CN1578650A - 治疗感染性疾病的组合物 - Google Patents
治疗感染性疾病的组合物 Download PDFInfo
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- CN1578650A CN1578650A CNA028216121A CN02821612A CN1578650A CN 1578650 A CN1578650 A CN 1578650A CN A028216121 A CNA028216121 A CN A028216121A CN 02821612 A CN02821612 A CN 02821612A CN 1578650 A CN1578650 A CN 1578650A
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- histamine
- release
- compound
- pharmaceutically acceptable
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Abstract
本文所述是治疗微生物感染的组合物和方法。
Description
发明背景
活性氧代谢产物常常通过氧的不完全还原产生。一分子O2完全还原为水是4电子过程。氧化代谢持续产生部分还原型氧,其比O2本身更具活性,因而更具毒性。一个电子还原O2产生超氧化离子(O2 -);被另一个电子还原产生过氧化氢(H2O2),被第三个电子还原产生羟基(hydroxylradical)(OH),再一个电子产生氢氧离子。氧化亚氮(nitrous oxide)(NO)是另一种引起关注的活性氧代谢产物,通过其他途径产生。特别地,羟基根有非常高的活性并表现为源自致电离辐射的最强诱变剂。如果有机体要存活,将产生所有这些类型并必须将其转化为低活性类型。
作为效应机制,免疫系统的特定细胞控制ROMs的毒性作用。专职吞噬细胞、多形核白细胞(中性白细胞,PMN)、单核细胞、巨噬细胞和嗜曙红细胞通过搜出并破坏侵入的微生物起到保护宿主免于感染的作用。这些吞噬细胞拥有膜结合酶系统,作为对广泛多样的刺激的反应,该系统可活化产生毒性氧根。
据报告并认为“吞噬作用增加的呼吸”(突发性呼吸)是为吞噬作用过程提供额外能量的线粒体活性增加的结果。其后证明在突发性呼吸持续以前,甚至在线粒体抑制剂诸如氰化物和抗霉素A存在下非线粒体酶系统产生氧代谢水平增加。1968年Paul和Sbarra明确证明刺激吞噬细胞产生过氧化氢,1973年Babior和同事证实超氧化物是氧化酶的主要产物。参见Paul and Sbarra,Biochim Biophys Acta156(1):168-78(1968);Babior,et al.,J Clin Invest52(3):741-4(1973)。目前一般公认该酶是膜结合的,显示对NADPH(Km=45μM)比对NADH(Km=450μM)优先选择,并且将氧转化为其一个电子还原产物,超氧化物。
过氧化氢引起随后的超氧化物歧化作用。
在静止的(未刺激的)吞噬细胞中该酶活性几乎无法测定,可是经刺激戏剧性增高。患罕见遗传性疾病慢性肉芽肿病(CGD)的患者具有严重慢性再发性感染倾向。这些患者的中性粒细胞正常吞噬外来物质,但是缺乏突发性呼吸并且NADPH氧化酶活性(和自由基(radical)产物)无法测定,表明氧化酶及其产物,活性氧代谢产物,具有重要的杀菌功能。
中性粒细胞和巨噬细胞产生氧化剂以突破保护细菌被吞噬的保护层或其他因子。大量的超氧化物、过氧化氢和羟基离子甚至当发现非常少量时对大多数细菌是致命的。
在这些氧代谢产物具有有益效应同时,氧代谢产物的不适当生产可导致严重的有害效应是清楚的。许多有害效应显示于宿主的皮肤组织和黏膜中。例如,有害的浓度的活性氧代谢产物可使多种感染包括幽门螺杆菌、癣和锥虫属感染加重。在患多种不同的疾病的患者中降低或最小化ROMs的生产和释放的有效组合物和方法对医药来说将受益匪浅并且将适于降低或消除大量人类病痛。
局部给予软膏、镇痛剂和其他这类药剂为本领域所熟知。应用泥浆或植物提取物诸如芦荟vera恰好是此类药剂的两个实例。关于芦荟vera的讨论,参见第4,857,328号美国专利。先前还讨论了两种不同组胺衍生物作为局部给药的皮肤药剂的用途。第一个可见于属于Jack等的系列美国专利,公开了水、水溶烯类聚合物凝胶胺醇分散体和1H-咪唑-4-乙烷磷酸盐的药物组合物治疗某些皮肤病的用途。参见第5,294,440、5,679,337和5,716,610号美国专利。第二个见于第5,792,784号美国专利中,公开了通过组胺或甲基取代的组胺与氨基酸耦合获得的假二肽产物。
优选实施方案的详细描述
下面的描述涉及治疗微生物感染诸如细菌、原生动物、酵母、真菌、寄生虫和其他寄生感染的组合物和方法。所述组合物和方法可用于治疗由多种疾病病因引起的某些病症。感染实例包括被认为引起溃疡和其他胃肠病症的幽门螺杆菌感染,和链球菌所导致的感染,其被认为引起脓疱病、丹毒、蜂窝组织炎、坏死性筋膜炎、伤口感染、链球菌所导致的毒性休克样综合征、产后发热、风湿热、肾小球性肾炎、结节性红斑和猩红热。
虽然本文中所述的组合物和方法作用的明确机制不很了解,但申请书猜测了本文所公开的物质在治疗如此宽范围感染性病症中有效的原因。一种理论支持一旦入侵的生物诸如细菌、原生动物、酵母、真菌、寄生虫和其他寄生物侵犯宿主,该宿主对入侵者立刻启动炎症反应。炎症的典型特征为局部血管舒张,局部血流增快,毛细血管渗透性升高伴大量液体渗漏入组织间隙,以及其他局部和全身效应。炎症发生后不久,中性粒细胞、巨噬细胞和其他细胞侵入炎症区。这些细胞开始清除组织感染或毒性成分。这些细胞用于保护机体免受有害外来物质损害的一种方法包括产生和释放活性氧代谢产物。
多种活性氧代谢产物(ROMs)在氧还原的单价途径中产生。这些ROMs由吞噬细胞诸如单核细胞和多形核中性粒细胞(PMNs)酶促产生,并在突发性呼吸中不断释放。过氧化氢和其他ROMs在宿主的免疫防御中起重要作用。然而ROMs产生过量或产生于不适当的时间或部位可表现为损伤宿主的细胞和组织,并可因此对该宿主有害。
ROMs产生的效应是多重的。已知在NK细胞中ROMs引起细胞凋亡。还知道在T-细胞中ROMs引起无反应性和细胞凋亡。不过,有些人相信ROMs通过破坏细胞膜和通过改变对细胞存活重要的细胞途径的pH引起细胞死亡。
此外,经历突发性呼吸以及产生和释放大量ROMs的吞噬细胞还产生和释放继发的细胞因子诸如肿瘤坏死因子-α(TNF-α)和白细胞介素-1(IL-1)。继发细胞因子介导的细胞损伤的一个实例发现于施瓦茨曼反应中,认为中性粒细胞介导的细胞损伤是由TNF和IL-1活化的(Imamura S,et al.,“Involvement of tumornecrosis factor-alpha,inter leukin-1 beta,interleukin-8,and interleukin-1 receptorantagonist in acute lung injury caused by local Shwartzmanreaction”Pathol Int.47(1):16-24(1997))。此ROM和细胞因子的释放为细胞损伤是由多种来源所造成的提供了论据,因为这些有力的化学化合物分布于全身。尽管作为保护性措施由免疫系统的细胞所释放,ROMs导致ROM-介导的细胞损伤,并且继发的细胞因子引起患者迅速恶化,常常导致死亡。
本文所述工作是一种惊人的发现,在受试者体内降低或抑制由多源产生或释放的ROMs数量的化合物可帮助治疗和恢复患多种微生物感染的个体。尽管可涉及唯一或涉及不同的(may be only be disparatelyrelated)这些微生物感染的潜在的病因学原因,本文所述组合物和方法在他们全部的治疗中具有广泛作用。对本文所述组合物和方法的普遍效力的可能解释是上面所谈论的每种不同生物具有共同特征,因为通过酶促产生的ROM介导的由不适当和有害浓度ROMs引起的氧化损伤使它们所引起的病情恶化。不顾及本文所述化合物和方法作用的明确机制,单独或与其他有益化合物联合给予抑制ROMs的产生或释放或清除ROMs的化合物,为多种微生物感染提供了有效治疗。
本文所述方法和化合物用于治疗多种微生物感染。例如,本文所述方法和化合物用于治疗寄生虫、真菌、酵母、原生动物和细菌感染,包括单独或与联合其他治疗化合物治疗例如葡萄球菌(Staphlococcal)、链球菌(Steptococcal)、Enterohemmorhagic、梭状芽孢杆菌、奈瑟菌属、螺旋菌属、衣原体、癣、念珠菌属、分支杆菌属和锥虫感染。本文中所述的化合物和方法还用于治疗皮肤病症诸如痤疮、颈部痤疮性疤痕疙瘩(acne keloidalis nuchae)、痤疮坏死(acne necrotica)、acne urticata、光化性角化病(actinic keratoses)、急性发热性中性粒细胞皮病、过敏性接触性皮炎、簇状脱发症、雄激素性(androgenetic)脱发症、特应性皮炎、蓝痣(blue naevus)、基细胞癌、疖、大疱性emphitigo、念珠菌属、冻疮、黄褐斑、氯痤疮、结节性软骨皮炎、着色真菌病、皮炎、皮肤纤维瘤、湿疹、红癣、毛囊炎、真菌感染、手足口病(hand foot and mouth disease)、头虱、脓疱病、黑素瘤、植物性皮炎、甲感染、脂质渐进性坏死、丘疹性荨麻疹、甲沟炎、牛皮癣、红斑痤疮、疥疮、头皮毛囊炎(scalp folliculitis)、硬皮病、皮脂溢性皮炎、带状疱疹、癣、荨麻疹和其他皮肤及粘膜情况或疾病状态。
本文中所述的化合物和方法还用于治疗胃肠道、肌肉、眼、泌尿生殖道、呼吸、血液、肝、肾、胰腺、腹部、咽喉、胃、鼻咽和牙齿疾病。这些化合物和方法与不同传统化疗剂结合,通常还用于促进切口愈合以及推动愈合过程,且近来用于治疗由寄生虫、原生动物、真菌、酵母、细菌和其他人类病原体引起的感染。
制剂
给予抑制或清除ROM产生或释放的化合物可通过静脉内、动脉内、直肠、口服、生殖、肌肉内、局部途径、透皮、结内或呼吸途径。为使这些给药途径方便,可应用所述化合物的多种制剂。所述制剂方便给予抑制活性氧代谢产物的产生或释放或一旦释放清除这些化合物的化合物。在一种实施方案中,此处所预期的制剂包含适合给予有效量抑制和/或清除ROM的化合物的局部载体。在另一实施方案中,此处所预期的制剂包含适合给予有效量抑制和/或清除ROM的化合物的全身载体。
在优选的实例中,可使用多种组胺或组胺-衍生化合物以得到酶促生成的ROM生产和释放的浓度有益的降低。本文总所用术语“组胺”具体表现为多种组胺和组胺-相关化合物。例如组胺、组胺的二盐酸盐形式(组胺二盐酸盐)、组胺二磷酸盐、其他组胺盐、酯或前药和H2受体激动剂可包括于组胺的定义中。
给予诱导内源性组胺从患者自身组织储存中释放的化合物还可用于治疗微生物感染。例如,这类化合物包括IL-3维甲酸、诸如9-顺维甲酸和全反式维甲酸的其他类维生素A和变态反应原。其他ROM产生和释放抑制化合物诸如NADPH氧化酶抑制剂象二亚苯基碘鎓(diphenlyeneiodonium)还用于与本文中所述的方法联合。而且,局部或全身给予5-羟色胺和5HT受体激动剂还用于治疗微生物感染。
含本文所述ROM抑制剂或清除化合物的制剂表现为有效治疗微生物疾病或感染的浓度。当制剂含ROM抑制剂化合物时,其优选含总浓度约0.0001%到约0.5%制剂重量的此种成分,更优选约0.001%到约0.01%制剂重量,最优选约0.002%到约0.05%制剂重量。
本文所述组合物和方法进一步计划与上述ROM产生和释放抑制化合物联合给予多种ROM清除剂。已知ROMs清除剂包括过氧化氢酶、超氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶和抗坏血酸盐过氧化物酶。另外,维生素A、E和C已知也具有清除活性。矿物质诸如硒和锰,也能有效对抗ROM-介导的损伤。本文所公开的方法意图包括上列化合物和具有相似ROM抑制活性的那些化合物的给药。
清除ROMs的化合物可以以约0.0001%到约0.5%制剂重量的总浓度给药,更优选约0.001%到约0.01%制剂重量,最优选约0.002%到约0.05%制剂重量。含ROM清除剂的制剂每天给药1-10次。在每个事例中,应用剂量和次数依赖于给药化合物的活性和感染性疾病的成因。前述的剂量对上列化合物是合适的。对任何特定宿主合适的剂量可容易地通过本领域普通技术人员所熟知的经验技术确定。
非酶促性ROM清除剂可以以通过本领域普通技术人员所熟知的经验确定的量给药。例如,维生素A和E可以以约1-5000IU每次、10-500和100-300IU的剂量给药。维生素C可以以1μg到10gm每次的剂量给药。矿物质诸如硒和锰可以以约1皮克到1毫克每次的量给药。这些化合物还可给药作为对ROM介导的疾病状态的保护或预防治疗。
上述优选的浓度范围通常有效抑制ROMs的产生或清除受试者治疗区域内已存在的ROMs。还可成功使用更高浓度。此外,可使用常规临床评估以优化本文所述化合物给药浓度。例如,组胺浓度可在所治疗感染的成因和阶段基础上调节治疗(accommodate)感染。浓度还可在用作制剂的载体的基础上变化。当与在所治疗受试者皮肤上变干的乳剂相比时,设计为不留可见痕迹融合入皮肤的洗剂可包含低浓度组胺。然而,可调节组胺的液体组合物以适应其静脉内单独或与化学治疗剂联合给药,以便于除去机体的病原微生物。
所述抑制或清除ROM化合物的浓度可根据用于制剂中的其他成分变化。例如,当包括降低皮肤刺激化合物,诸如锶、芦荟、春黄菊、a-红没药醇、光滑可乐果提取物、绿茶提取物、茶树油、甘草提取物、尿囊素、尿素、咖啡因或其他黄嘌呤和甘草酸及其衍生物的时候,组胺浓度可降低。同样地,在通过与静脉液体给药领域技术人员已知的盐溶液和添加剂混合的液体中,组胺浓度可降低。这些化合物还可用在与上述抑制或清除ROM的化合物联合的制剂中。可以将这些化合物单独或互相结合加入该组合物中。锶作为皮肤抗刺激剂的应用参见第5,804,203号美国专利。
此外,在本文所述组合物中含有的多种抗生素、抗真菌剂、抗寄生虫剂和抗原生动物剂可包括在本文所述的组合物中。这些药剂的实例包括氨基糖苷类、青霉素类、诸如两性霉素B的抗真菌类、氟喹诺酮类、四环素类、β-内酰胺类、磺胺类等。根据这些化学治疗剂推荐的给药途径,它们可以与本文所述组合物结合在不同的部位同时给药,或在本文所述组合物之前或之后给药。
