一步支持了這一結論。鄰位烷氧基的存在加強了抗氧化活性，正如在二（34二羥基苯乙烯?；┘淄橹性黾右粋€羥基組分。羥基組分的位置效應已在體內條件下研究，似乎2位羥苯比4位羥基活性更好，如在二（2羥基苯乙烯酰基）甲烷比4羥基苯組分在姜黃素中表現出更好的抗氧化活性。還原C7鏈上的CC鍵產生THC并沒有減少其抗氧化活性。構效關系研究表明，雖然酚羥基在抗氧化中作用至關重要，羰基和Β二酮結構對抗氧化活性也是有必要的。SARDIJIMANETAL研究了Β二酮基組分的重要性，應用二（4羥基苯亞甲基）丙酮，2，6二苯亞甲基環(huán)己酮和環(huán)戊酮類似物等C5連接鏈的類似物。結果表明4羥基組分有助于提高抗氧化活性，當羥基基團鄰位1或2個甲氧基取代時活性加強。這些5碳鏈的二（4羥苯基）1，4戊二烯3酮表現出了比姜黃素更強的抗氧化活性。YOUSSEFETAL測試了2，6二苯亞甲基哌啶酮，環(huán)己酮和丙酮類似物，得到了相似的實驗結果，他們發(fā)現結構中含有3烷氧基4羥基基團的類似物表現出更強的抗氧化活性。VENKATESWARLUETAL通過在姜黃素類化合物的苯環(huán)上添加羥基得到了大量多羥基類似物，測試結果表明其抗氧化活性也進一步增強。姜黃素配合物的抗氧化能力也可通過另一方法研究。姜黃素的錳絡合物及其衍生物表現出姜黃素更強的SOD活性，羥基自由基清除活性和氮氧化物自由基清除活性。研究報道姜黃素的銅絡合物比姜黃素本身有更好的抗氧化，自由基清徐能國和SOD酶活性。在以同等抗氧化能力分析的研究中發(fā)現姜黃素的釩、銦、鎵絡合物和姜黃素Ⅲ比它們各自的前體物活性更高。總之，抗氧化活性似乎要求有至少兩個通過長鏈連接的羥苯基結構，并且增加含氧基團其活性也隨之增加，尤其是同時具備這幾個因素時活性更強。到底長鏈單位應該是不飽和的還是含氧的至今還沒確定。232抗炎活性姜黃素C7連接鏈烯鍵的加氫以及羰基的還原都會使抗炎活性降低，它通過抑制IKB激酶的活性來阻止NFKB產生。早期研究指出羥基單位是提供抗炎活性的關鍵基團，因為酚羥基部位的?；饔煤屯榛饔脮蟠蠼档推淇寡谆钚浴?

簡介：中文中文3743字出處出處JOURNALOFTHESERBIANCHEMICALSOCIETY,2006,717733744譯文譯文一些席夫堿配合物的合成及抗菌活性研究一些席夫堿配合物的合成及抗菌活性研究SYNTHESISANDANTIBACTERIALACTIVITYOFSOMESCHIFFBASECOMPLEXESNAIRR,SHAHA,BALUJAS,CHANDAS摘要用2,4二羥基5乙基苯乙酮合成了兩個席夫堿A13硝基11,3二羥基4乙基6亞乙胺基苯；A32硝基11,3二羥基4乙基6亞乙胺基苯。然后，選擇金屬銅，鎳，鐵和鋅，形成其金屬配合物，合成8個金屬配合物。通過對抗一些臨床上重要的細菌，例如綠膿桿菌，變形桿菌，奇異變形桿菌，肺炎克雷伯菌和金黃色葡萄球菌，對其進行抗菌活性的篩選。體外抗菌活性的測定采用瓊脂壟溝技術，以DMF（極性）和1,4二氧雜環(huán)己烷（非極性）作為溶劑。金屬配合物在不同溶劑中對細菌菌株影響的調查表明，抗菌活性由化合物的分子結構、溶劑的使用和細菌菌株而定。在極性溶劑DMF中席夫堿A3對菌株表現出較好的抗菌活性。四種金屬配合物當中，鋅配合物在1,4二氧雜環(huán)己烷溶劑中表現出最好的抗菌活性、其次是鐵；鎳配合物在DMF溶劑中表現出最好的抗菌活性、其次是鋅和鐵。關鍵詞席夫堿配合物；抗菌活性；DMF二甲基甲酰胺；二氧六環(huán)引言為了克服微生物對抗生素耐藥這個令人焦慮的問題，迫切的需要發(fā)現對新目標有活性的新型化合物。藥物制劑來源于許多粗藥材，還來自日益增長的野生物質。然而，以植物為基礎的藥物受到物料的來源壽命的限制。因此，需要通過不斷尋求更有效和更便宜的原材料來延續(xù)這個行業(yè)?；衔锝怆x后產生的不是單純的離子，而是復雜離子被稱作配位化合物。配位化合物表現出不同的特征屬性，這依賴于金屬離子對它們的約束、金屬的性質以及配體的類型等。金屬配合物廣泛應用于人類利益的各個領域。一個配金屬離子的溶液，水浴中回流45小時。得到深褐色沉淀，將沉淀物干燥。鎳配合物的合成01MOL的配體和氯化鎳分別在1,4二氧雜環(huán)己烷溶液和蒸餾水中制備。向配體溶液中滴加金屬離子溶液。加入氫氧化銨使溶液PH值保持在10105。水浴回流45小時，得到黃色沉淀，過濾、分別用1,4二氧雜環(huán)己烷溶液和熱水洗滌，除去多余的配體和金屬離子。將沉淀物干燥。鐵配合物的合成將溶有01MOL配體的1,4二氧雜環(huán)己烷溶液滴入一個含有01MOL硫酸亞鐵銨的緩沖溶液氫氧化銨醋酸中，維持PH值在775?；亓?6個小時，得到黃棕色沉淀，過濾、分別用1,4二氧雜環(huán)己烷溶液和熱水除去多余的配體和金屬離子。將沉淀物干燥。鋅配合物的合成01MOL配位的1,4二氧雜環(huán)己烷溶液滴加至含有01MOL的鋅和氫氧化銨存在的溶液中，保持PH值在1011之間。水浴回流45小時，得到褐色沉淀。過濾、分別用1,4二氧雜環(huán)己烷溶液和熱水除去多余的配體和金屬離子。將沉淀物干燥?？咕钚钥咕钚詼y定方法采用瓊脂壟溝技術。被研究的微生物有綠膿桿菌，變形桿菌，奇異變形桿菌，肺炎克雷伯菌和金黃色葡萄球菌。將化合物溶解在溶劑1,4二氧雜環(huán)己烷或DMF二者之一中，調配成最終濃度為1MG/01ML的溶液。循環(huán)中給一個測試菌株接種于25ML的氮液營養(yǎng)液，在37℃的培養(yǎng)箱中培養(yǎng)24小時，來激活細菌。在一個100ML直徑的陪氏板中加入2830ML營養(yǎng)瓊脂培養(yǎng)基。當它達到4045℃時，取02ML的活性菌株用倒板接種技術接種到陪氏板上。在陪氏板完成準備的過程中，維持層流氣流來保持嚴格消毒和無菌條件。使培養(yǎng)基凝固。在凝固后的培養(yǎng)基板上打一個小洞085厘米，用來填充測試樣品。每個菌株和各種溶劑用純溶劑接種作對照組。培養(yǎng)板在37℃培養(yǎng)24小時。通過這些化合物對特定的測試菌株形成的抑菌圈來確定合成化合物的抗菌活性。用三次單獨重復實驗獲得的平均值來計算每個樣品的抑菌圈。結果與討論金屬離子通過合作酶系統(tǒng)在大量不同的的生物過程中發(fā)揮了重要的作用。這些離子通過相互螯合作用使化合物具有生物活性，但是，對金屬配合如何影響它們的活性卻知之甚少。八種金屬配合物及各自的控制對供試菌株生成不同程度的抑制作用區(qū)域。配合物的抗菌活性A1和A3和其金屬配合物在DMF和1,4二氧雜環(huán)己烷相反。

