CN105307648A - 去甲二氢愈创木酸和氨基糖苷的组合 - Google Patents
去甲二氢愈创木酸和氨基糖苷的组合 Download PDFInfo
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- CN105307648A CN105307648A CN201480024915.4A CN201480024915A CN105307648A CN 105307648 A CN105307648 A CN 105307648A CN 201480024915 A CN201480024915 A CN 201480024915A CN 105307648 A CN105307648 A CN 105307648A
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Abstract
本发明涉及去甲二氢愈创木酸和氨基糖苷类的组合在治疗微生物感染或杀灭微生物感染相关的临床上潜隐的微生物中的用途。
Description
本发明涉及去甲二氢愈创木酸(下称NDGA)作为氨基糖苷类例如庆大霉素的抗细菌活性增强剂的用途。
在引入抗生素之前,患有急性微生物感染(例如结核病或肺炎)的患者生存机会低。例如,结核病的死亡率大约为50%。尽管在1940年代和1950年代抗微生物剂的引入快速改变了这种情况,但是细菌通过对常用抗生素累进地产生耐药性而作出应对。目前,全球每个国家都有抗生素耐药性细菌。的确,在美国超过70%的导致医院获得性感染的细菌耐受至少一种通常用于对抗感染的主要抗微生物剂(Nature Reviews, Drug Discovery, 1, 895-910 (2002))。
解决耐药性细菌不断增加的问题的一种方式是开发新型抗微生物剂。然而,直至2000年引入利奈唑胺时,在37年间里都没有新型抗生素面世。此外,甚至新型抗生素的开发仅提供临时解决方案,并且的确已有某些细菌对利奈唑胺耐药的报告(Lancet, 357, 1179 (2001)和Lancet, 358, 207-208 (2001))。
为了开发针对细菌耐药性问题的更长久的解决方案,显然需要替代方法。一种这类替代方法是尽可能减少细菌发展出对重要抗生素的耐药性的机会。因此,可以采取的策略包括限制用于非急性感染治疗的抗生素,以及控制为促进生长将抗生素饲喂动物。
然而,为了更有效解决该问题,需要了解细菌对抗生素药剂产生耐药性的实际机制。为做到这一点首先考虑现有抗生素药剂是如何发挥作用杀伤细菌的。
抗微生物剂靶向细菌代谢的必要组分。例如,β-内酰胺类(例如,青霉素类和头孢菌素类)抑制细胞壁合成,而其它药剂抑制不同范围的靶标,例如DNA旋转酶(喹诺酮类)和蛋白质合成(例如,大环内酯类、氨基糖苷类、四环素类和噁唑烷酮类)。抗微生物剂所抗生物体的范围是很不同的,取决于哪种生物体高度依赖于被抑制的代谢步骤。此外,对细菌的作用可以不同,从仅仅是生长抑制(即抑菌效应,正如用诸如四环素类药剂所示)到完全杀灭(即杀菌效应,正如用青霉素所示)。
细菌在地球上已经生存超过30亿年,并且,在这段时间内,需要应对大量的环境压力。因此也许毫不奇怪的是,细菌已经发展出看似无穷无尽的多种机制,藉此它们可以响应由抗生素药剂强加于它们的代谢压力。的确,细菌可以通过其产生耐药性的机制包括以下多种策略:药物失活,作用位点的改变,细胞壁渗透性的改变,目标酶的过量产生,以及被抑制步骤的绕行旁路。然而,已经观察到对具体药剂而出现的耐药率变化很广,其取决于例如以下因素:药剂的作用机制(无论该药剂的杀伤模式是否是时间依赖性的还是浓度依赖性的),抗细菌群体的效力,以及可用的血清浓度的量和持续时间。
已经提出(Science,264, 388-393 (1994))靶向单一酶的药剂(例如,利福平)最易于发展出耐药性。此外,非最适宜水平(suboptimal level)的抗微生物剂与细菌接触得越长,越可能出现耐药性。
此外,现在已知许多微生物感染包括在表型上耐受抗微生物剂的细菌亚群(J. Antimicrob. Chemother.,
4, 395-404 (1988);J. Med. Microbiol., 38, 197-202 (1993);J.
Bacteriol., 182,
1794-1801 (2000);如上182,
6358-6365 (2000);如上183,
6746-6751 (2001);FEMS Microbiol. Lett., 202, 59-65 (2001);和Trends
in Microbiology, 13,
34-40 (2005))。似乎存在若干类型的这类表型上耐药的细菌,包括耐药株、稳定期细菌,以及在生物膜深处的那些。然而,这些类型的每一种的特征在于其低的生长率,相比在相同条件下的对数期细菌而言。营养饥饿和高细胞密度也是这类细菌的普遍特征。
尽管在它们的低生长状态中对抗微生物剂具有耐受性,但表型上耐药性细菌不同于基因型上耐药的那些,因为当它们返回快速生长状态(例如,当它们更容易得到营养物)时,它们重获对抗微生物剂的易感性。
在感染中表型上耐药性细菌的存在导致了对延长抗微生物剂疗程的需要,所述抗微生物剂疗程包括多剂量。这是因为耐药性的、缓慢繁殖的细菌提供了“潜隐的”生物体的贮库,其在条件允许时可转化为快速生长状态(从而有效地重新启动感染)。随时间给予的多剂量通过逐步杀灭转化为“活性”形式的“潜隐的”细菌而解决该问题。
然而,通过给予延长疗程的抗微生物剂来对付“潜隐的”细菌造成其自身问题。也就是说,延长细菌暴露给非最适宜浓度的抗微生物剂可导致基因型上耐药性细菌的出现,该菌随后甚至在高浓度抗微生物剂存在下可快速繁殖。
由于非繁殖的细菌将趋于存活,并且,有趣的是,很可能具有增强的突变为耐药性的能力,与较短的疗程相比抗微生物剂的长疗程更可能促进基因型上耐药性的出现(Proc. Natl. Acad. Sci. USA,
92, 11736-11740 (1995);J. Bacteriol., 179, 6688-6691 (1997);和Antimicrob.
Agents Chemother., 44, 1771-1777 (2000))。
根据上述,对抗细菌耐药性问题的新方法可以是基于其杀灭“潜隐的”微生物的能力选择并开发抗微生物剂。这类药剂的产生除此之外将允许缩短微生物感染治疗中的化疗方案,因而降低了在微生物中产生基因型耐药性的频率。
去甲二氢愈创木酸(NDGA)是天然存在的木质素,已知其具有作为抗菌剂(Clinical Microbiology Reviews 第12卷,第4期,564–582), 抗病毒剂(Huang
R等人,Antiviral Research 58 (2003) 57–64)和抗癌剂(Toyoda
T等人,Cancer Sci 2007 第98卷,第11期,1689–1695)的活性。也已显示出具有抗氧化活性并被证明能够增强两性霉素B抗酵母病原体的效果(Begg R等人,Antimicrobial Agents and Chemotherapy, 1978年2月, 第266-270页)。NDGA可得自商业来源,例如Sigma
Aldrich (www.sigmaaldrich.com)。
最近,已有报告称抗逆转录病毒药物齐多夫定在与庆大霉素组合时作为抗微生物剂具有活性。因此,Doléans-Jordheim A.等人, 公开了(Eur J
Clin Microbiol Infect Dis. 2011 Oct;30(10):1249-56)齐多夫定(AZT)对一些肠细菌具有杀菌效应,但能诱导大肠杆菌抗药性。这些耐药性与胸苷激酶基因中的多个修饰有关。此外,观察到了AZT与两种氨基糖苷类抗生素阿米卡星和庆大霉素之间的抗肠细菌的累加活性或协同活性。
考虑到氨基糖苷类在抗细菌感染的对抗中的重要性,鉴定能够增加其抗细菌活性的更多药剂的提出了重要需求。
发明概述
因此,在本发明的一个实施方案中提供了去甲二氢愈创木酸和选自以下的氨基糖苷类的组合在治疗微生物感染中的用途:庆大霉素、阿米卡星、奈替米星、新霉素、链霉素、妥布霉素、氨肽酶抑制剂、布替罗星、布替罗星A、柔红霉素、地贝卡星、二氢链霉素、G418、潮霉素B、卡那霉素B、卡那霉素、黄色霉素、巴龙霉素、核糖霉素、西索米星、壮观霉素、链佐星和硫链丝菌素。
在本发明的另外的实施方案中提供了用于治疗微生物感染的药物组合物,其包含去甲二氢愈创木酸和选自以下的氨基糖苷类:庆大霉素、阿米卡星、奈替米星、新霉素、链霉素、妥布霉素、氨肽酶抑制剂、布替罗星、布替罗星A、柔红霉素、地贝卡星、二氢链霉素、G418、潮霉素B、卡那霉素B、卡那霉素、黄色霉素、巴龙霉素、核糖霉素、西索米星、壮观霉素、链佐星和硫链丝菌素。
本发明也基于意想不到的发现:与每种单独给予时相比,本文所述的组合的活性被实质上改善了。此外,所述组合意想不到地显示出抗对数期(即繁殖的)和/或临床上潜隐的微生物的协同的抗微生物活性。本发明的组合的意想不到的生物活性提供了缩短化学疗法方案的机会并且可导致与使用这类抗细菌剂相关的微生物耐药性出现的减少。
在另一个实施方案中,本发明提供了去甲二氢愈创木酸和选自以下的氨基糖苷类在制备用于治疗微生物感染,优选杀灭微生物感染相关的临床上潜隐的微生物的药物中的用途:庆大霉素、阿米卡星、奈替米星、新霉素、链霉素、妥布霉素、氨肽酶抑制剂、布替罗星、布替罗星A、柔红霉素、地贝卡星、二氢链霉素、G418、潮霉素B、卡那霉素B、卡那霉素、黄色霉素、巴龙霉素、核糖霉素、西索米星、壮观霉素、链佐星和硫链丝菌素。
在另外的实施方案中,本发明提供了治疗微生物感染,优选杀灭微生物感染相关的临床上潜隐的微生物的方法,其包括将去甲二氢愈创木酸和选自以下的氨基糖苷类给予包括人在内的哺乳动物:庆大霉素、阿米卡星、奈替米星、新霉素、链霉素、妥布霉素、氨肽酶抑制剂、布替罗星、布替罗星A、柔红霉素、地贝卡星、二氢链霉素、G418、潮霉素B、卡那霉素B、卡那霉素、黄色霉素、巴龙霉素、核糖霉素、西索米星、壮观霉素、链佐星和硫链丝菌素。
