CN1980694B - 凝溶胶蛋白治疗感染的用途 - Google Patents
凝溶胶蛋白治疗感染的用途 Download PDFInfo
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- CN1980694B CN1980694B CN200580020340XA CN200580020340A CN1980694B CN 1980694 B CN1980694 B CN 1980694B CN 200580020340X A CN200580020340X A CN 200580020340XA CN 200580020340 A CN200580020340 A CN 200580020340A CN 1980694 B CN1980694 B CN 1980694B
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Abstract
本发明涉及凝溶胶蛋白用于治疗感染和监测感染治疗的用途。本发明也提供上调白介素表达的方法和下调促炎症细胞因子表达的方法。
Description
技术领域
本发明涉及凝溶胶蛋白用于治疗感染和脓毒症的用途和凝溶胶蛋白用于监测和评价感染治疗的用途。本发明也提供上调白介素表达的方法和下调促炎症细胞因子表达的方法。
背景技术
尽管诊断和治疗已有显著进展,在全世界感染和脓毒仍旧是造成发病率和死亡率的主要原因。即使有积极主动的处理,患有严重感染的许多患者也发生并发症,并且一些死亡。每年在美国脓毒症夺去了超过200,000个生命(Angus,D.C.&Wax,R.S.(2001)Crit Care Med 29,109-16)。除了其它生物化学的异常以外,脓毒症早期阶段伴随强烈的炎症反应,其中促炎症细胞因子的血浆水平大大增加(Riedemann,N.C.,Guo,R.F.& Ward,P. A.(2003)Nat Med 29,517-24)。许多联合研究已经尝试抑制特异性炎症介质,希望能开发脓毒症的药理治疗。然而,活化的蛋白C(APC)被证实是唯一可以降低严重脓毒症死亡率的药物,死亡率被绝对降低6%(Bernard,G.R.,Vincent,J.L,Laterre,P.E,LaRosa,S.P.,Dhainaut,J.E,Lopez-Rodriguez,A.,Steingrub,J.S.,Garber,GE.,Helterbrand,J.D.,Ely,E.W & Fisher,C.J.,Jr.(2001)N Engl J Med 344,699-709)。
感染和脓毒症的不良健康影响提供了强烈的动机去开发新的治疗和改进的测试以及评价感染和脓毒症的方法。
发明内容
本发明是基于这样的令人惊奇的发现:凝溶胶蛋白可以治疗感染和避免感染的毒性表现。我们已经发现注射凝溶胶蛋白的小鼠在暴露于感染因子后,出乎意料的比施用盐水的小鼠具有更好的存活率。因而,本发明在一方面涉及,向对象施用凝溶胶蛋白以治疗感染。本发明也涉及采用凝溶胶蛋白治疗感染的生物效应的方法。
凝溶胶蛋白(GSN),具体地细胞质凝溶胶蛋白(cGSN),首先发现是作为涉及细胞运动的细胞内肌动蛋白结合蛋白(Yin,H.L & Stossel,T.P(1979)Nature 281,583-6),也是丰富的分泌蛋白(Yin,H.L.,Kwiatkowski,D.J.,Mole,J.E.& Cole,F.S.(1984)JBiol Chem 259,5271-6)。凝溶胶蛋白的输出同种型,被命名为血浆凝溶胶蛋白(pGSN),具有另外的25个氨基酸,源于单个基因的选择性剪接(Kwiatkowski,D.J.,Stossel,T. P,Orkin,S.H.,Mole,J.E.,Colten,H.R.& Yin,H.L.(1986)Nature 323,455-8)。
在本发明的下述每个方面和实施方案中,优选使用pGSN。
根据本发明的一个方面,提供了治疗对象中感染的方法。该方法包括向具有感染或具有感染风险的对象施用治疗有效量的凝溶胶蛋白以治疗感染。可导致感染的原因有:革兰氏阳性菌、抗酸杆菌、螺旋体、放线菌、病毒、真菌、寄生虫、包括解脲尿支原体的尿支原体属、包括肺炎支原体的支原体属、立克次氏体属、包括鹦鹉热衣原体、沙眼衣原体和肺炎衣原体的衣原体属、包括卡氏肺囊虫的肺囊虫属。在一些实施方案中,没有症状的对象也要求用凝溶胶蛋白治疗。在一些实施方案中,对象被暴露于感染后施用凝溶胶蛋白。在某些实施方案中,在对象暴露于感染后至少约1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23或24小时施用凝溶胶蛋白。在一些实施方案中,在对象暴露于感染后至少约1、2、3、4、5、6、7或更多天施用凝溶胶蛋白。
根据本发明的另一个方面,提供了治疗对象中革兰氏阴性菌感染的方法。该方法包括在对象暴露于革兰氏阴性菌感染之后的时间向对象施用治疗有效量的凝溶胶蛋白。在一些实施方案中,没有症状的对象要求用凝溶胶蛋白治疗。在一些实施方案中,在对象暴露于革兰氏阴性菌感染后至少约一小时向对象施用凝溶胶蛋白。在某些实施方案中,在对象暴露于革兰氏阴性菌感染后至少约2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23或24小时施用凝溶胶蛋白。在一些实施方案中,在对象暴露于感染后至少约1、2、3、4、5、6、7或更多天施用凝溶胶蛋白。在一些实施方案中,在对象暴露于革兰氏阴性菌感染之前施用凝溶胶蛋白。
根据本发明的另一个方面,提供了治疗或预防对象中脂多糖内毒素(LPS)作用的方法。该方法包括在暴露于LPS之后的时间向暴露于LPS的对象施用治疗有效量的凝溶胶蛋白,以保护所述对象免于LPS的影响。在一些实施方案中,没有症状的对象要求用凝溶胶蛋白治疗。在一些实施方案中,在对象暴露于LPS后至少约一小时向对象施用凝溶胶蛋白。在某些实施方案中,在对象暴露于LPS后至少约2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23或24或更多小时施用凝溶胶蛋白。在一些实施方案中,在对象暴露于LPS后至少约1、2、3、4、5、6、7或更多天施用凝溶胶蛋白。
根据本发明的另一个方面,提供了治疗或预防暴露于LPS的对象中革兰氏阴性菌脓毒性休克的方法。该方法包括在暴露于LPS之后的时间向暴露于LPS的对象施用治疗有效量的凝溶胶蛋白,以治疗所述对象中革兰氏阴性菌脓毒性休克。在一些实施方案中,没有症状的对象要求用凝溶胶蛋白治疗。在一些实施方案中,在对象暴露于LPS后至少约一小时向对象施用凝溶胶蛋白。在某些实施方案中,在对象暴露于LPS后至少约2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23或24小时施用凝溶胶蛋白。在一些实施方案中,在对象暴露于LPS后至少约1、2、3、4、5、6、7或更多天施用凝溶胶蛋白。
根据本发明的另一个方面,提供了在对象中上调白介素(IL)表达的方法。该方法涉及向对象施用有效量的凝溶胶蛋白,以上调IL的表达。在一些实施方案中,没有症状的对象要求用凝溶胶蛋白治疗。上调IL表达可以是由于IL表达增加、或者是由于IL降解降低、或者是IL表达增加和IL降解降低的联合。
在一些实施方案中,IL的表达与对照相比至少增加约25%。在另一些实施方案中,IL的表达与对照相比至少增加约50%或75%。在一些实施方案中,IL的表达与对照相比至少增加约2倍。在一些实施方案中,IL的表达与对照相比至少增加约3倍、5倍、10倍、50倍、100倍、200倍、500倍或1000倍。通常,对照中IL的表达水平是未施用凝溶胶蛋白的对象中IL的表达水平,但也可以与治疗对象中的相同。测定IL水平的方法对于本领域普通技术人员来说是已知的。
根据本发明的另一个方面,提供了体外上调IL表达的方法。该方法涉及将能够表达IL的细胞与足够量的凝溶胶蛋白接触,以上调该细胞中IL的表达。在一些实施方案中,IL的表达与对照相比至少增加约25%。在另一些实施方案中,IL的表达与对照相比至少增加约50%或75%。在一些实施方案中,IL的表达与对照相比至少增加约2倍。通常,对照中IL的表达水平是未接触凝溶胶蛋白的细胞中的IL表达水平,但也可以与已接触凝溶胶蛋白的细胞中的相同。在一些实施方案中,IL的表达与对照相比至少增加约3倍、5倍、10倍、50倍、100倍、200倍、500倍或1000倍。测定IL水平的方法对于本领域普通技术人员来说是已知的。
IL表达增加的时间段,至少部分是,细胞类型和所用具体培养容器的函数。通常,这个时间段的范围在2-3小时(短期增加)到约2-3天(中期增加),甚至到几个星期(长期增加)。可采用本领域普通技术人员已知的常规方法测定IL表达水平,作为增加凝溶胶蛋白剂量或增加细胞与凝溶胶蛋白培育时间的函数作用。一种优选的IL是IL-10。
根据本发明的另一个方面,提供了在对象中下调促炎症细胞因子表达的方法。该方法涉及向对象施用有效量的凝溶胶蛋白,以下调对象中促炎症细胞因子的表达。在一些实施方案中,没有症状的对象要求用凝溶胶蛋白治疗。下调促炎症细胞因子表达可以是由于细胞因子的表达降低或者是由于细胞因子的降解增加或者细胞因子表达降低和细胞因子降解增加的联合。通常,促炎症细胞因子的表达与对照相比至少降低约10%。在一些实施方案中,促炎症细胞因子的表达与对照相比至少降低约20%、30%、40%、50%、60%、70%、80%、90%、95%或99%。在一些实施方案中,促炎症细胞因子的表达与对照相比降低100%。通常,对照中促炎症细胞因子的表达水平是未施用凝溶胶蛋白对象的促炎症细胞因子表达水平,但也可以与治疗对象中的相同。测定促炎症细胞因子水平的方法对于本领域普通技术人员来说是已知的。一种优选的促炎症细胞因子是IL-1β,另一种优选的促炎症细胞因子是IFN-α。
根据本发明的一个方面,提供了体外下调促炎症细胞因子表达的方法。该方法涉及将能表达促炎症细胞因子的细胞与足够量的凝溶胶蛋白接触,以下调细胞中促炎症细胞因子表达的水平。通常,促炎症细胞因子的表达与对照相比至少降低约10%。通常,对照中促炎症细胞因子的表达水平是未接触凝溶胶蛋白的细胞中的促炎症细胞因子表达水平,但也可以是与凝溶胶蛋白接触过的细胞相同。在一些实施方案中,促炎症细胞因子的表达与对照相比至少降低约20%、30%、40%、50%、60%、70%、80%、90%、95%或99%。在一些实施方案中,促炎症细胞因子的表达与对照相比降低100%。测定促炎症细胞因子水平的方法对于本领域普通技术人员来说是已知的。
促炎症细胞因子表达减少的时间段,至少部分是,细胞类型和所用具体培养容器的函数。通常,这个时间段的范围在2-3小时(短期减少)到约2-3天(中期减少),甚至到几个星期(长期减少)。可采用本领域普通技术人员已知的常规方法测定促炎症细胞因子表达水平,作为增加剂量的凝溶胶蛋白或细胞与凝溶胶蛋白接触的增加时间的函数。
根据本发明的另一个方面,提供了治疗对象以减少感染风险的方法。该方法包括基于已知对象具有低于正常水平的凝溶胶蛋白来选择对象,并向所述对象施用有效量的降低感染风险的因子,以减少对象发生感染的风险。所述因子可以是凝溶胶蛋白和/或抗感染因子。在一些实施方案中,没有症状的对象要求用凝溶胶蛋白治疗。
“低于正常水平的凝溶胶蛋白”是指凝溶胶蛋白水平与给定对象群体的平均测定水平相比至少低10%。平均凝溶胶蛋白水平依赖于特定的对象群体。例如,看起来健康的群体具有与那些先前感染过或有其他疾病的对象群体不同的“正常”范围的凝溶胶蛋白。在一些实施方案中,凝溶胶蛋白水平与给定对象群体的平均测定水平相比至少低约10%。在另一些实施方案中,凝溶胶蛋白水平与给定对象群体的平均测定水平相比至少低约20%。在再一些实施方案中,凝溶胶蛋白水平与给定对象群体的平均测定水平相比至少低约30%、40%、50%、60%、70%、80%、90%、95%、99%或100%。在一个优选的实施方案中,血浆中凝溶胶蛋白水平低于约2.4μM/L(微摩尔/升)。
在一些实施方案中,没有症状的对象要求用所述因子治疗。在所述因子是抗感染剂时,没有症状而要求用抗感染剂治疗的对象,是那些没有感染征候或症状的对象。感染的征候和症状是本领域普通技术人员已知的。凝溶胶蛋白适用于治疗肌动蛋白相关的疾病例如成人呼吸窘迫综合征(ARDS)、暴发性肝坏死、急性肾功能衰竭、肌肉损伤,以BUN和/或肌酸酐水平升高为特征的疾病。肌动蛋白相关疾病是本领域普通技术人员已知的。
在另一些实施方案中,对象是看起来健康的。此处所用的“看起来健康的对象”是那些没有疾病征候和/或症状的对象。
导致感染可以是一种或更多种有机体例如细菌、病毒、真菌或寄生虫。
