CN109862886A - 组合 - Google Patents
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- CN109862886A CN109862886A CN201780061957.9A CN201780061957A CN109862886A CN 109862886 A CN109862886 A CN 109862886A CN 201780061957 A CN201780061957 A CN 201780061957A CN 109862886 A CN109862886 A CN 109862886A
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- Prior art keywords
- infection
- pharmaceutically acceptable
- bacterium
- combination
- mycobacterium
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Landscapes
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
本发明提供一种组合,包含至少一种选自二氯芬、氯丙硫蒽、奋乃静、硫利达嗪、三氟拉嗪和乙二胺四乙酸盐或其药学上可接受的衍生物的化合物以及碳青霉烯或其药学上可接受的衍生物。该组合对于治疗微生物感染特别有用。
Description
发明领域
本发明涉及至少一种选自二氯芬、氯丙硫蒽(例如盐酸氯丙硫蒽)、奋乃静、硫利达嗪(例如盐酸硫利达嗪)、三氟拉嗪(例如盐酸三氟拉嗪)和乙二胺四乙酸盐(例如乙二胺四乙酸二钠)或其药学上可接受的衍生物的化合物与碳青霉烯或其药学上可接受的衍生物的组合,以及该组合用于治疗微生物感染的用途。特别地,它涉及这种组合用于杀灭与微生物感染例如革兰氏阴性细菌感染有关的繁殖或临床上潜伏的微生物的用途。
背景
碳青霉烯是用于治疗已知或怀疑由多重耐药(MDR)细菌引起的感染的抗生素。像盘尼西林和头孢菌素一样,它们是β-内酰胺类抗生素的成员,它们通过与盘尼西林结合蛋白结合并抑制细胞壁合成来杀灭细菌。然而,与头孢菌素和盘尼西林不同,碳青霉烯表现出广谱活性且具有对抗革兰氏阳性和革兰氏阴性细菌的更高效力。因此,当具有感染的患者病情严重或怀疑聚藏了耐药菌时,它们通常用作最后的手段(Antimicrob. Agents Chemother., 55, 4943-4960 (2011))。然而不幸的是,若干研究表明,全世界范围对碳青霉烯的耐药性正在增加。
已批准临床使用的碳青霉烯包括亚胺培南、美罗培南、厄他培南、多尼培南、帕尼培南/倍他米隆和比阿培南。其他碳青霉烯包括阿祖培南、泰比培南、来那培南、托莫培南和thienpenem。美罗培南在欧洲以商品名Optinem (三水合美罗培南)和Meronem (三水合美罗培南或美罗培南)销售。
鉴于细菌耐药的问题以及抗微生物剂如碳青霉烯在对抗细菌感染中的重要性,确定能够增强这些试剂的抗微生物活性的化合物解决重要的需求。作为WO2000/028074公布的国际专利申请描述筛选化合物以测定其杀灭对数期(即繁殖的)和/或临床上潜伏的微生物的能力的方法。使用该方法,申请人已经观察到许多已知的化合物,包括二氯芬、氯丙硫蒽(例如盐酸氯丙硫蒽)、奋乃静、硫利达嗪(例如盐酸硫利达嗪)、三氟拉嗪(例如盐酸三氟拉嗪)和乙二胺四乙酸盐(例如乙二胺四乙酸二钠)或其药学上可接受的衍生物,与碳青霉烯或其药学上可接受的衍生物、例如美罗培南(例如三水合美罗培南),对抗繁殖和/或临床上潜伏的微生物具有协同作用。
本发明基于以下意外发现:至少一种选自二氯芬,氯丙硫蒽,奋乃静,硫利达嗪,三氟拉嗪和乙二胺四乙酸盐或其药学上可接受的衍生物的化合物与碳青霉烯或其药学上可接受的衍生物(例如美罗培南或其药学上可接受的衍生物)的组合表现出对抗对数期(即繁殖的)和/或临床上潜伏的微生物的协同抗微生物活性。特别是对抗对数期细菌。换句话说,该组合具有比在所述剂量水平下每种试剂的预期加和效应更大的生物活性。本发明的组合的该令人惊讶的生物活性提供缩短化疗方案的机会,且可以导致与使用这种组合相关的微生物耐药性的出现减少。
在抗微生物药物的背景下的协同以多种方式测量,这些方式符合普遍接受的观点,即“协同是大于加和的作用”。评估是否已观察到协同的方法之一是使用“棋盘(chequerboard)”技术。这是一种广为接受的方法,其导致产生称为分级抑制浓度指数(FICI)的值。Orhan等人J. Clin. Microbiol. 2005, 43(1):140在桥接第140-141页的段落中描述了棋盘方法和分析,且解释了FICI值是单独的和在混合物中的每个单独组分的MIC(最小抑制浓度)水平之和的比率。当ΣFIC≤0.5时,该组合被认为是协同的,当ΣFIC>0.5但<2时,则认为是无关的,且当ΣFIC≥2时,是拮抗的。
确定存在或不存在协同的另一个接受的测试是使用时间-杀灭方法。这涉及在评估随时间对细菌对数或静止-生长的作用时,将药物组合的动态作用与单独的每种药物比较。同样,可能的结果是协同、加和或拮抗作用。
发明概述
因此,在一个实施方案中,本发明提供至少一种选自二氯芬、氯丙硫蒽、奋乃静、硫利达嗪、三氟拉嗪和乙二胺四乙酸盐或其药学上可接受的衍生物的化合物与碳青霉烯或其药学上可接受的衍生物的组合。
优选地,碳青霉烯是美罗培南、亚胺培南、多尼培南或厄他培南或其药学上可接受的衍生物。更优选地,碳青霉烯是美罗培南或其药学上可接受的衍生物,例如三水合美罗培南。
优选地,该化合物选自二氯芬、盐酸氯丙硫蒽、奋乃静、盐酸硫利达嗪、三氟拉嗪和乙二胺四乙酸二钠。更优选地,该化合物是乙二胺四乙酸二钠。
因此,本发明提供:
二氯芬或其药学上可接受的衍生物和碳青霉烯或其药学上可接受的衍生物(例如美罗培南或其药学上可接受的衍生物)的组合。
氯丙硫蒽或其药学上可接受的衍生物和碳青霉烯或其药学上可接受的衍生物(例如美罗培南或其药学上可接受的衍生物)的组合。
奋乃静或其药学上可接受的衍生物和碳青霉烯或其药学上可接受的衍生物(例如美罗培南或其药学上可接受的衍生物)的组合。
硫利达嗪或其药学上可接受的衍生物和碳青霉烯或其药学上可接受的衍生物(例如美罗培南或其药学上可接受的衍生物)的组合。
三氟拉嗪或其药学上可接受的衍生物和碳青霉烯或其药学上可接受的衍生物(例如美罗培南或其药学上可接受的衍生物)的组合。
乙二胺四乙酸盐或其药学上可接受的衍生物和碳青霉烯或其药学上可接受的衍生物(例如美罗培南或其药学上可接受的衍生物)的组合。
在另一个实施方案中,本发明提供上文定义的组合在制造用于治疗微生物感染的药物中的用途。
另外,本发明提供上文定义的组合,用于治疗微生物感染,优选用于治疗细菌感染。
在另一个实施方案中,本发明提供治疗微生物感染的方法,该方法包括向哺乳动物(包括人)施用至少一种上文定义的组合。