如本文使用的,术语“与...组合”包含了分别和序贯给予NDGA和氨基糖苷类。当序贯给予药剂时,可以首先给予NDGA或氨基糖苷类。当同时给予时,可以在相同或不同药物组合物中给予药剂。辅助治疗,即其中一种药剂用作主要治疗和另一药剂用于辅助该主要治疗,也是本发明的一个实施方案。
根据本发明的另外的实施方案,提供了包含NDGA和以上定义的氨基糖苷类的制品,作为同时、分别或序贯用于治疗微生物感染的组合制剂。
附图简述
图 1-4使用时间杀灭曲线,显示当分别和组合给予时,不同剂量的NDGA与庆大霉素组合抗对数期金黄色葡萄球菌(Stapylococcus aureus)的效果。
图 5a 和 5b显示不同剂量的NDGA与庆大霉素组合抗对数期甲氧西林(图5a)或庆大霉素(图5b)耐药性金黄色葡萄球菌的效果。
图 6通过时间杀灭显示当分别和组合给予时,NDGA、新霉素和这两种药物组合抗对数期金黄色葡萄球菌的效果。
优选的实施方案的描述
也提供了药物组合物,其包含NDGA和如上定义的氨基糖苷类的药物组合物,以及药学上可接受的佐剂、稀释剂或载体。这样的组合物可用于治疗微生物感染,尤其是用于治疗微生物感染,优选杀灭这类感染相关的临床上潜隐的微生物。
本发明的组合可用于治疗微生物感染。尤其是它们可用于杀灭微生物感染相关的繁殖的和/或临床上潜隐的微生物。本文提及微生物感染的治疗因此包括杀灭这类感染相关的繁殖的和/或临床上潜隐的微生物。优选地,本发明的组合用于杀灭微生物感染相关的临床上潜隐的微生物。
在所述的每个实施方案中,所述氨基糖苷类选自庆大霉素、阿米卡星、奈替米星、新霉素、链霉素、妥布霉素、氨肽酶抑制剂、布替罗星、布替罗星A、柔红霉素、地贝卡星、二氢链霉素、G418、潮霉素B、卡那霉素B、卡那霉素、黄色霉素、巴龙霉素、核糖霉素、西索米星、壮观霉素、链佐星和硫链丝菌素,最优选庆大霉素、新霉素或妥布霉素。
如本文使用的,“杀灭”是指通过代谢活性缺乏而评价的生活力的损失。
如本文使用的,“临床上潜隐的微生物”是指代谢上有活性,但生长率低于感染性疾病表达的阈值的微生物。感染性疾病表达的阈值是指这样的生长率阈值:低于该阈值时在宿主中缺乏感染性疾病的症状。
可通过本领域技术人员已知的若干方法,例如通过测量微生物中的mRNA水平或通过确定其尿苷摄取速率,来确定临床上潜隐的微生物的代谢活性。在这一方面,临床上潜隐的微生物,当与处于对数生长条件下的微生物相比时(体外或体内),具有减少的但仍然是显著水平的:
(Ⅰ)mRNA (例如,0.0001至50%,例如1至30、5至25或10至20%的水平的mRNA);和/或
(Ⅱ)尿苷(例如,[3H]尿苷)摄取(例如,0.0005至50%,例如1至40、15至35或20至30%的水平的[3H]尿苷摄取)。
临床上潜隐的微生物典型地具有许多可鉴定的特征。例如,它们可以是有生活力的,但非可培养的;即它们通常不能通过标准培养技术而检测到,但可通过诸如肉汤稀释计数、显微镜术等技术或诸如聚合酶链式反应等分子技术而检测和定量。另外,临床上潜隐的微生物是表型上耐药性的,如此对于常规抗微生物剂的生物静力学效应(biostatic effects)是敏感的(在对数期)(即常规抗微生物剂对微生物的最小抑制浓度(MIC)基本不变);但对于药物诱导的杀灭而言具有急剧地降低的易感性(例如,任何给定的常规抗微生物剂对微生物的最小杀微生物浓度(例如,最小杀菌浓度,MBC)与MIC的比例为10或更高)。
如本文使用的,术语“微生物”是指真菌和细菌。本文提及的“微生物”、“抗微生物的”和“抗微生物地”应作相应地解读。例如,术语“微生物”是指真菌或细菌,而“微生物感染”是指任何真菌或细菌感染。
如本文使用的,术语“细菌”(及其衍生词,例如“微生物感染”)包括但不限于对以下类型和具体种类的生物体(或由生物体所致的感染)的提及:
革兰氏阳性球菌,例如葡萄球菌(Staphylococci)(例如,金黄色葡萄球菌(Staph.
aureus)、表皮葡萄球菌(Staph. epidermidis)、腐生葡萄球菌(Staph.
saprophyticus)、耳葡萄球菌(Staph. auricularis)、头状葡萄球菌头状亚种(Staph. capitis capitis)、头状葡萄球菌解脲亚种(Staph. c.
ureolyticus)、山羊葡萄球菌(Staph. caprae)、科氏葡萄球菌(Staph. cohnii cohnii)、头状葡萄球菌解脲亚种(Staph. c.
urealyticus)、马胃葡萄球菌(Staph. equorum)、鸡葡萄球菌(Staph. gallinarum)、出血性葡萄球菌(Staph. haemolyticus)、人葡萄球菌人亚种(Staph. hominis hominis)、人葡萄球菌抗新霉素败血症亚种(Staph. h.
novobiosepticius)、猪葡萄球菌(Staph. hyicus)、中间葡萄球菌(Staph. intermedius)、路邓葡萄球菌(Staph. lugdunensis)、巴氏葡萄球菌(Staph. pasteuri)、解糖葡萄球菌(Staph. saccharolyticus)、施氏葡萄球菌施氏亚种(Staph. schleiferi schleiferi)、施氏葡萄球菌凝聚亚种(Staph. s. coagulans)、松鼠葡萄球菌(Staph. sciuri)、模仿葡萄球菌(Staph. simulans)、沃氏葡萄球菌(Staph. warneri)和木糖葡萄球菌(Staph. xylosus);
链球菌(Streptococci)(例如β-溶血性、酿脓链球菌(例如无乳链球菌(Strept. agalactiae)、狗链球菌(Strept. canis)、停乳链球菌停乳亚种(Strept. dysgalactiae dysgalactiae)、停乳链球菌似马亚种(Strept. dysgalactiae
equisimilis)、马链球菌马亚种(Strept. equi equi)、马链球菌兽瘟亚种(Strept. equi zooepidemicus)、海豚链球菌(Strept. iniae)、豕链球菌(Strept. porcinus)和酿脓链球菌(Strept. pyogenes)),微需氧的、酿脓链球菌(“米氏”链球菌(Streptococcus
“milleri”)),例如咽峡炎链球菌(Strept. anginosus)、星群链球菌星群亚种(Strept. constellatus
constellatus)、星群链球菌咽炎亚种(Strept. constellatus
pharyngidis)和中间链球菌(Strept. intermedius)),“缓症”(“mitis”)口腔链球菌(α-溶血性-“绿色”链球菌(Streptococcus
“viridans”),例如缓症链球菌(Strept. mitis)、口腔链球菌(Strept. oralis)、血链球菌(Strept. sanguinis)、嵴链球菌(Strept. cristatus)、格氏链球菌(Strept. gordonii)和副血链球菌(Strept. parasanguinis),“唾液”(“salivarius”) (非溶血性,例如唾液链球菌(Strept. salivarius)和前庭链球菌(Strept. vestibularis)和“变异”(“mutans” )(牙齿表面链球菌,例如仓鼠链球菌(Strept. criceti))、变异链球菌(Strept. mutans)、鼠链球菌(Strept. ratti)和表兄链球菌(Strept. sobrinus))组、少酸链球菌(Strept. acidominimus)、牛链球菌(Strept. bovis)、粪链球菌(Strept. faecalis)、马肠链球菌(Strept. equinus)、肺炎链球菌(Strept. pneumoniae)和猪链球菌(Strept. suis),或另外分类为A、B、C、D、E、G、L、P、U或V组链球菌的链球菌);
革兰氏阴性球菌,例如淋病奈氏球菌(Neisseria gonorrhoeae)、脑膜炎奈氏球菌(Neisseria
meningitidis)、灰色奈氏球菌(Neisseria cinerea)、长奈氏球菌(Neisseria
elongata)、浅黄奈氏球菌(Neisseria flavescens)、乳糖奈氏球菌(Neisseria
lactamica)、粘液奈氏球菌(Neisseria mucosa)、干燥奈氏球菌(Neisseria
sicca)、微黄奈氏球菌(Neisseria subflava)和编织奈氏球菌(Neisseria
weaveri);
芽孢杆菌科(Bacillaceae),例如炭疽芽孢杆菌(Bacillus
anthracis)、枯草芽孢杆菌(Bacillus subtilis)、苏云金芽孢杆菌(Bacillus
thuringiensis)、嗜热脂肪芽孢杆菌(Bacillus
stearothermophilus)和蜡状芽胞杆菌(Bacillus cereus);
肠杆菌科(Enterobacteriaceae),例如大肠杆菌(Escherichia coli) ,肠杆菌(例如,产气肠杆菌(Enterobacter
aerogenes)、聚团肠杆菌(Enterobacter agglomerans)和阴沟肠杆菌(Enterobacter
cloacae),柠檬酸杆菌(Citrobacter)(例如弗氏柠檬酸杆菌(Citrob. freundii)和差异柠檬酸杆菌(Citrob.