另外,含有诸如止痛剂的物质预期包含于所述组合物中。导致刺激宿主的免疫系统的化合物诸如细胞因子(例如,IL-1、IL-2、IL-12、IL-15、IFN-α、IFN-β、IFN-γ等)还可包含于本文所述组合物中。
与本文所述制剂一起使用的合适的载体和组分是本领域熟知的。此类载体包括水;有机溶剂诸如醇类(如乙醇);二元醇类(诸如丙二醇);脂族醇(羊毛脂);水与有机溶剂的混合物及有机溶剂诸如醇和甘油的混合物;基于脂类(lipid-based)物质诸如脂肪酸、酰基甘油(包括油类,诸如矿物油,和来自天然或合成的脂肪)、磷酸甘油酯、鞘脂类和蜡;基于蛋白的物质诸如胶原和凝胶;基于硅氧烷物质(非挥发性的和挥发性的);基于碳氢化合物的物质诸如微海绵(microsponges)和聚合物基体;稳定剂和悬浮剂;乳化剂;和其他适合于皮肤给药的载体成分,以及这些成分与本领域已知的其他成分的混合物。该载体另外可包括适合于改善所用制剂的稳定性和效力的成分,诸如防腐剂、抗氧化剂、透皮增强剂和持续释放物质。在下列参考文献中描述了这些成分的实例:Martindale-The Extra Pharmacopoeia(Pharmaceutical Press,London 1993)and Martin(ed.),Remington’s Pharmaceutical Sciences。
根据该制剂要达到的特定物质形式和呈递方式选择合适的载体。合适的形式的实例包括液体(例如,滴眼剂、烟雾剂、吹入剂、吸入剂、静脉内滴入袋、装置内注射器(on-site injection syringes)、含漱剂、肌肉内注射剂、腹膜内(intraparatoneal)注射剂、注射入中枢神经系统的脊髓液的皮下注射剂和漱口剂);固体和半固体诸如凝胶、泡沫、糊剂(诸如胶囊、口服药(包括subligual或口腔)、丸剂、可植入装置、可生物降解的时控释放装置、咀嚼剂、锭剂、特殊用途的糊剂以及牙膏组合物)、乳膏、软膏、“粘着剂”(诸如唇膏或腋下除臭粘着剂)、粉剂等;含例如通过凝聚技术或通过界面聚合制备的微胶囊,例如分别为羟甲基纤维素或凝胶微胶囊的制剂,或在胶质药物呈递系统中,例如脂质体、白蛋白微球、微乳液、纳米粒子和纳米胶囊,或在微乳液中的制剂;直肠或阴道栓剂、乳膏、泡沫、凝胶或其他软膏;和其他形式。牙膏的实例见于讨论了牙膏组合物第4,307,076号美国专利。
本文所述制剂可制备成多种物理形式。例如固体、糊剂、乳膏、洗剂、凝胶和含水液体都是合适的制剂形式。这些形式间的区别是它们的物理外观和粘性,其可通过存在于该制剂中的乳化剂和粘性调节剂的外观和数量调节。特定的局部制剂常可制备成这些形式的多种形式。固体通常坚硬和不可流动,且一般制备为条或棒,或以特定形式;固体可不透明或透明,且可任选包含溶剂、乳化剂、湿润剂(moisturizers)、润肤剂、香料、染料/着色剂、防腐剂和其他增加或增强最终产物效力的活性成分。乳膏和洗剂常互相类似,主要区别在于它们的粘性;乳膏和洗剂都可不透明、透明或清澈,且常包含乳化剂、溶剂和粘性调节剂,以及湿润剂、润肤剂、香料、染料/着色剂、防腐剂和其他增加或增强最终产物效力的活性成分。凝胶可以以一系列粘度,从稠或高粘度到稀或低粘度制备。这些制剂,象洗剂和乳膏的制剂还可包含溶剂、乳化剂、湿润剂、润肤剂、香料、染料/着色剂、防腐剂和其他增加或增强最终产物效力的活性成分。液体比乳膏、洗剂或凝胶稀疏且通常不含乳化剂。液体产品常常包含溶剂、乳化剂、湿润剂、润肤剂、香料、染料/着色剂、防腐剂和其他增加或增强最终产物效力的活性成分。
用在本文所述制剂中合适的乳化剂包括但不限于离子乳化剂;behentirmonium硫酸二甲酯、cetearyl alcohol;非离子乳化剂象聚氧乙烯油基醚(polyoxyethylene oleyl ether)、PEG-40硬脂酸酯(sterate)、ceteareth-12、ceteareth-20、ceteareth-30、cetearethalcohol、PEG-100硬脂酸酯、甘油硬脂酸酯或其结合或其混合物。
用在本文所述制剂中合适的粘性调节剂包括但不限于保护性胶体或非离子树脂诸如羟乙基纤维素、黄原胶、硅酸铝镁、硅石、微晶蜡、蜂蜡、石蜡和鲸蜡或其结合或其混合物。
用在本文所述制剂中合适的溶剂包括但不限于水、乙醇、丁二醇、丙二醇、异丙醇、异戊二烯二醇(isoprene glycol)和甘油。另外,这些溶剂的结合或混合物可用于本文所述制剂中。
用在本文所述制剂中合适的表面活性剂包括但不限于非离子、两性、离子和阴离子表面活性剂。例如,预期与本文所公开的制剂一起使用聚二甲基硅氧烷共聚醇、聚山梨醇酯20、聚山梨醇酯40、聚山梨醇酯60、聚山梨醇酯80、月桂酰胺DEA、cocamide DEA、和cocamide MEA、油基甜菜碱、cocamidopropyl磷脂酰基PG-dimonium氯化物和ammoniumlaureth sulfate。此外,这些表面活性剂的结合或混合物可用于所公开制剂的具体实施方案中。
用于所公开制剂的具体实施方案中的合适的防腐剂但不限于抗菌剂诸如甲基对羟基苯甲酸酯、丙基对羟基苯甲酸酯、山梨酸、安息香酸和甲醛,以及自然(physical)稳定剂,和抗氧化剂诸如维生素E、抗坏血酸钠/抗坏血酸和棓酸丙酯。此外,这些防腐剂的结合或混合物可用于所公开制剂的具体实施方案中。
用于所公开制剂的具体实施方案中的合适的湿润剂包括但不限于乳酸和其他羟基酸和它们的盐、甘油、proplyene glycol和丁二醇。合适的润肤剂包括羊毛脂醇、羊毛脂、羊毛脂衍生物、胆固醇、凡士林、新戊酸异硬脂酸酯和矿物油。此外,这些湿润剂和润肤剂的结合或混合物可用于所公开制剂的具体实施方案中。
除用于所公开制剂的具体实施方案中的ROM产生和释放抑制化合物之外,合适的活性成分包括但不限于果酸、防晒剂、抗痤疮药、维生素及矿物质和各种处方和非处方药。防晒剂的一个实例可见于第5,160,731号美国专利。所公开召集的实施方案还可包括诸如上述的多种添加的活性成分。
用于所公开制剂的具体实施方案中的合适的香料和颜料包括但不限于FD&C Red No.40和FD&C Yellow No.5。适合用于局部用产品的香料和颜料的其他实例是本领域已知的。
可包含在所公开制剂的具体实施方案中的其他合适的添加成分包括但不限于研磨剂、吸收剂、抗结块剂、防沫剂、抗静电剂、收敛剂(例如,金缕梅酊剂、醇和草药提取物诸如黄春菊提取物)、粘合剂/赋形剂、缓冲剂、螯合剂、成膜剂、调节剂、不透明剂、pH调节剂和杀虫剂。在局部用产品制剂中这些成分的各自实例可见于The Cosmetic,Toiletry,and Fragrance Association(CTFA)的出版物中。参见,例如,CTFA Cosmetic Ingredient Handbook,2nd edition,eds.John A.Wenninger and G.N.McEwen,Jr.(CTFA,1992)。
多种产品类型包括具体的化妆品,还可制备成每一种上面所述的形式(例如,固体、乳膏、洗剂、凝胶和液体)。例如,清洁剂(诸如肥皂)、洗发剂/调节剂、化妆品和其他面部、手和身体产品可制备成上述任何产品形式:固体、乳膏、洗剂、凝胶和液体。一般固体产品形式包括:栓剂、化妆品诸如唇膏、丸剂、胶囊、发白剂(blushes)、其他化妆品、锭剂、植入装置、控释装置、口服丸、除体臭剂和栓剂。一般乳膏和洗剂形式产品包括:泌尿生殖器发泡剂(urogenital foams)、润肤产品、防晒剂、洗发剂/调节剂和其他护发产品,以及其他化妆品诸如粉底霜。一般凝胶产品包括:口服胶囊、抗-痤疮药水(solutions)和皮肤调节剂。一般液体形式产品包括:静脉内滴入袋、动脉内滴入袋、肌肉内注射剂、吸入剂、气溶胶、脊髓液内注射剂、吹入剂、滴眼剂、喷鼻剂、装置内注射器(on-site injectable syringes)、气雾吸入剂(vapors)、浸泡剂、洗涤剂、swallows、指甲油(用于治疗癣和其他真菌性甲生长)、抗-痤疮药水、香水/科隆香膏、须后水、含漱剂/漱剂和音调/刺激(bracers)/皮肤调节剂。
在Anthony L.L.Hunting(ed.),“A Formulary of CosmeticPreparations(Vol.2)-Creams,Lotions and Milks,”Micelle Press(England,N.J.,1993)中也描述了用于以多种形式制备制剂的其他方法和物质。参见,例如,第7章5-14页(油和凝胶);第8章15-98页(bases和乳剂);第9章101-120页(“all-purpose products”);第11章185-208页(粉底霜、雪花膏和日霜);第12章209-254页(润肤剂);第13章297-324页(面部护理产品);第14章325-380页(护手产品);第15章381-460页(身体和皮肤乳膏和洗剂);和第16章461-484页(婴儿产品)。
本文公开的组合物和制剂还可合并入其他物品中使用。例如,本发明描述的实施方案的组合物可合并入绷带中以增高伤口愈合及降低受试者不适。该组合物可与静脉滴入袋中盐和化疗剂混合。ROM产生和释放抑制混合物合并入伤口敷料中的方法是本领域普通技术人员显而易见的。活性物质合并入伤口敷料中的讨论见于第5,116,620号美国专利。
通过注射给予化合物
可通过注射给予本文公开的化合物。具体的呈递方式包括使用静脉内的吻合分流、皮下注射器、静脉内滴入袋、肌肉内注射剂、腹膜内(intraparatoneal)注射剂、栓剂、吸入剂、气雾吸入剂、透皮使用、注入器、海绵、喷雾(包括药剂、气溶胶和泡,沫喷雾)、滴入使用、喷淋、药膏、浸泡和含漱或嗽口。
控释载体还可用于给予本文所述化合物的优选实施方案。可将本领域的技术和产品变化称为控释、持续释放、延长作用、贮库、贮室、延迟作用、迟缓释放和时控释放;本文所用的词汇“控释”意指各种前述技术的合并。
已知许多控释载体,包括可生物降解或可生物侵蚀聚合物诸如聚乳酸、聚乙醇酸和再生胶原。已知控释药物呈递装置包括乳膏、洗剂、片剂、胶囊、凝胶、微球和脂质体。活性成分从中缓慢释放的穿皮制剂也是熟知的并可与本文所述多种实施方案一起使用。
控释制剂可通过使用聚合物络合或吸收组胺得到。该控制呈递可通过选择适当的诸如聚酯、聚合氨基酸、聚乙烯吡咯烷酮、乙烯乙酸乙烯酯、甲基纤维素、羧甲基纤维素和硫酸鱼精蛋白大分子实行,且挑选这些大分子的浓度以及合并的方法以便于控制活性化合物的释放。
水凝胶,其中组胺化合物溶解于含水组分中以随着时间逐渐释放,可通过亲水单烯属单体诸如异丁烯酸乙二醇酯(ethylene glycolmethacrylate)共聚合来制备。可以使用基质装置,其中组胺分散在载体物质的基质中。该载体可以是多孔的、非多孔的、固体、半固体、可渗透的或不可渗透的。另外,含有围有速度控制膜的组胺中央贮存库的装置可用于控制组胺的释放。速度控制膜包括乙烯乙酸乙烯酯共聚物或对苯二酸丁烯酯/聚四亚甲基醚苯二酸酯。使用硅橡胶贮库也是预期的。
口服控释制剂也是熟知的。将活性化合物可溶的或易蚀的基质中。通常使用亲水树脂,诸如羟甲基纤维素。润滑剂诸如硬脂酸镁、硬脂酸或硬脂酸钙可用于帮助制片过程。
在一种优选实施方案中,给药方法可以是或局部或全身注射或输注。其他给药方法也是合适的。这些化合物可腹膜内或以另外的非肠道方法给药。游离酸或可药用盐形式的活性化合物的溶液可在伴或不伴诸如羟丙基纤维素的表面活性剂的水中给药。可以用使用了甘油、液体聚乙二醇或它们与油的混合物的分散剂。还可将抗菌剂加入该制剂。
注射剂可包括基于无菌水的溶液或分散剂和可溶解或悬浮于前面使用的无菌介质中的粉剂。还可添加诸如含例如水、乙醇多元醇(ethanolpolyols)、植物油等的溶剂或分散剂的载体。可使用诸如卵磷脂和表面活性剂的涂层以保持制剂合适的流动性。还可加入等张物质诸如糖或氯化钠,以及意图减缓活性成分吸收的产品诸如一硬脂酸铝和明胶。无菌注射剂以常见方法制备,并在储藏和/或给药前过滤。无菌粉剂从溶液或悬浮液真空干燥或冷冻干燥。
喷雾器疗法、喷雾器或吸入器可用于给予该制剂。该制剂的液体细薄雾,单独或加入感染特异性化疗药可给药治疗呼吸感染。
滴眼剂和眼药膏可用于本发明所述实施方案制剂的给药。该制剂可通过单独或与另外的感染特异性化疗药混合滴入呈递。伴或不伴抗菌剂、抗原生动物药、抗寄生虫药或抗真菌药的含所述实施方案制剂的眼药膏例如当睡眠时给药于眼以延长暴露。
外科植入物设计成含本文所述制剂。例如岁随时间释放所述实施方案化合物的牙科植入物用于降低由于蛀牙引起的齿龈炎症。此外,本文所述组合物与抑制口腔中链球菌生长的抗生素或杀菌剂混合。外科装置可沿着齿龈靠近蛀牙中心植入或附在牙齿表面。
将含本文所述制剂的栓剂和灌肠剂种植在感染孔以降低身体对感染的炎症反应。该制剂可通过栓剂单独或与其他化学疗法结合来呈递。对于在人胃肠道中微生物感染的位置较高,灌肠剂适合于单独呈递该制剂,或加入其他化学疗法。
本文所述制剂的静脉内给药通过注射入血流、肌肉、腹膜腔、个别感染器官或器官系统、骨、淋巴腔、脊髓腔、窦道腔等呈递,单独或与其他对意图治疗的感染特异的化学疗法联合。
在另一种优选实施方案中,透皮贴剂、夹在不能渗透背层和膜正面间稳态药库和透皮制剂,还可用于呈递组胺和组胺激动剂。透皮给药系统是本领域熟知的。在第4,573,996、4,597,961和4,839,174号美国专利中描述了用于向皮肤或粘膜给予活性成分的闭合透皮贴剂。一种透皮贴剂是聚合物基质,其中活性剂溶解在聚合物基质中,通过该聚合物基质活性成分扩散到皮肤。在第4,839,174、4,908,213和4,943,435号美国专利中公开了这些透皮贴剂。
当前的透皮贴剂系统设计成释放较小剂量经历较长一段间,达数天和数周,然而,本文所述的实施方案将根据剂量在约1和60分钟之间范围内特异性地释放有效量的组胺,伴在约5分钟内释放优选剂量。这些贴剂允许迅速和控制性释放组胺。这些贴剂的大小适应于直接放置在疣、伤口、疱疹性损害、感染灶等。速度控制外侧多微孔膜,或分散遍布硅树脂聚合物基质的微小组胺(micropocket of histamine)可用于控制释放速度。在第5,676,969号美国专利中描述了这种速度控制方法。在另一种优选实施方案中,在约30分钟或更少时间内组胺从贴剂释放到患者的皮肤中。在一种优选实施方案中,对于每贴剂约0.2mg和3mg之间剂量,组胺以每分钟约0.025mg到0.3mg从该贴剂释放。