还提供药物组合物,其包含与碳青霉烯或其药学上可接受的衍生物组合的至少一种选自二氯芬、氯丙硫蒽、奋乃静、硫利达嗪、三氟拉嗪和乙二胺四乙酸盐或其药学上可接受的衍生物的化合物,和药学上可接受的佐剂、稀释剂或载体。在一个实施方案中,药物组合物用于治疗微生物感染,优选其中所述微生物感染是细菌感染。
在另一个实施方案中,本发明涉及包含至少一种选自二氯芬、氯丙硫蒽、奋乃静、硫利达嗪、三氟拉嗪和乙二胺四乙酸盐或其药学上可接受的衍生物的化合物和碳青霉烯或其药学上可接受的衍生物的产品,作为用于同时、分开或依次用于杀灭与微生物感染相关的繁殖和/或临床上潜伏的微生物的组合制剂。优选用于杀灭与细菌感染相关的繁殖细菌。
附图简述
图1是时间-杀灭曲线(Log CFU/ml对时间(小时)),显示512 mg/L的浓度的三水合美罗培南、64 mg/L的浓度的二氯芬以及三水合美罗培南(512mg/L)和二氯芬(64mg/L)的组合对抗对数期NDM-1肺炎克雷伯氏菌的抗微生物活性。
发明详述
如下所述,已经证明本发明的组合对抗耐药细菌、特别是耐药革兰氏阴性细菌特别有效,这为所述组合施用于耐药菌株和建立耐药性前的所述菌株(即作为一线治疗)开辟了道路。
如本文所用,术语“与......组合”涵盖化合物与碳青霉烯或其药学上可接受的衍生物的分开和依次施用二者。当依次施用化合物和碳青霉烯时,可以首先施用化合物或碳青霉烯。当同时施用时,化合物和碳青霉烯可以在相同或不同的药物组合物中施用。辅助疗法,即其中一种试剂用作主要治疗而另一种试剂用于辅助该主要治疗,也是本发明的一个实施方案。
本发明的组合可用于治疗微生物感染。特别地,它们可用于杀灭与微生物感染相关的繁殖和/或临床上潜伏的微生物,优选与微生物感染相关的繁殖微生物,例如与革兰氏阴性细菌感染相关的繁殖细菌。因此,本文提及的微生物感染的治疗包括杀灭与这种感染相关的繁殖和/或临床上潜伏的微生物。
如本文所用,“杀灭”意指如通过缺乏代谢活性评定的生存能力的丧失。
如本文所用,“临床上潜伏的微生物”是指具有代谢活性但生长速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生长速率阈值,低于该阈值,则宿主中的感染性疾病症状不存在。
临床上潜伏的微生物的代谢活性可通过本领域技术人员已知的几种方法测定;例如,通过测量微生物中的mRNA水平或通过测定它们的尿苷摄取速率。在这方面,临床上潜伏的微生物,当与对数生长条件下(体外或体内)的微生物相比时,具有降低但仍然显著水平的:
(I) mRNA(例如0.0001至50%,例如1至30、5至25或10至20%的mRNA水平);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[3H]尿苷摄取水平)。
临床上潜伏的微生物通常具有许多可识别的特征。例如,它们可能是能存活的但不可培养的;即它们通常不能通过标准培养技术检测到,但通过诸如肉汤稀释计数、显微术或分子技术如聚合酶链式反应的技术可检测和可定量。此外,临床上潜伏的微生物是表型耐药的,且因此对常规抗微生物剂的生物抑制作用敏感(在对数期中) (即常规抗微生物剂的最小抑制浓度(MIC)基本上不变的微生物);但是对药物诱导的杀灭具有显著降低的易感性(例如,在任何给定的常规抗微生物剂的情况下,最小杀微生物浓度(例如最小杀菌浓度,MBC)与MIC的比率为10或更高的微生物)。
如本文所用,术语“微生物”是指真菌和细菌。本文中对“微生物”、“抗微生物”和“抗微生物地”的提及应相应地解释。例如,术语“微生物”是指真菌或细菌,且“微生物感染”是指任何真菌或细菌感染。
在本发明的一个实施方案中,一种或多种前述组合用于治疗细菌感染,特别是该组合可用于杀灭与细菌感染相关的繁殖和/或临床上潜伏的微生物。如本文所用,术语“细菌”(及其衍生词,例如“微生物感染”)包括但不限于提及的以下类别和特定类型的生物体(或由生物体引起的感染):
革兰氏阳性球菌,如葡萄球菌属(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)、科氏葡萄球菌科氏亚种(Staph. cohnii cohnii)、科氏葡萄球菌解脲亚种(Staph. c. urealyticus)、马胃葡萄球菌(Staph. equorum)、鸡葡萄球菌(Staph. gallinarum)、溶血性葡萄球菌(Staph. haemolyticus)、人葡萄球菌人亚种(Staph. hominis hominis)、人葡萄球菌新霉素败血症亚种(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));链球菌属(例如β-溶血性化脓链球菌(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)和化脓链球菌(Strept. pyogenes)),微需氧化脓链球菌(“米勒氏”链球菌(Streptococcus "milleri"),如咽峡炎链球菌(Strept. anginosus)、星座链球菌星座亚种(Strept. constellatus constellatus)、星座链球菌咽炎亚种(Strept. constellatus pharyngidis)和中间链球菌(Strept. intermedius)),“轻型”链球菌群(α-溶血性-“草绿色”链球菌,如轻型链球菌(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”链球菌群(非溶血性,如唾液链球菌(Strept. salivarius)和前庭链球菌(Strept. vestibularis))和“变形”链球菌群(牙齿表面链球菌,如仓鼠链球菌(Strept. criceti)、变形链球菌(Strept. mutans)、鼠链球菌(Strept. ratti)和表兄链球菌(Strept. sobrinus))的口腔链球菌,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),或替代地分类为A、B、C、D、E、G、L、P、U或V族链球菌的链球菌);