divernis)),哈夫尼菌(Hafnia)(例如蜂房哈夫尼菌(Hafnia
alvei)、欧文氏菌(Erwinia)(例如,桃色欧文氏菌(Erwinia
persicinus))、摩氏摩根氏菌(Morganella morganii),沙门氏菌(Salmonella)(肠沙门氏菌(Salmonella
enterica)和伤寒沙门氏菌(Salmonella typhi)),志贺氏菌(Shigella)(例如,痢疾志贺氏菌(Shigella dysenteriae)、弗氏志贺氏菌(Shigella
flexneri)、鲍氏志贺氏菌(Shigella boydii)和宋内志贺氏菌(Shigella sonnei)),克雷伯氏菌(Klebsiella)(例如,肺炎克雷伯氏菌(Klebs.
pneumoniae)、产酸克雷伯氏菌(Klebs. oxytoca)、解鸟氨酸克雷伯氏菌(Klebs. ornitholytica)、植生克雷伯氏菌(Klebs. planticola)、臭鼻克雷伯氏菌(Klebs. ozaenae)、土生克雷伯氏菌(Klebs. terrigena)、肉芽肿克雷伯氏菌(Klebs. Granulomatis)(肉芽肿鞘杆菌(Calymmatobacterium
granulomatis))和鼻硬结克雷伯氏菌((Klebs. rhinoscleromatis)),变形杆菌(Proteus)(例如,奇异变形杆菌(Pr. mirabilis)、雷氏变形杆菌(Pr. rettgeri)和普通变形杆菌(Pr. vulgaris))、普罗威登斯菌(Providencia)(例如,产碱普罗威登斯菌(Providencia alcalifaciens)、雷氏普罗威登斯菌(Providencia rettgeri )和斯氏普罗威登斯菌(Providencia stuartii),沙雷氏菌(Serratia)(例如,粘质沙雷氏菌(Serratia
marcescens)和液化沙雷氏菌(Serratia liquifaciens),和耶尔森菌(Yersinia)(例如,小肠结肠炎耶尔森菌(Yersinia enterocolitica)、鼠疫耶尔森菌(Yersinia
pestis)和假结核耶尔森菌(Yersinia pseudotuberculosis);
肠球菌(Enterococci)(例如,鸟肠球菌(Enterococcus avium)、铅黄肠球菌(Enterococcus
casseliflavus)、盲肠肠球菌(Enterococcus
cecorum)、殊异肠球菌(Enterococcus dispar)、耐久肠球菌(Enterococcus
durans)、粪肠球菌(Enterococcus faecalis)、屎肠球菌(Enterococcus
faecium)、黄色肠球菌(Enterococcus flavescens)、鹑鸡肠球菌(Enterococcus
gallinarum)、海氏肠球菌(Enterococcus hirae)、病臭肠球菌(Enterococcus
malodoratus)、蒙氏肠球菌(Enterococcus mundtii)、类鸟肠球菌(Enterococcus
pseudoavium)、棉子糖肠球菌(Enterococcus raffinosus)和孤立肠球菌(Enterococcus
solitarius);
螺杆菌(Helicobacter)(例如,幽门螺杆菌(Helicobacter
pylori)、同性恋螺杆菌(Helicobacter cinaedi)和芬纳尔螺杆菌(Helicobacter
fennelliae));
不动杆菌(例如,鲍氏不动杆菌(A. baumanii)、乙酸钙不动杆菌(A.
calcoaceticus)、溶血不动杆菌(A. haemolyticus)、约氏不动杆菌(A. johnsonii)、琼氏不动杆菌(A.
junii)、鲁氏不动杆菌(A. lwoffi)和抗辐射不动杆菌(A. radioresistens);
假单胞菌(Pseudomonas)(例如,铜绿假单胞菌(Ps.
aeruginosa)、嗜麦芽假单胞菌(Ps. Maltophilia)嗜麦芽糖寡养单胞菌(Stenotrophomonas maltophilia))、产碱假单胞菌(Ps.
alcaligenes)、绿针假单胞菌(Ps. chlororaphis)、荧光假单胞菌(Ps.
fluorescens)、浅黄假单胞菌(Ps. luteola)、门多萨假单胞菌(Ps. mendocina)、蒙氏假单胞菌(Ps.
monteilii)、栖稻假单胞菌(Ps. oryzihabitans)、穿孔素假单胞菌(Ps.
pertocinogena)、类产碱假单胞菌(Ps. pseudalcaligenes)、恶臭假单胞菌(Ps.
putida)和施氏假单胞菌(Ps. stutzeri);
脆弱类杆菌(Bacteriodes
fragilis);
消化球菌(Peptococcus)(例如,黑色消化球菌(Peptococcus
niger));
消化链球菌(Peptostreptococcus);
梭菌(Clostridium)(例如,产气荚膜梭菌(C.
perfringens)、艰难梭菌(C. difficile)、肉毒梭菌(C. botulinum)、破伤风梭菌(C.
tetani)、不同梭菌(C. absonum)、阿根廷梭菌(C. argentinense)、巴氏梭菌(C.
baratii)、双酶梭菌(C. bifermentans)、拜氏梭菌(C. beijerinckii)、丁酸梭菌(C.
butyricum)、尸毒梭菌(C. cadaveris)、肉梭菌(C. carnis)、隐藏梭菌(C.
celatum)、梭状梭菌(C. clostridioforme)、匙形梭菌(C.
cochlearium)、耳蜗形梭菌(C. cocleatum)、谲诈梭菌(C. fallax)、戈氏梭菌(C.
ghonii)、乙二醇梭菌(C. glycolicum)、溶血梭菌(C. haemolyticum)、矛形梭菌(C.
hastiforme)、溶组织梭菌(C. histolyticum)、吲哚梭菌(C. indolis)、无害梭菌(C.
innocuum)、不规则梭菌(C. irregulare)、柔嫩梭菌 (C. leptum)、泥渣梭菌(C.
limosum)、坏名梭菌(C. malenominatum)、诺氏梭菌(C.
novyi)、乳清酸梭菌(C. oroticum)、类腐败梭菌(C. paraputrificum)、毛状梭菌(C.
piliforme)、腐化梭菌(C. putrefasciens)、多枝梭菌(C.
ramosum)、败毒梭菌(C. septicum)、索氏梭菌(C. sordelii)、楔形梭菌(C.
sphenoides)、生孢梭菌(C. sporogenes)、近端梭菌(C. subterminale)、共生梭菌(C.
symbiosum)和第三梭菌(C. tertium);
支原体(Mycoplasma)(例如,肺炎支原体(M. pneumoniae) 、人型支原体(M.
hominis)、生殖器支原体(M. genitalium)和解脲支原体(M.
urealyticum);
分枝杆菌(Mycobacteria)(例如,结核分枝杆菌(Mycobacterium tuberculosis)、鸟分枝杆菌(Mycobacterium
avium)、偶发分枝杆菌(Mycobacterium fortuitum)、海洋分枝杆菌(Mycobacterium
marinum)、堪萨斯分枝杆菌(Mycobacterium kansasii)、龟分枝杆菌(Mycobacterium
chelonae)、脓肿分枝杆菌(Mycobacterium abscessus)、麻风分枝杆菌(Mycobacterium
leprae)、耻垢分枝杆菌(Mycobacterium smegmitis)、非洲分枝杆菌(Mycobacterium africanum)、蜂房分枝杆菌(Mycobacterium alvei)、亚洲分枝杆菌(Mycobacterium asiaticum)、金色分枝杆菌(Mycobacterium aurum)、(Mycobacterium bohemicum)、牛分枝杆菌(Mycobacterium bovis)、(Mycobacterium branderi)、冬天分枝杆菌(Mycobacterium brumae)、隐藏分枝杆菌(Mycobacterium celatum)、楚布分枝杆菌(Mycobacterium chubense)、汇合分枝杆菌(Mycobacterium confluentis)、(Mycobacterium conspicuum)、库氏分枝杆菌(Mycobacterium cookii)、微黄分枝杆菌(Mycobacterium flavescens)、加地斯分枝杆菌(Mycobacterium gadium)、胃分枝杆菌(Mycobacterium gastri)、日内瓦分枝杆菌(Mycobacterium genavense)、戈登分枝杆菌(Mycobacterium gordonae)、古德氏分枝杆菌(Mycobacterium goodii)、嗜血分枝杆菌(Mycobacterium haemophilum)、(Mycobacterium hassicum)、胞内分枝杆菌(Mycobacterium intracellulare)、中间分枝杆菌(Mycobacterium interjectum)、海得堡分枝杆菌(Mycobacterium heidelberense)、慢生黄分枝杆菌(Mycobacterium lentiflavum)、玛尔摩分枝杆菌(Mycobacterium malmoense)、微分枝杆菌(Mycobacterium microgenicum)、田鼠分枝杆菌(Mycobacterium microti)、产粘液分枝杆菌(Mycobacterium mucogenicum)、新金色分枝杆菌(Mycobacterium neoaurum)、无色分枝杆菌(Mycobacterium nonchromogenicum)、外来分枝杆菌(Mycobacterium peregrinum)、草分枝杆菌(Mycobacterium phlei)、瘰疬分枝杆菌(Mycobacterium scrofulaceum)、石氏分枝杆菌(Mycobacterium shimoidei)、猿分枝杆菌(Mycobacterium simiae)、斯氏分枝杆菌(Mycobacterium szulgai)、土分枝杆菌(Mycobacterium terrae)、抗热分枝杆菌(Mycobacterium thermoresistabile)、三重分枝杆菌(Mycobacterium triplex)、次要分枝杆菌(Mycobacterium triviale)、托斯卡分枝杆菌(Mycobacterium tusciae)、溃疡分枝杆菌(Mycobacterium ulcerans)、母牛分枝杆菌(Mycobacterium vaccae)、沃林斯基分枝杆菌(Mycobacterium wolinskyi)和蟾分枝杆菌(Mycobacterium xenopi);
嗜血菌(Haemophilus)(例如,流感嗜血菌(Haemophilus influenzae)、杜氏嗜血菌(Haemophilus
ducreyi)、埃及嗜血菌(Haemophilus aegyptius)、副流感嗜血菌(Haemophilus
parainfluenzae)、溶血嗜血菌(Haemophilus haemolyticus)和副溶血嗜血菌(Haemophilus
parahaemolyticus);
放线杆菌(Actinobacillus)(例如,伴放线放线杆菌(Actinobacillus
actinomycetemcomitans)、马驹放线杆菌(Actinobacillus equuli)、人放线杆菌(Actinobacillus
hominis)、李氏放线杆菌(Actinobacillus lignieresii)、猪放线杆菌(Actinobacillus
suis)和脲放线杆菌(Actinobacillus ureae);
放线菌(Actinomyces)(例如,衣氏放线菌(Actinomyces
israelii));
布鲁氏菌(Brucella)(例如,流产布鲁氏菌(Brucella abortus)、犬布鲁氏菌(Brucella
canis)、马尔他布鲁氏菌(Brucella melintensis)和猪布鲁氏菌(Brucella suis);
弯曲杆菌(Campylobacter)(例如,空肠弯曲杆菌(Campylobacter
jejuni)、大肠弯曲杆菌(Campylobacter coli)、红嘴鸥弯曲杆菌(Campylobacter
lari)和胚胎弯曲杆菌(Campylobacter