抗感染剂可以是抗细菌、抗病毒、和抗真菌或抗寄生虫剂。
抗细菌剂、抗病毒剂、抗真菌剂和抗寄生虫剂的例子在下面例出。
凝溶胶蛋白可通过口服、舌下、含服、鼻内、静脉、肌肉、鞘内、腹膜内、皮下、皮内、局部、直肠、阴道、滑膜腔内、或玻璃体内施用。
根据本发明的另一个方面,提供了评价除凝溶胶蛋白之外的治疗剂治疗或预防感染的疗效的方法。该方法包括获得接受治疗或预防感染的疗法的对象中的凝溶胶蛋白水平。凝溶胶蛋白水平与对应对照凝溶胶蛋白水平(例如,看起来健康群体中的)的预定值比较。确定凝溶胶蛋白水平是否低于预定水平是治疗是否有效的指标。在一些实施方案中,重复获得凝溶胶蛋白水平以在一段时间中监测人对象的凝溶胶蛋白水平。
根据本发明的另一个方面,提供了决定对象中治疗过程的方法。该方法包括获得接受治疗感染的疗法的对象中的凝溶胶蛋白水平。该凝溶胶蛋白水平与对应对照的凝溶胶蛋白水平(例如,看起来健康的群体中)的预定值比较。测定所得凝溶胶蛋白水平是高于还是低于预定水平,并基于该测定决定治疗过程。在一些实施方案中,重复获得凝溶胶蛋白水平以在一段时间中监测对象的凝溶胶蛋白水平。
根据本发明的另一个方面,提供了治疗凝溶胶蛋白水平降低的对象的方法。该方法包括用治疗感染的第一疗法治疗对象。获得所述对象的凝溶胶蛋白水平。对象的凝溶胶蛋白水平与对应对照凝溶胶蛋白水平(例如,看起来健康的群体中)的预定值比较。如果没有达到预定的凝溶胶蛋白水平,则对象用治疗感染的第二疗法治疗,测定凝溶胶蛋白水平并与预定的凝溶胶蛋白水平比较,直至达到预定的凝溶胶蛋白水平。
根据本发明的另一个方面,提供了表征对象未来发生感染的风险特性谱的方法。该方法包括获得对象的凝溶胶蛋白水平,并将标记水平与预定值比较。对象发生感染的风险特性谱基于其凝溶胶蛋白水平与预定值比较来表征。低于预定水平的凝溶胶蛋白水平指示对象发生感染的风险增加,而高于预定水平的凝溶胶蛋白水平指示对象不具有发生感染的增加的风险。
在一些实施方案中,预定值是约2.4μM/L血浆或更低。
在一些实施方案中,对象是看起来健康的对象。
本发明的每个限制可涉及本发明的不同实施方案。因此,可以预期涉及任一种要素或要素组合的本发明的每个限制包括在本发明的每个方面中。本发明能有其他实施方案,并能通过多种方式实施或进行。此处所用的短语或术语是为了说明,而不应当作是限制。使用“包括(including)”、“包含(comprising)”或“具有(having)”、“含有(containing)”、“涉及(involving)”、及其变体,意思包括其后面所列的项目、其等同物以及其他项目。
本发明的这些和另外的方面将结合具体实施方式在下面更加具体的描述。
本申请指出的所有文件以整体引入此处作为参考。
附图说明
图仅用于举例说明,而不是实施在此公开的本发明所必需的。
图1是脓毒症小鼠的血浆凝溶胶蛋白水平的图表。(A)向小鼠腹膜内(IP)注射增加剂量的非致死性LPS,24小时后采血。pGSN水平与LPS剂量逆相关(P<0.05,斯皮尔曼相关)。相反,白蛋白没有变化。(B)小鼠接受CLP(盲肠结扎和穿刺)或不接受手术,24小时后收集血浆。左边的图显示接受CLP的小鼠的pGSN水平显著低于对照小鼠(P<0.001),而右边的图显示血浆白蛋白水平在CLP小鼠中实际上更高(P=0.02)。
图2是脓毒症小鼠存活率的曲线图。(A)用致死性LPS攻击的小鼠中,那些用pGSN处理过的小鼠与BSA(P<0.001)或盐水(P<0.001)处理的小鼠相比,具有更好的存活率。(B)接受CLP的小鼠对pGSN具有相似的有利的反应,并具有好得多的存活率(P=0.001)。
图3是用或不用外源pGSN治疗的致死性内毒素血症小鼠中pGSN水平的图表。空心柱表示接受盐水处理的小鼠,实心柱表示接受外源pGSN治疗的小鼠。内源pGSN水平在致死性LPS攻击后6小时内降到正常值的约50%,并至少持续24小时(*P<0.015,与未攻击的小鼠相比)。在LPS攻击时施用外源pGSN成功提高了pGSN水平(*P<0.021,与同组内用及不用pGSN处理的小鼠比较)。
图4是LPS攻击后6小时和24小时用或不用pGSN处理处理的内毒素血症小鼠的细胞因子特征谱的图(y轴是log值)。(A)LPS攻击后6小时用pGSN处理(实心柱)和未用pGSN处理(空心柱)的细胞因子特征谱之间没有差异。(B)然而,LPS攻击后24小时,盐水处理的小鼠具有显著更高水平的GM-CSF、IFN-γ、和IL-1β(全部P<0.03),与pGSN处理小鼠相比高了10倍。与此相对,IL-10的水平在pGSN处理的小鼠中显著更高(P<0.03)。
图5是大肠杆菌LPS攻击和未攻击的C3H/HeJ小鼠中血浆凝溶胶蛋白水平的图。LPS对TLR4突变体中的pGSN水平没有影响。注射对C57BL/6小鼠为致死性的LPS的C3H/HeJ小鼠没有显示任何不良的疾病征兆,且具有不变的pGSN水平。
图6是用LPS攻击或未攻击的小鼠组织提取物的Western印迹,对pGSN染色。印迹显示与骨骼肌、心脏、肾和肝脏相比,在正常和内毒素血症小鼠中肺具有最高浓度的pGSN。
图7是比较LPS与pGSN和BSA结合的图。基于荧光的pGSN和LPS结合试验显示荧光LPS的典型结合曲线的平台值在250μg/孔pGSN。BSA蛋白作为对照,显示与LPS最小的亲合性。
图8是源自未用LPS(未刺激)、仅用LPS、仅用pGSN、用LPS和pGSN、用LPS和BSA、以及仅用BSA刺激的THP-1细胞的介质中TNF-α水平的图。LPS刺激的THP-1细胞用pGSN或BSA处理,具有相似的TNF-α水平(P>0.05)。
具体实施方式
本发明是部分基于这样的发现:施用凝溶胶蛋白保护对象免于感染。因而,在某些方面,本发明包括向对象施用凝溶胶蛋白以治疗对象的感染。我们已经发现凝溶胶蛋白拮抗脂多糖内毒素(LPS)的毒性,LPS是已知造成很多革兰氏阴性细菌感染的革兰氏阴性细菌的细胞壁材料。
我们也已经发现在对象暴露于感染后向对象施用凝溶胶蛋白可以治疗感染并可以减少或防止对象中感染的毒性作用。优选地,治疗感染涉及治疗感染的征候和症状。
术语“治疗(treatment或treating)”包括预防、改善、防止或治疗感染。
此处所用的术语“对象”指的是可以需要治疗的任何哺乳动物。对象包括,但不限于:人、非人灵长类、猫、狗、羊、猪、马、牛、啮齿动物如小鼠、仓鼠和大鼠。优选的对象是人对象。
此处所用的术语“凝溶胶蛋白”包括野生型凝溶胶蛋白(GenBank登记号:X04412)、凝溶胶蛋白的同种型、类似物、变体、片段或功能衍生物。凝溶胶蛋白包括天然的以及合成和重组的凝溶胶蛋白和凝溶胶蛋白类似物。凝溶胶蛋白,特别是cGSN,是丰富的分泌蛋白(Yin,H.L.,Kwiatkowski,D.J.,Mole,J.E.&Cole,F.S.(1984)JBiol Chem 259,5271-6)。凝溶胶蛋白的输出同种型,pGSN,具有另外的25个氨基酸,源于单个基因的选择性剪接(Kwiatkowski,D.J.,Stossel,T.P.,Orkin,S.H.,Mole,J.E.,Colten,H.R.& Yin,H.L.(1986)Nature323,455-8)。在本发明的不同方面和实施方案中,优选采用pGSN。
“凝溶胶蛋白类似物”指的是功能基本上与天然凝溶胶蛋白或其片段相似的化合物。凝溶胶蛋白类似物包括与凝溶胶蛋白序列基本相似的生物活性氨基酸序列并可以具有取代、缺失、延伸、替换或其他修饰且具有与凝溶胶蛋白基本相似生物活性的序列。例如,凝溶胶蛋白类似物可以是不具有与凝溶胶蛋白相同的氨基酸序列,但是与凝溶胶蛋白足够同源以保持凝溶胶蛋白的生物活性。测定生物活性,例如,可以通过测定凝溶胶蛋白类似物的特性和/或测定凝溶胶蛋白类似物减少或预防感染作用的能力。凝溶胶蛋白生物活性测定的一个例子是凝溶胶蛋白刺激肌动蛋白成核的能力。凝溶胶蛋白生物活性测试在实施例中描述,其对于本领域普通技术人员来说是已知的。
“片段”意思包括凝溶胶蛋白分子的任何部分,其是保留凝溶胶蛋白生物活性的凝溶胶蛋白的区段;该术语意思包括来自任何来源的凝溶胶蛋白片段,例如,源自天然存在的肽序列、合成或化学合成的肽序列、和遗传工程化的肽序列。
凝溶胶蛋白的“变体”意思是指结构和生物活性与天然凝溶胶蛋白或其片段基本上相同的化合物。
凝溶胶蛋白的“功能衍生物”是具有与凝溶胶蛋白基本相同的生物活性的衍生物。“基本相同”意思是指活性在量上不同但性质相同。例如,凝溶胶蛋白的功能衍生物可以含有与凝溶胶蛋白相同的氨基酸骨架,根据这种修饰对诊断测试或治疗性处理性能的必要性,还含有其他修饰如翻译后修饰,例如,结合的磷脂或共价连接的碳水化合物。如此处所用该术语意思还包括凝溶胶蛋白的化学衍生物。这样的衍生物可改善凝溶胶蛋白可溶性、吸收、生物学半衰期等等。所述衍生物也可降低凝溶胶蛋白的毒性,或消除或消弱凝溶胶蛋白的任何不期望的副作用等等。衍生物和尤其是能介导这些作用的化学结构描述于Remington′s Pharmaceutical Sciences(1980)中。将这样的结构偶联到分子如凝溶胶蛋白上的方法对于本领域普通技术人员来说是已知的。术语“功能衍生物”意思包括凝溶胶蛋白的“片段”、“变体”“类似物”或“化学衍生物”。
本发明在一些方面涉及治疗对象中感染的方法。该方法包括向对象施用凝溶胶蛋白以治疗感染。所述对象已知患有、怀疑曾经暴露于、或具有暴露的风险,或已经暴露于感染。向对象施用可有效治疗对象中感染的量的凝溶胶蛋白。
测定对本发明治疗方法的反应,例如,可通过测定治疗的生理效应,如施用治疗后症状的减少或缺乏。
此处所用的“感染”或“感染性疾病”,指的是由于传染性生物经表面、局部或全身性侵入宿主而导致的病症。传染性生物包括细菌、病毒、寄生虫、真菌和原生动物。
细菌包括革兰氏阴性和革兰氏阳性菌。革兰氏阳性菌的实例包括巴斯德氏菌属(Pasteurella),包括金黄色葡萄球菌(Staphylococcus aureus)的葡萄球菌属,包括A型化脓性链球菌(Streptococcus pyogenes group A)、绿色链球菌(Streptococcus viridans group)、B型无乳链球菌(Streptococcus agalactiaegroup B)、牛链球菌(Streptococcus bovis)、厌氧类链球菌、肺炎链球菌(Streptococcus pneumoniae)和粪链球菌(Streptococcus faecalis)的链球菌属,包括炭疽杆菌(Bacillus anthracis)的杆菌属,包括白喉棒杆菌(Corynebacteriumdiphtheriae)、需氧类棒杆菌和厌氧类棒杆菌的棒杆菌属、类白喉菌属(Diphthaeroids species)、包括单核细胞增多性利斯特氏菌(Listeriamonocytogenes)的利斯特氏菌属、包括猪红斑丹毒丝菌(Erysipelothrixrhusiopathiae)的丹毒丝菌属、包括产气英膜梭菌破伤风杆菌(Clostridiumperfringens)、破伤风杆菌(Clostridium tetani)和艰难梭菌(Clostridiumdifficile)的梭状芽孢杆菌属。
革兰氏阴性菌包括:包括淋病奈瑟氏菌(Neisseria gonorrhoeae)和脑膜炎奈瑟氏菌(Neisseria meningitidis)的奈瑟氏菌属,包括卡他布兰汉氏球菌(Branhamella catarrhalis)的布兰汉氏菌属,包括大肠埃希氏菌(Escherichiacoli)的埃希氏菌属、肠杆菌属(Enterobacter species),包括奇异变形菌(Proteusmirabilis)的变形菌属,包括绿脓假单胞菌(Pseudomonas aeruginosa)、鼻疽假单胞菌(Pseudomonas mallei)和类鼻疽假单胞菌(Pseudomonaspseudomallei)的假单胞菌属,包括肺炎克雷伯氏菌(Klebsiella pneumoniae)的克雷伯氏菌属,沙门氏菌属,志贺菌属,粘质沙雷氏菌,不动杆菌属,流感嗜血杆菌(Haemophilus influenzae)和杜克雷氏嗜血杆菌的嗜血杆菌属,布鲁氏杆菌属,包括鼠疫耶尔森氏菌(Yersinia pestis)和小肠结肠炎耶尔森氏菌(Yersinia enterocolitica)的耶尔森氏菌属,包括土拉热弗朗西丝氏菌(Francisella tularensis)的弗朗西丝氏菌属,包括出血败血性巴斯德氏菌(Pasteurella multocida)的巴斯德氏菌属,霍乱弧菌(Vibrio cholerae),脑膜脓毒性黄杆菌,包括空肠弯曲杆菌(Campylobacter jejuni)的弯曲杆菌属,包括脆弱拟杆菌(Bacteroides fragilis)的拟杆菌属(口、咽的),包括具核梭杆菌(Fusobacterium nucleatum)的梭形杆菌属,肉芽肿鞘杆菌(Calymmatobacterium granulomatis),包括念珠状链杆菌(Streptobacillusmoniliformis)的链杆菌,包括嗜肺性军团杆菌(Legionella pneumophila)的军团杆菌属。