使用这些透皮贴剂和制剂可以伴随或不伴随使用渗透增强剂诸如二甲亚砜(DMSO)、蔗糖脂肪酸酯与亚砜或氧化磷的结合物、或丁子香酚。应用电解透皮贴剂也可在所述实施方案的范围内。在第5,474,527、5,336,168和5,328,454号美国专利中描述了电解透皮贴剂。
在另一种实施方案中,设计为放置在创伤、伤口,或疣、擦伤、损伤,或感染灶的透皮贴剂可用于给予所述实施方案的活性成分。此种贴剂的实例见于第5,122,127号美国专利。所述贴剂包含能装入一些治疗剂的容器,此容器能粘附于粘膜组织,例如在口腔中。该装置的药物表面积代表接触宿主的粘膜组织。该装置设计成与药物/粘膜接触面面积大小成比例地释放药物。因此,药物释放速度可通过改变接触面积的大小调节。
容器优选由无毒性、化学稳定且与本文所述实施方案的化合物无反应的物质构成。合适的构成物质包括:聚乙烯、聚烯烃、聚酰胺、聚碳酸酯、乙烯基聚合物和本领域已知的其他类似物质。此容器可包含维持容器与粘膜相对位置的方式。此容器可包含固定位置的稳态药库以与粘膜保持流畅接触。
与所述实施方案一起使用的稳态药库将在预先设定时间内从头到尾释放合适剂量的这些化合物。在第5,288,497号美国专利中教导了组合物和生产能够通过粘膜吸收的组合物的方法。本领域技术人员能够容易地知道如何包括在这些和相关组合物中所述实施方案的化合物。
用于所述实施方案的稳态药库是由本领域已知控制药物释放速率的化合物组成的。在一种实施方案中,透黏膜贴剂历经约2至60分钟释放一定剂量的组胺。包含在容器内的稳态药库携带组胺和其他ROM产生与释放抑制性化合物,剂量从约0.2至5mg每贴。能够使用若干天并且历经这段时间释放所述实施方案的化合物的透皮贴剂也涵盖其中。药库还可以含有渗透或穿透增强剂,如上所述,以提高所述实施方案的活性成分跨越黏膜组织的渗透性。
另一种控制组胺释放的方法将组胺掺入聚合材料的颗粒中,例如聚酯、聚氨基酸、水凝胶、聚乳酸或乙烯乙酸乙烯酯共聚物。
作为替代选择,不将组胺掺入这些聚合颗粒中,而将组胺包埋在微胶囊中,微胶囊是这样制备的,例如借助凝聚技术,或者借助界面聚合作用,例如分别使用羟甲基纤维素或明胶微胶囊,或者包埋在胶体药物释放系统中,例如脂质体、白蛋白微球体、微乳剂、纳米粒和纳米胶囊,或者包埋在巨乳剂中。这类技术是药物科学领域普通技术人员所熟知的。
在另一种实施方案中,组胺,H2-受体激动剂以总浓度约0.0001到约0.5%制剂重量,更优选约0.001到约0.01%制剂重量,且最优选约0.002到0.05%制剂重量给药。ROM清除化合物还可与上面所述ROM产生和释放抑制性化合物联合给药。
每剂组胺的给药可以是一天一次至约一天二十次,一天五次是优选的。另外所述实施方案化合物、组合物和制剂可适量或达到可以减轻受试者的疼痛或不适的程度给药。每小时给药也可涵盖,不过,给药应不超过每天20次。
所述实施方案的化合物的给药可单独或者与其他有效治疗由本文所述实施方案涵盖的多种医学疾病的化合物联合。例如,组胺与其他化合物诸如头孢唑啉联合可用于治疗受克雷伯杆菌属感染困扰的患者,以减轻受试者的不适同时除去身体感染因素。另外,所述实施方案可以与多种为本领域技术人员已知和给药的抗菌、抗真菌、抗原生动物和抗寄生虫化合物一起使用。所述实施方案的化合物,诸如阿,还可与多种止痛剂、麻醉剂或抗焦虑药一起给药,以增高治疗期间患者的舒适度。
每剂导致组胺释放的化合物的给药可以是一天一次至约一天十次,一天五次是优选的。另外,给药次数可按受试者需要以减轻感染灶、创伤或皮肤伤口的不适。给药涵盖注射剂、口服药、吸入剂、栓剂或局部药并可合并为上述公开类型的控释机制。可以使用任何能够给予治疗有效量的诱导内源性组胺储存释放的化合物的控释载体。
与局部给予这些化合物联合,通过注射给予ROM产生和释放抑制化合物也被涵盖。在题目为“活性氧代谢产物诱导的细胞损伤的治疗和预防”的co-pending申请中教导了这些化合物的给药。
本发明所述实施方案的惊奇发现之一是降低由受试者体内来源的ROMs产生或释放数量的化合物可方便为多种医学疾病困扰个体的治疗和康复。这些疾病涵盖由大量病因导致的在所述实施方案之内可治疗的疾病。不过,它们有共同的特征即它们的病理状态为酶促产生的ROM-介导的由不适当的或有害浓度的ROMs引起的氧化损伤所引起或加重。因此,单独或与其他有益化合物联合给予抑制ROMs产生或释放或者清除ROMs的化合物,为多种医学疾病提供有效治疗。
本发明所述实施方案涵盖有效治疗ROMs在疾病病理状态中起到能动的有害的作用的多种医学疾病的化合物和方法。
加入制剂的所有物质必须可药用且在所用量内充分无毒。产生延迟释放的制剂和形式也是本发明的部分。
制剂提供统一剂量的剂量单位并方便给药。每剂量单位含预定量的活性成分连同必需量的药物载体以产生所需要的治疗效应。
尽管在实例中声明以单一剂量给药,但是很明显为治疗引起炎症的细菌、真菌、原生动物、寄生虫或其他寄生感染,化合物可分配较长时间。
每日剂量可作为单一剂量给药,或如果副作用发生其可分成数次药量。
这些疾病包括但不限于:细菌感染、真菌或酵母感染、原生动物感染、阿米巴感染和寄生虫感染。下列中的许多种已经或即将对当代化疗治疗抵抗。因此,考虑到以后,请注意应该具体分析任何具体感染的成因对化疗的易感性,以便实施对患者最适宜的治疗。而且每种微生物感染可对数类化疗化合物易感。
用阿托伐酮悬浮液或氨苯砜与三甲氧苄二氨嘧啶或喷他脒治疗卡氏肺孢子虫感染。参见Antimicrobial Use Guidelines;University ofWisconsin Hospital 8th Edition June 1996。克林霉素用于治疗脆弱似杆菌(Bacteroides fragilis)和金黄色葡萄球菌(Staphlococcusaureus)感染以及需氧革兰阴性杆菌感染。参见Young and Mangum,NeoFax,8th Edition,1995,page 18。灭滴灵用于治疗脆弱似杆菌、细菌性阴道病、毛滴虫性阴道炎(Trichomonal vaginitis)、贾第鞭毛虫病、艰难梭菌结肠炎、溶组织内阿米巴和幽门螺杆菌感染。参见Rollo IM:Miscellaneous drugs used in the treatment of protozoalinfections.In:Gilman AG et al,the Pharmacological Basis ofTherapeutics 6th ed,MacMillan Publ,New York,1980.p.1077。另外,幽门螺杆菌一般用羟氨苄青霉素、克拉霉素、四环素和灭滴灵治疗。参见Physicians’Desk Reference 58ed.2002,Medical Economics/Thomson Healthcare p.1471-1474,403-411,2893,and 1405-1406(以下称“PDR2002”)。麻风分支杆菌和鸟分支杆菌(M.avium)用氯法齐明治疗。参见National Institutes of Health(NIH),Warren GrantMagnuson Clinical Center(CC)Pharmacy Department,Bethesda,Maryland 20892。
幽门螺杆菌引起慢性的常常伴随一生的人类胃炎。宿主对幽门螺杆菌感染的免疫反应的一般特征是胃上皮下固有层为吞噬细胞,主要是单核细胞/巨噬细胞和中性粒细胞,和淋巴细胞,包括介导保护抗感染的细胞诸如自然杀伤(NK)细胞和T细胞大量浸润。
呋喃妥英用于治疗尿路感染。参见PDR2002,p.2891-2892。脆双核阿米巴和隐孢子虫性腹泻用巴龙霉素治疗。参见Clin Infect Dis1992;15:726;Am J Med 1996;100:370。淋病奈瑟菌用壮观霉素治疗。参见U.S.National Library of Medicine,8600 Rockville Pike,Bethesda,MD 20894。大肠埃希杆菌、奇异变形杆菌、肺炎克雷伯杆菌和肠杆菌属种类一般用三甲氧苄二氨嘧啶治疗。参见PDR2002,p.2265-2267。万古霉素还用于治疗新青霉素(methicillin)耐药的金黄色葡萄球菌、艰难梭菌和棒状杆菌感染。参见PDR2002,p.1970-1978。
下列类型感染已经用β-内酰胺类化疗药治疗。氨曲南用于治疗严重需氧革兰阴性杆菌。参见PDR2002,p.1276-1279。头孢美唑用于治疗软组织感染、骨感染和由穿透性腹部外伤引起的感染。参见Antimicrobial Use Guidelines,Eighth Edition,University ofWisconsin Hospital,June 1996。氯碳头孢(Loracarbef)用于治疗急性中耳炎和窦炎。参见PDR2002,p.2251-2254。亚胺培南和西司他丁用于治疗绿脓杆菌、肠杆菌属、沙雷氏菌属或枸橼酸菌属感染。参见PDR2002,p.2158-2164。
已经发现下列青霉素可用于治疗下列感染。羟氨苄青霉素(amoxicillin)用于治疗急性中耳炎、细菌性心内膜炎预防和肠球菌感染。参见PDR2002,p.1471-1474。氨苄青霉素用于治疗大肠埃希杆菌、奇异变形杆菌、肠球菌性心内膜炎、新生儿脑膜炎、李斯特菌脑膜炎/脓血症、流感嗜血杆菌、miningitis、志贺氏菌痢疾、沙门氏菌病或伤寒。参见Antimicrobial Use Guidelines,8th Edition,University of Wisconsin Hospital,June 1996。羟氨苄青霉素和克拉维酸用于治疗中耳炎和急性窦炎。参见PDR2002,p.1471-1474和1482-1490。双氯青霉素用于治疗由青霉素酶-抵抗、新青霉素-敏感的葡萄球菌引起的感染。参见Olin BR.Systemic Anti-infectives,Antibiotics,Penicillins。In Facts and comparisons DrugInformation.St.Louis,MO:Facts and Comparisons,1993,1686-732。青霉素G用于治疗的感染包括肺炎双球菌、β-溶血性链球菌、草绿色链球菌、脑膜炎球菌、梭状芽孢杆菌、敏感葡萄球菌和多杀巴斯德菌、神经梅毒、放线菌病、炭疽热、微球菌感染和螺旋体感染(莱姆病和梅毒)。参见PDR2002,p.2240-2243。青霉素VK用于治疗链球菌性咽炎、链球菌性咽炎、链球菌性中耳炎和窦炎。参见AntimicrobialUse Guidelines,8th Edition,University of Wisconsin Hospital,June 1996。萘夫西林用于治疗金黄色葡萄球菌和混合性革兰阳性感染。参见McCracken and Nelson,Antimicrobial Therapy for Newborns,2nd Edition,1983.Benitz & Tatro,Pediatric DrugHandbook,p.546,1988.Young &Mangum,NeoFax,p.34,1993。绿脓杆菌感染用替卡西林治疗。Id.at p.543。氨苄青霉素和舒巴坦用于治疗流感嗜血杆菌感染、人或动物咬伤、泌尿器感染和软组织感染诸如糖尿病性足部溃疡。Id.at p.535。
通过磷酸氯喹特异性预防和治疗由间日疟原虫、三日疟原虫、卵形疟原虫和恶性疟原虫敏感株引起的疟疾。称为磺胺药物的药物家族用语治疗下列感染。氯喹耐药的恶性疟原虫用磺胺嘧啶、奎宁和乙胺嘧啶治疗。参见Goldsmith,R.S.,Antiprotozoal Drugsin Basic andClinical Pharmacology(Katzung,B.G.,ed)Appleton-Lange,1998,pp.838-861。三甲氧苄二氨嘧啶与磺胺甲恶唑联合用于治疗泌尿道感染、急性前列腺炎、卡氏肺孢子虫、志贺氏菌痢疾、伤寒、致肠病性大肠埃希氏菌、旅行者腹泻、嗜麦芽寡养单胞菌(Stenotrophomonasmaltophilia)、洋葱伯克霍尔德菌、新青霉素抵抗的金黄色葡萄球菌和非典型的分支杆菌感染。Id.
Methicillan抵抗的金黄色葡萄球菌(MRSA)是对新青霉素和其他常用抗生素抵抗的葡萄球菌,且它们具有产生抵抗力独特基因。因此,必须使用备用抗生素治疗MRSA。在这些抗生素中万古霉素是最有效和可靠的。参见Koren et al,J Peds,V110 N5,p.797,May 1987.Benitz& Tatro,Pediatric Drug Handbook,p.571,1988.Leonard et al,Ped Inf Disease J.V8 N5,p.282,May 1989.Yeh,NeonatalTherapeutics,2nd Ed,p.198,1991。
已经发现以下微生物感染对所谓四环素族化疗敏感。参见Ziv &Sulman,Am.J.Vet.Res.35:1197,1974.USPDI,11th edition,1991USPDI,15th edition,1995 BM6th88,Huber,W.G.,Tetracyclines,in Veterinary Pharmacology and Therapeutics,6th edition,eds.Booth,N.H.and McDonald,L.E.,Iowa State University Press,1988.Rang,H.P.and M.M.Dale.Pharmacology,Churchill Livingstone,New York 1987,chapter 30.Bowersock,T.,1995.Personalcommunication.肺炎支原体、沙眼衣原体、布鲁菌病、巴尔通体病、立克次体感染、莱姆病、甲氟喹耐药的疟疾和幽门螺杆菌可以用强力霉素或四环素治疗。Id.二甲胺四环素用于治疗脑膜炎奈瑟球菌和海分支杆菌。Id.四环素用于治疗肺炎支原体和沙眼衣原体。Id.
