CN110049761A - N-乙酰半胱氨酸作为抗菌剂的用途 - Google Patents
N-乙酰半胱氨酸作为抗菌剂的用途 Download PDFInfo
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Abstract
本发明涉及N‑乙酰半胱氨酸在治疗由病原体导致的细菌感染中的用途，所述病原体选自洋葱伯克霍尔德杆菌(BCC)和嗜麦芽窄食单胞菌菌株。
Description
技术领域
本发明涉及N-乙酰半胱氨酸(下文称为NAC)在抑制或阻止选自洋葱伯克霍尔德菌群(Burkholderia cepacia complex)(下文称为BCC)和嗜麦芽窄食单胞菌(Stenotrophomonas maltophilia)(下文为嗜麦芽窄食单胞菌(S.maltophilia))的病原体的易感菌株的生长和/或杀灭它们中的用途。
更具体地，本发明涉及NAC在治疗至少部分由选自BCC和嗜麦芽窄食单胞菌菌株的病原体引起的疾病中的用途。
背景技术
BCC对健康人群几乎没有医疗风险。然而，具有免疫系统较弱或慢性肺病、特别是囊性纤维化的个体的呼吸道可能更容易受到BCC感染。BCC感染可导致肺部恶化加速的肺功能下降，例如在囊性纤维化患者中。
作为慢性定植者，BCC还可以引起具有除囊性纤维化之外的肺病的患者的感染，例如慢性阻塞性肺疾病和慢性肉芽肿病。
嗜麦芽窄食单胞菌感染主要发生在衰弱和免疫抑制的个体中，但不仅限于此。嗜麦芽窄食单胞菌通常与人体类呼吸道感染有关；例如，嗜麦芽窄食单胞菌可引发慢性阻塞性肺疾病和囊性纤维化的肺部恶化。
BCC和嗜麦芽窄食单胞菌的特征在于多药抗性表型和形成生物膜的能力。凭借这些特征，它们负责具有免疫系统减弱或慢性肺病、特别是囊性纤维化的个体的慢性肺定植，其可能持续数月或数年并且当前的抗生素治疗策略难以或不可能根除。
发明内容
申请人认为，BCC和嗜麦芽窄食单胞菌感染的发生可导致肺部恶化的发作，使受慢性疾病影响的个体的已经受损的临床状况恶化，所述慢性疾病也影响下呼吸系统，例如，囊性纤维化和慢性阻塞性肺疾病。
因此，申请人已经面临治疗BCC和/或嗜麦芽窄食单胞菌感染的问题，其导致患有也影响下呼吸系统(例如囊性纤维化和慢性阻塞性肺疾病)的慢性疾病的个体的肺部恶化的至少部分发作。
经过一系列的测试和实验后，申请人惊奇地发现NAC能够对一致数量的BCC和嗜麦芽窄食单胞菌临床分离株发挥抗菌活性，甚至产生杀菌作用。更引人注目的是，已经发现NAC在BCC和嗜麦芽窄食单胞菌的体外生物膜模型中具有抗生物膜活性。因此，可以设想NAC作为用于治疗BCC和/或嗜麦芽窄食单胞菌感染的治疗工具，因此有助于改善具有严重受损临床表现的患者，例如上述患者。NAC抑制BCC和/或嗜麦芽窄食单胞菌生物膜形成的能力预期还可用于预防那些病原体的肺定植，特别是在受也影响下呼吸系统的慢性疾病影响的个体中，例如，囊性纤维化和慢性阻塞性肺疾病。
发明详述
NAC是氨基酸L-半胱氨酸和还原型谷胱甘肽(GSH)的乙酰化前体。从历史上看，在患有慢性呼吸道疾病的粘质或增厚气道粘液的患者中，它已被用作粘液溶解剂，并且结合胸部理疗，作为对乙酰氨基酚超剂量的解毒剂，并且可作为以自由基氧化性损伤为特征的疾病的潜在治疗方法。
根据本发明，申请人现已惊奇地发现NAC还有效抑制或阻止BCC和嗜麦芽窄食单胞菌易感菌株的生长和/或杀灭它们，已知其至少部分的是肺部恶化发作的原因，使受慢性病影响的个体已经受损的临床状况恶化，所述慢性疾病也影响下呼吸系统，例如囊性纤维化和慢性阻塞性肺疾病。