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簡介：BIODRUGS20082213744NOVELTHERAPEUTICSTRATEGIES11738804/08/00010037/4800/0?2008ADISDATAINFORMATIONBVALLRIGHTSRESERVEDFIBROBLASTGROWTHFACTOR21ASATHERAPEUTICAGENTFORMETABOLICDISEASESALEXEIKHARITONENKOVANDARMENBSHANAFELTBIOTECHOLOGYDISCOVERYRESEARCH,LILLYRESEARCHLABORATORIES,LILLYCORPORATECENTER,INDIANAPOLIS,INDIANA,USACONTENTSABSTRACT371THEROLEOFFIBROBLASTGROWTHFACTORSFGFSINTHEREGULATIONOFMETABOLICPROCESSES372OVERVIEWOFFGF21ANDITSINVITROEFFECTS383FGF21INVIVOPHARMACOLOGY394INSIGHTSINTOFGF21MECHANISMOFACTION405CONCLUSION43FIBROBLASTGROWTHFACTORFGF21ISAUNIQUEMEMBEROFTHEFGFFAMILY,WITHSEVERALMOLECULARCHARACTERISABSTRACTTICSTHATDIFFERFROMCLASSICALFGFSANDEXHIBITINGAPHARMACOLOGICPROFILETHATINCLUDESAVARIETYOFMETABOLICRESPONSESINVITROANDWHENTESTEDINVIVOINANIMALMODELSFGF21REPRESENTSANOVELANDATTRACTIVETHERAPEUTICAGENTFORTYPE2DIABETESMELLITUS,BECAUSEOFITSABILITYTOMODULATEDISEASEPHENOTYPEINPRECLINICALSETTINGSWITHOUTINDUCINGANYAPPARENTADVERSEEFFECTSALTHOUGHFGF21WASDISCOVEREDRELATIVELYRECENTLY,THEUNDERSTANDINGOFITSBIOLOGYANDTHERAPEUTICUTILITYISRAPIDLYEVOLVINGANUMBEROFKEYMETABOLICALLYLINKEDMOLECULESANDPATHWAYSHAVEBEENSUGGESTEDTOBEINVOLVEDINTHEMECHANISMOFACTIONOFFGF21,DEPENDINGONTHESPECIFICTARGETTISSUE/ORGANFURTHERRESEARCHINTOTHESEMECHANISMSSHOULDLEADTOIMPORTANTADVANCESINTHEUNDERSTANDINGOFFGF21BIOLOGYANDPAVETHEWAYFORNOVELTHERAPEUTICSTRATEGIESTHESPECIFICSOFFGF21ACTIVITIESBOTHINCELLCULTUREANDINVIVO,ITSPOTENTIALASATARGETFORDIABETES,ANDINSIGHTSINTOTHEMOLECULARMECHANISMSOFFGF21METABOLICACTIONSWILLBEDISCUSSEDINTHISREVIEW1THEROLEOFFIBROBLASTGROWTHFACTORSFGFSINRODENTS,RESPECTIVELY8,9WHENTESTEDINMICE,FGF19PROVIDESTHEREGULATIONOFMETABOLICPROCESSESRESISTANCETOOBESITYANDINSULINDESENSITIZATION10,11ANOTHERMEMBEROFTHEFGFFAMILY,FGF23,ISAKEYPLAYERINTHEREGULAFIBROBLASTGROWTHFACTORSFGFSANDTHEIRCORRESPONDINGRETIONOFPHOSPHATEANDCALCIUMMETABOLISM12,13LIKEWISE,THECEPTORSFGFRSHAVEBEENPRIMARILYASSOCIATEDWITHTHEPROCESSESOFDEVELOPMENT,TRANSFORMATION,ANDANGIOGENESIS14HOWOVEREXPRESSIONOFADOMINANTNEGATIVEFORMOFFGFR1INPANCREEVER,OVERTHELASTDECADE,NEWDATAHAVEEMERGEDSHOWINGTHATATICΒCELLSLEADSTODIABETESMELLITUSINMICE14FGFR2APPEARSTOFGF/FGFRMEDIATEDPATHWAYSMAYPLAYIMPORTANTROLESINDEFINBEAKEYMOLECULEINTHEPROCESSOFPANCREATICDEVELOPMENT1517INGANDREGULATINGFUNCTIONSOFENDOCRINERELEVANTTISSUESANDFGFR3ISACRITICALPLAYERINBONE,18WHEREASFGFR4HASBEENORGANS,ASWELLASMODULATINGVARIOUSMETABOLICPROCESSESFORIMPLICATEDINCHOLESTEROLMETABOLISMANDBILEACIDSYNTHESIS19EXAMPLE,FGF10ANDFGF16PLAYIMPORTANTROLESINADIPOCYTEANDTHEMETABOLICROLESOFFGF/FGFRARESTILLNOTPRECISELYDEFINEDPANCREATICBIOLOGY,57ANDFGF19ANDITSMOUSEORTHOLOGFGF15,REGULATECHOLESTEROLANDBILEACIDMETABOLISMINHUMANSANDANDARECURRENTLYUNDERINTENSEINVESTIGATIONFGF21ANDMETABOLICDISEASES39INDUCESUPREGULATIONOFPPARΓPROTEINALTHOUGHITISCURRENTLYINCIDENCEOFHEPATOCELLULARCARCINOMASINFGF21TRANSGENICMICEUNCLEARWHATPARTICULARIMPACTEACHOFTHESEEFFECTSHASONGLUCOSEAT12MONTHSOFAGEWASSIMILARTOTHATINCONTROLANIMALSTHUS,IFTRANSPORT,THESEDATAREVEALPOTENTIALSYNERGYINTHEACTIONSBEFGF21NEGATIVELYREGULATESCHEMICALLYINDUCEDHEPATOCARCITWEENTHESETWOREGULATORSOFGLUCOSEHOMEOSTASIS,FGF21ANDNOGENESIS,ITISLIKELYTOINTERFEREWITHDISEASEPROGRESSIONATITSPPARΓ31EARLYSTAGES24RECENTLY,ANOTHERLINEOFFGF21TRANSGENICMICEONAC57BL/6JBACKGROUNDHASBEENDESCRIBED26THESEANIMALSHAD50–1503FGF21INVIVOPHARMACOLOGYTIMESHIGHERLEVELSOFFGF21MRNAINTHELIVERTHANCONTROLANIMALS,ANDHADLOWEREDLEVELSOFSERUMCHOLESTEROL,TRITHEINVIVOBIOACTIVITYOFFGF21HASBEENOBSERVEDUSINGGLYCERIDES,GLUCOSEANDINSULININDICATIVEOFTHEIMPROVEDLIPIDNUMEROUSBIOMARKERSTHATILLUSTRATETHEEFFECTSOFFGF21ACTIONSANDGLYCEMICMETABOLISM,ANDAMELIORATEDINSULINRESISTANCE,INABROADRANGEOFANIMALSTUDIESCOVERINGAVARIETYOFDISEASECONSISTENTWITHPREVIOUSLYPUBLISHEDDATA20FGF21TRANSGENICMODELS20,2326,35MICEWEREALSOFOUNDTOHAVEELEVATEDSERUMLEVELSOFΒHYDROXYTHECONSEQUENCESOFENFORCEDEXPRESSIONOFHUMAN20ANDBUTYRATE,SUGGESTINGTHEINDUCTIONOFKETOGENESIS,ASWELLASHAVMOUSEFGF2123,26HAVEBEENEVALUATEDINTRANSGENICMICE20,24,26INGADIPOCYTESOFSMALLERSIZE,INCREASEDLIPASEEXPRESSIONINWHITEFGF21TRANSGENICANIMALSAPPEARVIABLE,NORMALATBIRTH,ANDADIPOSETISSUEANDELEVATEDSERUMLEVELSOFFREEFATTYACIDS,ALLESSENTIALLYINDISTINGUISHABLEFROMTHEIRWILDTYPELITTERMATESNOEVOCATIVEOFTHEINDUCTIONOFLYPOLYSIS26IMPORTANTLY,ASURINETICEABLY,THEYDONOTPOSSESSSIGNSOFNEOPLASIA,TUMORS,ORANYCONCENTRATIONSOFADRENALINEANDNORADRENALINEWEREREDUCEDINOTHEROVERTABNORMALITIESTHROUGHOUTTHEIRLIFESPAN,ASDEMONSTRAFGF21TRANSGENICANIMALS,FGF21DOESNOTAPPEARTOSTIMULATETEDBYEXTENSIVEMORPHOLOGICANDHISTOLOGICANALYSES20,23THUS,LIPOLYSISTHROUGHASYSTEMICINCREASEINCATECHOLAMINES26SURPROLONGEDEXPOSUREOFMICETOFGF21DOESNOTLEADTOCARCINOGENPRISINGLY,THESEFGF21TRANSGENICMICEWEREALSOREPORTEDTOHAVEICEVENTSNEVERTHELESS,ASPECIFICPHENOTYPEOFFGF21TRANSGENIC1–2oCLOWERCOREBODYTEMPERATURES,REDUCEDLOCOMOTORACTIVITY,MICEWASREVEALEDUPONAVARIETYOFCHALLENGESANDENHANCEDTORPORDURING24HOURFASTINGCOMPAREDWITHTHEIRC57BL/6MICEOVEREXPRESSINGHUMANFGF21FROMTHELIVERCONTROLLITTERMATES26ALTHOUGHINTRIGUING,THELATTEROBSERVATIONSCIRCULATINGLEVELSOF70–150NG/MLWEREEVALUATEDFORCHANGESHAVENOTBEENREPORTEDBYOTHERS20,24AND,THEREFORE,NEEDTOBEINMETABOLICPARAMETERS20WHENFEDAHIGHFAT,HIGHCARBOHYEXPLOREDFURTHERDRATEHFHCDIETFOR15WEEKS,FGF21TRANSGENICMICEWEREADENOVIRUSMEDIATEDKNOCKDOWNOFFGF21WITHSHORTHAIRPINRESISTANTTOWEIGHTGAINANDFATACCUMULATION,DESPITEANINCREASEDRNASHFGF21INMICELEDTOASUBSTANTIALDECREASEINCIRCULATCALORICINTAKECONSISTENTWITHLOWADIPOSITY,THELEVELSOFLEPTININGFGF21LEVELSANDRESULTEDINSERIOUSMETABOLICABNORMALITIES,WERENOTICEABLYREDUCED,ASWELLASTHOSEOFGLUCAGONIMPORTANTSUCHASFATTYLIVER,SEVEREHYPERTRIGLYCERIDEMIAPREDOMINANTLYASLY,THESEEFFECTSWERENOTASSOCIATEDONLYWITHTHEHFHCDIET,ASARESULTOFTHEINCREASEINCHYLOMICRON/VERYLOWDENSITYLIPOTHEYWEREALSOOBSERVEDINAGEDFGF21TRANSGENICMICEONAPROTEINFRACTION,ASIGNIFICANTELEVATIONINSERUMFREEFATTYACIDSNORMALCHOWDIETAT9MONTHSOFAGE,THEYWEIGHEDSIGNIFICANTLYANDTOTALCHOLESTEROL,ANDAREDUCTIONINSERUMKETONES23IMPORLESS,HADLOWERFASTINGGLUCOSELEVELS,LESSTOTALANDLIVERFAT,MORETANTLY,THESECHANGESWEREAPPARENTONLYINANIMALSFEDAHIGHFATBROWNADIPOCYTES,ANDSHOWEDIMPROVEDGLUCOSECLEARANCEANDDIETANDNOTONANORMALCHOWDIETTHISCORRELATESWITHADRAMATICINSULINSENSITIVITYCOMPAREDWITHCONTROLANIMALS20ELEVATIONINTHEENDOGENOUSEXPRESSIONOFFGF21INANIMALSONAANALYSISOFFVBMICEWITHLIVERSPECIFICOVEREXPRESSIONOFKETOGENICDIET,ANDPROVIDESFURTHEREVIDENCETHATTHEOUTCOMESOFMOUSEFGF21CONFIRMEDTHEABSENCEOFNEOPLASIASORTUMORS24SHFGF21EXPERIMENTSAREINDEEDARESULTOFADIRECTATTENUATIONOFMOREOVER,WHENCOMPAREDWITHCONTROLANIMALS,NOCHANGEWASENDOGENOUSFGF21EXPRESSION/FUNCTION23OBSERVEDINTHEINCORPORATIONOFBROMODEOXYURIDINEBRDUINTOTHELIVERSOFFGF21TRANSGENICMICEAFTERPARTIALHEPATECTOMYORSYSTEMICADMINISTRATIONOFFGF21INRODENTSVIASUBCUTANEOUSCCL4INSULT,SUGGESTINGTHATFGF21ISUNLIKELYTOPLAYAROLEINAINJECTIONSORTHROUGHCONSTANTINFUSIONLEADSTOAVARIETYOFMETACOMPENSATORYLIVERRESTORATIONPROCESSUNEXPECTEDLY,FORCEDEXBOLICCONSEQUENCESFGF21EFFECTIVELYLOWERSFEDANDFASTEDPRESSIONOFFGF21MARKEDLYREDUCESTUMORINCIDENCE,MEASUREDPLASMAGLUCOSELEVELS,STIMULATESGLUCOSEDISPOSAL,ANDINCREASESBYTHEFREQUENCYOFDIETHYLNITROSAMINEINDUCEDADENOMASANDTHEINSULINSENSITIVITYINORALGLUCOSETOLERANCETESTS20IMPORTANTLY,TIMINGOFTHEIRFIRSTAPPEARANCE24HOWEVER,ALTHOUGHFGF21THEFGF21GLUCOSELOWERINGEFFECTSARELONGLASTING,ASTHEYAPPEARSTODELAYTHEPROCESSOFTUMORINITIATIONINTHELIVER,THEPERSISTFORATLEAST24HOURSFOLLOWINGTHECESSATIONOFFGF21?2008ADISDATAINFORMATIONBVALLRIGHTSRESERVEDBIODRUGS2008221