其他类型的细菌包括耐酸性杆菌、螺旋体和放线菌。
耐酸性杆菌的例子包括,包括结核分支杆菌(Mycobacterium tuberculosis)和麻风分枝杆菌(Mycobacterium leprae)的分枝杆菌属。
螺旋体的例子包括,包括梅毒螺旋体(Treponema pallidum)、细弱密螺旋体(Treponema pertenue)的密螺旋体属,包括包柔氏疏螺旋体(Borreliaburgdorferi)(莱姆病)和回归热疏螺旋体(Borrelia recurrentis)的疏螺旋体属,和钩端螺旋体属。
放线菌的例子包括:衣氏放线菌(Actinomyces israeli)的放线菌属,和包括星形诺卡菌(Nocardia asteroides)的诺卡氏菌属。
病毒的例子,包括但不限于:逆转录病毒,人免疫缺陷病毒包括HIV-1、HDTV-III、LAVE、HTLV-III/LAV、HIV-III、HIV-LP,巨细胞病毒(CMV),小RNA病毒,脊髓灰质炎病毒,甲型肝炎病毒,肠病毒,柯萨奇病毒,鼻病毒,埃可病毒,Calciviruses,披膜病毒,马脑炎病毒,风疹病毒,黄病毒,登革热病毒,脑炎病毒,黄热病毒,冠状病毒,杆状病毒,水泡性口炎病毒,狂犬病毒,丝状病毒,埃博拉病毒,副粘病毒,副流感病毒,腮腺炎病毒,麻疹病毒,呼吸道合胞病毒(RSV),正粘病毒,流感病毒,Bungaviruses,汉坦病毒,白蛉病毒(phlebovirus)和Nairo病毒,沙粒病毒,出血热病毒,呼肠孤病毒,环状病毒,轮状病毒,双RNA病毒(Birnaviruses),嗜肝DNA病毒,乙型肝炎病毒,细小病毒,乳多空病毒科,乳头瘤病毒,多瘤病毒,腺病毒,包括1-和2-型单纯疱疹病毒的疱疹病毒属,水痘-带状疱疹病毒,痘病毒,天花病毒,痘苗病毒,虹彩病毒,非洲猪瘟病毒,丁型肝炎病毒,非甲非乙型肝炎病毒,丙型肝炎,诺瓦克病毒,星状病毒和未分类的病毒。
真菌的例子包括,但不限于:包括新形隐球菌(Crytococcus neoformans)的隐球菌属,包括荚膜组织胞浆菌(Histoplasma capsulatum)的组织胞浆菌属,包括Coccidiodes immitis的球孢子菌属,包括巴西芽生菌(Paracoccidioidesbrasiliensis)的副球孢子菌属类,包括皮炎芽生菌(Blastomyces dermatitidis)的芽生菌属,包括沙眼衣原体(Chlamydia trachomatis)的衣原体属,包括白色念珠菌(Candida albicans)的念珠菌属,包括申氏孢子丝菌(Sporothrixschenckii)的孢子丝菌属,曲霉属和毛霉病(mucormycosis)的真菌类。
其他传染性生物包括寄生虫。寄生虫包括疟原虫属,如恶性疟原虫、三日疟原虫(Plasmodium malariae)、卵形疟原虫、和间日疟原虫(Plasmodiumvivax),以及鼠弓形体(Toxoplasma gondii)。血源和/或组织寄生虫包括疟原虫属,包括果氏巴贝虫(Babesia microti)和分歧巴贝虫(Babesia divergens)的巴贝虫属,包括热带利什曼原虫、利什曼原虫属、巴西利什曼原虫、杜氏利什曼原虫的利什曼原虫属,包括冈比亚锥虫、罗德西亚锥虫(非洲昏睡病)和克氏锥虫(查加斯病)的锥虫属。
其他医学相关的微生物已经在文献中广泛记载,例如,见C.G.A Thomas,Medical Microbiology,Bailliere Tindall,Great Britain 1983,其全文在此引入作为参考。
在本发明的另一个方面,提供了上调对象中白介素(IL)表达的方法。该方法包括向对象施用有效量的凝溶胶蛋白以上调IL表达。测定IL的上调可通过施用凝溶胶蛋白后测定IL的生理效应。IL的生理效应对于本领域普通技术人员来说是已知的。
在本发明的另一个方面,提供了下调对象中促炎症细胞因子表达的方法。该方法包括向对象施用有效量的凝溶胶蛋白以下调促炎症细胞因子表达。测定促炎症细胞因子的下调可通过施用凝溶胶蛋白后测定促炎症细胞因子的生理效应。促炎症细胞因子的生理效应对于本领域普通技术人员来说是已知的。
对于本领域普通技术人员已知的其他测定也可以用来测量应答水平。
在本发明的另一个方面,提供了监测对象的方法。该方法包括获得接受感染治疗的对象中的凝溶胶蛋白水平。凝溶胶蛋白水平与对应对照凝溶胶蛋白水平(例如,在看起来健康的群体中)的预定值比较。确定凝溶胶蛋白水平是否低于预先测定的水平指示所述对象是将从继续相同的治疗还是从改变治疗中受益。在一些实施方案中,重复获得凝溶胶蛋白水平以在一段时间中监测对象的凝溶胶蛋白水平。在一些实施方案中,对象可以已经接受治疗至少1、2、3、4、5、6、7或更多天。在一些实施方案中,对象可以已经接受治疗至少1、2、3、4或更多周。
凝溶胶蛋白治疗中的改变指的是凝溶胶蛋白剂量的增加、凝溶胶蛋白转换为另一种因子、凝溶胶蛋白治疗方案中添加另一种因子、或其组合。
根据本发明的另一个方面,提供了治疗或减少感染风险的疗法的疗效的评价方法。该方法包括获得接受治疗或预防感染的疗法的对象中的凝溶胶蛋白水平。该凝溶胶蛋白水平与对应对照凝溶胶蛋白水平(例如,在看起来健康的群体中)的预定值比较。确定凝溶胶蛋白水平是否低于预定水平可指示治疗是否有效。在一些实施方案中,对象可以已经接受治疗至少1、2、3、4、5、6、7或更多天。在一些实施方案中,人对象可以已经接受治疗至少1、2、3、4或更多周。
本发明的一个方面涉及测量凝溶胶蛋白来指导治疗以改善对象中的结果。治疗中凝溶胶蛋白水平是对感染或脓毒症治疗的反应的预测值。治疗中凝溶胶蛋白水平是现有技术预测感染结果之外另加的。
将从本发明此方面受益的对象是那些接受治疗或预防感染的疗法的对象(也就是“治疗中的”对象)。治疗中的对象是已经被诊断并且在治疗感染的疗法过程中的对象。治疗可以是此处所指的任何治疗剂。治疗也可以是非药物治疗。在重要的实施方案中,治疗可增加凝溶胶蛋白的水平。在一个特别重要的实施方案中,治疗是用凝溶胶蛋白的治疗。优选的对象是人对象。最可能从本发明受益的对象是治疗中的人患者,并且其血浆中凝溶胶蛋白的水平低于约2.4μM/L。
在一些实施方案中,对象已经或曾经感染。已经或曾经原发性(第一次)感染细菌、病毒、真菌、寄生虫或原生动物的对象可具有更高的继发(第二次)感染的风险。在一些实施方案中,对象没有经历原发性感染,但是具有提高的感染风险,因为对象具有一个或更多个发生感染的风险因素。原发性感染的风险因素包括:免疫抑制、免疫不足、年龄、外伤、烧伤(例如,热烧伤)、手术、异物、癌症、新生儿特别是早产的新生儿。感染风险的程度依赖于患者具有的风险因素的数量和严重性或程度。基于风险因素的存在和严重性,风险图表和预测算法可用于评估对象感染的风险。
其他评估对象感染风险的方法是本领域普通技术人员已知的。
在另一些实施方案中,对象已经历原发性感染,并且具有一或更多种其他风险因素。
本发明优选的治疗是凝溶胶蛋白。凝溶胶蛋白可单独使用、在药用组合物中施用或与其他疗法结合。凝溶胶蛋白和其他治疗剂可同时或依次施用。在所述其他治疗剂同时施用时,它们可以在同一或分开的制剂中,但在同一时间施用。当在时间上分开施用其他因子和凝溶胶蛋白时,相互依次施用其他治疗剂和凝溶胶蛋白。施用这些化合物之间的时间上的分开可以是几分钟或更长。其他治疗剂包括,但不限于抗感染剂。抗感染剂的例子包括:抗菌剂、抗病毒剂、抗真菌剂或抗原生动物剂。
术语如“抗感染剂”、“抗菌剂”、“抗病毒剂”、“抗真菌剂”或“抗寄生虫剂”和“杀寄生虫剂”都具有本领域普通技术人员所公知的意思,并按标准医学文本定义。简而言之,抗菌剂杀死或抑制细菌的生长或功能。抗菌剂包括抗生素和其他具有相似功能的合成或天然的化合物。抗生素,典型地,具有较小的分子量,是细胞如微生物的次级代谢产物。通常,抗生素干扰一种或多种细菌功能或结构,这种功能或结构是微生物特异的而不存在于宿主细胞中。
抗菌剂的一大类是抗生素。能有效杀死或抑制宽范围细菌的抗生素称作广谱抗生素。主要对革兰氏阳性或革兰氏阴性细菌有效的其他类型的抗生素,称作窄谱抗菌素。只对单一生物或疾病有效而对其他类型细菌无效的其他抗生素,称作限谱抗菌素。抗菌剂有时以其主要作用模式分类。通常,抗菌剂是细胞壁合成抑制剂、细胞膜抑制剂、蛋白质合成抑制剂、核酸合成或功能抑制剂、和竞争性抑制剂。
抗菌剂包括但不限于氨基糖苷类,β-内酰胺类,头孢菌素类,大环内酯类,青霉素类,喹诺酮类,磺胺类,和四环素类。抗菌剂的例子包括,但不限于醋氨苯砜,磺胺苯砜钠,阿拉霉素,阿来西定,氮脒青霉素,克拉维酸钾,氮脒青霉素匹酯,阿米环素,氨氟沙星,甲磺酸氨氟沙星,阿米卡星,硫酸阿米卡星,氨基水杨酸,氨基水杨酸钠,阿草西林,安福霉素,氨苄西林,氨苄西林钠,阿帕西林钠,安普霉素,天冬托星,硫酸阿司米星,阿维霉素,阿伏帕星,阿奇霉素,阿洛西林,阿洛西林钠,盐酸巴氨西林,杆菌肽,亚甲基二水杨酸杆菌肽,杆菌肽锌,班贝霉素,苯沙酸钙,红霉素B,硫酸倍他米星,比阿培南,比尼霉素,盐酸珍尼柳酯,硫酸镁双巯氧吡啶,布替卡星,硫酸布替罗星,硫酸卷曲霉素,卡巴多司,羧苄西林二钠,苄茚西林钠,卡非西林钠,羧苄西林钾,卡芦莫南钠,头孢克洛,头孢羟氨苄,头孢孟多,头孢孟多酯钠,头孢孟多钠,头孢帕罗,头孢曲秦,头孢氮氟钠,头孢唑啉,头孢唑啉钠,头孢拉宗,头孢托仑新戊酯,头孢地尼,盐酸头孢吡肟,头孢替考,头孢克肟,盐酸头孢甲肟,头孢美唑,头孢美唑钠,头孢尼西单钠,头孢尼西钠,头孢哌酮钠,头孢雷特,头孢噻肟,头孢噻肟钠,头孢替坦,头孢替坦二钠,盐酸头孢替安,头孢西丁,头孢西丁钠,头孢咪唑,头孢咪唑钠,头孢匹胺,头孢匹胺钠,硫酸头孢匹罗,头孢泊肟普塞酯,头孢丙烯,头孢沙定,头孢磺啶钠,头孢他啶,头孢他啶钠,头孢布烯,头孢唑肟钠,头孢曲松钠,头孢呋辛,头孢呋辛醋氧乙酯,头孢呋辛匹赛酯,头孢呋辛钠,头孢乙腈钠,头孢氨苄,盐酸头孢氨苄,头孢格来星,头孢噻啶,头孢噻吩钠,头孢匹林钠,头孢霉定,盐酸西托环素,乙酰氯霉素,氯霉素,棕榈氯霉素,氯霉素泛酸酯复合物,氯霉素琥珀酸钠,氨基苯磷酸氯己定,氯二甲酚,金霉素硫酸氢盐,盐酸金霉素,西司他丁,西诺沙星,环丙沙星,盐酸环丙沙星,西罗霉素,克拉霉素,克拉维酸钾,盐酸克林沙星,克林霉素,克林霉素葡萄糖,盐酸克林霉素,棕榈酸盐酸克林霉素,磷酸克林霉素,氯法齐明,苄星氯唑西林,氯唑西林钠,氯羟喹,多粘菌素E甲磺酸,多粘菌素E甲磺酸钠,硫酸多粘菌素E,青豆霉素,青豆霉素钠,环青霉素,环丝氨酸,达福普汀,氨苯砜,达托霉素,地美环素,盐酸地美环素,去甲环素,地诺芬净,二氨藜芦啶,双氯西林,双氯西林钠,硫酸双氢链霉素,双吡硫翁,地红霉素,多西环素,多西环素钙,多西环素磷酸复合物,盐酸多西环素,多西环素单水合物,屈克沙星钠,依诺沙星,依匹西林,盐酸表四环素,Ertapenem,红霉素,醋硬脂红霉素,依托红霉素,琥乙红霉素,葡庚糖酸红霉素,乳糖酸红霉素,丙酸红霉素,硬脂酸红霉素,盐酸乙胺丁醇,乙硫异烟胺,氟罗沙星,氟氯西林,氟氘丙氨酸,氟甲喹,磷霉素,磷霉素氨丁三醇,呋莫西林,呋唑氯铵,酒石酸呋噻咪唑,夫地酸钠,夫西地酸,加替沙星,Genifloxacin,硫酸庆大霉素,格洛美南,短杆菌肽,卤普罗近,海他西林,海他西林钾,海克西定,依巴沙星,亚胺培南,异康唑,异帕米星,异烟肼,交沙霉素,硫酸卡那霉素,吉他霉素,左呋喃他酮,左普匹西林钾,来红霉素,林可霉素,盐酸林可霉素,利奈唑胺,洛美沙星,盐酸洛美沙星,甲磺酸洛美沙星,氯碳头孢,磺胺米隆,甲氯环素,磺基水杨酸氯甲烯土霉素,巨霉素磷酸二氢钾,美喹多司,倍能,甲烯土霉素,盐酸甲烯土霉素,乌洛托品,乌洛托品马尿酸盐,孟德立酸乌洛托品,甲氧西林钠,美替普林,甲硝唑盐酸盐,磷酸甲硝唑,美洛西林,美洛西林钠,二甲胺四环素,盐酸二甲胺四环素,盐酸米林霉素,莫能星,莫能星钠,盐酸莫西沙星,萘夫西林钠,萘啶酸钠,萘啶酸,那他霉素,尼拉霉素,棕榈酸新霉素,硫酸新霉素,十一烯酸新霉素,硫酸萘替米星,中性霉素,硝呋拉定,硝呋地腙,硝呋太尔,硝呋隆,硝呋达齐,硝呋米特,硝呋吡醇,硝呋奎唑,硝呋噻唑,硝环素,呋喃妥因,硝米特,诺氟沙星,新生霉素钠,氧氟沙星,奥美普林,苯唑西林钠,肟莫南,肟莫南钠,奥索利酸,土霉素,土霉素钙,盐酸土霉素,帕地霉素,对氯酚,保洛霉素,培氟沙星,甲磺酸培氟沙星,培那西林,苄星青霉素G,青霉素G钾,普鲁卡因青霉素G,青霉素G钠,青霉素V,苄星青霉素V,哈胺青霉素V,青霉素V钾,戊胺唑酮钠,对氨水杨酸苯酯,哌拉西林,哌拉西林钠,吡苄西林钠,吡地西林钠,盐酸吡利霉素,盐酸匹氨青霉素,双羟萘酸匹氨西林,丙苯酸匹氨青霉素,硫酸多粘菌素B,泊非霉素,普匹卡星,吡嗪酰胺,吡硫翁锌,乙酸喹地卡明,奎奴普丁,消旋甲砜霉素,雷莫拉宁,雷尼霉素,瑞洛霉素,瑞普米星,利福布汀,利福美坦,利福克昔,利福米特,利福平,利福喷汀,利福昔明,罗利环素,硝酸罗利环素,罗沙米星,丁酸罗沙米星,丙酸罗沙米星,磷酸罗沙米星钠,硬脂酸罗沙米星,罗索沙星,罗沙胂,罗红霉素,山环素,山黄培南钠,沙莫西林,沙匹西林,可可芬净,西索米星,硫酸西索米星,司帕沙星,盐酸大观霉素,螺旋霉素,盐酸偏端菌素,司他霉素,司替霉素,无菌替卡西林二钠,硫酸链霉素,链霉素异烟肼,青霉烷砜钠,磺胺苯,磺胺苯酰,磺胺醋酰,磺胺醋酰钠,磺胺西汀,磺胺嘧啶,磺胺嘧啶钠,磺胺多辛,磺胺林,磺胺甲嘧啶,磺胺对甲氧嘧啶,磺胺二甲嘧啶,磺胺甲二唑,磺胺甲噁唑,磺胺间甲氧嘧啶,磺胺噁唑,磺胺酸锌,磺胺硝苯,柳氮磺吡啶,磺胺异噻唑,磺胺噻唑,磺胺吡唑,磺胺异噁唑,醋磺胺异噁唑,磺胺异噁唑二乙醇胺,磺粘菌素,硫培南,舒他西林,磺氨苄青霉素钠,氨苄青霉素酞酯盐酸盐,三唑巴坦,替考拉宁,盐酸替马沙星,替莫西林,四环素,盐酸四环素,四环素磷酸复盐,四氧普林,甲砜霉素,Thiphencillin Potassium,羧噻酚青霉素甲苯酯钠,替卡西林二钠,替卡西林单钠,替克拉酮,噻碘氯铵,妥布霉素,硫酸妥布霉素,托氟沙星,甲氧苄啶,硫酸甲氧苄啶,三磺嘧啶合剂,醋竹桃霉素,硫酸丙大观霉素,曲伐沙星,短杆菌素,万古霉素,盐酸万古霉素,维吉霉素,佐尔博霉素。