革兰氏阴性球菌,如淋病奈瑟氏菌(Neisseria gonorrhoeae)、脑膜炎奈瑟氏菌(Neisseria meningitidis)、灰色奈瑟氏菌(Neisseria cinerea)、长奈瑟氏菌(Neisseria elongata)、浅黄奈瑟氏菌(Neisseria flavescens)、乳糖奈瑟氏菌(Neisseria lactamica)、粘液奈瑟氏菌(Neisseria mucosa)、干燥奈瑟氏菌(Neisseria sicca)、微黄奈瑟氏菌(Neisseria subflava)和编织奈瑟氏菌(Neisseria weaveri);芽胞杆菌科,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)和蜡样芽孢杆菌(Bacillus cereus);肠杆菌科,如大肠杆菌(Escherichia coli)、肠杆菌属(例如产气肠杆菌(Enterobacter aerogenes)、聚团肠杆菌(Enterobacter agglomerans)和阴沟肠杆菌(Enterobacter cloacae))、柠檬酸杆菌属(如弗氏柠檬酸杆菌(Citrob. freundii)和Citrob. divernis)、哈夫尼菌属(例如蜂房哈夫尼菌(Hafnia alvei))、欧文氏菌属(例如桃红色欧文氏菌(Erwinia persicinus))、摩氏摩根氏菌(Morganella morganii)、沙门氏菌属(肠沙门氏菌(Salmonella enterica)和伤寒沙门氏菌(Salmonella typhi))、志贺氏菌属(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)和索氏志贺氏菌(Shigella sonnei))、克雷伯氏菌属(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)(肉芽肿荚膜杆菌(Calymmatobacterium granulomatis))和鼻硬结克雷伯氏菌(Klebs. rhinoscleromatis))、变形杆菌属(例如奇异变形杆菌(Pr. mirabilis)、雷极变形杆菌(Pr. rettgeri)和普通变形杆菌(Pr. vulgaris))、普罗威登斯菌属(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))、沙雷氏菌属(例如粘质沙雷氏菌(Serratia marcescens)和液化沙雷氏菌(Serratia liquifaciens))和耶尔森氏菌属(例如小肠结肠炎耶尔森氏菌(Yersinia enterocolitica)、鼠疫耶尔森氏菌(Yersinia pestis)和假结核耶尔森氏菌(Yersinia pseudotuberculosis));肠球菌(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));螺杆菌属(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));不动杆菌属(例如鲍曼不动杆菌(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));假单胞菌属(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)、稻皮假单胞菌(Ps. oryzihabitans)、穿孔假单胞菌(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));脆弱拟杆菌(Bacteriodes fragilis);消化球菌属(例如黑色消化球菌(Peptococcus niger));消化链球菌属;梭菌属(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)、恶名梭菌(C. malenominatum)、诺氏梭菌(C. novyi)、乳清酸梭菌(C. oroticum)、副腐化梭菌(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)、产芽孢梭菌(C. sporogenes)、近端梭菌(C. subterminale)、共生梭菌(C. symbiosum)和第三梭菌(C. tertium));支原体(例如肺炎支原体(M. pneumoniae)、人支原体(M. hominis)、生殖道支原体(M. genitalium)和解脲支原体(M. urealyticum));分枝杆菌(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)、波希米亚分枝杆菌(Mycobacterium bohemicum)、牛分枝杆菌(Mycobacterium bovis)、布兰德分枝杆菌(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)、出众分枝杆菌(Mycobacterium conspicuum)、库克氏分枝杆菌(Mycobacterium cookii)、浅黄分枝杆菌(Mycobacterium flavescens)、嘎地分枝杆菌(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)、古地分枝杆菌(Mycobacterium goodii)、嗜血分枝杆菌(Mycobacterium haemophilum)、 Mycobacterium hassicum、胞内分枝杆菌(Mycobacterium intracellulare)、中庸分枝杆菌(Mycobacterium interjectum)、海德堡分枝杆菌(Mycobacterium heidelberense)、慢生黄分枝杆菌(Mycobacterium lentiflavum)、玛尔摩分枝杆菌(Mycobacterium malmoense)、微小分枝杆菌(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)、不产色分枝杆菌(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)、土地分枝杆菌(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)、托斯卡纳分枝杆菌(Mycobacterium tusciae)、溃疡分枝杆菌(Mycobacterium ulcerans)、母牛分枝杆菌(Mycobacterium vaccae)、沃氏分枝杆菌(Mycobacterium wolinskyi)和蟾蜍分枝杆菌(Mycobacterium xenopi));嗜血杆菌属(例如流感嗜血杆菌(Haemophilus influenzae)、杜克雷嗜血杆菌(Haemophilus ducreyi)、埃及嗜血杆菌(Haemophilus aegyptius)、副流感嗜血杆菌(Haemophilus parainfluenzae)、溶血嗜血杆菌(Haemophilus haemolyticus)和副溶血嗜血杆菌(Haemophilus parahaemolyticus));放线杆菌属(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));放线菌属(例如衣氏放线菌(Actinomyces israelii));布鲁氏菌属(例如流产布鲁氏菌(Brucella abortus)、狗布鲁氏菌(Brucella canis)、马尔他布鲁氏菌(Brucella melintensis)和猪布鲁氏菌(Brucella