因此，本发明的目的在于NAC用于抑制或阻止选自BCC和嗜麦芽窄食单胞菌的病原体的易感菌株的生长和/或杀灭它们。
本发明的另一个目的在于NAC在治疗由选自BCC和嗜麦芽窄食单胞菌的病原体的易感菌株引起的细菌感染中的用途。
本发明的另一个目的在于NAC在治疗个体肺部恶化的发作中的用途，所述肺部恶化至少部分地由选自BCC和嗜麦芽窄食单胞菌的病原体的易感菌株引起，所述个体患有也影响下呼吸系统的慢性疾病，例如，囊性纤维化和慢性阻塞性肺疾病。
在本发明的一个特定方面，患有如上所述的慢性疾病的个体是免疫受损的和/或住院的患者。
另一方面，本发明涉及NAC在抑制BCC和/或嗜麦芽窄食单胞菌生物膜形成中的用途，尤其是NAC在通过抑制BCC和/或嗜麦芽窄食单胞菌生物膜的形成来预防肺定植中的用途，特别是在受也影响下呼吸系统的慢性疾病影响的个体中，例如，囊性纤维化和慢性阻塞性肺疾病。
根据本发明，术语“个体”或“患者”可互换使用，指哺乳动物物种的成员，优选人。
根据本发明，术语“抗微生物”是指通过抑制、阻止细菌的生长和/或杀死它们来减少细菌的有害作用。
根据本发明，术语“杀菌”是指对细菌具有破坏性杀灭作用。
根据本发明，“细菌感染”是指微生物群体的存在对宿主哺乳动物有害的任何情况。因此，当个体体内或体上存在过量的微生物群体时，或者当微生物群体的存在对个体细胞或其他组织造成损害时，个体就会"患有"微生物感染。
根据本发明，术语“恶化”是指疾病严重程度或其任何体征或症状的增加。特别地，肺部恶化可以通过患者呼吸症状的急性恶化间歇性发作来鉴定，这种情况超出了日常变化形式并导致用药变化，并且通常导致发病率，住院率，死亡率变化以及强烈影响与健康相关的生活质量。
根据本发明，术语“治疗”是指减小，减少，减弱，限制或减轻个体中由BCC和嗜麦芽窄食单胞菌的易感菌株导致的细菌感染的程度，强度，范围或由其引起的相关症状，所述个体患有也影响下呼吸系统的慢性疾病。
NAC可商购获得，也可通过本领域已知的方法合成。
包含用于本发明用途的NAC以及由一种或多种赋形剂组成的适于药学用途的载体的药物组合物也包括在本发明的范围内。
根据本发明，术语“载体”包含适合作为将NAC递送至适合的体内或体外部位的媒介物的任何物质。
根据本发明，术语“赋形剂”包含添加到药物组合物中的任何惰性物质，以进一步促进活性成分的施用。
任何适合的施用途径可用于本发明的组合物，包括口服，肠胃外(皮下，肌内或静脉内)和吸入途径。
根据本发明，术语“口服”或“通过口服”是指通过口腔导入体内，从而在身体的下列一个或多个区域中发生吸收：口腔，胃，小肠和口腔粘膜的小血管。
用于口服施用的NAC制剂的非限制性实例包括例如片剂，包衣片，颗粒剂，丸剂，胶囊剂，液体，凝胶，糖浆剂，悬浮剂等，其用于由个体口服摄取。用于口服施用的适合的载体是本领域熟知的。
对于肠胃外施用，NAC可以配制在水溶液中，例如在生理学相容的缓冲液或生理盐缓冲液中。用于注射的制剂可以以单位剂型存在，例如，在安瓿中，或在多剂量容器中，任选地，其中添加有防腐剂。
对于通过吸入途径施用，NAC典型地可以配制在水溶液中，并且通过使用由塑料或玻璃制成的常规喷雾器便利地以细小雾化方式递送，从而为患者提供最佳量的适合范围的粒度。NAC也可以通过气管内或粘膜施用直接滴入下呼吸道施用；或者，可以用肺内气雾器或超小型气雾器进行NAC的直接滴注。
本发明的药物组合物可以按照本领域熟知的方法以常规方式制备。
本发明的优选药物组合物是片剂和小瓶。
根据本发明使用的NAC的量可以根据施用途径，所选择的组合物种类，患者的个体特征，治疗持续时间和同时治疗的性质的不同而变化。