抗病毒剂分离自天然来源或合成,用于杀死或抑制病毒的生长或功能。抗病毒剂是防止细胞被病毒感染或防止病毒在细胞内复制的化合物。病毒感染过程中有好几个阶段可被抗病毒剂阻断或抑制。这些阶段包括,病毒粘附到宿主细胞(免疫球蛋白或结合肽),病毒脱衣壳(例如金刚烷胺)、病毒mRNA合成或翻译(例如干扰素)、病毒RNA或DNA复制(例如,核苷酸类似物)、病毒蛋白成熟(例如蛋白酶抑制剂),以及病毒出芽和释放。
用于本发明的抗病毒剂包括,但不限于:免疫球蛋白、金刚烷胺、干扰素、核苷酸类似物、和蛋白酶抑制剂。抗病毒剂的具体例子包括但不限于醋孟南、阿昔洛韦、阿昔洛韦钠、阿德福韦、阿洛夫定、阿韦舒托、盐酸金刚脘胺、阿拉诺丁、阿立酮、阿替韦啶甲磺酸、阿夫立定、西多福韦、西潘茶碱、盐酸阿糖胞苷、地拉韦定甲磺酸、地昔洛韦、地达诺新、二噁沙利、依度尿苷、恩韦拉登、恩韦肟、泛昔洛韦、盐酸氯苯氢异喹、非西他滨、非阿尿苷、膦酸利脂、Foscamet Sodium、膦乙醇钠、更昔洛韦、更昔洛韦钠、碘苷、乙氧丁酮醛、拉米夫定、洛布卡韦、盐酸甲氧苯异喹、甲吲噻踪、奈韦拉平、喷昔洛韦、吡罗达韦、利巴韦林、盐酸金刚乙胺、甲磺酸噻喹努佛、盐酸索金刚胺、索立夫定、匍枝青霉菌素、司他夫定、盐酸梯络龙、曲氟尿苷、盐酸伐昔洛韦、阿糖腺苷、磷酸阿糖腺苷、阿糖腺苷磷酸钠、韦罗肟、扎西他滨、齐多夫定、和净韦肟。
核苷酸类似物是与核甘酸类似的合成化合物,但其具有不完全或不正常的脱氧核糖或核糖基。一旦核苷酸类似物进入细胞,就磷酸化形成三磷酸盐形式,与正常核苷酸竞争掺入病毒DNA或RNA中。一旦核苷酸类似物的三磷酸盐形式掺入延伸的核酸链中,可导致不可逆的聚合酶结合而使得链终止。核苷酸类似物包括,但不限于,阿昔洛韦(用于治疗单纯疱疹病毒和水痘-带状疱疹病毒)、更昔洛韦(用于治疗巨细胞病毒)、碘苷、利巴韦林(用于治疗呼吸道合胞体病毒)、双脱氧肌苷、双脱氧胞苷、齐多夫定(叠氮胸苷)、咪喹莫特、和resimiquimod。
干扰素是感染病毒的细胞和免疫细胞分泌的细胞因子。干扰素的作用是通过结合感染细胞临近细胞上的特异性受体,导致细胞变化,使之免于被病毒感染。α和β-干扰素也诱导感染细胞表面表达I和II型MHC分子,导致抗原呈递增强用于宿主免疫细胞识别。可获得重组形式的α和β-干扰素,且已经用于治疗慢性乙型和丙型肝炎感染。在抗病毒治疗有效的剂量时,干扰素具有严重的副作用如发烧、不适和体重减轻。
抗真菌剂用于治疗表面真菌感染以及机会性和原发性系统性真菌感染。抗真菌剂用于治疗和预防传染性真菌。抗真菌剂有时按其作用机制分类。例如,一些抗真菌剂通过抑制葡萄糖合酶起细胞壁抑制剂作用。这些包括,但不限于basiungin/ECB。另一些抗真菌剂通过去稳定膜的完整性而起作用。这些包括,但不限于,咪唑类,如克霉唑、sertaconzole、氟康唑、伊曲康唑、酮康唑、咪康唑、和伏立康唑,以及FK 463、两性霉素B、BAY 38-9502、MK 991、普拉米星、UK 292、布替萘芬、和特比萘芬。另一些抗菌剂的作用是破坏壳多糖(例如壳多糖酶)和免疫抑制(501乳膏)。
抗寄生虫剂杀死和抑制寄生虫。抗寄生虫剂也称作杀寄生虫剂,可用于人的实例包括但不限于阿苯达唑、两性霉素B、苄硝唑、硫氯酚、盐酸氯喹、磷酸氯喹、克林霉素、去氢依米丁、乙胺嗪、糠二氯散、依氟鸟氨酸、furazolidaone、糖皮质激素类、卤泛群、双碘喹啉、伊维菌素、甲苯达唑、甲氟喹、锑酸葡甲胺、美拉胂醇、美曲磷酯、双唑泰栓、氯硝柳胺、硝呋替莫、奥沙尼喹、巴龙霉素、羟乙磺酸戊氧苯脒、哌嗪、吡喹酮、磷酸伯氨喹、氯胍、噻嘧啶、乙胺嘧啶-磺胺类药物、乙胺嘧啶-磺胺多辛、盐酸奎吖因、硫酸奎宁、奎尼丁葡萄糖酸盐、螺旋霉素、斯锑黑克(葡萄糖酸锑钠)、苏拉灭、四环素、多西环素、噻苯咪唑、替硝唑、甲氧苄啶-磺胺甲噁唑、合锥虫胂胺,其中一些单独使用或与其他联合使用。
在实施本发明的某些方法时,需要获得对象的凝溶胶蛋白水平。这个水平与预定值比较,其中凝溶胶蛋白水平与预定值的比较指示对象受益于连续治疗的可能性。然后可根据从治疗改变可能获得的净利益来表征对象。
获得对象的凝溶胶蛋白水平可通过任何本领域已知的方法。典型地,测定该水平可通过测定体液中标记物的水平,如血液、淋巴液、唾液、尿等。测定该水平可通过ELISA、或免疫测试或测定标记物存在的其他常规技术。常规方法包括将对象的体液样本交给商业测量实验室。测定凝溶胶蛋白的方法在实施例中描述。
本发明也包括将对象的凝溶胶蛋白水平与预定值比较。预定值可有多种形式。它可以是单个截断值,如中值或平均值。它可以在比较组的基础上建立,如,例如,一个定义组中的风险是另一个定义组中风险的两倍。其可以是一个范围,例如,测试群体等分(和不等分)为几组,如低风险组、中风险组和高风险组,或进行四分法,其中最低的四分之一是具有最高风险的对象而最高的四分之一是具有最低风险的对象;或进行三分,其中最低的三分之一是那些具有最高风险的对象和最高的三分之一是那些具有最低风险的对象。
预定值可依赖于所选择对象的特定群体。例如,与其他曾经感染过或有其他病况的对象群体相比,看起来健康的群体将具有不同的“正常”范围的凝溶胶蛋白。因此,所选预定值可以考虑对象所属的类别。适当范围和类别的选择不超过本领域普通技术人员进行的常规试验。
优选的体液是血液。一个优选的凝溶胶蛋白预定值是约2.4μM/L血浆。
一个重要的凝溶胶蛋白预定值是健康对象群体(也就是无任何疾病征候和症状的对象)的平均值。预定值当然依赖于对象所属对象群体的特征。在识别风险中,可建立许多预定值。
目前,存在制造凝溶胶蛋白测试试剂的商业来源。这些包括,例如Cytoskeleton(Denver,CO)、Sigma(St.Louis,MO)和Calbiochem(San Diego,CA)。
本发明进一步包括测定凝溶胶蛋白水平和另一种感染标志物的水平,如,例如,白细胞(WBC)水平,以识别对象发生感染的风险。获得对象的凝溶胶蛋白水平。将该凝溶胶蛋白水平与预定值比较,建立第一个风险值。也获得对象的WBC水平。将对象中该WBC水平与第二个预定值比较,建立第二个风险值。然后基于第一个风险值和第二个风险值的组合,表征对象发生感染的风险特性,其中第一个风险值和第二个风险值的结合建立了不同于第一和第二风险值的第三个风险值。在一些实施方案中,第三个风险值比第一或第二风险值大。上面描述了优选的测试对象和预定值。感染可以是例如上述的任何感染。
本发明提供确定对象是受益于继续治疗还是受益于治疗改变的方法。益处典型地是感染发生率的降低或从感染中更快恢复。确定对象是受益于继续治疗还是受益于治疗改变在临床上是有用的。本发明该方法的临床应用的一个例子包括识别对治疗反应可能性更低或可能性更高的对象。本发明的方法也可用于预测或确定对象将受益于继续治疗还是受益于治疗改变。临床有用性的另一个例子,例如在以人为对象时,包括辅助临床调查人员在临床试验中选择具有获得净利益的高可能性的对象。预期临床调查人员将利用本发明确定临床试验的入选标准。
将受益于连续治疗的对象是那些在治疗中凝溶胶蛋白水平达到某一个预定值或其凝溶胶蛋白水平增加的对象。凝溶胶蛋白的预定值如上描述。将受益于治疗改变的对象是那些在治疗中凝溶胶蛋白水平不能达到某一个预定值或其凝溶胶蛋白水平不增加的对象。
此处所用的“治疗改变”指的是增加或减少现有疗法中的剂量,一种疗法转换成另一种疗法,添加另一种疗法到现有疗法中,或其组合。一种疗法转换成另一种疗法可包括转换为具有高风险特性但预期受益可能性增加的疗法。在一些实施方案中,优选的疗法是那些增加凝溶胶蛋白水平的疗法。将通过增加现有疗法中剂量而受益于治疗改变的对象是,例如,处于治疗中但还没有达到治疗的最大耐受剂量或最大允许剂量的对象,并且其凝溶胶蛋白水平没有达到某一个预定值。在这样的情况下,增加现有疗法中的剂量直到凝溶胶蛋白水平达到某一个预定值。在一些情况下,将现有存疗法中的剂量从现有剂量增加到更高的剂量,但增加后剂量既不是治疗的最大耐受剂量也不是最大允许剂量。在另一些情况下,剂量增加到治疗的最大耐受剂量或最大允许剂量。将通过降低现有疗法的剂量而受益于治疗改变的对象是,例如,那些用较低治疗剂量就可以使治疗中凝溶胶蛋白水平达到或能达到某一预定值的对象。
将通过从一种疗法转换成另一种疗法中受益的对象是,例如,处于治疗的最大耐受剂量或最大允许剂量并且其凝溶胶蛋白水平没有达到某一预定值的对象。另一个例子是没有处于治疗的最大耐受剂量或最大允许剂量但是通过保健医生确定更可能从另一种疗法中受益的对象。这样的确定是基于,例如,初步疗法中对象中发生不想要的副作用或对初步疗法缺乏反应。
从添加另一种疗法到现有疗法中而受益的对象是,例如,处于治疗中但其凝溶胶蛋白水平未达到某一个预定值的对象。在这样的情况下,将另一种疗法添加到现有疗法中。添加到现有疗法中的疗法与现有疗法相比,具有增加凝溶胶蛋白水平的不同机制。在一些情况下,可以使用上述治疗改变的组合。
本发明也提供确定治疗的疗效的方法。疗效典型的是治疗中增加凝溶胶蛋白水平的功效。有时也指阳性反应或良性反应。疗效测定可通过凝溶胶蛋白血液检验确定凝溶胶蛋白水平增加是否是治疗的结果来进行。在一些实施方案中,疗效的测定基于疗法增加凝溶胶蛋白并校正WBC计数的功效。
凝溶胶蛋白测量结果表示为μM/L(微摩尔/升)、mg/dl(毫克/分升)、或mg/L(毫克/升)。
本发明也提供了确定接受治疗感染的对象中治疗过程的方法。确定这样的疗程是根据凝溶胶蛋白水平。治疗或降低感染风险的疗法如上所述。在一些实施方案中,对象已经感染过或具有感染的风险。曾经原发性(第一次)感染的对象由于其原发性感染而具有增加的继发性(第二次)感染的风险。在一些实施方案中,对象具有增加的感染风险,是因为对象具有患感染的一种或更多种风险因素。患感染的风险因素的例子如上描述。在一些实施方案中,具有增加的感染风险的对象,可以是看起来健康的对象。看起来健康的对象是那些没有任何疾病征候或症状的对象。
这些方法对于患者治疗以及临床开发新疗法都具有重要的启示。可预期现在临床调查将采用本发明的方法用于确定入选临床试验的人类对象的标准。保健医生选择治疗方案是基于对象预期的净受益。净受益来源于风险与受益的比值。本发明允许确定对象是受益于连续治疗还是受益于治疗改变,因此有助于医生选择疗法。
治疗的量是可以变化的,例如通过增加或减少凝溶胶蛋白或药理学剂或治疗组合物的量、通过改变所施用的治疗组合物、通过改变给药途径、通过给变给药时间方案等等。根据所治疗的具体感染或病况、治疗对象的年龄和身体条件、感染或病况的严重性、治疗持续的时间、同时进行的疗法(如果有的话)、具体给药途径、以及在医生知识和专业经验范围内的类似因素,有效量将会变化。例如,有效量可依赖于个体暴露感染的程度或受暴露于感染所影响的程度。
有效量是治疗剂足以提供期望医学结果的剂量。有效量,例如,也可以依赖于个体凝溶胶蛋白水平异常降低的程度。应该理解,本发明的治疗剂可用于治疗或预防感染,也就是说,它们可预防性地用于处于发生感染风险的对象。因而,有效量是可以降低风险、减缓或可能完全防止发生感染的量。应当认识到在治疗剂用于急性事件时,其可防止一种或多种医学上不希望的结果,这些不利事件典型地导致这些结果。