头孢唑林用于治疗克雷伯菌或大肠埃希菌肺炎或伤口感染。参见Harriet Lane Handbook,p.619,2000.CHLA Pediatric DosingHandbook and Formulary,p.182,1999.Neonatal Medications andNutrition,p.90,1999.头孢克肟用于治疗青霉素抵抗种类的淋病、急性窦炎和急性中耳炎。参见Girgis NI,Kilpatrick ME,Farid Z,etal:Cefixime in the treatment of enteric fever in children.DrugsExp Clin Res 1993;19:47-49;Johnson CE,Carlin SA,Super DM,etal:Cefixime compared with amoxicillin for treatment of acuteotitis media.J Pediatr 1991;119:117-122.头孢泊肟酯用于治疗窦炎。参见PDR 2002,p.2860-2864.绿脓杆菌用头孢他啶治疗。Id.at 1499-1502。肺炎链球菌、流感嗜血杆菌(布兰汉球菌)、卡他性莫拉菌、葡萄球菌和链球菌皮肤感染、由大肠埃希菌、奇异变形杆菌和克雷伯菌引起的前列腺炎用头孢氨苄治疗。Id.at 1237-1238。
所谓氟喹诺酮类药物用于治疗下列感染。脑膜炎奈瑟球菌、绿脓杆菌、伴沙门菌、志贺菌、弯曲杆菌或致肠病性大肠埃希菌的严重肠感染和革兰阴性骨髓炎用环丙沙星治疗。参见PDR 2002,p.893-903。淋病奈瑟球菌、非热性的旅行者腹泻、慢性前列腺炎包含于用诺氟沙星治疗的感染中。Id.at 2051-2053。
鼠弓形体是弓形体病的病因,并以乙胺嘧啶和磺胺嘧啶治疗。参见PDR 2002,p.1511-1512 and CDC.Availability ofsulfadiazine-United States.MMWR 1992;41:950-1。
鸟分支杆菌复合体、青霉素抵抗的肺炎链球菌用克拉霉素治疗。参见PDR 2002,p.403-411。沙眼衣原体、肺炎支原体、军团病、肺炎衣原体、空肠弯曲杆菌、百日咳杆菌、杜克雷嗜血杆菌、寻常痤疮和白喉棒杆菌感染用红霉素治疗。Id.at 455-457。
氨基糖苷类用语治疗下列微生物感染。鸟分支杆菌复合体和耐药性肺结核用阿米卡星治疗。参见Young and Mangum,NeoFax,8th Edition,1995,page 4。结核杆菌用异烟肼、利福平、乙胺丁醇、吡嗪酰胺和链霉素治疗。参见Core Curriculum on Tuberculosis What the ClinicianShould Know 4th.Ed.,2000.链霉素还用于治疗链球菌性心内膜炎。参见U.S.Environmental Protection Agency.1988.Fact SheetNumber 186 Streptomycin.USEPA.Washington,DC.妥布霉素用于治疗绿脓杆菌。参见McCracken and Nelson,Antimicrobial Therapy forNewborns,2nd Edition,1983.Benitz & Tatro,Pediatric DrugHandbook,p.510,1988.肠球菌性心内膜炎用庆大霉素和青霉素治疗。参见Antimicrobial Use Guidelines,University of WisconsinHospital 8th edition,June 1996.
下列抗真菌药用于治疗各自的真菌感染。灰黄霉素用于治疗皮肤、毛发、指甲的皮肤真菌感染(癣)(体癣、须癣、头癣、甲癣)。参见E Haneke,I Tausch,M Brutigam et al.Short-durtion treatmentof fingernail dermatophytosis:a randomized,double-blind studywith terbinafine and griseofulvin.参见Journal of the AmericanAcademy of Dermatology 1995 32:72-7。咪康唑用于治疗波伊德假霉菌样真菌和全身的糠秕马拉色霉菌。参见PDR 2002,p.2661-2662。两性霉素B用于治疗荚膜阿杰罗菌(即,荚膜组织胞浆菌)、皮炎阿杰罗菌(即,皮炎芽生菌病)、深部念珠菌感染,且厌酷球孢子菌用两性霉素B治疗。参见Benitz & Tatro,Pediatric Drug Handbook,p.621,1988.Medical Letter,February 21,1992.念珠菌感染包括泌尿生殖器和口腔白色念珠菌感染根据感染部位用制霉菌素、两性霉素B或氟康唑治疗。参见Harriet Lane Handbook,p.161,1975 Sims,Metal:Prophylactic oral nystatin and fungal infections invery-low-birthweight infants.Am J Perinatology 5(1):33,January 1988.隐球菌用两性霉素B或氟康唑治疗。参见Cooper CR Jr,McGinnis MR.Invitro susceptibility of clinical yeast isolatesto fluconazole and terconazole.Am J Obstet Gynecol 1996;175:1626-31.曲霉菌感染用两性霉素B或伊曲康唑治疗。参见Drake LA,Dinehart SM,Farmer ER,Goltz RR,Graham GF,et al.Guidelinesof care for superficial mycotic infections of the skin:onychomycosis.J Am Acad Dermatol.1996;34:116-21.球孢子菌感染用两性霉素B或酮康唑治疗。参见PRD 2002,p.2008-2009。
通常,拟杆菌、普雷沃菌、梭菌、双岐杆菌、Bilophila、弯曲杆菌、Centipeda、埃希菌、真细菌、梭杆菌、孪生球菌、嗜血杆菌、乳杆菌、Mitsuokella、奈瑟球菌、消化链球菌(PeptococcusPeptostreptococcus)、卟啉单胞菌、丙酸杆菌、变形杆菌、假单胞菌、八迭球菌、新月单胞菌、干朽菌(Serpula)、葡萄球菌、链球菌、韦荣球菌、沃林菌(Wolinella)属的厌氧种和大多数革兰阳性厌氧菌使用氯林可霉素、灭滴灵、cefriaxone、强力霉素、羟氨苄青霉素或β-内酰胺酶抑制剂的一种或联合。参见PDR 2002,p.1405-1406.对大多数革兰阴性厌氧菌,治疗通常以氧哌嗪青霉素或妥布霉素和他唑巴坦完成。参见Engelkirk,P.et al.Principles and Practice of ClinicalAhaerobic Bacteriology,Star Publishing Co.1992.
例如,坏死性筋膜炎的成因化脓链球菌(又名flesh eatingbacteria)用下列一种或数种治疗:头孢菌素;红霉素;青霉素;氯林可霉素;和万古霉素。参见Dellinger EP,Severe necrotizingsoft-tissue infections.JAMA 1981;246:1717-1720。
犁头霉属感染与高死亡率有关,特别是重病患者。该真菌常常通过呼吸道进入身体或直接传到擦伤的皮肤上。主要感染部位是窦腔、肺、皮肤、胃肠道和中枢神经系统。多烯,主要为两性霉素B、氟胞嘧啶和氮二烯五环是可用于预防治疗此种真菌感染主要的抗真菌药。参见Bennett,J.E.Fungal Infections(Section 15:InfectiousDiseases),In Harrison’s Principles of Internal Medicine 14thedition,(Isselbacher,K.J.,and Braunwald,E.,Wilson,J.D.,Martin,J.B.,Fauci,A.S.and Kasper,D.L.,eds)McGraw-Hill,Inc(Health Professions Division),1998,pp.1148-1163。
福氏耐格里原虫和棘阿米巴属某些种一般可在湖、游泳池、自来水和取暖和空调器中找到。虽然只有一种耐格里原虫已知感染人类,但牵涉数种棘阿米巴,包括A.culbertsoni、A.polyphaga、卡氏棘阿米巴、A.astronyxis、A.hatchetti和A.rhysodes。人类疾病Balamuthiamandrillaris的其他因素涉及leptomyxid ameba。棘阿米巴通过透镜或通过角膜切口或伤口进入眼。导致感染或角膜溃疡。另外,棘阿米巴属某些种可引起皮肤损害和/或系统性(全身)感染。通常认为局部使用0.1%二脒二苯氧基丙烷羟乙磺酸酯加新霉素-多粘菌素B-短杆菌肽眼药溶液是有效的治疗。参见The Pharmaceutical Journal,Vol 264 No7082 p212-218(Feb.2000)。角膜成形术通常是严重感染中必需的。Id.尽管伴棘阿米巴大多数脑(CNS)感染的病例导致死亡,但使用适当治疗患者从感染康复。另外,确定病例对磺胺有反应的棘阿米巴的新病例常常用两性霉素B治疗。参见De Jonckheere JF:Ecology ofAcanthamoeba.Rev Infect Dis 1991 Mar-Apr;13 Suppl 5:S 385-7;Martinez AJ:Infection of the central nervous system due toAcanthamoeba.Rev Infect Dis 1991 Mar-Apr;13 Suppl 5:S 399-402。
从人类分离了支原体种、两种无胆甾原体(Acholeplasma)和一种脲原体。参见Goodman and Gilman(9th Edition),Chapter 49,pp.1175-1188;10th Edition,Chapter 49,pp.1295-1312.HumanPharmacology by Brody,Larner and Minneman(Third Edition),Chapter 55,pp.735-744.这六种以泌尿生殖道作为主要移殖部位,但以口咽和呼吸道作为主要部位的其他种类由于口生殖道(orogenital)接触有时候可在泌尿生殖道中发现。Id.多烯抗生素常用于治疗。Id.然而其作用必须密切观察,因为此药作用于(act against)支原体膜上发现的胆固醇,它们也可作用于人类宿主细胞的质膜。Id.
无色杆菌属包括以下种:anitratus、baumannii、cystinovorum、lwoffi、putrefaciens、xylosoxidans。这是在水和土壤中出现的革兰阴性、需氧、能动的一属细菌。有些是脊椎动物肠道的常见栖息者。这些细菌有时候引起人类机会性感染。它们可用氯喹诺酮、哌拉西林或一种氨基糖苷与头孢他啶或培氟沙星联合治疗。参见PDR 2002,p.1499-1502。
近年,不动杆菌种已经显现为临床上重要的病原菌。尽管这些生物体在自然界中广泛流行,但大多数人类感染是医院的。鲍氏不动杆菌是主要的种类。参见Hsueh P-R,et al.Pandrug-resistantAcinetobacter baumannii causing nosocomial infections in auniversity hospital,Taiwan.Emerg Infect Dis(Aug.2002)。医院的鲍氏不动杆菌感染诸如呼吸道感染、泌尿道感染、神经外科处置后脑膜炎、和菌血症主要影响医院加护病房中严重潜在病患者且常常医院内暴发。联合化疗方法常常用于治疗此种类型感染。Id.
由HACEK微生物(副流感嗜血杆菌、嗜沫嗜血杆菌、伴放线放线杆菌、人心杆菌、啮蚀艾肯菌和金格杆菌)引起的心内膜炎可用cefriaxone钠、氨苄青霉素钠和硫酸庆大霉素治疗。参见Young and Mangum,NeoFax,5th Edition,1995,page 14。
放线菌,包括引起人类感染的种类诸如denticolens、eriksonii、georgiae、gerensceriae、hordeovuleris、howellii、伊氏放线菌、麦氏放线菌、内氏放线菌、龋齿放线菌、propionicus、pyogenes、ramosus、slackii、粘放线菌可用二甲胺四环素治疗。参见Newman,M.G.;Kornman,K.:Antibiotic/Antimicrobial Use in DentalPractice-Chapter 11,136-147,Quintes sence,1990。
产气气杆菌、大肠杆菌、各种变形杆菌、产气杆菌属、克雷伯菌属、志贺菌属和沙门菌属引起急性和慢性泌尿道感染、膀胱炎、肾盂肾炎、前列腺炎、产后肾盂炎、尿道炎、膀胱三角区炎。肠感染也可以是沙门菌属、志贺菌属、大肠杆菌和变形杆菌感染的结果。给予患者有效量萘啶酮酸(喹诺酮)以治疗这些革兰阴性感染。参见Kator,H.and M.Rhodes.1994.Microbial and chemical indicators.In:Environmental Indicators and Shellfish Safety.C.M.Hackney andM.D.Pierson.(Eds).pp.30-91.Chapman and Hall Publishers,NewYork,NY。
气单胞菌属,包括下列种:豚鼠气单胞菌、嗜水气单胞菌、jandaei、media、杀鲑气单胞菌、温和气单胞菌、trota、veronii可引起伤口感染。抗生素的选择包括氨基糖苷类、三代头孢菌素、亚胺培南、美罗培南、氨曲南、三甲氧苄二氨嘧啶-磺胺甲恶唑(SXT)、四环素、氯霉素和环丙沙星。参见Arias,et al.Antimicrobial susceptibilitypattern of Gram negative bacteria isolated from enteral feedingRev Biome.2000:11;169-174.庆大霉素、SXT、环丙沙星和三代头孢菌素可用于含这些细菌的伤口。参见Altwegg M.1999.Aeromonas andPlesiomonas.In PR Murray et al.(ed s.)Manual of ClinicalMicrobiology,7th ed.American Society for Microbiology,Washington D.C。
广州管圆线虫(嗜酸细胞性脑膜炎)或哥斯达黎加管圆线虫(腹部血管圆线虫病)感染的优选治疗是甲苯咪唑。参见Department ofPathology,The Johns Hopkins Medical Institutions,Vol.15 No.12,Microbiology Newsletter,Monday,March 18,1996.另外,乙胺嗪、噻苯咪唑和阿苯哒唑已经用于“减轻”症状。不过,手术常常用于除去身体的这些线虫。参见Barger,I.A.1992.Control ofgastrointestinal nematodes.Haemonchus Workshop,College Park,MD.化脓放线菌感染用抗生素和手术引流伤口治疗。Id.在所有放线菌感染中,青霉素都是首选药物。放线菌属,某些种和丙酸丙酸杆菌(P.propionicus)常常对青霉素、头孢菌素、四环素、氯霉素和多种其他抗生素敏感。Id.
对除青霉素和红霉素外的抗生素的溶血隐秘杆菌是断断续续的,并基于常规圆盘弥散实验和有限数目的菌株。McNeil MM,Brown JM.Themedically important aerobic actinomycetes:epidemiology andmicrobiology.Clin Microbiol Rev 1994;7:357-417.已经报道溶血隐秘杆菌对氯林可霉素、氯霉素、头孢菌素和梭链孢酸同样敏感。
似蚓蛔线虫,一般也称为“蛔虫”感染和鞭虫感染的鞭虫病,特别是蛔虫病继发的胃肠或胆梗阻可用柠檬酸哌嗪治疗。此药通过阻断寄生虫肌肉对乙酰胆碱反应引起寄生虫软瘫。甲苯咪唑也可用于治疗。参见Gilles HM:Intestinal nematode infections.In GT Strickland,ed.Hunter’s Tropical Medicine.Philadelphia:WB Saunders;1984;620-644.此药通过选择性和不可逆性阻断寄生虫寄居的敏感成人肠内葡萄糖和其他营养的吸收引起寄生虫死亡。另外,阿苯达唑、甲苯咪唑和双羟萘酸噻嘧啶用于治疗蛔虫病。参见Garcia,L.S.2001.Diagnostic Medical Parasitology,4th Ed.,ASM Press,Washington,D.C。
血吸虫病由两性血吸虫引起。感染人类的三个种是埃及血吸虫、日本血吸虫和曼氏血吸虫。参见Grove,D.I.and Warren,K.S.Relationof intensity of infection to disease in hamsters with acuteschistosomiasis mansoni.American Journal of Tropical Medicineand Hygiene 25:608 612,1976.选择的药物是用于血吸虫种引起感染的吡喹酮。参见Befidi Mengue,R.N.et al.(1993).Impact ofSchistosoma haematobium infection and of praziquantel treatmenton anemia of primary school children in Bertoua,Cameroon.J TropMed Hyg.96(4):225-30.在某些地区吡喹酮作用较小的曼氏血吸虫引起的感染用奥沙尼喹治疗有效。参见Brindley PJ.Drug resistance toschistosomicides and other anthelmintics of medical significance,Acta Trop 1994;56:213-31.