suis));弯曲杆菌属(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)和胎儿弯曲杆菌(Campylobacter fetus));单核细胞增生李斯特氏菌(Listeria monocytogenes);弧菌属(例如霍乱弧菌(Vibrio cholerae)和副溶血弧菌(Vibrio parahaemolyticus)、溶藻弧菌(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)、麦氏弧菌(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(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,如包柔氏螺旋体属(例如回归热包柔氏螺旋体(Borrelia recurrentis)、伯氏包柔氏螺旋体(Borrelia burgdorferi)、阿氏包柔氏螺旋体(Borrelia afzelii)、安德森包柔氏螺旋体(Borrelia andersonii)、比赛蒂包柔氏螺旋体(Borrelia bissettii)、嘎氏包柔氏螺旋体(Borrelia garinii)、日本包柔氏螺旋体(Borrelia japonica)、卢西塔尼亚包柔氏螺旋体(Borrelia lusitaniae)、坦尼基包柔氏螺旋体(Borrelia tanukii)、土德包柔氏螺旋体(Borrelia turdi)、瓦莱西亚包柔氏螺旋体(Borrelia valaisiana)、高加索包柔氏螺旋体(Borrelia caucasica)、麝鼠包柔氏螺旋体(Borrelia crocidurae)、达氏包柔氏螺旋体(Borrelia duttoni)、格氏包柔氏螺旋体(Borrelia graingeri)、赫姆斯氏包柔氏螺旋体(Borrelia hermsii)、西班牙包柔氏螺旋体(Borrelia hispanica)、拉氏包柔氏螺旋体(Borrelia latyschewii)、马氏包柔氏螺旋体(Borrelia mazzottii)、扁虱包柔氏螺旋体(Borrelia parkeri)、波斯包柔氏螺旋体(Borrelia persica)、特里蜱包柔氏螺旋体(Borrelia turicatae)和委内瑞拉包柔氏螺旋体(Borrelia venezuelensis))和密螺旋体属(苍白密螺旋体苍白亚种(Treponema pallidum ssp. pallidum)、苍白密螺旋体地方亚种(Treponema pallidum ssp.endemicum)、苍白密螺旋体纤细亚种(Treponema pallidum ssp. pertenue)和斑点病密螺旋体(Treponema carateum));巴斯德菌属(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)、多杀巴斯德菌鸡杀亚种(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));博德特氏菌属(例如支气管败血性博德特氏菌(Bordetella bronchiseptica)、欣茨博德特氏菌(Bordetella hinzii)、霍氏博德特氏菌(Bordetella holmseii)、副百日咳博德特氏菌(Bordetella parapertussis)、百日咳博德特氏菌(Bordetella pertussis)和创口博德特氏菌(Bordetella trematum));诺卡氏菌科,如诺卡氏菌属(例如星形诺卡氏菌(Nocardia asteroides)和巴西诺卡氏菌(Nocardia brasiliensis));立克次氏体(例如立氏立克次氏体(Ricksettsii)或伯纳特氏立克次氏体(Coxiella burnetii));军团菌属(例如茴芹军团菌(Legionalla anisa)、伯明瀚军团菌(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)、费勒氏军团菌(Legionalla feeleii)、戈氏军团菌(Legionalla gormanii)、哈开里军团菌(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)、马氏军团菌(Legionalla maceachernii)、麦氏军团菌(Legionalla micdadei)、橡树岭军团菌(Legionalla oakridgensis)、嗜肺军团菌(Legionalla pneumophila)、圣海伦军团菌(Legionalla sainthelensi)、图森军团菌(Legionalla tucsonensis)和沃斯沃军团菌(Legionalla wadsworthii));卡他莫拉菌(Moraxella catarrhalis);卡耶坦环孢子虫(Cyclospora cayetanensis);溶组织内变形虫(Entamoeba histolytica);兰伯贾第虫(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);洋葱伯克霍尔德氏菌(Burkholderia cepacia);鼻疽伯克霍尔德氏菌(Burkholderia mallei)和类鼻疽伯克霍尔德氏菌(Burkholderia pseudomallei);土拉热弗朗西斯菌(Francisella tularensis);加德纳氏菌属(例如阴道加德纳氏菌(Gardneralla vaginalis)和动弯加德纳氏菌(Gardneralla mobiluncus));念珠状链杆菌(Streptobacillus moniliformis);黄杆菌科,如二氧化碳嗜纤维菌属(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));巴尔通氏体属(杆菌状巴尔通氏体(Bartonella bacilliformis)、克氏巴尔通氏体(Bartonella clarridgeiae)、伊丽莎白巴尔通氏体(Bartonella elizabethae)、汉氏巴尔通氏体(Bartonella henselae)、五日热巴尔通氏体(Bartonella quintana)和文森氏巴尔通氏体阿茹朋亚种(Bartonella vinsonii arupensis));钩端螺旋体属(例如双曲钩端螺旋体(Leptospira biflexa)、博氏钩端螺旋体(Leptospira borgpetersenii)、稻田氏钩端螺旋体(Leptospira inadai)、问号钩端螺旋体(Leptospira interrogans)、克氏钩端螺旋体(Leptospira kirschneri)、野口氏钩端螺旋体(Leptospira