fetus);
单核细胞增生利斯特氏菌(Listeria monocytogenes);
弧菌(Vibrio)(例如,霍乱弧菌(Vibrio
cholerae)和副溶血弧菌(Vibrio parahaemolyticus)、解藻朊酸弧菌(Vibrio alginolyticus)、鲨鱼弧菌(Vibrio carchariae)、河流弧菌(Vibrio fluvialis)、弗氏弧菌(Vibrio furnissii)、霍氏弧菌(Vibrio hollisae)、梅氏弧菌(Vibrio metschnikovii)、最小弧菌(Vibrio mimicus)和创伤弧菌(Vibrio vulnificus);
猪红斑丹毒丝菌(Erysipelothrix rhusopathiae);
棒杆菌科(Corynebacteriaceae)(例如,白喉棒杆菌(Corynebacterium
diphtheriae)、杰氏棒杆菌(Corynebacterium jeikeum)和解脲棒杆菌(Corynebacterium
urealyticum);
螺旋体科(Spirochaetaceae),例如疏螺旋体(Borrelia)(例如,回归热疏螺旋体(Borrelia
recurrentis)、布氏疏螺旋体(Borrelia burgdorferi)、阿氏疏螺旋体(Borrelia afzelii)、安德森疏螺旋体(Borrelia andersonii)、比赛蒂疏螺旋体(Borrelia bissettii)、嘎氏疏螺旋体(Borrelia garinii)、日本疏螺旋体(Borrelia japonica)、卢西塔尼亚疏螺旋体(Borrelia lusitaniae)、坦尼基疏螺旋体(Borrelia tanukii)、土德疏螺旋体(Borrelia turdi)、法雷斯疏螺旋体(Borrelia valaisiana)、高加索疏螺旋体(Borrelia caucasica)、麝香鼠疏螺旋体(Borrelia crocidurae)、达氏疏螺旋体(Borrelia duttoni)、格氏蜱疏螺旋体(Borrelia graingeri)、赫氏疏螺旋体(Borrelia hermsii)、西班牙疏螺旋体(Borrelia hispanica)、拉氏疏螺旋体(Borrelia latyschewii)、马氏疏螺旋体(Borrelia mazzottii)、扁虱疏螺旋体(Borrelia parkeri)、波斯疏螺旋体(Borrelia persica)、特里疏螺旋体(Borrelia turicatae)和委内瑞拉疏螺旋体(Borrelia venezuelensis)和密螺旋体(Treponema)(苍白密螺旋体苍白亚种(Treponema pallidum
ssp. pallidum))、苍白密螺旋体皮下亚种(Treponema pallidum
ssp. endemicum)、苍白密螺旋体细长亚种(Treponema pallidum
ssp. pertenue)和斑点病密螺旋体(Treponema carateum);
巴斯德菌(Pasteurella)(例如,产气巴斯德菌(Pasteurella
aerogenes)、贝氏巴斯德菌(Pasteurella bettyae)、犬巴斯德菌(Pasteurella
canis)、达可马巴斯德菌(Pasteurella dagmatis)、鸡巴斯德菌(Pasteurella
gallinarum)、溶血巴斯德菌(Pasteurella haemolytica)、多杀巴斯德菌多杀亚种(Pasteurella
multocida multocida)、多杀巴斯德菌鸡杀巴斯德菌(Pasteurella multocida
gallicida)、多杀巴斯德菌败血亚种(Pasteurella multocida
septica)、侵肺巴斯德菌(Pasteurella pneumotropica)和口巴斯德菌(Pasteurella
stomatis);
博德特菌(Bordetella)(例如,支气管炎博德特菌(Bordetella
bronchiseptica)、欣氏博德特菌(Bordetella hinzii)、霍氏博德特菌(Bordetella
holmseii)、副百日咳博德特菌(Bordetella parapertussis)、百日咳博德特菌(Bordetella
pertussis)和创口博德特菌(Bordetella
trematum);
诺卡氏菌科(Nocardiaceae),例如诺卡氏菌(Nocardia)(例如,星形诺卡氏菌(Nocardia
asteroides)和巴西诺卡氏菌(Nocardia brasiliensis);
立克次氏体(Rickettsia)(例如,立克次氏体(Ricksettsii)或伯氏立克次体(Coxiella burnetii);
军团菌(Legionella)(例如,茴芹军团菌(Legionalla anisa)、伯明翰军团菌(Legionalla
birminghamensis)、博氏军团菌(Legionalla bozemanii)、辛辛那提军团菌(Legionalla
cincinnatiensis)、杜氏军团菌(Legionalla dumoffii)、菲氏军团菌(Legionalla
feeleii)、戈氏军团菌(Legionalla gormanii)、哈氏军团菌(Legionalla
hackeliae)、以色列军团菌(Legionalla israelensis)、约旦军团菌(Legionalla
jordanis)、兰斯格军团菌(Legionalla lansingensis)、长滩军团菌(Legionalla
longbeachae)、梅氏军团菌(Legionalla maceachernii)、麦氏军团菌(Legionalla
micdadei)、橡树岭军团菌(Legionalla oakridgensis)、侵肺军团菌(Legionalla
pneumophila)、赫伦荒原军团菌(Legionalla sainthelensi)、图森军团菌(Legionalla
tucsonensis)和沃氏军团菌(Legionalla wadsworthii);
粘膜炎莫拉氏菌(Moraxella catarrhalis);
皮盖特氏解环菌(Cyclospora cayetanensis) ;
溶组织内阿米巴(Entamoeba histolytica) ;
肠兰伯氏鞭毛虫(Giardia lamblia) ;
阴道毛滴虫(Trichomonas vaginalis) ;
鼠弓形体(Toxoplasma gondii) ;
嗜麦芽糖寡养单胞菌(Stenotrophomonas maltophilia);
洋葱伯克霍尔德菌(Burkholderia cepacia);鼻疽伯克霍尔德菌(Burkholderia mallei)和类鼻疽伯克霍尔德菌(Burkholderia pseudomallei);
土拉热弗朗西丝菌(Francisella tularensis);
加德纳氏菌(Gardneralla)(例如,阴道加德纳氏菌(Gardneralla
vaginalis)和(Gardneralla mobiluncus);
念珠状链杆菌(Streptobacillus moniliformis);
黄杆菌科(Flavobacteriaceae),例如二氧化碳嗜纤维菌(Capnocytophaga)(例如,狗咬二氧化碳嗜纤维菌(Capnocytophaga
canimorsus)、犬咬二氧化碳嗜纤维菌(Capnocytophaga cynodegmi)、牙龈二氧化碳嗜纤维菌(Capnocytophaga
gingivalis)、颗粒二氧化碳嗜纤维菌(Capnocytophaga granulosa)、溶血二氧化碳嗜纤维菌(Capnocytophaga
haemolytica)、黄褐二氧化碳嗜纤维菌(Capnocytophaga ochracea)和生痰二氧化碳嗜纤维菌(Capnocytophaga sputigena);
巴尔通体(Bartonella)(杆菌巴尔通体(Bartonella bacilliformis)、豚鼠巴尔通体(Bartonella
clarridgeiae)、伊丽莎白巴尔通体(Bartonella elizabethae)、汉氏巴尔通体(Bartonella
henselae)、五日热巴尔通体(Bartonella quintana)和文氏巴尔通体阿氏亚种(Bartonella
vinsonii arupensis);
钩端螺旋体(Leptospira)(例如,双曲钩端螺旋体(Leptospira biflexa)、博氏钩端螺旋体(Leptospira
borgpetersenii)、稻田钩端螺旋体(Leptospira inadai)、问号钩端螺旋体(Leptospira
interrogans)、科氏钩端螺旋体(Leptospira kirschneri)、野口钩端螺旋体(Leptospira
noguchii)、圣地罗斯钩端螺旋体(Leptospira santarosai)和韦氏钩端螺旋体(Leptospira
weilii);
螺菌(Spirillum)(例如,减少螺菌(Spirillum minus));
拟杆菌(Bacteroides)(例如,粪拟杆菌(Bacteroides caccae)、多毛拟杆菌(Bacteroides
capillosus)、凝固拟杆菌(Bacteroides coagulans)、吉氏拟杆菌(Bacteroides
distasonis)、埃氏拟杆菌(Bacteroides eggerthii)、福赛斯拟杆菌(Bacteroides
forsythus)、脆弱拟杆菌(Bacteroides fragilis)、屎拟杆菌(Bacteroides
merdae)、卵形拟杆菌(Bacteroides ovatus)、腐败拟杆菌(Bacteroides
putredinis)、化脓拟杆菌(Bacteroides pyogenes)、内脏拟杆菌(Bacteroides
splanchinicus)、粪便拟杆菌(Bacteroides stercoris)、隐藏拟杆菌(Bacteroides
tectus)、多形拟杆菌(Bacteroides thetaiotaomicron)、单形拟杆菌(Bacteroides
uniformis)、解脲拟杆菌(Bacteroides ureolyticus)和普通拟杆菌(Bacteroides
vulgatus);
普雷沃氏菌(Prevotella)(例如,二路普雷沃氏菌(Prevotella
bivia)、颊普雷沃氏菌(Prevotella buccae)、人体普雷沃氏菌(Prevotella
corporis)、牙普雷沃氏菌(Prevotella dentalis)(齿光岗菌(Mitsuokella dentalis))、栖牙普雷沃氏菌(Prevotella
denticola)、解糖胨普雷沃氏菌(Prevotella disiens)、抑制普雷沃氏菌(Prevotella
enoeca)、解肝素普雷沃氏菌(Prevotella heparinolytica)、中间普雷沃氏菌(Prevotella
intermedia)、洛氏普雷沃氏菌(Prevotella loeschii)、产黑素普雷沃氏菌(Prevotella
melaninogenica)、变黑普雷沃氏菌(Prevotella nigrescens)、口腔普雷沃氏菌(Prevotella oralis)、口普雷沃氏菌(Prevotella
oris)、龈炎普雷沃氏菌(Prevotella oulora)、谭氏普雷沃氏菌(Prevotella
tannerae)、真口普雷沃氏菌(Prevotella venoralis)和动胶普雷沃氏菌(Prevotella
zoogleoformans);
卟啉单胞菌(Porphyromonas)(例如,不解糖卟啉单胞菌(Porphyromonas
asaccharolytica)、犬齿龈液卟啉单胞菌(Porphyromonas
cangingivalis)、犬嘴卟啉单胞菌(Porphyromonas canoris)、犬口腔卟啉单胞菌(Porphyromonas
cansulci)、口腔卟啉单胞菌(Porphyromonas catoniae)、牙周卟啉单胞菌(Porphyromonas
circumdentaria)、狗口腔卟啉单胞菌(Porphyromonas
crevioricanis)、牙髓卟啉单胞菌(Porphyromonas endodontalis)、牙龈卟啉单胞菌(Porphyromonas
gingivalis)、狗齿龈卟啉单胞菌(Porphyromonas gingivicanis)、利氏卟啉单胞菌(Porphyromonas
levii)和猕猴卟啉单胞菌(Porphyromonas macacae);
梭杆菌(Fusobacterium)(例如,微生子梭杆菌( F.
gonadiaformans)、死亡梭杆菌(F. mortiferum)、舟形梭杆菌(F. naviforme)、坏疽梭杆菌(F.
necrogenes)、坏死梭杆菌坏死亚种(F. necrophorum necrophorum)、坏死梭杆菌亚种(F.
necrophorum fundiliforme)、具核梭杆菌具核亚种(F. nucleatum nucleatum)、具核梭杆菌梭形亚种(F.
nucleatum fusiforme)、具核梭杆菌多型亚种(F. nucleatum polymorphum)、具核梭杆菌文氏亚种(F.
nucleatum vincentii)、牙周梭杆菌(F. periodonticum)、拉氏梭杆菌(F.
russii)、溃疡梭杆菌(F. ulcerans)和可变梭杆菌(F. varium);
衣原体(Chlamydia)(例如,沙眼衣原体(Chlamydia trachomatis));
隐孢子虫(Cryptosporidium)(例如,微小球隐孢子虫(C.
parvum) 、人隐孢子虫(C. hominis)、犬隐孢子虫(C. canis) 、猫隐孢子虫(C. felis) 、火鸡隐孢子虫(C.
meleagridis)和鼠隐孢子虫(C.
muris);
嗜衣原体(Chlamydophila)(例如,流产嗜衣原体(Chlamydophila abortus )(鹦鹉热衣原体(Chlamydia psittaci))、肺炎嗜衣原体(Chlamydophila
pneumoniae)(肺炎衣原体(Chlamydia
pneumoniae)和鹦鹉热嗜衣原体(Chlamydophila
psittaci)(鹦鹉热衣原体(Chlamydia
psittaci));
明串珠菌(Leuconostoc)(例如,柠檬明串珠菌(Leuconostoc citreum)、乳脂明串珠菌(Leuconostoc
cremoris)、葡萄聚糖明串珠菌(Leuconostoc dextranicum)、乳明串珠菌(Leuconostoc
lactis)、肠膜明串珠菌(Leuconostoc mesenteroides)和假肠膜明串珠菌(Leuconostoc
pseudomesenteroides);
孪生球菌(Gemella)(例如,伯氏孪生球菌(Gemella bergeri)、溶血孪生球菌(Gemella
haemolysans)、麻疹孪生球菌(Gemella morbillorum)和血孪生球菌(Gemella
sanguinis);和
脲枝原体(Ureaplasma)(例如,细小尿枝原体(Ureaplasma parvum)和解脲枝原体(Ureaplasma
urealyticum)。
优选地,通过本文所述的组合而治疗的细菌感染是革兰氏阴性感染。可使用本发明的组合而治疗的具体细菌包括:
可使用本发明的组合而治疗的具体细菌包括:
革兰氏阳性菌;
葡萄球菌,例如金黄色葡萄球菌(甲氧西林-敏感性(即MSSA)或甲氧西林-耐药性(即MRSA))和表皮葡萄球菌;
链球菌,例如无乳链球菌和酿脓链球菌;
芽孢杆菌科,例如炭疽芽孢杆菌;
肠球菌,例如粪肠球菌和屎肠球菌;和
革兰氏阴性菌;
肠杆菌科,例如大肠杆菌、克雷伯氏菌(例如,肺炎克雷伯氏菌和产酸克雷伯氏菌)和变形杆菌(例如,奇异变形杆菌、雷氏变形杆菌和普通变形杆菌);
流感嗜血菌;
分枝杆菌,例如结核分枝杆菌。
优选地,通过本文所述的组合而治疗的细菌感染是革兰氏阴性感染。
优选地,细菌是肠杆菌科,例如大肠杆菌、克雷伯氏菌(例如,肺炎克雷伯氏菌和产酸克雷伯氏菌)和变形杆菌(例如,奇异变形杆菌、雷氏变形杆菌和普通变形杆菌)。本发明的组合在治疗(多重)-药物-耐药性((M)DR)细菌中是特别有益的。对于肠杆菌科,耐药性最经常增进(builds up to)碳青霉烯酶上即碳青霉烯酶-耐药性菌株和“扩大谱β–内酰胺酶”(ESBL)菌株例如New
Delhi Metallo-β-内酰胺酶-1 (NDM-1)耐药性肺炎克雷伯氏菌。最优选地,所治疗的微生物感染是由以下的一种或多种所致的感染:大肠杆菌、肺炎克雷伯氏菌或一种KES (克雷伯氏菌、肠杆菌和沙雷氏菌)组细菌。在所有实施方案中,优选组合治疗是协同作用的,相比单独给予所述组合的组分而言。
应当记住的是,尽管组合(例如要求保护的)可能最初在治疗(M)DR菌株中显示是有功能的,然后它们可以用于治疗非耐药性菌株。在本文要求保护的组合的背景下这是特别有价值的,所述背景是对于肠杆菌科例如大肠杆菌、克雷伯氏菌(例如,肺炎克雷伯氏菌和产酸克雷伯氏菌)和变形杆菌(例如,奇异变形杆菌、雷氏变形杆菌和普通变形杆菌)的主要治疗是因普遍的专利保护而昂贵的抗微生物药物。用“通用”抗生素组合代替这类“处方(ethical)”药从治疗观点以及财务/经济观点来看在政府正在寻求降低医疗保健成本之时被认为是有益的。
本发明的组合可用于治疗任何上述细菌生物体相关的感染,并且尤其是它们可用于杀灭这类感染相关的繁殖的和/或临床上潜隐的微生物。一方面本发明提供NDGA与氨基糖苷类组合在治疗微生物感染中的用途。
可使用本发明的组合来治疗的具体病况包括结核病(例如,肺结核、非-肺结核(例如淋巴结结核、泌尿-生殖结核、骨和关节结核、脑膜炎结核)和粟粒性结核)、炭疽、脓肿、寻常痤疮、放线菌病、哮喘、细菌性痢疾(bacilliary dysentry)、细菌性结膜炎、细菌性角膜炎、细菌性阴道病、肉毒中毒、布鲁里溃疡、骨和关节感染、支气管炎(急性或慢性)、布鲁氏菌病、烧伤伤口、猫爪热、蜂窝组织炎、软下疳、胆管炎、胆囊炎、皮肤白喉、囊性纤维化、膀胱炎、弥漫性泛细支气管炎、白喉、龋齿、上呼吸道疾病、湿疹、积脓症(empymea)、心内膜炎、子宫内膜炎、肠热病、肠炎、附睾炎、会厌炎、丹毒(erysipelis)、丹毒(erysipclas)、类丹毒、红癣、眼睛感染、疖、加德钠菌性阴道炎、胃肠道感染(肠胃炎)、生殖器感染、牙龈炎、淋病、腹股沟肉芽肿、哈佛希耳热(Haverhill fever)、受感染的烧伤、牙科术后感染、口腔区感染、假体相关的感染、腹内脓肿、军团病、麻风病、钩端螺旋体病、李斯特氏菌病、肝脓肿、莱姆病、性病淋巴肉芽肿、乳腺炎、乳突炎、脑膜炎和神经系统感染、足分枝菌病、诺卡氏菌病(例如,马杜拉足(Madura
foot))、非特异性尿道炎、眼炎(例如,新生儿眼炎)、骨髓炎、耳炎(例如,外耳炎和中耳炎)、睾丸炎、胰腺炎、甲沟炎、盆腔腹膜炎、腹膜炎、腹膜炎伴随阑尾炎、咽炎、蜂窝织炎、品他病、鼠疫、胸膜积液、肺炎、术后伤口感染、术后气性坏疽、前列腺炎、伪膜性结肠炎、鹦鹉热、肺气肿、肾盂肾炎、脓皮病(例如,脓包病)、Q热病、鼠咬热、网状细胞增多症、蓖麻毒素中毒、里特病(Ritter’s disease)、沙门氏菌病、输卵管炎、脓毒性关节炎、脓毒性感染、败血症(septicameia)、鼻窦炎、皮肤感染(例如,皮肤肉芽肿、脓包病、毛囊炎和疖病)、梅毒、全身性感染、扁桃体炎、中毒性休克综合征、沙眼、土拉菌病、伤寒、斑疹伤寒(例如,流行性斑疹伤寒、鼠型斑疹伤寒、丛林斑疹伤寒和斑疹热)、尿道炎、伤口感染、雅司病、曲霉病、念珠菌病(例如,口咽念珠菌病、阴道念珠菌病或龟头炎)、隐球菌病、黄癣、组织胞浆菌病、擦烂、毛霉菌病、癣(例如,体癣、头癣、股癣、脚癣和甲癣)、甲癣(onychomycosis)、花斑糠疹、环癣和孢子丝菌病;或者MSSA、MRSA、表皮葡萄球菌、无乳链球菌、酿脓链球菌、大肠杆菌、肺炎克雷伯氏菌、产酸克雷伯氏菌、奇异变形杆菌、雷氏变形杆菌、普通变形杆菌、流感嗜血菌、粪肠球菌和屎肠球菌的感染。
可以理解,本文提及的“治疗”延伸到已确定疾病或症状的预防以及治疗。
可与本文所述的组合联合使用的进一步优选的抗微生物化合物包括能够杀灭临床上潜隐的微生物的那些。确定抗临床上潜隐的细菌的活性的方法包括在本领域技术人员已知条件(例如描述于以下文献的那些:Nature Reviews, Drug Discovery, 1, 895-910 (2002),其公开内容通过引用结合到本文中)下确定试验化合物的最小Stationary-cidal浓度(“MSC”)或最小Dormicidal
浓度(“MDC”)。抗临床上潜隐的微生物的合适的化合物筛选方法描述于WO2000028074,其公开内容通过引用结合到本文中,如同该公开被具体而全部列举在本文中一样。