确定有效量所涉及的因素是本领域普通技术人员已知的,并且只要通过常规试验就可确定。通常优选采用最大剂量的本发明药理学剂(单独或与其他治疗剂联用),即,根据可靠医学判断的最安全剂量。然而本领域普通技术人员可以理解,由于医学原因、心理原因或几乎任何其他原因,患者可坚持用较低剂量或可耐受剂量。
本发明药物剂的治疗有效量是治疗疾病如感染有效的量。对于感染,期望的反应是抑制感染进行。这可以包括只是暂时减缓感染进行,虽然更优选地,它包括永久阻止感染进行。这可以通过本领域普通技术人员已知的常规诊断方法监测。对治疗感染所期望的反应也可以是延迟或甚至阻止感染发作。
本发明方法中所用的药剂优选是无菌的并以适于施用于对象的单位重量或体积含有可有效产生期望反应的量的凝溶胶蛋白。可根据不同的参数选择向对象施用的药物剂的剂量,特别是根据给药地模式和对象的状态。其他因素包括期望治疗时间。在使用最初剂量而对象体内反应不够时,可采用患者能耐受的更高剂量(或通过不同的、更定位的给药途径而有效性更高的剂量)。药物剂的剂量可由个体医生或兽医调节,特别是在任何并发症的时候。治疗有效量典型地从0.01mg/kg到约1000mg/kg变化,优选从约0.1mg/kg到约200mg/kg,和最优选从约0.2mg/kg到约20mg/kg,每天施用一或多个剂量,持续一天或更多天。
本领域普通技术人员已知多种给药方式可以有效地递送本发明药剂到所期望组织、细胞或体液。给药方法在本申请的其他地方有论述。本发明并不限于此处公开的具体给药模式。本领域中的标准参考(例如,Remington′sPharmaceutical Sciences,20th版,Lippincott,Williams and Wilkins,BaltimoreMD,2001)提供了给药模式和剂型,用于递送在药物载体中的不同药物制剂。其他可用于施用本发明药剂的方案是本领域普通技术人员已知的,其中剂量、施用方案、施用部位、施用方式等等不同于此处公开的那些。
向人以外的哺乳动物施用本发明药物剂,例如为了测试目的或兽医治疗目的,可基本按上述描述的相同条件进行。本领域普通技术人员可以理解本发明可用于人和动物疾病。因而,本发明意图用于饲养业和兽医学以及人类治疗。
在给药时,本发明的药物制剂以药学上可接受的量和药学上可接受的组合物使用。术语“药学上可接受的”指的是非毒性材料,其不干扰活性成份生物活性的有效性。这样的制剂常规可含有盐、缓冲剂、防腐剂、兼容的载体和任选地其他治疗剂。在用于药物时,所述盐应该是药学上可接受的,但是非药学上可接受的盐可方便的用于制备其药学上可接受的盐,因此也不排除在本发明的范围之外。这样的药理学和药学上可接受的盐包括,但不限于,那些从下述酸中制备的:盐酸、氢溴酸、硫酸、硝酸、磷酸、马来酸、乙酸、水杨酸、柠檬、甲酸、丙二酸、琥珀酸等等。另外,药学上可接受的盐可制成碱金属或碱土金属盐,如纳、钾或钙盐。
如果需要的话,药物剂或组合物可结合药学上可接受的载体。此处所用的术语“药学上可接受的载体”指的是一种或更多种兼容的固体或液体填充剂、稀释剂或成胶囊物质,其适合施用于人。术语“载体”表示有机或无机成分、天然或合成的,活性成份与其结合以辅助应用。药用组合物的组分也能与本发明的药物剂混合,并且是以相互之间没有实质性阻碍期望药物功效的相互作用的方式。
药用组合物可以含有合适的缓冲剂,如上所述,包括醋酸、磷酸、柠檬酸、甘氨酸、硼酸、碳酸、重碳酸、氢氧化物(和其他碱)和前述化合物的药学上可接受的盐。药用组合物也可以含有,任选地,合适的防腐剂,如苯扎氯铵、氯丁醇、尼波金酯和硫柳汞。
药用组合物可方便地以单位剂量的形式存在,并且可按照药学领域所知的任何方法制备。所有的方法包括将活性剂与载体结合的步骤,所述载体构成一种或更多种助剂。通常,组合物的制备是通过均匀地和密切地混合活性化合物与液体载体、精细分开的固体载体、或两者结合,然后如果需要话,将产物成型。
适合口服的组合物可以提供为分散的单位形式,如胶囊、片剂、丸、锭剂,每种都含有预定量的活性化合物(例如凝溶胶蛋白)。其他组合物包括水相或非水相中的悬液如糖浆、酏剂、乳剂或凝胶。
用于口服的药物制剂可以如此获得,作为固体赋形剂,任选地,研磨所得混合物,并加工混合物成颗粒,如果需要,在添加合适的助剂以后,获得片剂或锭剂的核。合适的赋性剂是,具体地,填充剂如糖,包括乳糖、蔗糖、甘露醇、或山梨糖醇;纤维素制剂如,例如,玉米淀粉、小麦淀粉、大米淀粉、马铃薯淀粉、明胶、黄蓍胶、甲基纤维素、羟丙基甲基纤维素、羧甲基纤维素钠、和/或聚乙烯吡咯酮(PVP)。如果需要,可加入崩解剂,如交联聚乙烯吡咯酮、琼脂、或海藻酸或其盐如藻酸钠。任选地口服制剂也可在盐或缓冲液中配制,也就是,EDTA用于中和内部的酸性环境,或可以不用任何载体来施用。
具体也要考虑上述组分的口服剂量形式。所述组分可被化学修饰以便有效地口服递送所述衍生物。通常,所考虑的化学修饰是连接至少一种结构到组分分子自身,其中所述结构允许(a)抑制蛋白质裂解,和(b)从胃或肠中吸收进血流。也期望增加组分的总体稳定性并增加在体内的循环时间。这种结构的例子包括:聚乙二醇、乙二醇和丙二醇的共聚物、羧甲基纤维素、葡聚糖、聚乙烯醇、聚乙烯吡咯烷酮、和聚脯氨酸。Abuchowski和Davis,1981,″SolublePolymer-Enzyme Adducts″In:Enzymes as Drugs,Hocenberg和Roberts,编辑,Wiley-Interscience,New York,NY,pp.367-383;Newmark,等,1982,J.Appl.Biochem.4:185-189。其他可以使用的聚合物有聚-1,3-二氧戊环和聚-1,3,6-三氧戊烷(tioxocane)。制药学上优选采用,如上所示,聚乙二醇结构。
对于所述组分(或衍生物)其释放位置可以是胃、小肠(十二指肠、空肠或回肠)或大肠。本领域普通技术人员可以获得这样的制剂,其在胃中不溶,但在十二指肠或肠的其他地方释放物质。优选地,释放将避开胃环境的有害作用,要么保护凝溶胶蛋白,要么在胃环境以外如肠中释放生物活性物质。
为了确保完全的胃抗性,在至少pH 5.0时不能渗透的包衣是必要的。更加常见的可用作肠包衣的惰性成分的例子是,乙酸-偏苯三酸纤维素(CAT)、羟丙基甲基纤维素邻苯二甲酸酯(HPMCP)、HPMCP 50、HPMCP 55、聚醋酸乙烯邻苯二甲酸酯(PVAP)、Eudragit L30D、Aquateric、醋酞纤维素(CAP)、Eudragit L、Eudragit S和紫胶。这些包衣可用作混合膜。
包衣或包衣的混合物也可用于片剂上,其目的不是保护免受胃的侵蚀。这些可以包括糖衣、或者是可以使片剂更易于吞服的包衣。胶囊可包括硬壳(如明胶),用于递送干燥的治疗剂,也就是粉末;对于液体形式,可使用软明胶壳。囊片的壳材料可以是稠淀粉或其他可食的纸。对于丸剂、锭剂、模制片、或模印片(triturates),可使用湿法聚集技术。
治疗剂可包括在制剂中,作为以大小约1mm的颗粒或小丸形式的精细多颗粒。用于胶囊施用的材料的剂型可以是粉末、轻微压缩的栓剂或甚至是片剂。治疗剂可通过压缩制备。
着色剂和调味剂都可以包括。例如,可以配制凝溶胶蛋白(如通过脂质体或微球胶囊化),随后进一步包含在可食用制品内,如包含着色剂和调味剂的冷饮。
可用惰性材料稀释或增加治疗剂的体积。这些稀释剂可以包括碳水化合物,特别是甘露醇、α-乳糖、无水乳糖、纤维素、蔗糖、修饰的葡聚糖和淀粉。某些无机盐也可用作填充剂,包括三磷酸钙、碳酸镁和氯化钠。一些商业可获得的稀释剂有Fast-Flo、Emdex、STA-Rx 1500、Emcompress和Avicell。
在将治疗剂配制成固体剂型时可以包括崩解剂。可用作崩解剂的物质包括,但不限于淀粉,包括基于淀粉的商品崩解剂,Explotab。淀粉乙醇酸钠、Amberlite、羧甲基纤维素钠、ultramylopectin、海藻酸钠、明胶、橙皮、酸性羧甲基纤维素、天然海绵和膨润土都可以使用。另一种形式的崩解剂是不溶的阳离子交换树脂。粉状树胶也可用作崩解剂和粘合剂,这些可包括粉状树胶,如琼脂、卡接牙胶(Karaya)或黄蓍胶。海藻酸和其钠盐也可用作崩解剂。
粘合剂可用于将治疗剂保持在一起以形成硬的片剂,包括源于天然产物的材料,如阿拉伯胶、黄蓍胶、淀粉和明胶。其他包括甲基纤维素(MC)、乙基纤维素(EC)和羧甲基纤维素(CMC)。聚乙烯吡咯烷酮(PVP)和羟丙基甲基纤维素(HPMC)都可以用于醇溶液,从而将治疗剂制成颗粒。
治疗剂的制剂中可以包括抗摩擦剂,以防止在制剂形成过程中发粘。润滑剂可用作治疗剂和模具壁之间的层,这些可以包括但不限于:硬脂酸包括其镁和钙盐、聚四氟乙烯(PTFE)、液体石蜡、植物油和蜡。还可以使用可溶性润滑剂,如月桂基硫酸钠、月桂基硫酸镁、各种分子量的聚乙二醇、Carbowax 4000和6000。
助流剂可提高药物在配制过程中的流动特性,有助于在压缩时重新排列。助流剂可包括淀粉、滑石粉、热解硅胶和含水的铝酸硅。
为了辅助治疗剂溶解在水环境中,可以加入表面活性剂作为湿润剂。表面活性剂可以包括阴离子去污剂如月桂基硫酸钠、二辛基磺基琥珀酸钠和二辛基磺酸钠。也可以用阳离子去污剂,可包括苯扎氯胺或氯化苯乙铵(benzethomium)。作为表面活性剂可以包括在制剂中的潜在非离子型去污剂的清单中包括聚桂醇400(lauromacrogol 400)、聚氧乙烯40单硬脂酸酯、聚氧乙烯氢化蓖麻油10、50和60、单硬脂酸甘油酯、聚山梨酯40、60、65和80、蔗糖脂肪酸酯、甲基纤维素和羧甲基纤维素。这些表面活性剂可以单独或以不同比率的混合物存在于凝溶胶蛋白制剂中。
可口服使用的药物制剂包括明胶制备的压入式胶囊,以及软的、由明胶和增塑剂如甘油或山梨醇制备的密封胶囊。压入式胶囊可以含有活性成分并混有填充剂如乳糖、粘合剂如淀粉、和/或润滑剂如滑石粉或硬脂酸镁、以及任选的稳定剂。在软胶囊中,活性化合物可以溶解或悬浮在合适的液体中,如脂肪油、液体石蜡、或液体聚乙二醇。另外,可加入稳定剂。
也可以使用用于口服的微球剂型。这样的微球在本领域已经被明确定义。所有口服给药的剂型都应当是适于这样给药的剂型。
对于口腔含服给药,组合物可以是以常规方式配制的片剂或锭剂的形式。
对于吸入给药,根据本发明所用的化合物可方便地以从压缩包装或喷雾器中呈递的气雾剂形式递送,其中使用合适的抛射剂,例如,二氯二氟甲烷、三氯氟甲烷、二氯四氟乙烷、二氧化碳或其他合适的气体。在压缩的气雾剂中,剂量单位可以通过提供递送计算量的阀来确定。胶囊和药筒,例如明胶制成用于吸入器或吹入器中的,可配制成含有所述化合物和合适粉末基如乳糖或淀粉的粉末混合物。
此处也涉及经肺递送凝溶胶蛋白。在吸入并穿过肺上皮衬层到血液中时,凝溶胶蛋白被递送给哺乳动物的肺。吸入分子的其他报道包括Adjei等,1990,Pharmaceutical Research,7:565-569;Adjei等,1990,International Journal ofPharmaceutics,63:135-144(亮丙瑞林);Braquet等,1989,Journal ofCardiovascular Pharmacology,13(suppl.5):143-146(内皮素-1);Hubbard等,1989,Annals of Internal Medicine,Vol.III,pp.206-212(α-1-抗胰蛋白酶);Smith等,1989,J.Clin.Invest.84:1145-1146(α-1-蛋白水解酶);Oswein等,1990,″Aerosolization of Proteins″,Proceedings of Symposium on Respiratory DrugDelivery II,Keystone,Colorado,March,(重组人生长激素);Debs等,1988,J.Immunol.140:3482-3488(干扰素-γ和肿瘤坏死因子α)和Platz等,U.S.PatentNo.5,284,656(粒细胞集落刺激因子)。用于全身作用的经肺递送药物的方法和组合物描述于Wong等,美国专利号5,451,569(1995-9-19授权)。
很大范围的机械设备都可以用于实施本发明,所述没备设计用于经肺施用治疗产物,包括但不限于喷雾器、定量剂量吸入器和粉末吸入器,所有的都是本领域普通技术人员熟知的。