簡介：CEFOSELISCFSL,AFOURTHGENERATIONPARENTERALCEPHALOSPORIN,HASBEENMARKETEDINJAPANSINCESEPTEMBER1998INDECEMBER1998,WARNINGSOFCENTRALNERVOUSSYSTEMCNSADVERSEEFFECTSSUCHASSEIZURESANDCONFUSIONALSTATESWEREADDEDTOTHELABELINGOFCFSLINMANYCASES,THESEADVERSEEFFECTSWEREOBSERVEDINPATIENTSWHOWEREELDERLYAND/ORHADRENALFAILURETHEREFORERENALFAILUREISCONSIDEREDASONEOFTHERISKFACTORSFORNEUROTOXICITYOFCFSLSINCECFSLISMAINLYELIMINATEDBYRENALEXCRETION,1RENALFAILUREWOULDBEASSOCIATEDWITHINCREASEDSERUMCONCENTRATIONSOFCFSLONTHEOTHERHAND,ITISSTILLUNKNOWNWHETHERRENALFAILURECANALTERTHEPHARMACODYNAMICSOFCFSLINDUCEDSEIZURESDRUGADMINISTRATIONCANBEDIVIDEDINTOTWOPHASESAPHARMACOKINETICPHASEINWHICHDOSE,DOSAGEFORM,FREQUENCY,ANDROUTEOFADMINISTRATIONARERELATEDTODRUGCONCENTRATION–TIMERELATIONSHIPSINTHEBODYANDAPHARMACODYNAMICPHASEINWHICHTHECONCENTRATIONOFDRUGATTHESITESOFACTIONISRELATEDTOTHEMAGNITUDESOFTHEEFFECTSPRODUCED2THEPATHOPHYSIOLOGICSTATUSOFPATIENTSCANAFFECTBOTHTHEPHARMACOKINETICSANDTHEPHARMACODYNAMICSOFADRUGOURKNOWLEDGEOFTHEEFFECTSOFDISEASEONTHEPHARMACOKINETICSOFADRUGCANNOTBEUSEDTOOPTIMIZETHEDRUGDOSAGEOFAPATIENTWITHOUTINFORMATIONONDISEASEEFFECTSONTHEPHARMACODYNAMICS3THEREFOREITISIMPORTANTTODISTINGUISHTHEEFFECTSOFDISEASEONTHEPHARMACOKINETICSFROMTHOSEONTHEPHARMACODYNAMICSDANHOFANDLEVY3REPORTEDANEXPERIMENTALSTRATEGYTOASSESSTHEEFFECTSOFDISEASEANDOTHERVARIABLESONTHEPHARMACODYNAMICSOFDRUGSWITHCNSACTIVITYTHEEFFECTSOFEXPERIMENTALRENALFAILUREONTHEPHARMACODYNAMICSOFCNSSTIMULANTDRUGSSUCHASTHEOPHYLLINE,4PENTYLENTETRAZOLE,5ANDCIMETIDINE6WEREINVESTIGATEDPREVIOUSLYTHEREHAVEBEENCLINICALCASEREPORTSOFSEIZURESCAUSEDBYVARIOUSBLACTAMANTIBIOTICSSUCHASPENICILLIN,7CEFAZOLINE,8AMPICILLIN,9ANDIMIPENEM10HOWEVER,TOOURKNOWLEDGE,THEREHAVEBEENNOREPORTSTHATCLARIFIEDTHEEFFECTOFRENALFAILUREONTHEPHARMACODYNAMICSOFBLACTAMANTIBIOTICINDUCEDSEIZURESTOASSURESAFEANDEFFECTIVEANTIBIOTICDRUGTHERAPY,ITMUSTBEDETERMINEDIFRENALFAILURECANCHANGETHERELATIONSHIPBETWEENTHECONCENTRATIONANDINTENSITYOFPHARMACOLOGICACTIVITYOFDRUGSTHEPRESENTSTUDYWASDESIGNEDTODETERMINE1THESUITABILITYOFTHERATASANANIMALMODELOFCFSLINDUCEDSEIZURES2THESAMPLINGSITEWHERECFSLCONCENTRATIONSREFLECTTHEDRUGCONCENTRATIONATTHESITEOFNEUROTOXICACTIONAND3THEEFFECTOFRENALFAILUREONTHEPHARMACODYNAMICSOFCFSLINDUCEDSEIZURESMATERIALSANDMETHODSANIMALSMALEWISTARRATSWEIGHING240TO300GWEREUSEDINTHISINVESTIGATIONTHERATSHADANINDWELLINGCANNULAIMPLANTEDINTHELEFTJUGLARVEINUNDERLIGHTETHERANESTHESIAONEDAYBEFORETHEEXPERIMENTANDTHEYWEREFASTEDUNTILTHECFSLINFUSIONBEGANCHEMICALSCFSLSULFATEWINCEF?FORINFUSIONUSEDFORANIMALEXPERIMENTSWASOBTAINEDFROMFUJISAWAPHARMACEUTICALCO,LTDCEFPIROMESULFATEBROACT?INJECTIONUSEDASANINTERNALSTANDARDWASOBTAINEDFROMSHIONOGICO,LTDALLOTHERCHEMICALSWEREPURCHASEDFROMCOMMERCIALSOURCESANDUSEDWITHOUTFURTHERPURIFICATIONEFFECTOFINFUSIONRATEONTHECONCENTRATIONSOFCFSLINSERUM,BRAIN,ANDCSFATONSETOFMAXIMALSEIZURESCFSLWASINFUSEDTHROUGHTHECANNULAATONEOFTHREEDIFFERENTRATES14,29,OR58G/HINRATSTHEINFUSIONWASSTOPPEDIMMEDIATELYATTHEONSETOFMAXIMALSEIZURESTHERATSWERETHENLIGHTLYANESTHETIZEDWITHETHER,ANDSAMPLESOFCSF,BLOOD,ANDBRAINWEREOBTAINED,INTHATORDERCSFWASOBTAINEDBYCISTERNALPUNCTUREBLOODWASOBTAINEDFROMTHEABDOMINALAORTAANDCENTRIFUGEDTOOBTAINSERUMTHEWHOLEBRAINWASREMOVEDANDTHERIGHTHALFOFTHECEREBRUMWASUSEDFORDRUGASSAYSEPTEMBER2001BIOLPHARMBULL2491049105220011049?TOWHOMCORRESPONDENCESHOULDBEADDRESSEDEMAILYASUHARAMPHAMEDTMDACJP?2001PHARMACEUTICALSOCIETYOFJAPANEFFECTOFEXPERIMENTALRENALFAILUREONTHEPHARMACODYNAMICSOFCEFOSELISINDUCEDSEIZURESINRATSMASASHINAGATAANDMASATOYASUHARADEPARTMENTOFHOSPITALPHARMACY,SCHOOLOFMEDICINE,TOKYOMEDICALANDDENTALUNIVERSITY,1–5–45YUSHIMA,BUNKYOKU,TOKYO113–8519,JAPANRECEIVEDAPRIL17,2001ACCEPTEDJUNE12,2001WEINVESTIGATEDTHEEFFECTOFINFUSIONRATEANDEXPERIMENTALRENALFAILUREONTHEPHARMACODYNAMICSOFCEFOSELISCFSLINDUCEDSEIZURESASANANIMALMODELOFCFSLINDUCEDSEIZURES,MALEWISTARRATSRECEIVEDANINTRAVENOUSINFUSIONOFCFSLATONEOFTHREEDIFFERENTRATES1458G/H/RATUNTILTHEONSETOFMAXIMALSEIZURESWHICHOCCURREDAFTER80TO360MINOFINFUSIONSAMPLESOFCEREBROSPINALFLUIDCSF,BLOODFORSERUM,ANDBRAINWEREOBTAINEDIMMEDIATELYAFTERSTOPPINGINFUSIONOFCSFLTHESERUMCONCENTRATIONOFCFSLATTHEONSETOFSEIZURESINCREASEDWITHINCREASINGINFUSIONRATE,BUTBRAINANDCSFCONCENTRATIONSOFCFSLATTHEONSETOFSEIZURESWERENOTAFFECTEDBYTHEINFUSIONRATEURETERLIGATEDULANDCONTROLRATSRECEIVEDANINTRAVENOUSINFUSIONOFCFSLAT14G/H/RATUNTILTHEONSETOFSEIZURESTHENTHESAMEPROCEDUREASUSEDTODETERMINETHEEFFECTOFINFUSIONRATEONTHECONCENTRATIONSOFCFSLWASCARRIEDOUTRENALFAILUREWASASSOCIATEDWITHASIGNIFICANTDECREASEINTHEAMOUNTOFCFSLREQUIREDTOINDUCESEIZURESSERUM,BRAIN,ANDCSFCONCENTRATIONSOFCFSLINULRATSWERESIGNIFICANTLYLOWERTHANTHOSEINCONTROLRATSTHESERESULTSINDICATETHATTHEEXPERIMENTALSTRATEGYANDANIMALMODELINTHISINVESTIGATIONWOULDBEUSEFULTOASSESSTHEEFFECTSOFDISEASESANDOTHERVARIABLESONTHEPHARMACODYNAMICSOFCFSLINDUCEDSEIZURESANDTHATRENALFAILUREISONEOFTHERISKFACTORSFORNEUROTOXICITYOFCFSLKEYWORDSCEFOSELISRENALFAILURESEIZUREPHARMACODYNAMICSDISCUSSIONDRUGSTHATACTDIRECTLYANDREVERSIBLY,HAVENOPHARMACOLOGICALLYACTIVEMETABOLITES,ANDARENOTSUBJECTTOTHEDEVE