如本文使用的术语“药学上可接受的衍生物”是指:
(a) 与或酸或碱形成的药学上可接受的盐(例如,酸加成盐);和/或
(b) 溶剂合物(包括水合物)。
可以被提及的酸加成盐包括羧酸盐(例如,甲酸盐、乙酸盐、三氟乙酸盐、丙酸盐、异丁酸盐、庚酸盐、癸酸盐(decanoate)、癸酸盐(caprate)、辛酸盐、硬脂酸盐、丙烯酸盐、己酸盐、丙炔酸盐、抗坏血酸盐、柠檬酸盐、葡萄糖醛酸盐、谷氨酸盐、乙醇酸盐、α-羟基丁酸盐、乳酸盐、酒石酸盐、苯乙酸盐、扁桃酸盐、苯基丙酸盐、苯基丁酸盐、苯甲酸盐、氯苯甲酸盐、甲基苯甲酸盐、羟基苯甲酸盐、甲氧基苯甲酸盐、二硝基苯甲酸盐、o-乙酰氧基苯甲酸盐、水杨酸盐、烟酸盐、异烟酸盐、肉桂酸盐、草酸盐、丙二酸盐、琥珀酸盐、辛二酸盐、癸二酸盐、富马酸盐、苹果酸盐、马来酸盐、羟基马来酸盐、马尿酸盐、邻苯二甲酸盐或对苯二甲酸盐);卤盐(例如,氯化物、溴化物或碘化物盐)、磺酸盐(例如,苯磺酸盐、甲基-、溴-或氯-苯磺酸盐、二甲苯磺酸盐、甲磺酸盐、乙磺酸盐、丙磺酸盐、羟基乙磺酸盐、1-或2-萘-磺酸盐或1,5-萘二磺酸盐)或硫酸盐、焦硫酸盐、硫酸氢盐、亚硫酸盐、亚硫酸氢盐、磷酸盐、磷酸氢二盐、磷酸二氢盐、偏磷酸盐、焦磷酸盐或硝酸盐,等等。
可以原料形式给予用于本发明的化合物,但活性成分优选地是以药物组合物形式提供。
活性成分可以作为分开的配方或作为单一组合配方使用。当在同一配方中组合时,可以理解,两种化合物必须稳定和彼此相容并与制剂的其它组分相容。
本发明的制剂包括适于口服、胃肠外(包括皮下,例如,通过注射或通过缓释型片剂、皮内、鞘内、肌内例如通过缓释型制剂和静脉内)、直肠和局部(包括皮肤、口腔和舌下)的那些或呈适于通过吸入或吹入给药的形式。最合适的给药途径可取决于患者的病况和病症。
优选地,将本发明的组合物配制用于口服或局部给药。在一个优选的实施方案中,组合物是使得适应于鼻腔给予,尤其是递送到鼻前孔的乳膏剂或软膏剂。
制剂可以方便地呈单位剂型形式并且可以通过药学领域众所周知的任何方法来制备,例如,描述于“Remington:
The Science and Practice of Pharmacy (雷明顿:药学的科学和实施) ”, Lippincott Williams和Wilkins, 第21版(2005)。合适的方法包括将活性成分与构成一种或多种赋形剂的载体缔合的步骤。一般而言,通过如下制备配方:将活性成分与液体载体或细微分开的固体载体或这两者均匀和密切地缔合,随后,如果有必要,将产物成型为所需配方。可以理解,当独立地给予两种活性成分时,每种都可通过不同方式给予。
当与赋形剂配制时,活性成分可以以以下浓度存在:占总混合物重量的0.1至99.5% (例如0.5至95%);对于片剂和胶囊剂常规为30至95%,而对于体液制剂为0.01至50% (例如3至50%)。
适于口服给药的配方可以作为离散单位存在,例如胶囊剂、扁囊剂或片剂(例如,尤其是用于儿科给药的可咀嚼的片剂),其各自含有预定量的活性成分;作为粉剂或粒剂;作为在水性液体或非水性液体中的溶液剂或混悬剂;或作为水包油液体乳剂或油包水液体乳剂。活性成分也可作为大丸剂、药糖剂或糊剂存在。
片剂可通过压制或模制而制备,任选与一种或多种赋形剂一起。压制片剂可通过在合适机器中压制呈自由流动形式(例如粉剂或粒剂)的活性成分而制备,所述活性成分任选与其它常规赋形剂混合,所述赋形剂例如粘合剂(例如,糖浆、阿拉伯胶、明胶、山梨醇、西黄蓍胶、淀粉的粘液、聚乙烯吡咯烷酮和/或羟甲基纤维素)、填充剂(例如,乳糖、糖、微晶纤维素、玉米淀粉、磷酸钙和/或山梨醇)、润滑剂(例如,硬脂酸镁、硬脂酸、滑石粉、聚乙二醇和/或硅石)、崩解剂(例如,马铃薯淀粉、交联羧甲基纤维素钠和/或淀粉乙醇酸钠)和润湿剂(例如,月桂基硫酸钠)。模制片剂可通过在合适机器中模制粉状活性成分与惰性液体稀释剂的混合物而制备。片剂可以任选地被包衣或刻痕并且可经配制以便提供活性成分的控制释放(例如,延迟、持续或脉冲释放,或者立即释放和控制释放的组合)。
或者,可将活性成分掺入口服液体制剂中,例如水性或油性混悬剂、溶液剂、乳剂、糖浆剂或酏剂。含有活性成分的配方也可作为干制品存在用于在使用前用水和另一合适溶媒构成。这样的液体制剂可含有常规添加剂,例如悬浮剂(例如,山梨醇浆、甲基纤维素、葡萄糖/白糖糖浆剂、明胶、羟甲基纤维素、羧甲基纤维素、硬脂酸铝凝胶和/或氢化食用脂肪)、乳化剂(例如,卵磷脂、山梨坦单油酸酯和/或阿拉伯胶)、非水性溶媒(例如,食用油,例如杏仁油、分级的椰子油、含油酯、丙二醇和/或乙醇),和防腐剂(例如,对羟基苯甲酸甲酯或对羟基苯甲酸丙酯和/或山梨酸)。
可用于治疗通过指状突起可进入的皮肤或膜(例如口腔、阴道、宫颈、肛门和直肠的膜)的病症的局部组合物,包括乳膏剂、软膏剂、洗剂、喷雾剂、凝胶剂和无菌水性溶液剂或混悬剂。同样,局部组合物包括其中活性成分溶于或分散于本领域已知的皮肤学溶媒的那些(例如,水性或非水性凝胶剂、软膏剂、油包水或水包油乳剂)。这类溶媒的成分可包含水、水性缓冲溶液、非水性溶剂(例如乙醇、异丙醇、苯甲醇、2-(2-乙氧基乙氧基)乙醇、丙二醇、丙二醇单月桂酸酯、四氢呋喃聚乙二醇醚(glycofurol)或甘油)、油类(例如矿物油如液体石蜡,天然或合成的甘油三酯类例如Miglyol™,或硅油类例如二甲聚硅氧烷)。尤其根据制剂性质及其预期用途和施用位置等,所用的皮肤学溶媒可含有一种或多种选自以下列表的组分:溶解剂或溶剂(例如,β-环糊精,例如羟丙基β-环糊精,或醇或多元醇,例如乙醇、丙二醇或甘油);增稠剂(例如,羟甲基纤维素、羟丙基纤维素、羧甲基纤维素或卡波姆);胶凝剂(例如,聚氧乙烯-聚氧丙烯共聚物);防腐剂(例如,苯甲醇、苯扎氯铵、氯己定、氯丁醇、苯甲酸酯、山梨酸钾或EDTA或其盐);和pH缓冲剂(例如,磷酸二氢盐和磷酸氢二盐的混合物,或柠檬酸和磷酸氢盐的混合物)。局部配方也可配制为透皮贴剂。
制备局部药物组合物例如乳膏剂、软膏剂、洗剂、喷雾剂和无菌水性溶液剂或混悬剂的方法是本领域众所周知的。制备局部药物组合物的合适方法描述于例如WO9510999、US6974585、WO2006048747,以及任何这些参考文献中引用的文件。
本发明的局部药物组合物可用于治疗各种皮肤或膜病症,例如上述任何细菌、真菌(例如,前述的任何葡萄球菌、链球菌、分枝杆菌或假单胞菌生物体,例如金黄色葡萄球菌(例如,甲氧西林耐药性金黄色葡萄球菌(MRSA)))所致的皮肤或膜(例如,鼻膜、腋窝、腹股沟、会阴、直肠、发炎的皮肤(dermatitic skin)、皮肤溃疡和医疗器械插入部位的感染,所述医疗器械例如静脉内针头、导管和气管造口术或喂食管)的感染。
可通过本发明的局部药物组合物治疗的具体细菌病况也包括以上公开的皮肤和膜相关的病况,以及:寻常痤疮;酒渣鼻(包括红斑毛细血管扩张性酒渣鼻(erythematotelangiectatic
rosacea)、丘疹脓疱性酒渣鼻(papulopustular rosacea)、鼻赘性酒渣鼻(phymatous
rosacea)和眼酒渣鼻(ocular rosacea));丹毒;红癣;深脓疱;坏疽性深脓疱病;脓疱病;甲沟炎;蜂窝组织炎;毛囊炎(包括热水浴毛囊炎(hot
tub folliculitis));疖病;痈病;葡萄球菌性烫伤皮肤综合征;外科型猩红热;链球菌性肛周病;链球菌性中毒性休克综合征;凹痕角质层分离;腋毛菌病;脓皮病;外耳道性耳部感染;绿甲综合征;螺旋体;坏死性筋膜炎;分枝杆菌性皮肤感染(例如寻常狼疮、瘰疬性皮肤结核、疣状结核、结核症、结节性红斑、硬结性红斑、结核样型麻风或麻风结节的麻风的皮肤表现、麻风结节性红斑、皮肤堪萨斯分枝杆菌、玛尔摩分枝杆菌、斯氏分枝杆菌、猿分枝杆菌、戈登分枝杆菌、嗜血分枝杆菌、鸟分枝杆菌、胞内分枝杆菌、龟分枝杆菌(包括脓肿分枝杆菌)或偶发分枝杆菌感染、游泳池(或鱼缸)肉芽肿、淋巴结炎和布鲁里溃疡(Bairnsdale溃疡、Searles'溃疡、Kakerifu溃疡或Toro溃疡));以及受感染的湿疹、烧伤、擦伤和皮肤伤口。
对于每种氨基糖苷类而言,现有已知的配方都可以使用。例如,可使用以下已知组合物;