noguchii)、圣他罗西钩端螺旋体(Leptospira santarosai)和韦氏钩端螺旋体(Leptospira weilii));螺菌属(例如减少螺菌(Spirillum minus));拟杆菌属(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)、隐蔽拟杆菌(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));普雷沃氏菌属(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)、齿普雷沃氏菌(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));卟啉单胞菌属(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)、卡托氏卟啉单胞菌(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)、犬牙龈卟啉单胞菌(Porphyromonas gingivicanis)、利氏卟啉单胞菌(Porphyromonas levii)和猕猴卟啉单胞菌(Porphyromonas macacae));梭杆菌属(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)、坏死梭杆菌肠形亚种(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)、具核梭杆菌多态亚种(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)和变形梭杆菌(F. Varium));衣原体(例如沙眼衣原体(Chlamydia trachomatis));隐孢子虫(例如小球隐孢子虫(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(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)));明串珠菌属(例如柠檬明串珠菌(Leuconostoc citreum)、乳脂明串珠菌(Leuconostoc cremoris)、葡聚糖明串珠菌(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));孪生球菌属(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));和脲原体属(例如微小脲原体(Ureaplasma parvum)和解脲脲原体(Ureaplasma urealyticum))。
优选地,通过本文描述的组合治疗的细菌感染是革兰氏阴性细菌感染。可以使用本发明的组合治疗的特定革兰氏阴性细菌包括:
肠杆菌科,例如大肠杆菌,克雷伯氏菌属(例如肺炎克雷伯氏菌和产酸克雷伯氏菌)和变形杆菌属(例如奇异变形杆菌(Pr. mirabilis)、雷极变形杆菌(Pr. rettgeri)和普通变形杆菌);流感嗜血杆菌;分枝杆菌,如结核分枝杆菌;和肠杆菌属(例如阴沟肠杆菌)。
优选地,细菌是肠杆菌科例如大肠杆菌和克雷伯氏菌(例如肺炎克雷伯氏菌和产酸克雷伯氏菌)。特别优选的是大肠杆菌和肺炎克雷伯氏菌(例如肺炎克雷伯氏菌肺炎亚种)。
在所有实施方案中,优选与单独进行的组合组分的施用相比,组合疗法是协同的。
本发明的组合特别有益于治疗(多重)耐药((M)DR)细菌。关于肠杆菌科,耐药性最常增进至碳青霉烯酶,即碳青霉烯酶耐药菌株和“超广谱β-内酰胺酶”(ESBL)菌株,例如新德里金属-β-内酰胺酶-1(NDM-1)耐药肺炎克雷伯氏菌和NDM-1大肠杆菌。
应当记住,尽管如所要求保护的组合可能最初被证实在治疗(M)DR菌株中起作用,但它们可以另外用于治疗非耐药菌株。在本发明要求保护的组合的背景下这是极其有价值的,其中肠杆菌科例如大肠杆菌和克雷伯氏菌属(例如肺炎克雷伯氏菌和产酸克雷伯氏菌)的主要疗法是由于普遍的专利保护而昂贵的抗微生物药。从治疗角度以及在政府正在寻求降低卫生保健成本的时候从财政/经济角度来看,通过“未注册的”抗生素的组合替代这种“处方”药物被认为是有益的。
本发明的组合可用于治疗与任何上述细菌生物体有关的感染,且特别是它们可用于杀灭与这种感染(例如革兰氏阴性细菌感染)有关的繁殖和/或临床上潜伏的微生物。
可以使用本发明的组合治疗的具体病症包括由革兰氏阴性细菌引起的那些,例如脓肿、哮喘、杆菌性痢疾、细菌性结膜炎、细菌性角膜炎、细菌性阴道病、骨和关节感染、支气管炎(急性或慢性)、布鲁氏菌病、烧伤创面、猫抓热、蜂窝织炎、软性下疳、胆管炎、胆囊炎、囊性纤维化、膀胱炎、肾炎、弥漫性泛细支气管炎、龋齿、上呼吸道疾病、积脓(empymea)、心内膜炎、子宫内膜炎、肠热病、肠炎、附睾炎、会厌炎、眼部感染、疖、加德纳菌属阴道炎、胃肠道感染(肠胃炎)、生殖器感染、龈炎、淋病、腹股沟肉芽肿、哈弗希尔热、烧伤感染、牙科手术后感染、口区感染、假体相关感染、腹内脓肿、军团病、钩端螺旋体病、李斯特菌病、肝脓肿、莱姆病、性病性淋巴肉芽肿、乳腺炎、乳突炎、脑膜炎和神经系统感染、非特异性尿道炎、眼炎(例如新生儿眼炎)、骨髓炎、耳炎(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、腹膜炎伴阑尾炎、咽炎、胸腔积液、肺炎、术后伤口感染、术后气性坏疽、前列腺炎、假膜性结肠炎、鹦鹉热、肾盂肾炎、Q热、鼠咬热、里特氏病、沙门氏菌病、输卵管炎、脓毒性关节炎、脓毒性感染、败血症、全身感染、扁桃腺炎、沙眼、伤寒、尿道炎、尿路感染、伤口感染;或被大肠杆菌、肺炎克雷伯氏菌、产酸克雷伯氏菌、奇异变形杆菌、雷极变形杆菌、普通变形杆菌、流感嗜血杆菌、粪肠球菌、屎肠球菌和阴沟肠杆菌感染。
应当理解,本文提及的“治疗”延伸至预防以及已确诊的疾病或症状的治疗。
如本文所用,术语“药学上可接受的衍生物”是指:
(a)药学上可接受的盐;和/或
(b)溶剂化物(包括水合物)。
合适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、苯丙酸盐、苯丁酸盐、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、邻乙酰氧基苯甲酸盐、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),卤化物盐(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,磷酸一氢盐,磷酸二氢盐,偏磷酸盐,焦磷酸盐,或硝酸盐等。
本文提及的碳青霉烯是指具有以下核心化学结构的化合物:
其中R1、R2和R3是不同的取代基。碳青霉烯可以选自亚胺培南、美罗培南、厄他培南、多尼培南、帕尼培南、比阿培南、阿祖培南、泰比培南、来那培南、托莫培南和thienpenem或其药学衍生物,例如三水合美罗培南。这些化合物具有以下化学结构,包括上述化学核心。