人酵母菌是偶见于人类肠道的原生动物,其致病性有争议。此微生物感染还发生于其他动物。即使此生物的临床重要性有争论,已经报道灭滴灵或双碘喹啉是有效的。参见Benitz & Tatro,Pediatric DrugHandbook,p.650,1988.Seminars in Pediatric Inf.Diseases,5(1):15-19,Jan.1994.
包括以下种:黄曲霉、烟曲霉、灰绿曲霉、构巢曲霉、黑曲霉、土曲霉的人类曲霉属感染可用两性霉素B、伊曲康唑、粒细胞-巨噬细胞集落刺激因子治疗。参见Geissmann F et al.Aspergillus brainabscesses:Therapeutic effect of G-CSF and liposomalamphotericin B.Abstract #PB0602,X Int Conf AIDS,Yokohama,1994.研究的用于曲霉病治疗的其他选择包括脂粒化(liposomal)两性霉素B和帕地霉素(pradimicin)。鼻内和烟雾状两性霉素B可能具有预防作用以减少伴随延迟的中性粒细胞减少患者的鼻部用量(carriage)。Id.
巴贝西虫的转播通过感染的蜱(丹明尼硬蜱)叮咬发生,但也认识到输血引起的感染。参见Epidemiologic Notes and ReportsClindamycin and Quinine Treatment for Babesia microti InfectionsCDC MMWR Weekly February 11,1983/32(5);65-6,72.可发生的感染范围从无症状到严重的、伴随发热、寒战和溶血性贫血的危及生命的疾病。此种疾病的治疗可用氯林可霉素和奎宁完成。Id.
芽胞杆菌属包括下列种:海马(alvei)炭疽杆菌、短芽胞杆菌、蜡样芽胞杆菌、环状芽胞杆菌、凝结芽胞杆菌、duplexnonliquefaciens、firmus、laterosporus、lentus、licheniformis、macerans、巨大芽胞杆菌、mycoides、多粘芽胞杆菌、pumilus、spaericus、stearothermophilys、枯草杆菌、thrungiensis。参见Turnbull PCB,Kramer JM,Melling J:Bacillus.p.187.In ParkerMT,Duerden BI(eds):Systematic Bacteriol ogy.Topley and Wilson’sPrinciples of Bacteriology,Virology and Immunity.Vol.2.EdwardArnold,sevenoaks,England,1990.临床型包括(1)皮肤炭疽病(焦痂伴水肿),源于处理感染的物质(95%病例属于此类);(2)肠炭疽病,源于进食感染的肉类;和(3)肺炭疽病,源于吸入粘有孢子的灰尘。Id.人类芽胞杆菌属感染的治疗用治疗革兰阳性细菌的非β-内酰胺类抗生素完成。食物中毒通过适当烹调、避免烹饪的食物再污染和适当储藏(有效冷藏)控制。Id.
拟杆菌属包括下列种:amylophilus、asaccharolyticus、bivius、buccae、buccalis、粪拟杆菌、多毛拟杆菌、cellulosolvens、corporis、corrodens、denticola、disiens、distasonis、埃氏拟杆菌、endodontalis、forsythus、脆弱拟杆菌、脆弱拟杆菌、furcosus、galacturonicus、gingivalix、gracilis、hearinolyticus、hypermegas、intermedius、利氏拟杆菌、loescheii、macacae、产黑素拟杆菌、屎拟杆菌、microfusus、multiacidus、nodosus、ochraceus、oralis、oris、oulorum、卵形拟杆菌、pectinophilus、precutus、ruminocola、salivosus、splanchnicus、粪便拟杆菌、succinogenes、tectum、termitidis、多形拟杆菌、单形拟杆菌、解脲拟杆菌、veroralis、普通拟杆菌、xylanolyticus、zoogleoformans。在拟杆菌属于正常植物中占有重要位置的同时,它们也是机会病原体,主要在腹腔感染。参见Appelbaum PC,Spangler SK,Jacobs MR:Susceptibilities of 394Bacteroides fragilis,non-B.fragilis group Bacteroides species,and Fusobacterium species to newer antimicrobial agents.Antimicrob Agents Chemother 1991 Jun;35(6):1214-8.脆弱拟杆菌是最显著的病原体。Id.已经发现抗生素治疗包括青霉素和氯林可霉素与脓肿引流和清除坏死组织联合是有效治疗方案。Id.
人类感染包括Bilophila wadsworthia最好以灭滴灵、亚胺培南、氯霉素,或羟氨苄青霉素、替卡西林、氨苄青霉素或哌拉西林与β-内酰胺酶抑制剂联合。此外,这类感染最有效治疗包括手术引流脓肿和清除坏死组织。参见Brook I:Pediatric anaerobic infection:diagnosis and management.2nd ed.St Louis,Mo:Mosby;1989.
博代杆菌属包括下列种:鸟博代杆菌、bronchicanis、支气管败血性博代杆菌、副百日咳博代杆菌、百日咳博代杆菌。百日咳博代杆菌,百日咳(又名whooping cough,百日咳)的原因,是非常小的革兰阴性需氧球杆菌。参见McCracken and Nelson,Antimicrobial Therapyfor Newborns,2nd Edition,1983.Benitz & Tatro,Pediatric DrugHandbook,p.559,1988.Young and Mangum,NeoFax,8th Edition,1995,page 20.Janssens,J et al:“Improvement of GastricEmptying in Diabetic Gastroparesis by Erythromycin,”NEJM322(15):1028,April 12,1990.在治疗百日咳感染中已经发现有效的抗生素是红霉素。另外,对严重环病婴儿推荐住院治疗和隔离。Id.
莱姆病是由螺旋形细菌伯氏疏螺旋体引起的感染。此细菌通过鹿蜱(肩突硬蜱)和西方黑脚硬蜱(太平洋硬蜱)的叮咬传播给人。数种抗生素在莱姆病治疗中有效。目前首选药物是强力霉素,为四环素的半合成衍生物。头孢呋辛酯和红霉素可用于对青霉素过敏或不能服用四环素的患者。莱姆病晚期,特别是伴随客观神经表现的,根据疾病严重性可用静脉内头孢曲松或青霉素进行必要的治疗4周或更长。参见BarbourAG.Lyme Disease:The Cause,the Cure,the Controversy.1996.TheJohns Hopkins University Press,Baltimore,MD.
粘膜炎莫拉菌(旧称布兰汉球菌)仅在人类中发现。推测其在人与人间传播。一旦某人传染(acquires)该细菌,其常常在不引起任何即刻症状下移植到此人。此后可变成全身感染。治疗此种感染是简单的。多种抗生素对该生物体有效。参见Physicians’Desk Reference.Montvale,NJ:Medical Economics Co;2001.
布鲁菌属感染主要通过暴露于感染的牛或猪发生,但是也通过饮用未经高温消毒的奶发生。布鲁菌病是全身性感染,特征是交互的发热、出汗和寒战期。感染由中性粒细胞携带到许多身体器官。McCracken andNelson,Antimicrobial Therapy for Newborns,2nd Edition,1983.Benitz & Tatro,Pediatric Drug Handbook,p.559,1988.Young andMangum,NeoFax,8th Edition,1995,page 20.Janssens,J et al:“Improvement of Gastric Emptying in Diabetic Gastroparesis byErythromycin,”NEJM 322(15):1028,April 12,1990.联合药物治疗,通常包括红霉素,已经发现是有效的。Id.
事实上所有感染弯曲杆菌属的人可无任何特殊治疗情况下恢复。弯曲菌属的种包括:butzleri、cinaedi、大肠弯曲菌、concisus、cryaerophilus、curvus、fennelliae、胎儿弯曲菌、豚肠弯曲菌、空肠弯曲菌、红嘴鸥弯曲菌、aridis、粘膜弯曲菌、mucosalisnitrofigilis、幽门弯曲菌、pyloridis、rectus、痰液弯曲菌、乌普萨拉弯曲菌。只要腹泻持续,患者应该饮用大量液体。在更多严重病例,可以使用诸如红霉素或氯喹诺酮的抗生素,如果在疾病早期给予抗生素可缩短症状持续时间。Id.
霍乱可通过立刻补充由腹泻丢失的体液和盐来简单且成功地治疗。患者可以用口服再水合溶液,事先做好包装的糖和盐的混合物,与水混合并大量饮用治疗。此溶液遍布世界使用以治疗腹泻。严重病例还要求静脉内补充液体。在即时的再水合情况下,低于1%的霍乱患者死亡。参见De S,Choudhuri A,Dutta P,Dutta D,De SP,Pal SC.Doxycyclinein the treatment of cholera.Bull WHO 1976;54:177-9.
大多数华支睾吸虫的病理表现由炎症和胆道的间歇梗阻产生。已发现吡喹酮或阿苯达唑成功治疗此种感染。参见Bource P.Successfultreatment of Taenia saginata and Hymenolepsis nana by a singleoral dose of praziquantel.Journal of the Egyptian Society ofParasitology,1991,21(2):303-7.
Q热是由伯纳特立克次体引起的动物传染性疾病。人类发生感染常常是通过从含空气传播的被感染的动物群的干胎盘物质、分娩液体和排泄物污染了的牛圈灰尘的空气中吸入这些生物体。人类通常非常容易感染该疾病,且引起感染所需生物体极少。一般,大多数患者未经任何治疗在数月内可恢复健康。然而,严重的病例中,100mg剂量的强力霉素每天口服2次,持续15-21天,是经常处方的治疗。参见Bartlett JG,Dowell SF,Mandell LA,et al:Guidelines from the InfectiousDiseases Society of America.Clini Infect Dis.2000;31.Reprinted with permission of The University of Chicago Press.
细菌属衣原体包括以下种:肺炎衣原体、鹦鹉热衣原体和沙眼衣原体,引起从眼、肺和生殖泌尿道感染的一系列疾病。衣原体属的治疗以多种抗生素完成。强力霉素是选择的抗生素,因为它用于长期治疗,可与食物一起服用且价格便宜。不过,四环素、氯霉素、利福平和氯喹诺酮也可使用。参见MR Howell,TC Quinn,CA Gaydos.Screening forChlamydia trachomatis in asymptomatic women attending familyplanning clinics.Annals of Internal Medicine 1998 128:277-84.
埃希菌、克雷伯菌、肠球菌、沙雷菌和枸橼酸菌属(合称大肠菌)和变形杆菌属包括造成广泛感染的公开的和机会的病菌。很多种是正常的肠内菌丛。大肠杆菌(E.coli)是临床实验室中最常分离到的生物体。多种抗生素是治疗的骨干。
梭菌属包括以下种:aerotolerans、aldrichii、argentinense、巴氏梭菌、拜氏梭菌、双酶梭菌、肉毒梭菌、丁酸梭菌、尸毒梭菌、carnis、celerecrescens、cellulofermentans、梭状梭菌、clostridioforme、coccoides、cocleatum、cloinum、cylindrosporum、艰难梭菌、disporicum、fervidus、ghoni、乙二醇梭菌、溶血梭菌、溶组织梭菌、homopropionicum、indolis、无害梭菌、intestinalis、josui、lentocellum、泥渣梭菌、litorale、magnum、malenominatum、methylpentosum、诺氏梭菌、orbiscindens、oxalicum、类腐败梭菌、产气荚膜梭菌、pfennigii、populeti、proteolyticum、putificum、多枝梭菌、roseum、scindens、败血梭菌、污泥梭菌、楔形梭菌、产孢梭菌、近端梭菌、symbiosum、第三梭菌、破伤风梭菌、tetanomorphorum、thermobutyricum、thermocopriate、thermopalmarium、thermopapyrolyticum和xylanolyticum。由此属细菌引起的感染范围为腹泻、破伤风、肉毒中毒和气性坏疽。由于给予有效量口服万古霉素或灭滴灵,在许多病例中治疗成功。参见Pothoulakis,M.D.,et al.Division of Gastroenterology,Beth Israel Deaconess MedicalCenter,Harvard Medical School,Boston MA.,Participate(Fall2001).
隐孢子虫属的症状包括腹泻、稀便或水便、胃的痛性痉挛、肚子痛和轻微发热。有人没有症状,而继续感染作为携带者。参见Petersen C.Cryptosporidiosis in patients infected with the humanimmunodediciency virus.Clin Infect Dis 1992;15:903-9.对人类隐孢子虫病没有确定的特异性治疗。由于腹泻所致迅速的体液丢失可通过补充体液和平衡电解质控制。Id.健康的、有免疫力的人的感染是自限性的,但免疫妥协和健康状态差的人的感染患更严重疾病的危险更高。对AIDS患者,巴龙霉素已经用于治疗。
环孢子病(cyclosporiasis)的原因最近才确定为单细胞球虫寄生虫,卡晏环孢子球虫(cyclospora cayetanensis)。它出现于所有由这一种寄生虫引起的人类病例中。对环孢子病的推荐治疗是联合三甲氧苄二氨嘧啶和磺胺甲恶唑两种抗生素,又名Bactrim、Septra或Cotrim。支持疗法包括休息和处理体液和电解质平衡。参见Remington & Klein,Infectious Diseases of the Fetus & Newborn,p.559,1990.Benitz& Tatro,Pediatric Drug Handbook,p.576-7,1988.
多节绦虫亚纲的阔节裂头绦虫(the fish or broad tapeworm,阔节裂头绦虫)是最大的人类绦虫。已经报道数种其他的裂头绦虫种感染人类,但少见;它们包括D.pacificum、心形裂头绦虫、D.ursi、D.dendriticum、D.lanceolatum、D.dalliae和D.yonagoensis。使用药物吡喹酮成功治疗了此种寄生虫。参见Bource P.Successfultreatment of Taenia saginata and Hymenolepsis nana by a singleoral dose of praziquantel.Journal of the Egyptian Society ofParasitology,1991,21(2):303-7。
棒状杆菌属包括下列种:水生棒状杆菌、牛棒状杆菌、白喉棒状杆菌、马棒状杆菌、溶血棒状杆菌、杰氏棒状杆菌、库氏棒状杆菌、matruchotii、微小棒状杆菌、假白喉棒状杆菌、假结核棒状杆菌、化脓棒状杆菌、肾棒状杆菌、纹带棒状杆菌、溃疡棒状杆菌、解脲棒状杆菌(ureolyticum)、泡囊棒状杆菌、干燥棒状杆菌。白喉棒状杆菌已经用对抗(counter)白喉毒素的白喉抗毒素,和对抗白喉菌的诸如青霉素或红霉素的抗生素治疗。参见PDR 2002,at p.2240-2243.