对于庆大霉素给药用的合适剂量和配方描述于注射用Cidomycin®的产品标签,其可在以下找到:http://www.medicines.org.uk/emc/medicine/28271/SPC/Cidomycin+Injection/或用于注射或作为口服滴剂或滴耳剂的通用庆大霉素制剂配方。
对于新霉素给药用的合适剂量和配方描述于Nivemycin®的产品标签,其可在以下找到:http://www.medicines.org.uk/emc/medicine/10826/SPC/Nivemycin+500+mg+Tablets/或作为乳膏剂、软膏剂或滴剂,当与其它药物例如地塞米松组合使用时。
对于妥布霉素给药用的合适剂量和配方描述于喷雾器制品Tobi®,其可在以下找到:
http://www.medicines.org.uk/emc/medicine/19020/SPC/Tobi+300+mg+5+ml+Nebuliser+Solution/或作为滴眼剂制品Tobravisc
http://www.medicines.org.uk/emc/medicine/21263/SPC/Tobravisc+3.0+mg+ml+eye+drops%2c+solution/
用于本发明的组合物可以在包装或分配器装置中存在,其可含有具有活性成分的一个或多个单位剂型。包装可以包括例如金属或塑料箔,例如泡包装。当组合物预期作为两个单独的组合物给予时,这些可以呈成对的包装的形式。
也可向患者开具在“患者包装”中的药物组合物,所述患者包装在一个单一包装内(通常是泡包装)包含整个疗程。患者包装具有优于传统处方的优势,其中药剂师从大包装供应中分出给患者供应的药物,因为患者通常得到使用患者包装中含有的包装插页,而这在传统处方中通常是缺失的。包装插页的内容已经被证明改善患者对医师指示的依从性。
通过单一患者包装,或每一组合物的患者包装的方式(包括指导患者正确使用本发明的包装插页)给予本发明的组合,是本发明的合意的特征。
按照本发明的另外的实施方案提供了患者包装,其包含本发明的组合的至少一种活性成分和含有指导使用本发明的组合的信息插页。
在本发明的另一实施方案中,提供了双包装,其包含联合在一起的用于分开给予的NDGA和如上定义的氨基糖苷类。
用于治疗所需的活性成分的量将根据要治疗的病况的性质、患者的年龄和病况而变化,并且最终由值班医师或兽医决断。然而,一般而言,对于成人治疗所用的剂量范围通常会在0.02-5000 mg/天,优选1-1500
mg/天。所需剂量可以便利地呈单一剂量或作为在合适间隔时给予的分开的剂量,例如每天2、3、4或更多个子剂量。
生物试验
可用于确定活性成分的生物(例如杀菌或抗微生物)活性的试验程序包括本领域技术人员已知用于确定以下的那些:
(a) 抗临床上潜隐的细菌的杀菌活性;和
(b) 抗对数期细菌的抗微生物活性。
对于以上的(a),确定抗临床上潜隐的细菌的活性的方法包括在本领域技术人员已知条件下确定(例如描述于以下的那些:Nature
Reviews, Drug Discovery 1, 895-910 (2002),其公开内容通过引用结合到本文中)试验化合物的最小Stationary-cidal浓度(“MSC”)或最小Dormicidal
浓度(“MDC”)。
举例来说,WO2000028074描述了筛选化合物的合适方法,以确定它们杀灭临床上潜隐的微生物的能力。典型的方法可包括以下步骤:
(1) 让细菌培养物生长至稳定期;
(2) 以浓度和或时间足以杀灭生长的细菌的方式,用一种或多种抗微生物剂处理稳定期培养物,从而选择表型上耐药性的亚群;
(3) 将表型上耐药性的亚群的样品与一种或多种试验化合物或试剂一起孵育;和
(4) 评价抗表型上耐药性的亚群的任何抗微生物效应。
按照此方法,表型上耐药性的亚群可以视为临床上潜隐的细菌的代表,其在体内保持代谢活性并且其可以导致疾病的复发或发作。
对于上述(b),确定抗对数期细菌的活性的方法包括在标准条件下确定(即本领域技术人员已知的条件,例如描述于WO2005014585的那些,所述文件的公开内容通过引用结合到本文中)试验化合物的最小抑制浓度(“MIC”)或最小杀菌浓度(“MBC”)。这类方法的具体实施例描述于以下。
实施例
实施例
1:
使用棋盘法(
chequerboard
method
)
,
将
NDGA
与庆大霉素组合在一起抗对数期金黄色葡萄球菌的体外活性
细菌的生长
金黄色葡萄球菌的对数期生长如本领域所述地进行。
化合物和制备
HT013006: NDGA (可得自Sigma)
使用棋盘法,将HT013006与庆大霉素组合,抗对数期金黄色葡萄球菌
通过计算各组合的部分抑制浓度指数(FICI)确定组合的效应,如下:(药物A的MIC,在组合中试验)/(药物A的MIC,单独试验)+(药物B的MIC,在组合中试验)/(药物B的MIC,单独试验)。组合的相互作用定义为:如果FICI ≤0.5,表现协同作用;如果FICI >0.5,但<4.0,表现无相互作用;而如果FICI >4.0,表现拮抗作用。
HT013006:组合前MIC为64 µg/ml,如与0.25 µg/ml庆大霉素组合则降低至1 µg/ml。
庆大霉素:庆大霉素在组合前的MIC为0.5 µg/ml,在与16 µg/ml 的HT0120663组合时则降低至0.0078
µg/ml。
FIC指数为0.0234,指示协同组合。
该协同组合在65个FIC指数小于0.5的金黄色葡萄球菌的临床分离物中得以证实。
使用稳定期金黄色葡萄球菌得到类似结果。对于56个经试验显示出明显协同活性的临床菌株,FIC指数小于0.5。(335)
实施例
2:
使用时间杀灭曲线
,
NDGA
与庆大霉素组合在一起抗对数期金黄色葡萄球菌的体外活性
使用时间杀灭曲线,HT013006单独和与庆大霉素组合,抗对数期金黄色葡萄球菌。
如图1a-1d所示,16、8、4和2 µg/ml的HT013006显示无抗对数期金黄色葡萄球菌的活性。0.5 µg/ml的庆大霉素在孵育2小时时杀灭3.5 log,在2小时后观察到再次生长。然而,当16、8、4、2 µg/ml的HT013006分别与0.5 µg/ml的庆大霉素组合时,在2小时时观察到细菌全部杀灭并且在剩余的治疗周期中CFU计数保持为零。
如图2a-2c所示,16、8、4和2 µg/ml的HT013006显示无抗对数期金黄色葡萄球菌的活性。0.25
µg/ml的庆大霉素在孵育4小时时杀灭3 log,在4小时后观察到再次生长。然而,当16、8、4 µg/ml的HT013006分别与0.25
µg/ml的庆大霉素组合时,在2小时时观察到细菌全部杀灭并且在剩余的治疗周期中CFU计数保持为零。
如图3a和3b所示,16和8 µg/ml的HT013006显示无抗对数期金黄色葡萄球菌的活性。0.125
µg/ml的庆大霉素在处理8小时内显示抑制,然后观察到再次生长。然而,当16和8 µg/ml的HT013006分别与0.125
µg/ml的庆大霉素组合时,在2小时时观察到细菌全部杀灭并且在剩余的治疗周期中CFU计数保持为零。
如图4a和4b所示,16和8 µg/ml的HT013006显示无抗对数期金黄色葡萄球菌的活性。0.0625
µg/ml的庆大霉素显示无活性。然而,当16和8 µg/ml的HT013006分别与0.0625
µg/ml的庆大霉素组合时,在2小时时观察到细菌全部杀灭并且在剩余的治疗周期中CFU计数保持为零。
实施例
3:
使用相同技术,NDGA显示出增强庆大霉素抗以下的效应;
(a) 对数期甲氧西林耐药性金黄色葡萄球菌临床菌株,通过时间杀灭(341)
结果
1. 16和8
μg/ml的HT013006无抗对数期MRSA的活性。
2. 当HT013006与庆大霉素组合时,有抗对数期细菌的明显的协同效应,参见作为代表性结果的图5a。
3. 当与0.5和0.25 μg/ml的庆大霉素组合时,HT013006的最小浓度为2 μg/ml。
(b) 对数期金黄色葡萄球菌庆大霉素耐药性临床菌株,通过时间杀灭(340)
结果
1. 16、8、4和2 μg/ml的HT013006无抗对数期金黄色葡萄球菌的活性。
2. 4、2、1和0.5 ug/ml的庆大霉素无抗菌株17的活性。
3. 当HT013006与庆大霉素组合时,有抗对数期细菌的明显的协同效应,参见作为代表性结果的图5b。