优选地,碳青霉烯选自亚胺培南、美罗培南、厄他培南、多尼培南、帕尼培南和比阿培南,或其药学上可接受的衍生物。更优选地,碳青霉烯选自美罗培南、亚胺培南、多尼培南和厄他培南或其药学上可接受的衍生物。最优选地,碳青霉烯是美罗培南或其药学上可接受的衍生物,例如三水合美罗培南。
二氯芬是一种驱绦虫剂(anticestodal agent),通常与甲苯组合用于除去狗和猫的寄生虫。它也被称为4-氯-2-[(5-氯-2-羟基苯基)甲基]苯酚、二氯酚或双(5-氯-2-羟基苯基)甲烷,且具有以下化学结构:
氯丙硫蒽是噻吨类的抗精神病药物。它也被称为(Z)-3-(2-氯噻吨-9-亚基)-N,N-二甲基-丙-1-胺,且具有以下化学结构:
氯丙硫蒽可以其盐酸盐的形式使用。在本发明中,它优选为盐形式,即盐酸氯丙硫蒽。
奋乃静是一种抗精神病药,其化学分类为哌嗪基吩噻嗪且可以商品名Trilafon、Fentazin或Triptafen商购。它的化学名称为2-[4-[3-(2-氯-10H-吩噻嗪-10-基)丙基]哌嗪-1-基]乙醇且具有以下化学结构:
奋乃静可以其亚砜盐的形式使用。在本发明中,它优选为非盐形式,即作为奋乃静。
硫利达嗪是属于吩噻嗪药物组的抗精神病药物。它也被称为10-{2-[(RS)-1-甲基哌啶-2-基]乙基}-2-甲基磺酰基吩噻嗪或10-[2-(1-甲基-2-哌啶基)乙基]-2-(甲硫基)-10H-吩噻嗪,且具有以下化学结构:
硫利达嗪可以其盐酸盐的形式使用。在本发明中,它优选为盐形式,即作为盐酸硫利达嗪。
三氟拉嗪是吩噻嗪化学类的抗精神病药物。它也被称为10-[3-(4-甲基哌嗪-1-基)丙基]-2-(三氟甲基)-10H-吩噻嗪且具有以下化学结构:
三氟拉嗪可以其盐酸盐或其二盐酸盐的形式使用。在本发明中,它优选为盐酸盐形式,即作为盐酸三氟拉嗪。
乙二胺四乙酸盐(或乙二胺四乙酸(EDTA))是一种广泛用于溶解水垢的氨基多羧酸。它也被称为2-({2-[双(羧甲基)氨基]乙基}(羧甲基)氨基)乙酸且具有以下化学结构:
乙二胺四乙酸盐(或EDTA)可以许多盐和/或水合物的形式使用,包括二钠乙二胺四乙酸盐、乙二胺四乙酸二钠、乙二胺四乙酸钙二钠、钠钙乙二胺四乙酸盐、无水EDTA二钠盐、无水EDTA四钠盐、EDTA铁钠盐、EDTA铁(III)钠盐或EDTA铁(III)钠盐水合物。在本发明中,它优选用作乙二胺四乙酸二钠。
根据本发明使用的化合物可以作为原料施用,但活性成分优选以药物组合物的形式提供。活性成分可以用作分开的制剂或用作单一的组合制剂。当在同一制剂中组合时,应理解这两种化合物必须是稳定的且彼此相容并与制剂的其他组分相容。
本发明的制剂包括适合于口服、肠胃外(包括皮下(例如通过注射或通过贮库片剂)、鞘内、肌内(例如通过贮库)和静脉内)和直肠或为适合于通过吸入或吹入施用来施用的形式的那些。最合适的施用途径可取决于患者的病症和障碍。优选地,配制本发明的组合物用于肠胃外施用。更优选地,配制本发明的组合物用于静脉内或肌内施用。
制剂可以方便地以单位剂型存在,且可以通过药学领域熟知的任何方法制备,例如如“Remington: The Science and Practice of Pharmacy”, Lippincott Williamsand Wilkins, 第21版, (2005)中所述。合适的方法包括使活性成分与构成一种或多种赋形剂的载体缔合的步骤。通常,通过如下制备制剂:将活性成分与液体载体或细碎的固体载体或二者均匀且紧密地缔合,且然后,如果需要,将产品成形为所需的制剂。应当理解,当两种活性成分独立施用时,每种可以通过不同方式施用。
当与赋形剂一起配制时,活性成分可以总混合物重量的0.1至99.5%(例如0.5至95%)的浓度存在;对于片剂和胶囊便利地为30至95%,且对于液体制剂为0.01至50%(例如3至50%)。
适合于口服施用的制剂可以存在为:离散单元,例如胶囊、扁囊剂或片剂(例如特别用于儿科施用的可咀嚼片剂),各自含有预定量的活性成分;粉末或颗粒;水性液体或非水性液体中的溶液或悬浮液;或水包油液体乳液或油包水液体乳液。活性成分也可以作为大丸剂、药糖剂或糊剂存在。
片剂可以通过压缩或模制制备,任选地使用一种或多种赋形剂。压缩片剂可以通过在合适的机器中压缩自由流动形式的活性成分如粉末或颗粒来制备,所述活性成分任选地与其他常规赋形剂如粘合剂(例如糖浆、阿拉伯胶、明胶、山梨糖醇、黄蓍胶、淀粉粘胶、聚乙烯吡咯烷酮和/或羟甲基纤维素)、填料(例如乳糖、糖、微晶纤维素、玉米淀粉、磷酸钙和/或山梨糖醇)、润滑剂(例如硬脂酸镁、硬脂酸、滑石、聚乙二醇和/或二氧化硅)、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)混合。模制片剂可以通过在合适的机器中模制粉末状活性成分与惰性液体稀释剂的混合物来制备。片剂可以任选地包衣或刻痕,且可以配制成提供活性成分的受控释放(例如延迟、持续或脉冲释放,或立即释放和受控释放的组合)。
或者,可将活性成分掺入口服液体制剂例如水性或油性悬浮液、溶液、乳液、糖浆或酏剂中。含有活性成分的制剂也可以作为干燥产品存在,以在使用前用水或另一合适的载体构造。这种液体制剂可含有常规添加剂,例如悬浮剂(例如山梨糖醇糖浆、甲基纤维素、葡萄糖/糖浆、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、山梨聚糖单油酸酯和/或阿拉伯胶)、非水性载体(例如食用油,例如杏仁油、分馏椰子油、油性酯、丙二醇和/或乙醇)和防腐剂(例如对羟基苯甲酸甲酯或丙酯和/或山梨酸)。
根据本发明使用的组合可以存在于包装或分配器设备中,所述包装或分配器设备可以包含一个或多个含有活性成分的单位剂型。包装可以例如包含金属或塑料箔,例如泡罩包装。当组合物旨在作为两种分开的组合物施用时,这些组合物可以双包装的形式存在。
药物组合物也可以以“患者包”开药给患者,所述“患者包”包含在单个包装、通常是泡罩包装中的整个疗程。患者包具有优于传统处方(其中药剂师将患者的药物供应从散装供应分出)的优势,因为患者始终能够获得患者包中所含的包装插页,这在传统处方中经常遗失。包装插页的包含已显示改善患者对医师指示的遵从性。。
用于本发明的组合的化合物是可商购的或可通过本领域已知的合成方法制备。亚胺培南、一水合亚胺培南、美罗培南、三水合美罗培南、厄他培南、厄他培南钠、多尼培南水合物、一水合多尼培南、比阿培南、二氯芬、盐酸氯丙硫蒽、奋乃静、奋乃静亚砜、硫利达嗪、盐酸硫利达嗪、二盐酸三氟拉嗪、盐酸三氟拉嗪和乙二胺四乙酸二钠例如可得自Sigma-Aldrich®。