肠杆菌科(临床重要的肠细菌)包括:弗氏枸橼酸杆菌;Citrobacterdiversus;肠杆菌属某些种;Enterobacter aerogenes;Enterobacteragglomerans;阴沟肠杆菌;大肠杆菌;机会致病的(Opportunistic)大肠杆菌;产肠毒素的大肠杆菌(ETEC);enteroinvasive大肠杆菌(EIEC);致肠病大肠杆菌(EPEC);enterohemorrhagic大肠杆菌(EHEC);enteroaggregative E.coli(EaggEc);uropathogenic大肠杆菌(UPEC);肺炎克雷伯菌;产酸克雷伯菌;摩氏摩根菌;奇异变形杆菌;普通变形杆菌;普罗威登斯菌属;产碱普罗威登斯菌;雷氏普罗威登斯菌;斯氏普罗威登斯菌;enterrica沙门菌;伤寒沙门菌;副伤寒沙门菌;肠炎沙门菌;猪霍乱沙门菌;鼠伤寒沙门菌;粘质沙雷菌;液化沙雷菌;痢疾志贺菌;弗氏志贺菌;鲍氏志贺菌;索氏志贺菌;小肠结肠炎耶尔森菌;鼠疫耶尔森菌和假结核耶尔森菌。包括这些细菌的感染常常可用或者氨基糖苷类、氯霉素,或者三甲氧苄二氨嘧啶磺胺甲恶唑治疗。由小肠结肠炎耶尔森菌所致的简单腹泻病例通常无须抗生素治疗靠他们自身消除。然而,在更严重或复杂的感染,诸如氨基糖苷类、强力霉素、三甲氧苄二氨嘧啶磺胺甲恶唑或氟喹诺酮的抗生素可以是有帮助的。参见Harrison’s Principles of Internal Medicine 15th Ed.Chapter31,(2001).
对成年患者中侵害和旅行者腹泻综合征,环丙沙星和氟喹诺酮是经验治疗的选择药物。当治疗需要且病因已知是弯曲杆菌、大肠杆菌(非0157:H7)、沙门菌属-非伤寒(虽然抗生素治疗可延迟细菌脱落)、志贺菌属和耶尔森菌属时,它们也是选择的药物。常用于治疗志贺氏菌病的抗生素是氨苄青霉素、三甲氧苄二氨嘧啶/磺胺甲恶唑、萘啶酮酸或环丙沙星。参见Litt JZ,Drug Eruption Reference Manual,New York,Parthenon Publishing(2000)。
沙门菌属感染常在5-7天内消除,且一般不需要治疗,除非患者严重脱水或感染从肠扩散。伴严重腹泻患者可能需要再水化,常用静脉内液体。抗生素通常不是必需的,除非感染从肠扩散,那么可用氨苄青霉素、庆大霉素、三甲氧苄二氨嘧啶/磺胺甲恶唑或环丙沙星治疗。参见PDR 2002,at p.887-902。
埃利希病可以是严重的疾病,如果未治疗尤其可能是,且多至半数患者需要住院治疗。该病的严重表现可包括长期发热、肾衰、播散性血管内凝血、脑膜炎、成人呼吸窘迫综合征、癫痫发作或昏迷。治疗所用药物常为四环素类抗生素,诸如强力霉素。参见PDR 2002,at p.2735-2738。
布氏锥虫感染的治疗应尽快开始并根据感染者症状和实验室结果。药物治疗方案根据感染种类和感染阶段。依西酸喷他脒和苏拉明(根据来自CDC药物服务的新药试验方案)分别是治疗西部和东部非洲锥虫病的hemolymphatic阶段的首选药物。美拉胂醇是伴随中枢神经系统受累的疾病晚期的首选药物。参见Bryan R,Waskin J,Richarcs F,et al.African Trypanosomiasis in American travelers:a 20-year review.Travel Medicine.Steffen R,Lobel HO,Haworth J,Bradley DJ,eds.Berlin:Springer-Verlag,1989:384-8。
原生动物寄生虫,克氏锥虫,引起南美锥虫病,一种可通过猎蝽臭虫(bug)传播给人的动物传染病。参见Hagar JM,Rahitoola SH.Chagas’heart disease.Curr Prol Cardiol 1995;20:825-924。当在感染的急性期给药时,南美锥虫病的药物治疗通常有效。Id.选择的药物是benznidazole或硝呋莫司(根据来自CDC药物服务的新药试验方案)。参见Veloso,VM.et al.Variationin Susceptibility toBenznidazole in Isolates Derived from Trypanosoma cruzi ParentalStrains Memorias do Instituto Oswaldo Cruz Vol.96(7):1005-1011,(Oct.2001)。一旦疾病进展到晚期,无药物治疗被证明有效。在慢性期,治疗包括控制与疾病相关的症状。Id.
链霉菌感染需要长期抗生素治疗和手术控制。参见McNeil MM,Brown JM.The medically important aerobic actinomycetes:epidemiology and microbiology.Clin Microbiol Rev 1994;7:357-417。在体外,索马里(somaliensis)链霉菌对利福平、红霉素、妥布霉素、梭链孢酸和链霉素敏感。菌株检测对三甲氧苄二氨嘧啶抵抗。对索马里链霉菌感染,推荐用复方新诺明或氨苯砜与链霉素治疗。平均治疗期约为10个月。Id.
麦地那龙线虫,the guinea worm,常通过缠绕其于棒上小心除去该虫治疗。然而,也使用化疗疗法,诸如噻苯咪唑和灭滴灵。参见WorldHealth Organization,Fact Sheet No.98 DracunculiasisEradication(March 1998)。
蠕虫(roundworm nematode)蠕形住肠线虫(前称Oxyurisvermicularis)也称人蛲虫,引起人类感染。其感染通过使用称作双羟萘酸噻嘧啶的药物进行治疗。参见RIM Han-Jong;Antihelminticeffect of oxantel pamoate and pyrantel pamoate suspension againstintestinal nematode infestations SO:Korean-J-Parasitol 1975 Dec;13(2):97-101。
吸虫,肝片吸虫(羊肝吸虫)(the sheep liver fluke)和大片吸虫一般是食草类动物寄生虫,但偶可感染人类。与其他吸虫感染不同,肝片吸虫感染可不对吡喹酮反应。选择药物是三氯苯达唑,硫氯酚作为替代品。参见World Health Organization,Fact Sheet No.191Triclabendazole and Fascioliasis-A New Drug to Combat and Age OldDisease(April 1998)。
吸虫,布氏姜片虫,是人类最大的肠吸虫。其感染用药物吡喹酮已经成功进行了治疗。参见Brown and Neva.Basic ClinicalParasitology(6th ed.),pp 217-261。
丝虫病由栖息于淋巴和皮下组织的线虫(蛔虫)引起。它们中的三种是造成大部分归因于丝虫病的发病率的原因:班氏线虫和马来丝虫引起淋巴性丝虫病,而旋盘尾丝虫引起盘尾丝虫病(river blinding)。其他5种是眼丝虫、常现曼森线虫、链尾曼森线虫、奥氏曼森线虫和Brugia timori(最后一种也引起淋巴丝虫病)。参见Hotez.P.J.etal.Emerging and Reemerging Helminthiases and the Public Healthof China Emerging Infectious Diseases Vol.3,No.3(July-September 1993);Gubler,D.J.Resurgent Vector-BorneDiseasesasa Global Health Problem Emerging Infectious DiseasesVol.4,No.3(July-September 1998).抗菌乳膏用于伤口作为其感染的局部治疗。Id.此治疗阻止细菌感染并防止肿胀恶化。乙氨嗪(根据来自CDC药物服务的新药试验方案)和伊维菌素治疗丝虫病有效。
兰氏贾第鞭毛虫,一种原生动物鞭毛虫(双滴虫目)可引起人类严重腹泻感染。数种处方药可用于治疗贾第鞭毛虫病,不过,灭滴灵是选择药物。参见Hill DR.Giardial amblia.In:Mandell GL.,BennettJE,Dolin RD,editors.Mandell,Douglas,and Bennett’s principlesand practice of infectious diseases.4th ed.New York:ChurchillLivingstone Inc.;1995.p.2487-91。
线虫(蛔虫)棘颚口线虫感染脊椎动物,包括人类。人颚口线虫病是归因于迁移的幼虫。用阿苯达唑以及同时手术切除治疗已经成功。参见Garcia LS.Practical Guide to Diagnostic Parasitology.Washington DC,American Society for Microbiology,1999.GarciaLS and DA Bruckner.Diagnostic Medical Parasitology.3rd Edition.Washing DC,American Society for Microbiology,1997.The MedicalLetter On Drugs and Therapeutics.April 2002.Drugs For ParasiticInfections.Mark Abramowicz(Editor).The Medical Letter,Inc.New Rochelle,NY。
已经发现广谱头孢菌素和氯喹诺酮成功治疗由淋病奈瑟球菌引起的简单的生殖泌尿道感染。参见The Merck Manual of Diagnosis andTherapy,Sec.13 Infectious Disease,Ch.164 Sexually TransmittedDiseases(1995-2000)。
化脓链球菌对β-内酰胺抗生素持续高度敏感,且多项研究已经证明了青霉素制剂对链球菌咽炎的临床效力。参见Sin,FP.et al.Aretrospective review of patients with necrotizing fasciitispresenting to an emergency department in Hong Kong,Hong KongJournal of Emergency Medicine Vol.9,No.l(Jan.2002).类似地,已经证明青霉素和头孢菌素在治疗丹毒、脓疱病和蜂窝织炎中的效力,它们全都最常由化脓链球菌引起。Id.B族脓链球菌病常以青霉素G治疗。Id.
军团杆菌可见于许多类型的水系中。然而,该细菌在温暖、不流动的水(90°-105°F)中大量繁殖,诸如见于一些管道系统和热水槽、大型空调系统的冷却塔和蒸发冷凝器、和旋流温泉中的军团杆菌。参见Legionella pneumophila infections.In:Pickering LK,ed.Red Book2000;Report of the Committee on Infectious Diseases.25th ed.American Academy of Pediatrics;2000:364-5.红霉素当前推荐的用于治疗军团杆菌病患者的抗生素。Id.在严重病例,除红霉素外,可用二线药物利福平。其他药物可用于不能耐受红霉素的患者。Id.
利什曼病是由专性细胞内原生动物利什曼原虫属引起的,白蛉传播的媒介传播疾病。参见Boelaert M.,et al.Cost-effectiveness ofcompeting diagnostic-therapeutic strategies for visceralleishmaniasis.Bull World Health Organ 1999;77:667-74.人感染由感染哺乳动物的30种种约21种引起。Id.其包括有3个种的杜氏利什曼原虫复合体(杜氏利什曼原虫、婴儿利什曼原虫、杜氏利什曼原虫恰加斯亚种);有2个种的墨西哥利什曼原虫(墨西哥利什曼原虫、墨西哥利什曼原虫亚马逊亚种);热带利什曼原虫;大型利什曼原虫;埃塞俄比亚利什曼原虫;和有4个种的vianna亚属(巴西V.利什曼原虫、圭亚那(guyanensis)V.利什曼原虫、巴拿马(panamensis)V.利什曼原虫、秘鲁V.利什曼原虫)。由此属原生动物引起的感染的治疗是葡萄糖酸锑钠。Id.
钩端螺旋体病是影响人和动物的细菌性疾病。它由钩端螺旋体属细菌引起。参见Radostitis,O.et al.Verternary Medicine Textbookof the Diseases of Cattle,Sheep,Goats,Pigs and Horses 8th Ed.London,Balliere Tindall,1994 884-898.它引起人一系列症状,而部分感染的患者可没有症状。Id.钩端螺旋体病的症状包括高热、严重头痛、寒战、肌肉疼痛和呕吐,并可包括黄疸(皮肤和眼睛黄染)、眼睛充血、腹部疼痛、腹泻或皮疹。如果疾病未经治疗,患者可能发展成肾损害、脑膜炎(脑和脊髓周围的膜感染)、肝功能衰竭和呼吸困难。钩端螺旋体病用抗生素诸如强力霉素或青霉素治疗,它们应在该疾病过程中的早期给予。对更严重症状患者需要静脉注射抗生素。Id.
头部虱子,头虱是虱目昆虫,是一种体外寄生虫,其唯一宿主是人类。参见Borror,D.J.,C.A.Triplehorn and N.F.Johnson.1989.An introduction to the study of insects.6th Ed.Harcourt Brace,New York.P.875.虱子每天数次以血为食,并靠近头皮居住以维持其体温。其感染的治疗常通过应用所谓杀虱剂的局部药物获得,同时从宿主身上物理去除虱子。Id.
李斯特菌病是主要由产单核细胞李斯特菌引起的食物传播疾病。最易于患此病的人是孕妇、新生儿、老人和伴HIV或其他免疫力降低疾病的患者。氨苄青霉素单独或与庆大霉素联合一直是首选治疗。参见Calder,Jennifer.“Listeria Meningitis in Adults.”Lancet 350(1997):307。
术语微孢子目也用作属于微孢子门的专性细胞内原生动物寄生虫的通常命名法。参见Sandfort J et al.Albendazole treatment inpatients with intestinal microsporidiosis.Abstract PO-B10-1491,IX Intl Conf AIDS,Berlin,1993.目前,属于143个属的超过1200个种已经描述为感染广泛的脊椎动物和无脊椎动物宿主的寄生虫。Id.由Encephalitozoon hellem、家兔脑胞内原虫或Vittaforma corneae引起的眼微孢子病的首选治疗是阿苯达唑加局部烟曲霉素。Id.阿苯达唑是治疗由Encephalitozoon bieneus和Encephalitozoonintestinalis引起的肠感染的首选药。Id.
落矶山斑疹热是美国最严重和最常报道的立克次氏体病。参见Archibald LK,Sexton DJ:Long-term sequelae of Rocky Mounta inspotted fever.Clin Infect Dis 1995 May;20(5):1122-5.该病由立氏立克次氏体,一种通过硬(hard)蜱传播给人的细菌引起。Id.该病最初的体征和症状包括突发性发热、头痛和肌肉疼痛,之后发展为皮疹。Id.治疗包括有效给予强力霉素。Id.
阴道毛滴虫,一种鞭毛虫,是工业化国家中最常见的人类病源性原生动物。参见Wolner-Hanssen P,Krieger J,Stevens CE,Kiviat NB,Koutsky L,Critchlow C,et al.Clinical manifestations of vaginaltrichomoniasis JAMA 1989;261:571-6.治疗应在医疗监护下执行,且应包括感染患者的所有性伴侣。Id.治疗首选药是灭滴灵。Id.治疗一般非常成功。良好耐受的替代药替硝唑在美国没有供应。然而,已经有对两种药物抵抗的阴道毛滴虫菌株报道。Id.
孢子丝菌病是由称作schenckii孢子丝菌的真菌引起的真菌感染。参见Ajello Land R.J.Hay.1997.Medical Mycology Vol 4 Topley& wilson’s Microbiology and Infectious Infections.9th Edition,Arnold London.它常感染皮肤。孢子丝菌病一般用碘化钾治疗,以滴剂形式口服。一种称作伊曲康唑的新药可用于治疗,但使用此药的经验仍有限。治疗常常超过几周,直到皮损完全愈合。Id.
梅毒是由梅毒螺旋体细菌引起的复合(complex)性传播疾病(STD)。参见Centers for Disease Control and Prevention.1998 guidelinesfor the treatment of sexually transmitted diseases.MMWR 47(RR-1):1,1997.它常常被称作最大模仿者,因为非常多的体征和症状与其他疾病无法区分。Id.抗生素青霉素一次给药可治愈患梅毒少于1年的患者。治愈患梅毒长于1年的患者需要多次给药。Id.出生患该病的婴儿需要青霉素治疗10天。没有家庭治疗方案或治愈梅毒的非处方药物。青霉素治疗将杀死梅毒菌并防止进一步损害,但是它不修复任何已经发生的损害。Id.