适于实施本发明的商业可获得设备的一些具体例子是Ultravent喷雾器,由Mallinckrodt,Inc.,St.Louis,Missouri制造;Acorn II喷雾器,由MarquestMedical Products,Englewood,Colorado制造;Ventolin定量剂量吸入器,由Glaxo Inc.,Research Triangle Park,North Carolina制造;Spinhaler粉末吸入器,由Fisons Corp.,Bedford,Massachusetts制造。
所有这样的设备都需要使用适于分散凝溶胶蛋白的制剂。典型地,每种剂型具体对应于所用设备类型,除治疗中可用的常规稀释剂、佐剂和/或载体之外,并可以包括采用合适的抛射剂材料。也可以考虑使用脂质体、微囊或微球,包合复合物,或其他类型的载体。依据化学修饰的类型或所用设备的类型,化学修饰的凝溶胶蛋白也可制备成不同的剂型。
适于喷射或超声喷雾器的制剂典型地包含溶于水的凝溶胶蛋白,浓度为约0.1-25mg生物活性凝溶胶蛋白/mL溶液。此制剂也可以包括缓冲剂和简单的糖(例如,用于稳定凝溶胶蛋白和调节渗透压)。喷雾器制剂也可以含有表面活性剂,以减少或防止表面诱导的凝溶胶蛋白聚集,所述聚集是溶液雾化形成气溶胶时导致的。
用于定量剂量吸入器设备的制剂通常包含精细分散的含凝溶胶蛋白的粉末,所述粉末在表面活性剂的帮助下悬浮在抛射剂中。抛射剂可以是任何常规的用于此目的的物质,如氯氟烃、氢氯氟烃、氢氟烃、或烃,包括三氯氟甲烷、二氯二氟甲烷、二氯四氟乙烷和1,1,1,2-四氟乙烷,或其组合。合适的表面活性剂包括失水山梨醇三油酸酯和大豆卵磷脂。油酸也可用作表面活性剂。
从粉末吸入装置分散的制剂将包含精细分散的含凝溶胶蛋白的干粉,也可以包括填充剂,如乳糖、山梨醇、蔗糖或甘露醇,其量有助于将干粉从设备中分散,例如制剂重量的50-90%。为了最有效的递送给远端肺,凝溶胶蛋白应当最优先地制成平均粒径小于10mm(或微米)的颗粒形式,最优选0.5到5mm。
也可以采用经鼻(或鼻内)递送本发明药用组合物。经鼻递送允许在将治疗产物施用鼻子之后本发明药用组合物直接传到血流中,而不需要将产物保存在肺中。经鼻递送的制剂包括那些用葡聚糖或环葡聚糖的。
对于鼻内给药,可用的设备是小的、硬的瓶子并连接有定量剂量喷雾器。在一个实施方案中,定量剂量是通过将本发明药用组合物吸取到确定体积的腔室内,该腔室具有适于气溶胶化的孔,当液体在腔室内压缩时通过形成喷雾而形成气溶胶。所述腔室压缩以施用本发明药用组合物。在一个具体的实施方案中,该腔室是活塞构造。这样的设备可商业获得。
作为替代,可使用具有孔或开口的塑料挤瓶,当挤压时所述孔或开口大小适于通过形成喷雾而使气雾剂气溶胶化。开口通常在瓶子的顶部,顶部通常逐渐变细,以部分适合放入鼻腔,以有效地施用气雾剂。优选地,鼻吸入器提供定量的气雾剂,用于施用测定剂量的药物。
当期望全身递送时,化合物可通过注射肠胃外给药,例如快速推注或连续灌注。注射制剂可以单位剂量形式存在,例如,在安瓿或在多剂量容器中,并另外加入防腐剂。组合物可采取这样的形式如油或水性载体中的悬液、溶液或乳液,可包含配方试剂如助悬剂、稳定剂和/或分散剂。
肠胃外给药的药物制剂包括水溶形式的活性化合物的水溶液。另外,活性化合物的悬浮液可制备成合适的油性注射悬液。合适的亲脂溶剂或载体包括脂肪油如麻油、或合成脂肪酸酯如油酸乙酯或甘油三酯、或脂质体。水性注射悬液可含有增加悬液粘度的物质如羧甲基纤维素钠、山梨糖醇、或葡聚糖。任选地,悬液还可含有合适的稳定剂或增加化合物溶解度的试剂,以制备高浓缩的溶液。
作为替代,活性化合物可以是粉末形式,使用前用合适的载体如无菌无热原水重构。
化合物也可配制成直肠或阴道用的组合物如阴道栓剂或保留灌肠剂,例如含常规栓剂基质如可可脂或其他甘油酯。
除了前面描述的制剂以外,化合物也可配制成储库(depot)制剂。这种长期作用的制剂可以用合适的聚合物或疏水材料(例如作为可接受油中的乳液)或用离子交换树脂配制,或配制成微溶的衍生物,例如微溶的盐。
药用组合物也包含合适的固体或凝胶相载体或赋形剂。这种载体或赋形剂的例子包括但不限于碳酸钙、磷酸钙、许多糖、淀粉、纤维素衍生物、明胶、和聚合物如聚乙二醇。
合适的液体或固体药物制剂形式是,例如,水或盐溶液,用于吸入、微囊化、encochleated、包被在显微金颗粒上、包含在脂质体中、喷雾、气雾剂、植入皮肤的丸剂、或干燥成尖锐物体以刮蹭入皮肤中。所述药用组合物也包括颗粒、粉末、片剂、包衣片、(微)胶囊、栓剂、糖浆、乳剂、悬液、霜剂、滴剂或延迟释放活性化合物的制剂,在这些制剂中,如上所述常规使用赋性剂和添加剂和/或辅料如崩解剂、粘合剂、包衣剂、溶胀剂、润滑剂、调味剂、增甜剂或增溶剂。所述药物制剂适合用于多种药物递送系统。对于药物递送方法的简短评述,参考Langer,Science 249:1527-1533,1990,其在此引入作为参考。
可以其本身或者其药学上可接受盐的形式施用凝溶胶蛋白和任选的其他治疗剂。
所述治疗剂,具体地包括但不限于凝溶胶蛋白,可以颗粒提供。此处所用的颗粒是指纳米或微米颗粒(或在一些情况下更大),其可以全部或部分由此处所述的凝溶胶蛋白组成或其他治疗剂组成。所述颗粒可以在核心含有所述治疗剂并有环绕核心的包衣,其包括但不限于肠溶包衣。所述治疗剂也可分散在整个的颗粒中。治疗剂也可被吸附入颗粒中。颗粒可以具有任何级别的释放动力学,包括零级释放、一级释放、二级释放、延迟释放、持续释放、立即释放、和其任意组合,等等。除了治疗剂以外,颗粒可包括任何常规用于药学和药物中的那些材料,包括但不限于,可蚀性、难蚀性、可生物降解、或不可生物降解的材料或其组合。颗粒可以是溶液或半固体状态的微胶囊,其中包含凝溶胶蛋白。颗粒几乎可以是任何形状。
不可生物降解和可生物降解的聚合物材料都可以用于制备递送治疗剂的颗粒。这样的聚合物可以是天然的或是合成的聚合物。聚合物的选择是基于释放所期望的时段。特别感兴趣的生物粘性聚合物包括可生物蚀解的水凝胶,描述在H.S.Sawhney,C.P. Pathak和J.A.Hubell,Macromolecules,(1993)26:581-587,其中教导在此引入。这些包括聚透明质酸、酯蛋白、明胶、明胶蛋白、聚酐、聚丙烯酸、藻酸盐、脱乙酰壳聚糖、聚(甲基丙烯酸甲酯)、聚(甲基丙烯酸乙酯)、聚(甲基丙烯酸丁酯)、聚(甲基丙烯酸异丁酯)、聚(甲基丙烯酸己酯)、聚(甲基丙烯酸异癸酯)、聚(甲基丙烯酸月桂基酯)、聚(甲基丙烯酸苯酯)、聚(丙烯酸甲酯)、聚(丙烯酸异丙基酯)、聚(丙烯酸异丁基酯)、聚(丙烯酸十八烷基酯)。
治疗剂也可包含在控制释放系统中。术语“控制释放”指的是任何含药制剂,其中药物从制剂中释放的方式和特征谱是受控制的。这涉及立即和非立即释放制剂,非立即释放制剂包括但不限于持续释放和延迟释放制剂。一般意义上术语“持续释放”(也称“延长释放”)指的是能够在延长的时间段里逐渐释放药物的药物制剂,优选地,尽管不是必须地,导致药物在延长的时间段里基本保持恒定的血液水平。一般意义上术语“延迟释放”指的是在施用制剂和释放药物之间有时间延迟的药物制剂。“延迟释放”可包括或不包括在延长的时间段里逐渐释放药物,因而其可能是或不是“持续释放”。
使用长期持续释放植入物特别适用于治疗慢性疾病。在此所用的“长期释放”,指的是植入物被构造和安排成递送治疗水平的活性组分至少达7天,优选30-60天。长期持续释放植入物是本领域普通技术人员公知的,包括上述的一些释放系统。
本发明也涉及试剂盒的用法。在本发明的一些方面,试剂盒可包括药物制剂瓶、药物制剂稀释剂瓶和凝溶胶蛋白。含用于药物制剂的稀释剂的瓶是任选的。稀释剂瓶含有稀释剂如生理盐水,用于稀释凝溶胶蛋白的可能的浓缩溶液或冻干粉。说明书可以包括指导混合具体量的稀释剂和具体量的浓缩药物制剂,以制备用于注射或输注的最终制剂。说明书可包括用有效量凝溶胶蛋白治疗患者的说明。也可以理解,无论容器是瓶子、带隔膜的小瓶、带隔膜的安瓿、输注袋等等,含制剂的容器可以含有标记如常规记号,当制剂被高压灭菌或其他灭菌时所述标记改变颜色。
本发明进一步由下述实施例举例说明,其毫无疑问不应理解为进一步的限制。本申请中所提到的所有文献(包括参考文献、授权专利、公开专利申请和共同未决的专利申请)的所有内容都在此引入作为参考。
实施例
脓毒症与多种生物化学异常相关,包括血浆凝溶胶蛋白消耗。在血浆凝溶胶蛋白的真正功能未知时,临床和动物研究已经表明因损伤和炎症而造成的血浆凝溶胶蛋白消耗与不利结果相关。我们检查了脓毒症小鼠的血浆凝溶胶蛋白,发现在脓毒症攻击后发生血浆凝溶胶蛋白消耗,并且严重消耗伴随致死性脓毒症。补充血浆凝溶胶蛋白导致更加有利的细胞因子特征谱并改善死亡率。血浆凝溶胶蛋白在全身性炎症中具有生理作用,凝溶胶蛋白替代可以代表感染和脓毒症的新疗法。
凝溶胶蛋白,具体是胞质凝溶胶蛋白(cGSN),首先作为涉及细胞运动的细胞内肌动蛋白结合蛋白被发现(Yin,H.L.& Stossel,T.P.(1979)Nature 281,583-6),它也是丰富的分泌蛋白(Yin,H.L.,Kwiatkowski,D.J.,Mole,J.E.&Cole,F.S.(1984)J Biol Chem 259,5271-6)。凝溶胶蛋白的输出同种型,被命名为血浆凝溶胶蛋白(pGSN),具有另外的25个氨基酸,源于单个基因的选择性剪接(Kwiatkowski,D.J.,Stossel,T.P.,Orkin,S.H.,Mole,J.E.,Colten,H.R.& Yin,H.L.(1986)Nature 323,455-8)。尽管被认为是“肌动蛋白清除剂”(Lee,W.M.& Galbraith,R.M.(1992)NEngl J Med326,1335-41),pGSN的生物学功能仍旧是个谜。pGSN存在于复杂生物体,包括果蝇(Stella,M.C.,Schauerte,H.,Straub,K.L.& Leptin,M.(1994)J Cell Biol 125,607-16),与它具有重要的生理作用相一致。在人体中,创伤、大出血、急性呼吸窘迫综合征(ARDS)、造血干细胞移植(HSCT)、急性肝功能衰竭、肌肉坏死、胰腺炎和脓毒症都可导致pGSN消耗(Dahl,B.,Schiodt,F.V.,Ott,P.,Gvozdenovic,R.,Yin,H.L.& Lee,W.M.(1999)Shock 12,102-4;Suhle,E.,Lin,W,Yin,H.L.& Lee,W.M.(1997)Crit Care Med 25,594-8;DiNubile,M.J.,Stossel,T.P.,Ljunghusen,O.C.,Ferrara,J.L.& Antin,J.H.(2002)Blood 100,4367-71;和Lind,S.E.,Smith,D.B.,Janmey,P.A.& Stossel,T.P.(1988)Am Rev Respir Dis138,429-34)。而且,在创伤患者和HSCT接受者中,较低水平的pGSN预示着增加的发病率和死亡率(DiNubile,M.J.,Stossel,T.P.,Ljunghusen,O.C.,Ferrara,J.L.&Antin,J.H.(2002)Blood 100,4367-71;Mounzer,K.C.,Moncure,M.,Smith,Y.R.& Dinubile,M.J.(1 999)Am J Respir Crit Care Med 160,1673-81)。
在动物中,烧伤和氧化应激诱导的急性肺损伤、辐射和氧过多也可导致pGSN消耗(Rothenbach,P.A.,Dahl,B.,Schwartz,J.J.,O′Keefe,G.E.,Yamamoto,M.,Lee,W.M.,Horton,J.W.,Yin,H.L.& Tumage,R.H.(2004)JAppl Physiol 96,25-31;Christofidou-Solomidou,M.,Scherpereel,A.,Solomides,C.C.,Christie,J.D.,Stossel,T.P.,Goelz,S.& DiNubile,M.J.(2002)J InvestigMed 50,54-60;和Christofidou-Solomidou,M.,Scherpereel,A.,Solomides,C.C.,Muzykantov,V.R.,Machtay,M.,Albelda,S.M.& DiNubile,M.J.(2002)Lung180,91-104)。向这些动物中的一些施用pGSN可减轻伤害(Rothenbach,P.A.,Dahl,B.,Schwartz,J.J.,O′Keefe,G.E.,Yamamoto,M.,Lee,W.M.,Horton,J.W.,Yin,H.L.& Tumage,R.H.(2004)J Appl Physiol 96,25-31;和Christofidou-Solomidou,M.,Scherpereel,A.,Solomides,C.C.,Christie,J.D.,Stossel,T.P.,Goelz,S.& DiNubile,M.J.(2002)J lnvestig Med 50,54-60)。