4. 当与4和2 μg/ml的庆大霉素组合时显示增强的活性的HT013006的最小浓度为2 μg/ml。
实施例
4:
通过时间杀灭
,
NDGA
(HT013006)
、新霉素和这两种药物组合时抗对数期金黄色葡萄球菌的体外协同效应
使用实施例2所述的方法,试验HT013006与新霉素组合,在24小时的时间周期内抗对数期金黄色葡萄球菌牛津菌株。
结果
1. 16、8、4和2 μg/ml的HT013006无抗对数期金黄色葡萄球菌的活性。
2. 当HT013006与新霉素组合使用时,有抗对数期细菌的明显的协同效应,参见作为代表性结果的图6。
3. 显示出最大增强效应的HT013006的最小浓度为8 µg/ml。
实施例 5: 通过棋盘法,HT013006和新霉素抗对数期金黄色葡萄球菌的体外协同效应
使用实施例1所述的方法,评价HT013006与新霉素抗对数期金黄色葡萄球菌牛津菌株的效应。
结果
1. HT013006与新霉素组合显示,对于所测的45个临床金黄色葡萄球菌菌株而言,FIC指数小于0.5,这显示明显的协同活性。
2. HT013006与新霉素组合显示,对于两个MRSA临床菌株而言,FIC指数小于0.5。
Claims (10)
1. 去甲二氢愈创木酸和选自以下的氨基糖苷类在治疗微生物感染中的用途:庆大霉素、阿米卡星、奈替米星、新霉素、链霉素、妥布霉素、氨肽酶抑制剂、布替罗星、布替罗星A、柔红霉素、地贝卡星、二氢链霉素、G418、潮霉素B、卡那霉素B、卡那霉素、黄色霉素、巴龙霉素、核糖霉素、西索米星、壮观霉素、链佐星和硫链丝菌素。
2. 权利要求1的用途,其中所述氨基糖苷类是庆大霉素、新霉素或妥布霉素。
3. 权利要求3的用途,其中所述抗微生物剂是庆大霉素或新霉素。
4. 权利要求1、2或3中任一项的用途,其中所述微生物感染是细菌感染。
5. 前述权利要求中任一项的用途,其中所述微生物感染是由以下所致:大肠杆菌、葡萄球菌、链球菌、芽孢杆菌科、肠杆菌科、流感嗜血杆菌、肠球菌、分枝杆菌或克雷伯氏菌。
6. 权利要求的用途,其中所述感染是由金黄色葡萄球菌所致。
7. 权利要求1-6中任一项的用途,用于治疗结核病、炭疽、脓肿、寻常痤疮、抗非霉菌病、哮喘、细菌性痢疾(bacilliary dysentry)、细菌性结膜炎、细菌性角膜炎、细菌性阴道病、肉毒中毒、布鲁里溃疡、骨和关节感染、支气管炎(急性或慢性)、布鲁氏菌病、烧伤伤口、猫爪热、蜂窝组织炎、软下疳、胆管炎、胆囊炎、皮肤白喉、囊性纤维化、膀胱炎、弥漫性泛细支气管炎、白喉、龋齿、上呼吸道疾病、湿疹、积脓症(empymea)、心内膜炎、子宫内膜炎、肠热病、肠炎、附睾炎、会厌炎、丹毒(erysipelis)、丹毒(erysipclas)、类丹毒、红癣、眼睛感染、疖、加德钠菌性阴道炎、胃肠道感染(肠胃炎)、生殖器感染、牙龈炎、淋病、腹股沟肉芽肿、哈佛希耳热(Haverhill fever)、受感染的烧伤、牙科术后感染、口腔区感染、假体相关的感染、腹内脓肿、军团病、麻风病、钩端螺旋体病、李斯特氏菌病、肝脓肿、莱姆病、性病淋巴肉芽肿、乳腺炎、乳突炎、脑膜炎和神经系统感染、足分枝菌病、诺卡氏菌病、非特异性尿道炎、眼炎、骨髓炎、耳炎、睾丸炎、胰腺炎、甲沟炎、盆腔腹膜炎、腹膜炎、腹膜炎伴随阑尾炎、咽炎、蜂窝织炎、品他病、鼠疫、胸膜积液、肺炎、术后伤口感染、术后气性坏疽、前列腺炎、伪膜性结肠炎、鹦鹉热、肺气肿、肾盂肾炎、脓皮病、Q热病、鼠咬热、网状细胞增多症、蓖麻毒素中毒、里特病(Ritter’s disease)、沙门氏菌病、输卵管炎(salpingitis)、脓毒性关节炎、脓毒性感染、败血症、鼻窦炎、皮肤感染、梅毒、全身性感染、扁桃体炎、中毒性休克综合征、沙眼、土拉菌病、伤寒、斑疹伤寒、尿道炎、伤口感染、雅司病、曲霉病、念珠菌病、隐球菌病、黄癣、组织胞浆菌病、擦烂、毛霉菌病、癣、甲癣、花斑糠疹、环癣和孢子丝菌病;或者MSSA、MRSA、表皮葡萄球菌、无乳链球菌、酿脓链球菌、大肠杆菌、肺炎克雷伯氏菌、产酸克雷伯氏菌、奇异变形杆菌、雷氏变形杆菌、普通变形杆菌、流感嗜血菌、粪肠球菌和屎肠球菌的感染。
8. 用于治疗微生物感染的药物组合物,其包含去甲二氢愈创木酸和选自以下的氨基糖苷类:庆大霉素、阿米卡星、奈替米星、新霉素、链霉素、妥布霉素、氨肽酶抑制剂、布替罗星、布替罗星A、柔红霉素、地贝卡星、二氢链霉素、G418、潮霉素B、卡那霉素B、卡那霉素、黄色霉素、巴龙霉素、核糖霉素、西索米星、壮观霉素、链佐星和硫链丝菌素;
以及药学上可接受的佐剂、稀释剂或载体。
9. 权利要求8的药物组合物,其配制用于口服或局部给药。
10. 包含去甲二氢愈创木酸和氨基糖苷类的制品,作为同时、分别或序贯用于治疗微生物感染的组合制剂;所述氨基糖苷类选自:庆大霉素、阿米卡星、奈替米星、新霉素、链霉素、妥布霉素、氨肽酶抑制剂、布替罗星、布替罗星A、柔红霉素、地贝卡星、二氢链霉素、G418、潮霉素B、卡那霉素B、卡那霉素、黄色霉素、巴龙霉素、核糖霉素、西索米星、壮观霉素、链佐星和硫链丝菌素。
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2013
- 2013-05-02 GB GBGB1307989.2A patent/GB201307989D0/en not_active Ceased
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2014
- 2014-05-02 WO PCT/GB2014/051374 patent/WO2014177885A1/en active Application Filing
- 2014-05-02 EP EP14724788.6A patent/EP2991636A1/en not_active Withdrawn
- 2014-05-02 CA CA2908665A patent/CA2908665A1/en not_active Abandoned
- 2014-05-02 CN CN201480024915.4A patent/CN105307648A/zh active Pending
- 2014-05-02 US US14/782,096 patent/US20160038438A1/en not_active Abandoned
- 2014-05-02 JP JP2016511134A patent/JP6282337B2/ja not_active Expired - Fee Related
-
2016
- 2016-08-01 HK HK16109122.4A patent/HK1220915A1/zh unknown
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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CN111588682A (zh) * | 2020-05-28 | 2020-08-28 | 广州百媚化妆品有限公司 | 一种平衡肌肤微生态的护肤组合物 |
CN113209058A (zh) * | 2021-05-14 | 2021-08-06 | 吉林大学 | 去甲二氢愈创木酸在制备mcr-1酶抑制剂中的应用 |
Also Published As
Publication number | Publication date |
---|---|
WO2014177885A1 (en) | 2014-11-06 |
CA2908665A1 (en) | 2014-11-06 |
EP2991636A1 (en) | 2016-03-09 |
US20160038438A1 (en) | 2016-02-11 |
JP6282337B2 (ja) | 2018-02-21 |
GB201307989D0 (en) | 2013-06-12 |
JP2016521278A (ja) | 2016-07-21 |
HK1220915A1 (zh) | 2017-05-19 |
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