鼠弓形体是原生动物寄生虫,其感染温血动物包括人类的大部分种,引起弓形体病。参见Torres,G.Toxoplasmosis:New TreatmentAdvances The Gay Men’s Health Crisis Newsletter of ExperimentalAIDS Therapies;Volume 5 Number 3(Mar.28,1991).未妊娠的健康人不需要治疗。症状一般在几周内消除。对妊娠妇女或免疫系统变弱的患者,乙嘧啶加磺胺嘧啶合甲酰四氢叶酸是有效的治疗。Id.
旋毛虫病由毛线虫属线虫(蛔虫)引起。除传统病因旋毛线虫(见于全世界许多食肉类和杂食性动物)之外,现在认识到其他4种毛线虫:T.pseudospiralis(全世界的哺乳动物和鸟类)、T.nativa(北极熊)、T.nelsoni(非洲食肉动物和食腐动物)和T.britovi(欧洲和西亚的食肉类动物)。参见J Dupouy-Camet,W Kociecka,F Bruschi,FBolas-Fernandez,E Pozio Opinion on the diagnosis and treatmentof human trichinellosis Expert Opinion on Pharmacology Vol.3(2002).治疗这些寄生虫感染包括给予类固醇加灭滴灵。Id.
线虫(蛔虫)毛首鞭虫引起已知是鞭虫的人类感染。参见Cooper,E.S.& Bundy,D.A.P.(1988).Trichuris is not trivial.Parasitology Today.4(11):301-306.治疗包括给予药物灭滴灵。另外,阿苯达唑用作治疗。Id.
伤寒发热是由伤寒沙门菌细菌引起的有生命危险的疾病。参见Ryan,Kenneth J.and Stanley Falkow.“Salmonellosis.”In SherrisMedical Microbiology:An Introduction to Infectious Diseases,edited by Kenneth J.Ryan.Norwalk,CT:Appleton and Lange,1994.三种常见处方抗生素是氨苄青霉素、三甲氧苄二氨嘧啶/磺胺甲恶唑和环丙沙星。Id.
副溶血性弧菌是与引起霍乱的细菌同族的细菌。其生活于稍有咸味的盐水中,引起人类胃肠疾病。参见World Health Organization FactSheet No.107 Cholera(March 2000).多数副溶血性弧菌感染病例不需要治疗。没有证据表明抗生素治疗降低该病的严重性或病程。患者应饮大量液体以补充由腹泻丢失的液体。在严重或延展性疾病中,抗生素诸如四环素、氨苄青霉素或环丙沙星可以使用。Vibrio vulnificus感染用强力霉素或三代头孢菌素(例如头孢他啶)治疗。Id.
细菌性阴道病(BV)是由多种厌氧性细菌包括:阴道加德纳氏菌、动弯杆菌属某些种、拟杆菌属某些种和人支原体引起的生殖-泌尿道感染。参见Ferris DG,Litakers MS,Woodward L,Mathis D,HendrichJ.Treatment of bacterial vaginosis:a comparison of oralmetfonidazole,metronidazole vaginal gel,and clindamycinvaginal cream.J Fam Pract Vol.41(1995).已经发现灭滴灵成功治疗此系列感染。Id.
麻风是皮肤、外周神经和粘膜的感染,导致特别是在身体温度较低区域损伤、色素减退和感觉丧失(麻醉)。参见World HealthOrganization Fact Sheet No.101(Jan.2000).用由氨苯砜、利福平和clofazimine组成的多药疗法对门诊病人进行基础治疗(包括在密切接触中预防)3-5年;在一些地方流行地区用Mbovis BCG接种有效。Id.
应该进行消化链球菌培养和敏感性研究以确定病原生物及它们对灭滴灵的敏感性。参见Ralph,E.D.,and Kirby,W.M.M.:Bioassay ofMetronidazole With Either Anaerobic or Aerobic Incubation,J.Infect.Dis.132:587-591(Nov.)1975;or Gulaid,et al.:Determination of Metronidazole and Its Major Metabolites inBiological Fluids by High Pressure Liquid Chromatography,Br.J.Clin.Pharmacol.6:430-432,1978。
下列实施例教导本文所述实施方案的方法和所公开的ROM产生和释放抑制化合物的用途。这些实施例只是说明而不限制所述实施方案的范围。下面所述的治疗方法可用本领域普通技术人员熟知的经验技术优化。此外,普通技工能使用在下列实施例中所述的教导实现所述实施方案的全部范围。
实施例1
幽门螺杆菌[Hp(2-20)]衍生的cecropin样肽活化的人单核细胞
引发自然杀伤细胞和T细胞程序性死亡(凋亡)
幽门螺杆菌感染引起慢性胃炎,其特征是诸如单核细胞/巨噬细胞的炎症细胞大量粘膜浸润。用cecropin样幽门螺杆菌肽,[Hp(2-20)],处理人单核细胞,诱导CD3ε+表型T淋巴细胞和CD56+表型自然杀伤细胞的凋亡。胃粘膜成分组胺减少(resuced)T细胞和NK细胞凋亡。组胺可用作添加剂增加幽门螺杆菌疫苗试验方案的效力。
幽门螺杆菌引起人类慢性的、常常伴随一生的胃炎。宿主对幽门螺杆菌感染的免疫反应的一般特征是胃上皮下层被主要是单核细胞/巨噬细胞和中性粒细胞的吞噬细胞,和包括介导抗感染保护作用的诸如自然杀伤(NK)细胞和T细胞的淋巴细胞的大量浸润。参见Agnihotri et al.1988 Characterization of lymphocytic subsets and cytokingproduction in gas tric biopsy samples from Helicobacter pyloripatients.Scand J Gastroenterol.33:704-9;Li et al.1999Reactions from rat gastric mucosa duting one year of Helicobacterpylori infection Dig Dis Sci.44:116-24;Takeuchi et al,2001Prognostic significance of natural killer cell activity inpatients with gastric carcinoma:a multivariate analysis,Am JGastroenterol.96:574-8;Ishigami et al.2000 Prognostic valueof intratumoral natural killer cells in gastric carcinoma.Cancer.88:577-83。
幽门螺杆菌[Hp(2-20)]衍生的cecropin样肽活化的人单核细胞引发自然杀伤细胞和T细胞程序性死亡(凋亡)。这些抑制活动由氧自由基介导,氧自由基由Hp(2-20)诱导并通过单核细胞NADPH氧化酶活化产生。二盐酸组胺通过抑制单核细胞中产生的氧自由基保护NK细胞/T细胞免于单核细胞诱导的细胞凋亡。组胺的这些作用由组胺H2型受体介导。我们假定(propose)组胺、其具有H2受体激动剂活性的类似物、或氧自由基清除剂/抑制剂可有助于增强宿主对幽门螺杆菌的免疫反应。
试剂
所用Hp(2-20)肽,AKKVFKRLEKLFSKIQNDK,按照在Bylund et al.2001.Proinflammatory activity of a cecropin-like antibacterialpeptide from Helicobacter pylori.Antimicrob Agents Chemother.In press中所述合成和操作。二盐酸组胺产自MaximPharmaceuticals,(San Diego),盐酸雷尼替丁产自Glaxo(Mlndal,Sweden)。超氧化物歧化酶(SOD)和过氧化氢酶购自Boehringer-Mannheim,Germany。
分离白细胞
外周血获自Sahlgren’s Hospital,Gteborg的健康献血员。Ficoll-Hypaque浓度梯度离心后,按照文献的详细描述,用对流离心淘洗(CCE)技术将单个核细胞分离为淋巴细胞和单核细胞,得到有>90%单核细胞的一部分(20-22ml/min的流速)和两部分淋巴细胞,其中一个富含CD3ε-/56+NK细胞(45-50%;于15-16ml/min),一个富含CD3ε+/56-T细胞(70-80%,于13-14ml/min)。参见Hansson et al.1996.Induction of apoptosis in NK cells by monocyte-derived reactiveoxygen metabolites.J Immunol.156:42-7。
单核细胞趋化和NADPH-氧化酶活性
测定NADPH-氧化酶活性使用定量细胞外活性氧种类(ROS)的异鲁米诺增强化学发光系统(isoluminol-enhanced chemiluminescene(CL)system)。参见Dahlgren,C.,Karlsson,A.1999.Respiratory burstin human neutrophils.J.Immunol Methods 232:3-14。
凋亡分析
细胞凋亡按照文献所述方法通过使用流式细胞仪监测。参见Mellqvist et al.2000.Natural killer cell dysfunction andapoptosis induced by chronic myelogenous leukemia cells:role ofreactive oxygen species and regulation by histamine.Blood.96:1961-8.单核细胞显示后为T细胞或NK细胞设门,并设定门比较具有降低的前向散射和增高的直角散射凋亡特征的淋巴细胞。参见Hansson et al.1996.使用另外两种方法测定NK细胞和T细胞中的凋亡:按照文献所述方法通过末端脱氧核苷酸转移酶介导的溴化dUTP切口末端标记DNA片断和Annexin-V染色DNA链断裂分析(analysis ofDNA strand breaks)。参见Mellqvist et al,;Hansson et al.1999.Histamine protects T cells and natural killer cells againstoxidative stress.J Interferon Cytokine Res.19:1135-44。
淋巴细胞表面和细胞内抗原检测
按照文献所述方法以合适的异硫氰酸荧光素(FITC)-和藻红蛋白(PE)-标记的单克隆抗体(Becton & Dickinson,Stockholm,Sweden;10ul/106cells)染色1百万个细胞。参见Hansson et al.1999.通过在有Lysys II软件系统的FACSort(Becton & Dickinson)上使用流式细胞术分析细胞。根据前向和直角散射为淋巴细胞设门。流速调节到<200个细胞每秒且每个样品至少分析5000个细胞。
Hp(2-20)诱导的淋巴细胞凋亡
早期研究揭示单核细胞/巨噬细胞引发NK细胞功能抑制。Hp(2-20)强力引发吞噬细胞中超氧化离子形成的发现促使我们研究Hp(2-20)对单核细胞/NK细胞或T细胞相互作用的影响。参见Bylund et al.2001.为此,我们将不同浓度单核细胞与自体富含NK细胞的淋巴细胞一起培养,并观测NK细胞生存能力。
淋巴细胞与Hp(2-20)活化的单核细胞培养过夜后观察到了淋巴细胞凋亡的特征性形态学改变。在NK细胞和CD3ε+T细胞中Hp(2-20)诱导的凋亡显著。门内淋巴细胞的凋亡通过DNA片断分析(TUNEL分析)和annexin V染色[未显示]证实,并为SOD和过氧化氢酶彻底预防(图1)。参见Mellqvist et al,2000;Hansson et al.1999。
图1显示Hp(2-20)引发NK细胞和T细胞凋亡。培养后,通过使用流式细胞仪分析淋巴细胞门内的细胞的凋亡形态学特征(前向散射减少和直角散射增高)。A中,数据是经下列处理后凋亡的CD56+(NK;暗灰色条)或CD3ε+(T;open bar)的频次:
在培养基中培养的细胞[对照;(1)]
淋巴细胞+25%单核细胞(2)
淋巴细胞+25%单核细胞+Hp(2-20)[50μM;(3)]
淋巴细胞+50%单核细胞(4)
淋巴细胞+50%单核细胞+Hp(2-20)(5)。
插图显示淋巴细胞中由Hp(2-20)-活化的单核细胞诱导的细胞凋亡,这些数据是三个独立实验的均数±s.e.m.。B中的结果显示在用SOD+过氧化氢酶或组胺(50μM),单独或在H2受体拮抗剂雷尼替丁(50μM)存在下,处理过的细胞混合物中,由以Hp(2-20)活化的25%单核细胞(淡灰色条)或50%单核细胞(暗灰色条)诱导的淋巴细胞凋亡。
组胺对NADPH-氧化酶活性的作用
组胺抑制Hp(2-20)-诱导的自由基产生并恢复淋巴细胞功能和生存能力。前期研究表明,组胺通过单核细胞和其他吞噬细胞降低或抑制NADPH-氧化酶依赖的氧自由基形成。参见Mellqvist et al.2000.在胃粘膜中正常出现的相当高浓度的组胺[约10-100μM]使我们研究组胺对单核细胞中Hp(2-20)-诱导的氧自由基形成的作用。参见Bechi etal.1993.Reflux-related gastric mucosal injury is associatedwith increased mucosal histamine content in humans.Gastroenterology.104:1057-63;Lonroth,et al.1990.Histaminemetabolism in human gastric mucosa.Effect of pentagastrinstimulation.Gastroenterology.98:921-8.组胺显著抑制由Hp(2-20)-诱导的氧自由基形成,特异性组胺H2受体拮抗剂雷尼替丁抵消(reversed)这种抑制。(图2)
图2显示了由Hp(2-20)-诱导的氧自由基形成和被组胺的抑制。通过异鲁米诺-放大CL研究了淘选单核细胞中超氧化离子产生(A)。用组胺(50μM)或H2受体拮抗剂雷尼替丁(50μM)处理细胞。数据是四个独立实验的均数值±s.e.m.。
组胺对NK细胞和T细胞功能的作用
早期研究表明组胺通过抑制氧自由基的产生表现为抑制吞噬细胞保护NK细胞和T细胞功能。参见Mellqvist et al.2000;Hansson etal.1999.我们因此研究了组胺是否保护NK细胞和T细胞免于单核细胞依赖的Hp(2-20)-诱导的凋亡。发现组胺防止NK细胞和T细胞的凋亡。组胺诱导的NK细胞和T细胞保护作用被H2受体拮抗剂雷尼替丁拮抗(图3)。
图3显示Hp(2-20)-诱导的凋亡:被二盐酸组胺抑制。按照方法中所述制备单核细胞和/或淋巴细胞。培养16小时后,在淋巴门内的细胞通过使用流式细胞仪分析凋亡形态学特征(前向散射减少和直角散射增高)。数据是凋亡的淋巴细胞的频次。二盐酸组胺、雷尼替丁和Hp(2-20)用50μM,过氧化氢酶用100U/ml,SOD用50U/ml。