我们假设如果与脓毒症相关的全身性炎症抑制pGSN,那么恢复pGSN则可以是有利的。在此,我们显示内毒素血症或腹膜炎的小鼠中pGSN水平降低,补充pGSN导致在脓毒症小鼠中改善的存活率和细胞因子特征谱转变。
材料和方法
动物
野生型C57BL/6雄性小鼠购买自Charles River Laboratories(Wilmington,MA)。Toll样受体4(TLR4)突变体C3H/HeJ雄性小鼠购买自theJackson Laboratory(Bar Harbor,ME)。小鼠自由获取标准饲料和饮水,根据实验室动物护理和使用指南(The Guide for the Care and Use of LaboratoryAnimals)的标准,在此描述的所有操作和研究都已经征得哈佛医学领域关于动物的常务委员会(Harvard Medical Area Standing Committee on Animals)同意。
LPS剂量反应
重18-20g的6-8周龄雄性C57BL/6小鼠,腹膜内注射(i.p.)LPS(绿脓假单胞菌血清型10,源自Sigma(St.Louis,MO)),剂量分别为100μl磷酸盐缓冲液(PBS)中含0、10、20和40mg/kg,每组用3-4只。LPS施用后24小时,用0.015-0.017mg/g阿佛丁i.p.麻醉小鼠(Fluka Chemie,Buchs,Switzerland)。采用眼窝后取血法收集血液到0.1体积的Aster-Jandl抗凝血溶液中(Gamulescu,M.A.,Seifert,K.,Tingart,M.,Falet,H.& Hoffmeister,K.M.(2003)Platelets14,211-7),1000xg离心10分钟产生血浆。血浆在液氮中冷冻,保存在-80℃。
CLP(盲肠结扎和穿刺)导致的小鼠脓毒症
8-10周龄雄性C57BL/6小鼠首先用0.015-0.017mg/g阿佛丁i.p.麻醉。在腹部的前下方切小口暴露出每只麻醉动物的盲肠,并用19号针穿刺。挤出小量的肠内容物,用6-0丝缝合线结扎盲肠,而不阻塞肠道。在替换掉肠内容物后,腹部用4-0丝缝合线关闭。对于pGSN水平研究,5只动物在手术后立即皮下施用1ml PBS。5只没有接受CLP的动物作为对照。动物恢复自由取食和喝水。CLP后24小时,然后麻醉动物并如前述收集血浆。另外,收集每只动物的心、肺、肝、肾和后肢的骨骼肌,冷冻在-80℃。首先穿刺右心室并注射1ml PBS到左心室,这样灌注后收集肺。对于死亡率研究,20只动物进行CLP,并且10只在立即和CLP后24小时时皮下(s.c.)注射1ml的1)150mM NaCl(盐水)或2)8mg/ml重组人pGSN(Biogen,Boston,MA)和含0.4mM Ca的盐水。
LPS死亡率和血浆细胞因子
6-8周龄雄性C57BL/6小鼠重18-20g,i.p.注射25mg/kg LPS(E.coliO55:B5,St.Louis,Sigma),并在LPS注射后立即和在24、48、和72小时分别接受背侧皮下注射400μl剂量的1)pGSN:20mg/ml重组人pGSN和含1mM Ca的盐水(8只动物),2)BSA:20mg/ml牛血清白蛋白(Serologicals,Norcross,GA)和含1mM Ca的盐水(9只动物),或3)盐水:单独用无菌盐水(9只动物)。频繁监测动物并记录7天内的死亡率。存活的小鼠进行安乐死。在一个分开的试验中,小鼠接受相同的LPS攻击,并如上述分别接受pGSN或盐水处理,在LPS刺激后6小时(每个处理组有5只小鼠)和24小时(每个处理组有4只小鼠)处死并收集血浆和器官。另外,未用LPS攻击的对照小鼠仅s.c.施用盐水(5只小鼠)或pGSN(3只小鼠),24小时后处死并收集血液和器官。如所述收集每只小鼠的血浆和器官。
LPS抗性小鼠中的pGSN
6-8周龄雄性C3H/Hej小鼠重19-20g,i.p.注射25mg/kg E.coli LPS(4只小鼠),未攻击的小鼠作为对照(4只小鼠)。LPS攻击后24小时,如上述麻醉小鼠后收集血浆样本。测定每个血浆样本的凝溶胶蛋白水平。
小鼠细胞因子测定
用ELISA分析(LINCO Research,St.Charles,MO)测定血浆GM-CSF、IFN-γ、IL-1β、IL-6、IL-10和TNF-α细胞因子。每种细胞因子测试的较低范围是≤3.2pg/ml,而浓度≤3.2pg/ml的水平被设定为0数值。
凝溶胶蛋白和白蛋白测定
根据血浆凝溶胶蛋白刺激肌动蛋白成核的能力测定双份样本中的血浆凝溶胶蛋白(Janmey,P.A.,Chaponnier,C.,Lind,S.E.,Zaner,K.S.,Stossel,T.P.& Yin,H.L.(1985)Biochemistry 24,3714-23)。小鼠血浆1.5倍稀释于0.1M KCl、0.2mM MgCl2、1mM EGTA、0.5mM ATP、0.5mM β-巯基乙醇、10mMTris-HCl缓冲液、pH 7.4(缓冲液B)中。取5μl稀释的血浆样本加入在6×50mm硼硅酸盐培养管中的280μl缓冲液B中,其中缓冲液B中补充1.5mM CaCl4和0.4μM类鬼笔环肽。通过将15μl 20μM芘肌动蛋白加入0.5mM ATP、5mMβ-巯基乙醇、0.2mM CaCl2、0.2mM Tris-HCl缓冲液pH 7.4(缓冲液A)中来启动肌动蛋白的聚合反应。荧光分光光度计监测聚合过程200秒,其中激发和发射波长分别为366和386nm。从用人重组pGSN的标准曲线上估算凝溶胶蛋白的浓度。用于这些测试中的储备芘肌动蛋白通过Kouyama和Mihashi(Kouyama,Y.& Mihashi,K.(1981)Eur J Biochem 114,33-8)的方法制备,分批保存在-80℃,解冻并用缓冲液A按10倍稀释,静置过夜后在250,000xg离心30分钟。
通过肌动蛋白成核测试定量凝溶胶蛋白与Western印迹测定获得的水平相关性良好(Mounzer,K.C.,Moncure,M.,Smith,Y.R.& Dinubile,M.J.(1999)Am J Respir Crit Care Med 160,1673-81)。该测试是高度特异性的,LPS处理的凝溶胶蛋白缺陷小鼠的血浆中几乎是零活性证实了这一点(数据未公开);然而该测试并未区分cGSN和pGSN。这也不是物种特异性的,因此能大致估计重组人pGSN处理小鼠中的总凝溶胶蛋白水平。脂质与pGSN络合并不影响pGSN的肌动蛋白成核活性(Janmey,P.A.,Iida,K.,Yin,H.L.& Stossel,T.P.(1987)JBiol Chem 262,12228-36)。
采用商品试剂盒(Stanbio,Boerne,TX),根据产品说明比色法测定白蛋白水平。
从器官中提取蛋白质
在用25mg/kg i.p.E.coli LPS攻击、或CLP后6小时后收集器官进行分析。源自未攻击小鼠的器官作为对照。每种器官在RIPA缓冲液(BostonBioproducts,Ashland,MA)中匀浆,缓冲液中补充以1∶100浓度的蛋白酶抑制剂混合物(Calbiochem,La Jolla,CA)和原钒酸钠(othovanadate),冰上放置30分钟后4℃ 2,000xg离心30分钟。去除上清液后,再次在4℃ 10,000xg离心30分钟。去除上清液,保存在-80℃待分析。
Western印迹分析
用DC蛋白质测定试剂盒(Bio-Rad,Hercules,CA)按照产品说明测定每个样本中的蛋白质浓度。10μg每种样品在SDS-样品缓冲液(BostonBioproducts)中在85℃加热3分钟,然后用12%Tris-甘氨酸凝胶(Invitrogen,Carlsbad,CA)经SDS-PAGE分析,并转移到PVDF膜上(Millipore,Bedford,MA)。在含5%脱脂奶粉的Tris-缓冲盐水(含0.05%Tween 20)中封闭过夜,以1∶1000的比例加入小鼠pGSN抗血清,然后以1∶2000比例用偶联HRP的抗兔IgG(Cell Signaling,Beverly,MA)进行检测。用LumiGLO(Cell Signaling,Beverly,MA)进行化学发光,对胶片曝光并显影。通过免疫兔子抗来源于小鼠pGSN血浆延长部分的肽用商业服务(Invitrogen,Carlsbad,CA)制备抗小鼠pGSN血清。用ELISA检验抗血清的特异性和敏感度,Western印迹显示其对仅小鼠pGSN是特异性的,而对胞质凝溶胶蛋白(cGSN)没有特异性(数据未显示)。
凝溶胶蛋白-LPS结合
所有的研究都是双份的。Microlite 2,白色96-孔平底板(DynexTechnologies,Chantilly,VA)的每个孔都用不同量的重组人pGSN或BSA包被,并在4℃温育过夜。在用PB缓冲液(145mM NaCl,5mM KCl,2mM MgCl2,3.5mM NaH2PO4,10mM葡萄糖,10mM Hepes,3mg/ml BSA,1mM CaCl2,pH7.4)冲洗4次后,每孔加入2μg Alexa488-标记的LPS(E.coli血清型055:B5,分子探针,Eugene,OR)和100μl PB缓冲液,在室温放置1个小时。在用PB缓冲液冲洗4次后,在荧光分光光度计上荧光分析每个孔,其中激发和发射波长分别为488和520nm。从标准曲线推算出Alexa488-LPS的结合量,所述标准曲线是通过包含不同量的Alexa488-LPS的PB缓冲液产生的。
LPS刺激单核细胞
人单核细胞系THP-1从美国典型培养物保藏中心(American TypeCulture Collection,Manassas,VA)购买。细胞在37℃维持于添加10%小牛血清和2%青霉素-链霉素(GIBCO)的RPMI(GIBCO,Grand Island,NY)中。在24-孔板的每孔中接种50,000个细胞,用或不用100ng E.coli LPS刺激,后用200μg/ml人重组pGSN或BSA处理。LPS后2小时,收集200μl培养基,在1000xg离心10分钟去除细胞。ELISA(R&D Systems,Minneapolis,MN)测定无细胞培养基中的TNF-α水平。
统计
数值表示为平均值±SD。非参数检验,斯皮尔曼等级相关性(SpearmanRank Correlation)用于分析剂量效应研究中的相关性。动物的死亡率表示为卡普兰-迈耶曲线,时序检验(log-rank test)用于分析处理作用对动物死亡率的影响。Mann-Whiney U检验用于评价细胞因子和pGSN水平之间的差异。小于0.05的P值被认为是显著的。
结果
接受LPS或CLP的小鼠中pGSN水平降低
图1A显示注射逐渐增加的非致死性剂量的假单胞菌属LPS导致小鼠中pGSN水平进行性降低,最大值在20mg/kg剂量(P<0.05)。血浆白蛋白水平并不随LPS处理而改变。类似地,CLP后小鼠中pGSN水平降低(P<0.05),而白蛋白水平增加(P=0.02)。这些数据显示脓毒症导致的全身炎症对pGSN有特异性影响。
补充pGSN提高脓毒症小鼠的存活率
E.coli LPS 25mg/kg剂量i.p.在注射7天内导致>90%的死亡率,存活的小鼠看起来完全康复,没有显示出任何不良的征候。如图2A所示,与那些用盐水(P<0.001)或BSA(P<0.001)处理的相比,在LPS攻击时施用外源pGSN显著提高了内毒素血症小鼠的存活率。图2B显示在CLP后接受pGSN的小鼠也比那些接受盐水的小鼠具有显著更好的存活率(P=0.001)。
施用外源pGSN有效提高内毒素血症小鼠中的pGSN水平
图3所示用致死剂量的E.coli LPS攻击小鼠中的pGSN水平。与仅造成pGSN降低10%的非致死性假单胞菌属LPS不同,致死剂量的E.coli LPS导致在LPS攻击后6小时内pGSN降低50%。皮下注射8mg重组pGSN成功地保持内毒素血症小鼠中的pGSN在正常范围或正常范围以上。
补充pGSN对内毒血症小鼠中细胞因子特征谱的影响