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簡介：INTENSIVECAREMED2007331162–1167DOI101007/S0013400706752ORIGINALHKALLELLHERGAFIMBAHLOULAHAKIMHDAMMAKHCHELLYCBENHAMIDAACHAARINREKIKMBOUAZIZSAFETYANDEFFICACYOFCOLISTINCOMPAREDWITHIMIPENEMINTHETREATMENTOFVENTILATORASSOCIATEDPNEUMONIAAMATCHEDCASE–CONTROLSTUDYRECEIVED26JULY2006ACCEPTED23APRIL2007PUBLISHEDONLINE25MAY2007?SPRINGERVERLAG2007HKALLELULHERGAFIMBAHLOULHDAMMAKHCHELLYCBHAMIDAACHAARINREKIKMBOUAZIZCHUHABIBBOURGUIBA,SERVICEDERéANIMATIONMéDICALE,ROUTEELAINKM1,3029SFAX,TUNISIAEMAILKALLELHATYAHOOFRTEL21698415299FAX21674243427AHAKIMFACULTéDEMéDECINEDESFAX,LABORATOIREDEPHARMACOLOGIE,ROUTEELAINKM1,3029SFAX,TUNISIAABSTRACTOBJECTIVEOURSTUDYAIMEDTODETERMINETHEEFFICACYANDSAFETYOFCOLISTININTHETREATMENTOFVENTILATORASSOCIATEDPNEUMONIAVAPCAUSEDBYPANDRUGRESISTANTPSEUDOMONASAERUGINOSAORACINETOBACTERBAUMANIIDESIGNPAIRWISE,RETROSPECTIVEEXPOSED–UNEXPOSEDSTUDYSETTINGCOMBINEDMEDICALANDSURGICALINTENSIVECAREUNITOFHABIBBOURGUIBAUNIVERSITYHOSPITALSFAX,TUNISIAPATIENTSSIXTYPATIENTSWITHVAPCAUSEDBYPANDRUGRESISTANTABAUMANIIORPAERUGINOSAMATCHEDTO60CONTROLSWITHVAPCAUSEDBYABAUMANIIORPAERUGINOSASUSCEPTIBLETOIMIPENEMALLPATIENTSHADNORMALRENALFUNCTIONATTHEONSETOFANTIBIOTICTHERAPYINTERVENTIONSCASEPATIENTSWERETREATEDBYCOLISTININTRAVENOUSLYANDCONTROLPATIENTSWERETREATEDBYIMIPENEMINTRAVENOUSLYMEASUREMENTSANDRESULTSBASELINECHARACTERISTICSWERESIMILARBETWEENTHECOLISTINANDIMIPENEMGROUPSTHEMEANDURATIONOFANTIBIOTICTHERAPYFORVAPWAS95±38DAYSRANGE5–22DAYSWITHCOLISTINAND89±28DAYSRANGE5–20DAYSWITHIMIPENEMP032AFAVORABLECLINICALRESPONSETOANTIBIOTICTHERAPYFORVAPOCCURREDIN45PATIENTS75INTHECOLISTINGROUPANDIN43PATIENTS717INTHEIMIPENEMGROUPP068THETIMETORESOLUTIONOFINFECTIOUSPARAMETERSAFTERTHEINITIATIONOFANTIBIOTICTHERAPYWASNOTSTATISTICALLYDIFFERENTBETWEENTHETWOGROUPSDURINGTHEANTIBIOTICCOURSE,NONEOFTHEPATIENTSINEITHERGROUPDEVELOPEDRENALFAILURECONCLUSIONSWECONCLUDETHATCOLISTINCANBEASAFEANDEFFECTIVEOPTIONINTHETREATMENTSOFVAPCAUSEDBYPANDRUGRESISTANTPAERUGINOSAORABAUMANIIKEYWORDSCOLISTINVENTILATORASSOCIATEDPNEUMONIANEPHROTOXICITYIMIPENEMINTRODUCTIONPANDRUGRESISTANTPDRGRAMNEGATIVEBACTERIAAREANIMPORTANTPROBLEMWORLDWIDE,ESPECIALLYINTHEINTENSIVECAREUNITICU1,2MULTIPLEDRUGRESISTANCEMAKESDIFFICULTTHECHOICEOFTHEEMPIRICANTIMICROBIALMOLECULEANDISRESPONSIBLEFORDELAYEDADAPTEDANTIMICROBIALTREATMENT3INTHERECENTLYPUBLISHEDLITERATURE,PSEUDOMONASAERUGINOSAANDACINETOBACTERBAUMANIIARETHETWOMOSTWIDELYDESCRIBEDMICROORGANISMSTOBERESISTANTTOTHEMOSTOFAVAILABLEANTIBIOTICS4FORTHISREASON,COLISTINHASBEENRECENTLYCONSIDEREDASALASTTHERAPEUTICOPTIONFORTHETREATMENTOFPATIENTSWITHINFECTIONSCAUSEDBYTHESEMICROORGANISMS4COLISTINISANOLDANTIBIOTICWHICHWASUSEDUNTILTHEEARLY1980STOTREATINFECTIONSCAUSEDBYGRAMNEGATIVERODSWHENGENTAMICINANDSECONDANDTHIRDGENERATIONCEPHALOSPORINSBECAMEAVAILABLE,COLISTINWASDROPPED,MAINLYBECAUSEOFITSNEUROANDNEPHROTOXICITY5–8THEINCREASINGPREVALENCEOFPDRGRAMNEGATIVEORGANISMS,1164TREATMENTREGIMENINTHECOLISTINGROUP,PATIENTSWERETREATEDWITHCOLISTINSULFOMETHATESODIUMBELLONRH?NEPOULENCRORERADMINISTEREDINTRAVENOUSLYTHEDOSAGEWAS6MILLIONUNITS≈100,000U/KGOFCOLISTINDAILY,DIVIDEDINTOTHREEDOSESINTHEIMIPENEMGROUP,PATIENTSWERETREATEDWITHIMIPENEMIMIPENEM/CILASTATINMSDADMINISTEREDINTRAVENOUSLYTHEDOSAGEWAS2GOFIMIPENEMDAILY,DIVIDEDINTOFOURDOSESINTHISSTUDY,ALLPATIENTSRECEIVEDCOLISTINORIMIPENEMONANEMPIRICALBASIS,WHICHMADETHEINITIALANTIBIOTICTREATMENTAPPROPRIATEINALLCASESSTATISTICALANALYSISCATEGORICALVARIABLESWEREEXPRESSEDASPERCENTAGESANDCONTINUOUSVARIABLESASMEANVALUESSDPERCENTAGESWERECOMPAREDUSINGTHECHISQUARETESTANDMEANSWITHTHETTESTTHEWILCOXONMATCHEDPAIRSTESTWASUSEDTOCOMPARETHEMATCHINGCRITERIAAGE,SAPSII,ANDPAO2/FIO2KAPLAN–MEIERCURVESWEREUSEDTOASSESSDIFFERENCESBETWEENTHECOLISTINGROUPANDTHEIMIPENEMGROUPIN1RESOLUTIONOFINFECTIOUSPARAMETERSAFTERTHEINITIATIONOFANTIBIOTICTHERAPYAND2MORTALITYAT28DAYSAFTERTHEONSETOFCOLISTINORIMIPENEMTHERAPYFORVAPCURVESWERECOMPAREDUSINGTHELOGRANKTESTAPVALUE≤005INATWOTAILEDTESTWASCONSIDEREDTOINDICATESTATISTICALSIGNIFICANCERESULTSDURINGTHESTUDYPERIOD,1,208PATIENTSWEREADMITTEDTOTHEUNITONETHOUSANDANDSEVENTYSIXOFTHEM891RETABLE1MATCHINGCRITERIAOFTHESTUDYPOPULATIONCOLISTINGROUPN60IMIPENEMGROUPN60PEFFECTIVENESSOFMATCHINGAGEYEARS434±188414±167060100SAPS352±123332±108035100PAO2/FIO2ONDAYOFINITIATIONOFANTIBIOTICS213±79215±81087100TABLE2BASELINECHARACTERISTICSOFTHESTUDYPOPULATIONCOLISTINGROUPN60IMIPENEMGROUPN60PREASONFORADMISSIONNACUTERESPIRATORYFAILURE71178133078COMA8133466022MULTIPLETRAUMA42704880020POSTOPERATIVERESUSCITATION3500024SEXRATIOMALE/FEMALE65445045SHOCKN183014233040ANTIBIOTICSN467673965016PAO2/FIO2ATADMISSION311±82313±8409UREANITROGENMMOL/L59±1964±20018SERUMCREATININEΜMOL/L797±178820±154046CEIVEDMECHANICALVENTILATIONAND123114DEVELOPEDVAPIN78634OFTHESEPATIENTSTHEVAPCAUSEDBYPDRABAUMANIIORPAERUGINOSAANDWASTREATEDWITHCOLISTINOFTHESE78PATIENTSPOTENTIALLYELIGIBLEASCASES,12WEREEXCLUDEDBECAUSEOFRENALFAILUREATTHEONSETOFCOLISTINTHERAPYOFTHE66REMAININGCASEPATIENTSENROLLEDINTHESTUDY,MATCHINGWASPOSSIBLEFORONLY60909ALLPATIENTSWEREMATCHEDFORAGE,SAPSII,ANDPAO2/FIO2ATTHEONSETOFANTIBIOTICTHERAPYFORVAP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