加Hp(2-20)到淋巴细胞和单核细胞中,目的是模仿幽门螺杆菌感染的胃组织的单个核细胞浸润,引发NK细胞和T细胞的凋亡。参见Agnihotri et al.1998;Li et al.1999.这些抑制活动被NADPH氧化酶衍生的氧自由基清除剂所防止,并因此全部能被由Hp(2-20)诱导的FPRL1/FPRL2介导的氧自由基解释。组胺被发现降低或抑制Hp(2-20)诱导的氧自由基的形成,并因而保护NK细胞和T细胞免于凋亡性细胞死亡。组胺的这种作用是通过由单核细胞表达的组胺H2受体介导的,且近似于人胃粘膜组织中检测到的组胺浓度足以介导保护性作用。参见Bechi et al.1993;Lonroth et al.1990。
实施例2
二盐酸组胺治疗癣感染
根据本领域已知方法将本发明实施方案所述的化合物制备为用于局部应用的乳膏。将制剂重量0.08%浓度的ROM产生和释放抑制化合物二盐酸组胺加入乳膏中。选择患活动性癣感染的受试者2组各10例。第一组患真菌感染的10例受试者,试验组用含二盐酸组胺乳膏治疗。第二组,对照组,用由试验乳膏的相同成分和化合物组成,但缺少二盐酸组胺的乳膏治疗。
受试者的治疗包括在病损部位局部用药每天4-5次。当处理真菌新生物(growth)时,注意不要将真菌孢子污染新的区域。与对照组比较,试验组受试者治愈的时间缩短。
实施例3
联合其他化疗药治疗微生物感染
下一步使用标准组合物研究所述实施方案中组合物促进由微生物引起的感染复原的能力,所述微生物包括酵母、真菌、细菌、原生动物、寄生虫和阿米巴。以2组受试者,每组10例评估所述实施方案的ROM产生和释放抑制化合物增加抗菌剂效力的能力。研究开始时无受试者患活动性感染。I组受试者根据生产商给出的剂量接受用于治疗特异性感染的典型抗菌剂。II组受试者接受同等剂量的同种抗菌剂并以0.08%重量应用适合于微生物感染类型和部位的ROM产生和释放抑制化合物二盐酸组胺。然后监测各组患者恢复的时间。接受抗菌剂和ROM抑制化合物二者的受试者证明恢复时间加快。
实施例4
使用控释装置治疗由幽门螺杆菌引起的溃疡
用所述实施方案的化合物治疗诊断为幽门螺杆菌引起的溃疡患者。用有效量ROM抑制化合物NADPH氧化酶抑制剂二亚苯基碘鎓补充控释装置,并通过口服该装置向患者给药。由于该装置停留在患者的胃内,其持续呈递所述实施方案的化合物并分解以允许从身体泌出。将所述实施方案的化合物用于此类感染诸如羟氨苄青霉素、克拉霉素、四环素或灭滴灵的典型化疗药联合给药。在加速胃肠溃疡治疗中给药二亚苯基碘鎓有效。
实施例5
使用喷雾剂治疗肺炎链球菌肺部感染
用所述实施方案的化合物以喷雾剂形式治疗诊断有肺炎链球菌的受试者。将喷雾剂稳固对着伴随呼吸道感染患者的口-鼻腔。喷雾剂用于当患者深吸气时呈递气溶胶薄雾。喷雾剂或者单独地含有效量本文所述制剂,或者含该制剂与常用于此类感染给药的化疗药如头孢氨苄的混合物。通过喷雾剂将0.05%制剂重量浓度的ROM抑制化合物NADPH氧化酶抑制剂二亚苯基碘鎓作为薄雾呈递到患者肺中。给予二亚苯基碘鎓促进肺炎患者的恢复。
实施例6
使用滴眼剂和/或眼膏治疗沙眼衣原体眼部感染
以所述实施方案的组合物用0.09%制剂重量的二盐酸组胺眼药水治疗患沙眼衣原体眼部感染的受试者。可商购到的眼药水是本领域熟知的。另外,眼药水,优选滴剂形式,含合霉素。每3小时给眼部应用1次该眼药水。只含ROM产生和释放抑制化合物的溶液每小时给药以减轻受试者的不适。应用该眼药水减少了细菌感染的时间、由细菌感染引起的损害,并减轻患者的不适。
实施例7
使用栓剂和/或灌肠剂治疗鞭虫(ASCARIS TRICHURIASIS)胃肠感染
用所述实施方案的化合物治疗表现寄生虫感染症状的儿童。将含本文所述制剂的栓剂放入伴Ascaris trichuriasis(“鞭虫”)感染患者的直肠。位于栓剂上的制剂逐渐释放将减轻炎症。另外,含本文所述制剂的栓剂直肠给药,此外向感染Ascaris trichuriasis患者适当给予抗寄生虫药诸如柠檬酸哌嗪、甲苯咪唑、阿苯达唑或双羟萘酸噻嘧啶,以杀死寄生虫和减轻炎症。同样地,对处于人胃肠道较高位置的寄生虫,诸如蛔虫(蛔虫)感染,出于消除寄生虫和减轻炎症的同样目的,灌肠剂用于呈递除抗寄生虫药之外的上述化合物。除其他化疗药之外更换栓剂和重复灌肠给药以缩短治愈时间及排出寄生虫。
实施例8
使用静脉内或动脉内注射剂治疗疟原虫血液感染
采用静脉内输注袋或动脉内注射器通过注射呈递所述实施方案的组合物治疗由4种疟原虫中任何一种引起的疟疾确诊患者。静脉内或动脉内注射剂或者仅含有效量本文公开的组合物,或者含有效量该组合物与有效量适当化疗药,诸如磷酸氯喹、磺胺药物和primethamine的混合物。通过注射该组合物分散到原生动物居住的血流和肝脏中,以从患者消灭疟原虫和减轻炎症。静脉内或动脉内给药每小时1次,以减轻受试者的不适。该溶液的应用将加快患者摆脱疟原虫。
实施例9
通过口服给予胶囊治疗腹泻
除给予适当化疗药诸如氨基糖苷、氯霉素、三甲氧苄二氨嘧啶磺胺-甲恶唑、强力霉素或氟喹诺酮之外,用含ROM抑制化合物NADPH氧化酶抑制剂二亚苯基碘鎓以0.8%制剂重量浓度的胶囊治疗患腹泻的受试者。所述腹泻归因于造成腹泻或类似形式胃肠病的大肠杆菌、奇异变形杆菌、肠炎沙门菌、克雷伯菌、耶尔森菌、志贺菌、沙雷菌、念珠菌、贾第鞭毛虫、隐孢子虫、霍乱弧菌、弯曲杆菌、蛔虫等的任何数量的致病属、种或菌株。治疗由每天服用3-10个胶囊,持续7-30天(根据感染的成因)。给予二亚苯基碘鎓在加速受试者腹泻治疗中有效。
实施例10
使用静脉内或动脉内注射剂治疗脓毒病
采用静脉内输注袋或动脉内注射器通过注射呈递所述实施方案的组合物治疗确诊脓毒病患者。静脉内或动脉内注射剂或者仅含有效量本文公开的组合物,或者含有效量该组合物与对造成脓毒病生物体特异的有效量适当化疗药。通过注射该组合物分散到脓毒病生物体栖息的血流中,以从患者消灭疟原虫和减轻炎症。静脉内或动脉内给药每小时1次,以减轻受试者的不适。该溶液的应用将加快患者摆脱脓毒病的成因。
实施例11
使用牙膏和漱口液治疗牙齿感染
用含0.05%制剂重量浓度的ROM抑制化合物NADPH氧化酶抑制剂二亚苯基碘鎓牙膏和漱口液治疗患变异链球菌引起的牙齿感染的患者。治疗由每天用此牙刷刷牙5次并使用漱口液,持续7天。在治疗受试者牙齿感染中给予二亚苯基碘鎓有效。
Claims (45)
1.一种抑制或减少对患者皮肤或粘膜酶促产生的ROM-介导的氧化损伤的方法,所述方法包括对受试者在药物可接受载体中局部给予有效量ROM产生和释放抑制化合物的步骤,所述受试者患有所述患者感染部位的ROM-介导氧化损伤。
2.权利要求1的方法,其中所述对患者感染部位的ROM-介导的氧化损伤是选自下列组的细菌疾病:链球菌、葡萄球菌、肠球菌家族成员、螺杆菌、奈瑟球菌、衣原体、分枝杆菌、密螺旋体、假单胞菌、嗜血杆菌、支原体、梭菌、放线杆菌、立克次氏体、军团杆菌、李斯特菌、钩端螺旋体等。
3.权利要求1的方法,其中所述对患者皮肤或粘膜的ROM-介导的氧化损伤是选自下列组的真菌疾病:癣、念珠菌、组织胞浆菌、孢子丝菌、芽生菌、隐球菌、曲霉、马拉色霉菌等。
4.权利要求1的方法,其中所述对患者皮肤或粘膜的ROM-介导的氧化损伤是选自下列组的寄生虫疾病:蛔虫、裂头绦虫(diphyllobothrium)、颚口线虫、吴策线虫、布氏丝虫、盘尾丝虫、眼丝虫、曼森线虫等。
5.权利要求1的方法,其中所述对患者皮肤或粘膜的ROM-介导的氧化损伤是选自下列组的原生动物疾病:疟原虫、贾第鞭毛虫、毛滴虫、弓形虫、利什曼原虫等。
6.权利要求1的方法,其中所述ROM产生和释放抑制化合物选自组胺、二盐酸组胺、二磷酸组胺、其他组胺盐、酯、前药、H2受体激动剂、5-羟色胺和5-HT激动剂组成的组。
7.权利要求1的方法,其中所述ROM产生和释放抑制化合物促进内源性组胺储存的释放。
8.权利要求7的方法,其中所述促进内源性组胺储存释放的化合物选自IL-3、视黄酸、9-顺-视黄酸、全反式视黄酸和变应原组成的组。
9.一种含有效量化合物的组合物,所述化合物抑制酶促反应的ROMs产生或释放,所述化合物在药物可接受载体中适合于静脉内、动脉内、局部、口服、肛门、生殖器、透皮、吸入、结内(intranodal)和肌肉内给药。
10.权利要求9的组合物,其中所述化合物选自组胺、二盐酸组胺、二磷酸组胺、其他组胺盐、酯、前药、H2受体激动剂、5-羟色胺和5-HT激动剂组成的组。
11.权利要求9的组合物,其中所述化合物是促进内源性组胺储存的释放的化合物。
12.权利要求11的组合物,其中所述促进促进内源性组胺储存的释放的化合物选自IL-3、视黄酸、9-顺-视黄酸、全反式视黄酸和变应原组成的组。
13.权利要求9的组合物,其中所述药物可接受载体是化妆品。
14.权利要求13的组合物,其中所述药物可接受载体是肥皂。
15.权利要求13的组合物,其中所述药物可接受载体是伤口敷料。
16.权利要求13的组合物,其中所述药物可接受载体是喷雾器。
17.权利要求13的组合物,其中所述药物可接受载体是透皮贴剂。
18.权利要求13的组合物,其中所述药物可接受载体是牙膏。
19.权利要求13的组合物,其中所述药物可接受载体是漱口液。
20.权利要求13的组合物,其中所述药物可接受载体是洗剂。
21.权利要求9的组合物,其中所述药物可接受载体是栓剂。
22.权利要求9的组合物,其中所述药物可接受载体是能静脉内或动脉内给药的液体。
23.权利要求9的组合物,其中所述药物可接受载体是能吸入的吸入剂。
24.权利要求9的组合物,其中所述吸入剂通过喷雾器或吸入器给药。
25.权利要求9的组合物,其中所述药物可接受载体是口服给药。
26.权利要求9的组合物,其中所述口服给药是通过丸剂、胶囊或锭剂给药。
27.权利要求9的组合物,其中所述药物可接受载体是眼药水或眼膏。
28.权利要求9的组合物,其中所述药物可接受载体是控释装置。
29.权利要求9的组合物,其中所述控释装置是受试者体内可生物降解的。
30.权利要求9的组合物,其中所述控释装置不是可生物降解的,但是通过受试者排泄物排泄。
31.权利要求9的组合物,其中所述药物可接受载体是手术种植物。
32.权利要求9的组合物,其中所述手术种植物埋入受试者的组织内。
33.权利要求9的组合物,其中所述手术种植物附在受试者体内或体表的感染部位。
34.一种制备用于局部给予化合物的组合物的方法,所述化合物抑制酶促反应产生的ROMs的产生和释放,所述方法包括:
提供药物可接受载体和有效浓度的组胺以治疗由微生物感染引起的ROM介导的对皮肤的损伤;和
形成含药物可接受载体与所述抑制酶促产生的ROMs产生和释放的化合物的组合物。
35.权利要求34的方法,其中所述化合物选自组胺、二盐酸组胺、磷酸组胺、其他组胺盐、酯、前药、H2受体激动剂、5-羟色胺和5-HT激动剂组成的组。
36.权利要求34的组合物,其中其中所述化合物是促进内源性组胺储存的释放的化合物。
37.权利要求34的方法,其中所述药物可接受载体是糖锭、漱口液、牙膏、化妆品、透皮贴剂、静脉内注射剂、动脉内注射剂、栓剂、灌肠剂、眼药水、眼膏、洗剂、手术种植物、控释装置、肥皂、丸剂、胶囊、吸入剂、喷雾器或伤口敷料。
38.权利要求34的方法,其中所述治疗方法是关于寄生虫、酵母、真菌、原生动物或其他引起炎症的寄生感染性疾病。
39.一种治疗微生物感染的方法,所述方法由以下步骤组成:
诊断患者伴随微生物感染
给予该患者有效量的适当的化疗药;和
给予该患者有效抑制细胞内过氧化氢的产生和释放的,选自组胺、其他H2受体激动剂和5-羟色胺组成的组的化合物。
40.权利要求39的方法,其中优选同时给予所述适当的化疗药和所述有效抑制细胞内过氧化氢的产生和释放的化合物。
41.权利要求39的方法,其中给予所述适当的化疗药优选在给予所述有效抑制细胞内过氧化氢的产生和释放的化合物的1小时之内。
42.权利要求39的方法,其中所述有效抑制细胞内过氧化氢的产生和释放的化合物给药剂量从约0.1到约10毫克/天。
43.权利要求39的方法,其中所述有效抑制细胞内过氧化氢的产生和释放的化合物单独给药。
44.权利要求39的方法,其中所述有效抑制细胞内过氧化氢的产生和释放的化合物与有效量适当的化疗药联合给药。
45.一种治疗微生物感染的方法,所述方法包括:
给予接受化疗的患者有效抑制细胞内过氧化氢的产生和释放的,选自
组胺、其他H2受体激动剂和5-羟色胺组成的组的有效量化合物。
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- 2002-11-05 CA CA002466083A patent/CA2466083A1/en not_active Abandoned
- 2002-11-05 KR KR1020047006871A patent/KR20050043763A/ko not_active Application Discontinuation
- 2002-11-05 CN CNA028216121A patent/CN1578650A/zh active Pending
- 2002-11-05 WO PCT/US2002/037275 patent/WO2003039418A1/en not_active Application Discontinuation
- 2002-11-05 NZ NZ532074A patent/NZ532074A/en unknown
- 2002-11-05 JP JP2003541513A patent/JP2005508366A/ja active Pending
- 2002-11-05 IL IL16107002A patent/IL161070A0/xx unknown
- 2002-11-05 EP EP02791284A patent/EP1448127A1/en not_active Withdrawn
-
2004
- 2004-03-30 ZA ZA200402494A patent/ZA200402494B/en unknown
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN114601840A (zh) * | 2020-12-08 | 2022-06-10 | 复旦大学附属中山医院 | 一种联合用药,用于治疗卡氏肺孢子虫肺炎 |
CN115212340A (zh) * | 2022-07-25 | 2022-10-21 | 广西福莱明生物制药有限公司 | 一种预防治疗手足口病感染的生物组合物敷料 |
CN115414360A (zh) * | 2022-08-30 | 2022-12-02 | 上海交通大学医学院附属仁济医院 | 全反式维甲酸联合抗生素在治疗假体周围感染中的应用 |
Also Published As
Publication number | Publication date |
---|---|
EP1448127A1 (en) | 2004-08-25 |
JP2005508366A (ja) | 2005-03-31 |
CA2466083A1 (en) | 2003-05-15 |
US20030149090A1 (en) | 2003-08-07 |
WO2003039418A1 (en) | 2003-05-15 |
IL161070A0 (en) | 2004-08-31 |
NZ532074A (en) | 2006-02-24 |
ZA200402494B (en) | 2004-10-05 |
KR20050043763A (ko) | 2005-05-11 |
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