我们检验施用pGSN是否改变内毒素血症小鼠中的细胞因子特征谱。图4A显示在LPS刺激后6小时pGSN处理和盐水处理的内毒素血症小鼠中的血浆细胞因子特征谱没有差异(对显示的所有细胞因子P>0.05)。TFN-α水平接近基线,与公开的报道一致,小鼠中TFN-α在LPS攻击后2-3小时内达到峰值并开始降低(Villa,P.,Sartor,G.,Angelini,M.,Sironi,M.,Conni,M.,Gnocchi,P.,Isetta,A.M.,Grau,G.,Buurman,W.,van Tits,L. J.& et al.(1 995)Clin DiagnLab Immunol 2,549-53)。
然而LPS攻击后24小时,pGSN处理小鼠中的几种促炎症细胞因子水平显著降低(GM-CSF、IFN-γ、IL-1β),尽管IL-6和TNF-α的水平没有检测到差异(图4B)。另外,pGSN处理导致IL-10水平显著提高。pGSN显示并不直接刺激IL-10分泌,因为施用或不施用pGSN的未攻击小鼠中细胞因子特征谱没有显著差异;具体地,IL-10在pGSN处理的未攻击小鼠中没有增加(数据未示出)。
pGSN的组织分布
图6显示用小鼠pGSN抗血清对骨骼肌、心、肾、肝和肺的代表性Western印迹分析,这些组织在用或不用25mg/kg E.coli LPS处理小鼠后6小时收集。我们发现在正常和内毒素血症小鼠中肺中的pGSN浓度最高。因为肺在收集前用PBS灌注以去除血管内的血,血液污染不可能解释我们的结果。我们发现在接受CLP的小鼠中具有相似的pGSN组织分布(数据未示出)。
pGSN结膈LPS但不抑制LPS激活单核细胞
因为pGSN能结合生物活性脂类如溶血磷脂酸(Goetzl,E.J.,Lee,H.,Azuma,T.,Stossel,T.P.,Turck,C.W.& Karliner,J.S.(2000)J Biol Chem 275,14573-8),我们研究了pGSN也能结合LPS的可能性。图7显示pGSN特异性结合荧光LPS,而对照蛋白BSA表现出与LPS很小的亲合性。然而,pGSN似乎并不干扰LPS引起从人单核细胞分泌TFF-α的能力,因为用pGSN或BSA处理LPS刺激的THP-1细胞分泌相似量的TFF-α到细胞培养基中(图8)。
LPS攻击的TLR4-突变体小鼠中pGSN不受影响
为了检验LPS是否直接导致pGSN消耗,我们研究了C3H/HeJ小鼠中的pGSN水平,所述小鼠是一种表达突变体TLR4的品系,该突变使得小鼠对LPS诱导的炎症有抗性(Beutler,B.& Poltorak,A.(2001)Crit Care Med 29,S2-6;discussion S6-7)。图5显示pGSN水平在E coli LPS攻击和未攻击的C3H/HeJ小鼠中并没有显著差异。与其已知对LPS有抗性一致,C3H/HeJ小鼠在LPS攻击后也显示完全正常。
讨论
我们在此已经证实在内毒素或腹膜炎造成的脓毒性损伤后发生pGSN的显著消耗,外源pGSN能大大改善脓毒性小鼠的存活率。这些数据表明pGSN在脓毒症中具有重要的促存活作用。
pGSN是“肌动蛋白-清除剂”的假说是根源于细胞质凝溶胶蛋白(cGSN)的研究,其中一个报道证实灌注肌动蛋白分子到大鼠中可导致死亡。然而,pGSN可能并不是作为脓毒症中循环肌动蛋白的清除剂,因为并不知道早期脓毒症导致肌动蛋白释放,并且我们也未能证明内毒素血症小鼠的血浆中的凝溶胶蛋白-肌动蛋白复合物(未公开数据)。
我们研究了pGSN直接与LPS相互作用的可能性。尽管pGSN可结合LPS,我们发现没有证据证明pGSN干扰LPS在培养细胞中启动炎症的能力。尽管pGSN在LPS攻击后立即注射给小鼠,由于皮下给药路径,pGSN递送至循环系统中还有延迟。因此,pGSN作用不可能是通过直接干扰LPS,并且处理和未处理的内毒素血症小鼠中的早期细胞因子特征谱支持这个结论。pGSN结合LPS的能力有可能改变LPS诱导炎症反应中的晚期事件。我们的对照和pGSN处理小鼠中相似的早期阶段细胞因子特征谱也提示pGSN不可能通过干扰早期细胞因子信号传递特别是TNF-α而发挥功能,因为内毒素血症小鼠模型中的TNF-α抑制在LPS攻击后3-4小时内降低了血浆IL-1β和IL-6水平(Fong,Y.,Tracey,K.J.,Moldawer,L.L.,Hesse,D.G.,Manogue,K.B.,Kenney,J.S.,Lee,A.T.,Kuo,G.C.,Allison,A.C.,Lowry,S.F.&等,(1989)J Exp Med170,1627-33)。另一方面,LPS刺激后24时处理和未处理小鼠中细胞因子特征谱表明pGSN能使几种促炎症细胞因子降低达90%,而上调IL-10,IL-10被认为是一种在脓毒症和炎症中具有抗炎症作用的细胞因子(Moore,K.W,de WaalMalefyt,R.,Coffman,R.L.& O′Garra,A.(2001)Annu Rev Immunol 19,683-765)。因为致死剂量的LPS与持续增加的促炎症细胞因子相关,如IL-1β和IFN-γ(Joshi,V.D.,Kalvakolanu,D.V.,Hebel,J.R.,Hasday,J.D.& Cross,A.S.(2002)Infect Immun 70,6896-903),我们相信细胞因子特征谱转变是与pGSN促进炎症解除相一致。
Western印迹分析显示,与其他器官相比,肺具有最高浓度的pGSN,其可能是pGSN的主要来源。这与先前的研究形成对照,在先前的研究中用Northern印迹分析得出的结论认为骨骼肌是主要的pGSN来源(Kwiatkowski,D.J.,Mehl,R.,Izumo,S.,Nadal-Ginard,B.&Yin,H.L.(1988)J Biol Chem 263,8239-43)。这种矛盾可能是由于Northern印迹分析的有限的定量能力或者是mRNA表达不能代表蛋白酯生成。
LPS抗性小鼠中pGSN缺少改变提示pGSN消耗是在TLR4的LPS活化下游,需要启动炎症级联反应。然而,目前的研究未阐明脓毒症中pGSN消耗的机制。
自从20多年前发现凝溶胶蛋白,大多数的研究都注重于cGSN以及其与肌动蛋白的相互作用(Kwiatkowski,D.J.(1999)Curr Opin Cell Biol 11,103-8),而很少关注pGSN。我们的研究显示pGSN在全身性炎症中具有重要作用,施用pGSN能够改善脓毒症小鼠的存活率并促进细胞因子转变以解决炎症。
上述的书面说明被认为已足够使得本领域普通技术人员实施本发明。本发明也不限于所提供实施例的范围,因为实施例只是为了举例说明本发明的一个方面,其他功能性等同的实施方案也在本发明的范围内。除了在此描述和显示的那些以外,从前述说明书中对于本领域普通技术人员来说对本发明进行多种修饰也是显而易见的,这些修饰也在所附的权利要求范围内。本发明的好处和目的并不一定包含在本发明的每个实施方案中。
Claims (39)
1.凝溶胶蛋白在制备用于治疗具有感染或有发生感染风险的对象之药剂中的用途,其中:
向需要这样治疗的对象施用有效量的凝溶胶蛋白,以治疗该感染,其中所述感染是由革兰氏阳性菌、抗酸杆菌、螺旋体、放线菌、病毒、真菌、寄生虫、尿支原体属、支原体属、衣原体属、和肺囊虫属引起,
其中凝溶胶蛋白是血浆凝溶胶蛋白(pGSN)。
2.权利要求1的用途,其中所述对象另外没有适应症而要求凝溶胶蛋白治疗。
3.权利要求1的用途,其中革兰氏阳性菌选自:巴斯德氏菌属、葡萄球菌属、链球菌属、炭疽杆菌、棒杆菌属、类白喉菌属、利斯特氏菌属、丹毒丝菌属、和梭状芽孢杆菌属。
4.权利要求1的用途,其中抗酸杆菌是分支杆菌属。
5.权利要求1的用途,其中螺旋体选自:密螺旋体属、疏螺旋体属、和钩端螺旋体属。
6.权利要求1的用途,其中病毒选自:逆转录病毒、人免疫缺陷病毒、巨细胞病毒、小RNA病毒、脊髓灰质炎病毒、甲型肝炎病毒、肠病毒、柯萨奇病毒、鼻病毒、埃可病毒、Calciviruses、披膜病毒、马脑炎病毒、风疹病毒、黄病毒、登革热病毒、脑炎病毒、黄热病毒、冠状病毒、杆状病毒、水泡性口炎病毒、狂犬病毒、丝状病毒、埃博拉病毒、副粘病毒、副流感病毒、腮腺炎病毒、麻疹病毒、呼吸道合胞体病毒、正粘病毒、流感病毒、汉坦病毒、Bunga viruses、白蛉病毒、Nairo病毒、沙粒病毒、出血热病毒、呼肠孤病毒、环状病毒、轮状病毒、双RNA病毒、嗜肝DNA病毒、乙型肝炎病毒、细小病毒、乳多空病毒、乳头瘤病毒、多瘤病毒、腺病毒、疱疹病毒、水痘-带状疱疹病毒、痘病毒、天花病毒、痘苗病毒、虹彩病毒、非洲猪瘟病毒、丁型肝炎病毒、非甲非乙型肝炎病毒、丙型肝炎、诺瓦克病毒、星状病毒和未分类的病毒。
7.权利要求1的用途,其中真菌选自:隐球菌属、组织胞浆菌属、球孢子菌属、副球孢子菌属、芽生菌属、衣原体属、念珠菌属、孢子丝菌属、曲霉属和毛霉病的真菌。
8.权利要求1的用途,其中寄生虫选自:疟原虫属、弓形体属、巴贝虫属、利什曼原虫属、和锥虫属。
9.权利要求1的用途,其中所述药剂适于通过口服、舌下、含服、鼻内、静脉内、肌内、鞘内、腹膜内、皮下、皮内、局部、直肠、阴道、滑膜腔内、或玻璃体内施用。
10.权利要求1的用途,其中所述药剂适于在对象暴露于感染后施用。
11.权利要求1的用途,其中所述药剂适于在对象暴露于感染之前施用。
12.凝溶胶蛋白在制备用于治疗具有革兰氏阴性细菌感染或具有发生该感染风险的对象之药剂中的用途,其中:
所述药剂适于以有效量在暴露于感染后的时间向需要这样治疗的对象施用,以治疗革兰氏阴性细菌感染,
其中凝溶胶蛋白是血浆凝溶胶蛋白(pGSN)。
13.权利要求12的用途,其中革兰氏阴性菌感染是由以下引起:奈瑟氏菌属、布兰汉氏菌属、埃希氏菌属、肠杆菌属、变形菌属、假单胞菌属、克雷伯氏菌属、沙门氏菌属、志贺菌属、粘质沙雷氏菌属、不动杆菌属、嗜血杆菌属、布鲁氏杆菌属、耶尔森氏菌属、弗朗西丝氏菌属、巴斯德氏菌、霍乱弧菌类、黄杆菌属、假单胞菌属、弯曲杆菌属、拟杆菌属、梭形杆菌属、鞘杆菌属、链杆菌属、和军团杆菌属。
14.权利要求12的用途,其中对象另外没有适应症而要求凝溶胶蛋白治疗。
15.权利要求12的用途,其中凝溶胶蛋白适于通过口服、舌下、含服、鼻内、静脉内、肌内、鞘内、腹膜内、皮下、皮内、局部、直肠、阴道、滑膜腔内、或玻璃体内施用。
16.凝溶胶蛋白在制备用于治疗或预防对象中脂多糖内毒素(LPS)影响的药剂中的用途,其中:
所述药剂适于在LPS暴露后的时间向对象施用,以保护对象免于LPS的影响,
其中凝溶胶蛋白是血浆凝溶胶蛋白(pGSN)。
17.权利要求16的用途,其中对象另外没有适应症而要求凝溶胶蛋白治疗。
18.凝溶胶蛋白在制备用于治疗或预防暴露于脂多糖内毒素(LPS)的对象中革兰氏阴性细菌脓毒症休克的药剂中的用途。
19.权利要求18的用途,其中对象另外没有适应症而要求凝溶胶蛋白治疗。
20.权利要求18的用途,其中凝溶胶蛋白是血浆凝溶胶蛋白(pGSN)。
21.凝溶胶蛋白在制备上调对象中白介素(IL)表达的药剂中的用途,其中凝溶胶蛋白是血浆凝溶胶蛋白(pGSN)。
22.权利要求21的用途,其中IL是IL-10。
23.权利要求21的用途,其中对象另外没有适应症而要求凝溶胶蛋白治疗。
24.一种体外上调白介素(IL)表达的方法,包括:
将能表达IL的细胞与有效量的凝溶胶蛋白接触以上调细胞中白介素(IL)的表达,其中凝溶胶蛋白是血浆凝溶胶蛋白(pGSN)。
25.权利要求24的方法,其中的IL是IL-10。
26.权利要求24的方法,其中对象另外没有适应症而要求凝溶胶蛋白治疗。
27.凝溶胶蛋白在制备下调对象中促炎症细胞因子表达的药剂中的用途,其中凝溶胶蛋白是血浆凝溶胶蛋白(pGSN)。
28.权利要求27的用途,其中对象另外没有适应症而要求凝溶胶蛋白治疗。
29.权利要求27的用途,其中促炎症细胞因子是IL-1β。
30.权利要求27的用途,其中促炎症细胞因子是IFN-α。
31.一种体外下调促炎症细胞因子表达的方法,包括:
将能表达促炎症细胞因子的细胞与有效量的凝溶胶蛋白接触以下调细胞中促炎症细胞因子的表达,其中凝溶胶蛋白是血浆凝溶胶蛋白(pGSN)。
32.权利要求31的方法,其中促炎症细胞因子是IL-1β。
33.权利要求31的方法,其中促炎症细胞因子是IFN-α。
34.权利要求31的方法,其中对象另外没有适应症而要求凝溶胶蛋白治疗。
35.凝溶胶蛋白在制备用于治疗对象以减少感染风险的药剂中的用途,其中:
在已知对象具有低于正常水平的凝溶胶蛋白基础上选择对象,其中凝溶胶蛋白是血浆凝溶胶蛋白(pGSN)。
36.权利要求35的用途,其中对象另外没有适应症而要求凝溶胶蛋白治疗。
37.权利要求35的用途,其中对象是看起来健康的。
38.权利要求35的用途,其中感染是由细菌、病毒、真菌或寄生虫引起的。
39.权利要求35的用途,其中抗感染剂是抗细菌剂、抗病毒剂、抗真菌剂、或抗寄生虫剂。
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