合适的剂量和制剂是本领域已知的。例如,奋乃静的合适剂量和制剂描述于Fentazin的产品标签中,其可以在https://www.medicines.org.uk/emc/medicine/22596中找到。盐酸三氟拉嗪的合适剂量和制剂作为1 mg片剂、1 mg/5 ml糖浆、5 mg片剂或5 mg/5 ml口服溶液描述于三氟拉嗪的产品标签中,其可以在https://www.medicines.org.uk/emc/medicine/22564;https://www.medicines.org.uk/emc/medicine/22934;https://www.medicines.org.uk/emc/medicine/23635;和https://www.medicines.org.uk/emc/medicine/7909中找到。
用于施用亚胺培南的合适剂量和制剂描述于如下中:用于输注溶液的亚胺培南/西司他丁500mg/500mg粉末的产品标签,其可以在https://www.medicines.org.uk/emc/medicine/24538中找到;和Primaxin IV注射的产品标签,其可以在https://www.medicines.org.uk/emc/medicine/7456中找到。用于施用美罗培南的合适剂量和制剂描述于如下中:Meronem IV的产品标签,其可以在https://www.medicines.org.uk/emc/medicine/11215中找到;或用于注射或输注溶液的美罗培南1 g粉末的产品标签,其可以在https://www.medicines.org.uk/emc/medicine/24151中找到。美罗培南静脉内施用。它作为待溶解在5%磷酸二氢钾溶液中的白色结晶粉末提供。用于施用厄他培南的合适剂量和制剂描述于用于输注溶液的浓缩物的INVANZ® 1g粉末的产品标签中,其可以在https://www.medicines.org.uk/emc/medicine/10421中找到。
通过包括指导患者正确使用本发明的包装插页的单个患者包、或每种组合物的患者包来施用本发明的组合,是本发明的理想特征。
根据本发明的另一个实施方案,提供一种患者包,其包含至少一种根据本发明的组合的活性成分和包含关于使用本发明的组合的指导的信息插页。
在本发明的另一个实施方案中,提供双重包(double pack),其包含与分开施用相关的抗微生物剂(优选具有对抗临床上潜伏的微生物的生物活性),和本文公开的一种或多种化合物(优选具有对抗临床上潜伏的微生物的生物活性)。
用于治疗所需的活性成分的量将随所治疗的病症的性质和患者的年龄和状况而变化,且最终将由主治医师或兽医决定。然而,一般而言,用于成人治疗的剂量将通常为每天0.02至5000mg、优选每天1至1500mg范围。所需剂量可方便地以单剂量存在,或作为以适当间隔施用的分剂量、例如作为每天二、三、四或更多个亚剂量存在。
生物测试
可用于测定活性成分的生物学(例如杀菌或抗微生物)活性的测试程序包括本领域技术人员已知的用于测定以下的那些:
(a)对抗临床上潜伏的细菌的杀菌活性;和
(b)对抗对数期细菌的抗微生物活性。
关于上述(a),测定对抗临床上潜伏的细菌的活性的方法包括在本领域技术人员已知的条件(例如在Nature Reviews, Drug Discovery 1, 895-910 (2002)中描述的那些,其公开内容通过引用并入本文)下,测定测试化合物的最小静止期杀灭浓度(MinimumStationary-cidal Concentration,“MSC”)或最小休眠杀灭浓度(Minimum DormicidalConcentration,“MDC”)。
举例来说,WO2000028074描述了筛选化合物以测定其杀灭临床上潜伏的微生物的能力的合适方法。典型的方法可以包括以下步骤:
(1)使细菌培养物生长到静止期;
(2)在足以杀灭生长中的细菌的浓度和或时间下用一种或多种抗微生物剂处理所述静止期培养物,从而选择表型耐药亚群;
(3)将所述表型耐药亚群的样品与一种或多种测试化合物或试剂一起温育;和
(4)评估对抗所述表型耐药亚群的任何抗微生物作用。
根据该方法,表型耐药亚群可以被视为临床上潜伏的细菌的代表,其在体内保持代谢活性且可以导致疾病的复发或发作。
关于上述(b),用于测定对抗对数期细菌的活性的方法包括在标准条件(即本领域技术人员已知的条件,例如WO 2005014585中描述的那些,该文献的公开内容通过引用并入本文)下,测定测试化合物的最小抑制浓度(“MIC”)或最小杀菌浓度(“MBC”)。下面描述这些方法的具体实施例。
实施例
实施例1:使用棋盘方法的二氯芬和三水合美罗培南对抗对数期NDM-1肺炎克雷伯氏菌肺炎亚种(Klebsiella pneumoniae subsp. pneumoniae)的体外协同作用
实施例1中使用的棋盘方法遵循Antimicrob Chemo (2013) 68, 374-384中详述的方案。NDM-1肺炎克雷伯氏菌肺炎亚种的对数期生长如本领域所述进行。二氯芬和三水合美罗培南从可商购来源(例如,Sigma-Aldrich® UK)获得。通过如下计算每种组合的分级抑制浓度指数(FICI)来检查本发明的组合的作用:
(组合中测试的药物A的MIC)/(单独测试的药物A的MIC)+(组合中测试的药物B的MIC)/(单独测试的药物B的MIC)。
如果FICI≤0.5,组合的相互作用被定义为显示协同,如果FICI>0.5但<2则没有相互作用,且如果FICI≥2,则是拮抗的。
FICI(FIC指数)等于0.38和0.5,表明二氯芬和三水合美罗培南在组合用于对抗对数期NDM-1肺炎克雷伯氏菌肺炎亚种时具有协同作用。
实施例2:盐酸硫利达嗪与三水合美罗培南组合对抗对数期NDM-1大肠杆菌的体外协同作用
如本领域所述进行NDM-1大肠杆菌的对数期生长。盐酸硫利达嗪和三水合美罗培南从商业来源(例如,Sigma Aldrich® UK)获得。通过使用棋盘方法并以与实施例1相同的方式计算每种组合的分级抑制浓度指数(FICI)来检查本发明的组合的作用。棋盘数据如下所示:
FICI等于0.28,表明盐酸硫利达嗪和三水合美罗培南表现出对抗对数期NDM-1大肠杆菌的协同作用。
实施例3:使用棋盘方法的盐酸三氟拉嗪和三水合美罗培南对抗对数期NDM-1大肠杆菌的体外协同作用
如本领域所述进行NDM-1大肠杆菌的对数期生长。盐酸三氟拉嗪和三水合美罗培南从商业来源(例如,Sigma Aldrich® UK)获得。通过使用棋盘方法和以与实施例1相同的方式计算每种组合的分级抑制浓度指数(FICI)来检查本发明的每种组合的作用。棋盘数据如下所示:
FICI等于0.25,表明盐酸三氟拉嗪和三水合美罗培南表现出对抗对数期NDM-1大肠杆菌的协同作用。
实施例4:使用棋盘方法的盐酸氯丙硫蒽和三水合美罗培南对抗对数期NDM-1肺炎克雷伯氏菌肺炎亚种的体外协同作用
如本领域所述进行NDM-1肺炎克雷伯氏菌肺炎亚种的对数期生长。盐酸氯丙硫蒽和三水合美罗培南从商业来源(例如,Sigma Aldrich® UK)获得。通过使用棋盘方法和以与实施例1相同的方式计算每种组合的分级抑制浓度指数(FICI)来检查本发明的每种组合的作用。棋盘数据如下所示:
FICI等于0.28,表明盐酸氯丙硫蒽和三水合美罗培南表现出对抗对数期NDM-1肺炎克雷伯氏菌肺炎亚种的协同作用。
实施例5:使用棋盘方法的奋乃静和三水合美罗培南对抗对数期NDM-1大肠杆菌的体外协同作用
如本领域所述进行NDM-1大肠杆菌的对数期生长。奋乃静和三水合美罗培南从商业来源(例如,Sigma Aldrich® UK)获得。通过使用棋盘方法和以与实施例1相同的方式计算每种组合的分级抑制浓度指数(FICI)来检查本发明的每种组合的作用。棋盘数据如下所示:
FICI等于0.27,表明奋乃静和三水合美罗培南表现出对抗对数期NDM-1大肠杆菌的协同作用。
实施例6:使用棋盘方法的盐酸硫利达嗪和三水合美罗培南对抗对数期NDM-1肺炎克雷伯氏菌肺炎亚种的体外协同作用
如本领域所述进行NDM-1肺炎克雷伯氏菌肺炎亚种的对数期生长。盐酸硫利达嗪和三水合美罗培南从商业来源(例如,Sigma Aldrich® UK)获得。通过使用棋盘方法和以与实施例1相同的方式计算每种组合的分级抑制浓度指数(FICI)来检查本发明的每种组合的作用。棋盘数据如下所示:
FICI等于0.19,表明盐酸硫利达嗪和三水合美罗培南表现出对抗对数期NDM-1肺炎克雷伯氏菌肺炎亚种的协同作用。
实施例7:使用棋盘方法的乙二胺四乙酸二钠和三水合美罗培南对抗对数期NDM-1肺炎克雷伯氏菌肺炎亚种的体外协同作用
如本领域所述进行NDM-1肺炎克雷伯氏菌肺炎亚种的对数期生长。乙二胺四乙酸二钠和三水合美罗培南从商业来源(例如,Sigma Aldrich® UK)获得。通过使用棋盘方法和以与实施例1相同的方式计算每种组合的分级抑制浓度指数(FICI)来检查本发明的每种组合的作用。棋盘数据如下所示:
FICI等于0.07,表明乙二胺四乙酸二钠和三水合美罗培南表现出对抗对数期NDM-1肺炎克雷伯氏菌肺炎亚种的协同作用。
实施例8:二氯芬与三水合美罗培南组合对抗对数期NDM-1肺炎克雷伯氏菌的体外协同作用
该实施例的目的是通过时间-杀灭方法在24小时的时间段内测试二氯芬和三水合美罗培南组合对抗对数期NDM-1肺炎克雷伯氏菌(NCTC13443)的协同作用。如上所述,时间-杀灭方法是用于确定协同作用的存在或不存在的另一种可接受的测试,且涉及在评估对细菌对数生长或静止生长随时间的作用时将药物组合的动态作用与单独的每种药物进行比较。结果可以显示药物组合是协同、加和或拮抗的。这种结果不能从单独或与另一种试剂组合的药物的活性预测。
材料和方法
1. 使用的细菌菌株:肺炎克雷伯氏菌的NCTC13443菌株
2. 细菌的生长:NCTC13443的对数期生长根据本领域已知的方法进行,例如细菌的SOPR-005-00对数期生长。
3. 化合物预备:二氯芬和三水合美罗培南均得自商业来源(例如Sigma-Aldrich® UK)。
4. 将过夜培养物用营养肉汤(Oxoid)稀释至107 CFU/ml且将280μl和290μl培养物分别加入到每个组合孔和药物中,以使最终浓度为300μl。
5. 将化合物与细菌悬浮液一起温育24小时。在0、2、4、7和24小时时,进行CFU计数以测量药物组合的杀灭作用。
结果和讨论
结果显示在图1中,其中可以看出,单独使用64mg/L的浓度的二氯芬和单独使用512mg/L的浓度的三水合美罗培南几乎没有或没有对抗对数期NDM-1肺炎克雷伯氏菌的作用。然而,当组合使用时,可以看到显著的协同作用:在7小时时发生完全的长期细菌杀灭。鉴于每种单独的药物缺乏活性,对所要求保护的发明的组合所见的协同对于治疗微生物感染是令人惊讶且有利的技术效果。
Claims (15)
1.一种组合,包含至少一种选自二氯芬、氯丙硫蒽、奋乃静、硫利达嗪、三氟拉嗪和乙二胺四乙酸盐或其药学上可接受的衍生物的化合物以及碳青霉烯或其药学上可接受的衍生物。
2.根据权利要求1的组合,其中碳青霉烯选自亚胺培南、美罗培南、多尼培南和厄他培南或其药学上可接受的衍生物。
3.根据权利要求1或2的组合,其中碳青霉烯是美罗培南或其药学上可接受的衍生物。
4.根据权利要求1至3中任一项的组合,其用于治疗微生物感染,优选用于杀灭与微生物感染相关的繁殖和/或临床上潜伏的微生物。
5.根据权利要求4所用的组合,其中所述微生物感染是细菌感染,优选革兰氏阴性细菌感染。
6.根据权利要求5所用的组合,其中所述细菌感染是由大肠杆菌或肺炎克雷伯氏菌引起。
7.根据权利要求5或6所用的组合,其中所述感染通过细菌的耐药菌株引起。
8.至少一种选自二氯芬、氯丙硫蒽、奋乃静、硫利达嗪、三氟拉嗪和乙二胺四乙酸盐或其药学上可接受的衍生物的化合物与碳青霉烯或其药学上可接受的衍生物的组合在制造用于治疗微生物感染的药物中的用途。
9.根据权利要求8的用途,其中碳青霉烯选自亚胺培南、美罗培南、多尼培南和厄他培南或其药学上可接受的衍生物,优选美罗培南或其药学上可接受的衍生物。
10.根据权利要求8或9的用途,其中所述微生物感染是细菌感染。
11.根据权利要求10的用途,其中所述细菌感染是革兰氏阴性细菌感染,优选由大肠杆菌或肺炎克雷伯氏菌引起。
12.根据权利要求11的用途,其中所述感染由耐药菌株引起。
13.根据权利要求8至12中任一项的用途,用于治疗脓肿、哮喘、杆菌性痢疾、细菌性结膜炎、细菌性角膜炎、细菌性阴道病、骨和关节感染、支气管炎(急性或慢性)、布鲁氏菌病、烧伤创面、猫抓热、蜂窝织炎、软性下疳、胆管炎、胆囊炎、囊性纤维化、膀胱炎、肾炎、弥漫性泛细支气管炎、龋齿、上呼吸道疾病、积脓、心内膜炎、子宫内膜炎、肠热病、肠炎、附睾炎、会厌炎、眼部感染、疖、加德纳菌属阴道炎、胃肠道感染(肠胃炎)、生殖器感染、龈炎、淋病、腹股沟肉芽肿、哈弗希尔热、烧伤感染、牙科手术后感染、口区感染、假体相关感染、腹内脓肿、军团病、钩端螺旋体病、李斯特菌病、肝脓肿、莱姆病、性病性淋巴肉芽肿、乳腺炎、乳突炎、脑膜炎和神经系统感染、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、腹膜炎伴阑尾炎、咽炎、胸腔积液、肺炎、术后伤口感染、术后气性坏疽、前列腺炎、假膜性结肠炎、鹦鹉热、肾盂肾炎、Q热、鼠咬热、里特氏病、沙门氏菌病、输卵管炎、脓毒性关节炎、脓毒性感染、败血症、全身感染、扁桃腺炎、沙眼、伤寒、尿道炎、尿路感染、伤口感染;或被大肠杆菌、肺炎克雷伯氏菌、产酸克雷伯氏菌、奇异变形杆菌、雷极变形杆菌、普通变形杆菌、流感嗜血杆菌、粪肠球菌、屎肠球菌和阴沟肠杆菌感染。
14.一种药物组合物,其包含与碳青霉烯或其药学上可接受的衍生物组合的至少一种选自二氯芬、氯丙硫蒽、奋乃静、硫利达嗪、三氟拉嗪和乙二胺四乙酸盐或其药学上可接受的衍生物的化合物,以及药学上可接受的佐剂、稀释剂或载体。
15.一种产品,包含至少一种选自二氯芬、氯丙硫蒽、奋乃静、硫利达嗪、三氟拉嗪和乙二胺四乙酸盐或其药学上可接受的衍生物的化合物以及碳青霉烯或其药学上可接受的衍生物,作为用于同时、分开或依次用于治疗微生物感染的组合制剂。
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