例如，NAC的有效量可以在个体中产生减小，减少，减弱，限制或减轻由BCC和嗜麦芽窄食单胞菌的易感菌株引起的细菌感染的程度，强度，范围或其相关症状，所述个体患有也影响下呼吸系统的慢性疾病，例如，囊性纤维化和慢性阻塞性肺疾病。
在一个特定方面，NAC的有效量可以减少个体中至少部分是由敏感的BCC和嗜麦芽窄食单胞菌菌株引起的肺部恶化发作的严重性的频率，持续时间或减轻/减弱/减少至少部分是由敏感的BCC和嗜麦芽窄食单胞菌菌株引起的肺部恶化发作的严重性，所述个体患有也影响下呼吸系统的慢性疾病，例如，囊性纤维化和慢性阻塞性肺疾病；和/或加速所述发作的症状改善的时间。
根据一个实施方案，NAC的有效量可以在100至5800mg/天之间变化，以单剂量或更多重复剂量施用。优选地，NAC的有效量可以在100至4600mg/天之间变化。
含有用于不同适应症的NAC的不同剂型可在欧盟和美国商购获得。包含NAC的药物组合物例如在意大利以商标出售。
确切的组合物，施用途径和剂量可以由个体医生根据患者的病情选择。
为了更好地示例本发明，现在给出以下非限制性实施例。
具体实施方案
材料/方法：通过肉汤微量稀释法确定NAC对16种嗜麦芽窄食单胞菌和16种BCC(即洋葱伯克霍尔德菌，B.cenocepacia，B.multivorans，B.metallica，B.seminalis，B.stabilis)临床分离株的最小抑制浓度(MIC)。用8种选择的菌株(4种嗜麦芽窄食单胞菌和4种BCC分离物)进一步研究了NAC的抗微生物和抗生物膜活性，其显示出16mg/ml的MIC。通过监测亚MIC浓度(即4和8mg/ml)对生长曲线的影响，并通过进行时间杀灭测定(于16和32mg/ml)来评估抗微生物活性。使用MBEC高通量测定法研究NAC抑制生物膜形成(于4、8和16mg/ml)的能力，并通过活细胞计数(VCC)评估。
结果：对于9种和7种嗜麦芽窄食单胞菌和BCC分离株，NAC的MIC分别为16mg/ml，其余为32mg/ml。在亚MIC浓度下，NAC减缓了所有测试分离株的生长。在时间杀灭测定中，32mg/ml的NAC对一种嗜麦芽窄食单胞菌和一种BCC分离物具有杀菌作用(即以超过3倍对数导致细菌接种物减少)，并且对于三个另外的分离株(即两个嗜麦芽窄食单胞菌和一个BCC)减少的范围为1.1至1.7log CFU/ml，而观察到其余的分离株减少<1log CFU/ml。对于嗜麦芽窄食单胞菌和BCC，生物膜生长范围分别为6.7至7.1log CFU/peg和5.1至6.6log CFU/peg。发现NAC以对所有嗜麦芽窄食单胞菌和两种BCC分离物的剂量依赖性方式抑制生物膜形成。在NAC 8mg/ml和NAC 16mg/ml下，与对照相比，Δlog CFU/peg范围分别为0.75至3.8log CFU/peg和2.5至5.8log CFU/peg。
总之，NAC显示出针对BCC和嗜麦芽窄食单胞菌菌株的内在抗微生物活性。除了在NAC浓度≥16mg/ml下抑制生长，并在亚MIC浓度下减缓生长速率外，还发现NAC对BCC和嗜麦芽窄食单胞菌具有一定的杀灭活性，有时达到杀菌效果(即常规定义为以超过3倍对数减少细菌接种量)。引人注目的是，NAC在防止这些病原体形成生物膜方面也显示出有希望的功效。
Claims (7)
1.用于抑制或阻止选自BCC和嗜麦芽窄食单胞菌的易感菌株的生长和/或杀伤它们中的用途的NAC。
2.用于治疗由选自BCC和嗜麦芽窄食单胞菌的病原体的易感菌株导致的细菌感染中的用途的NAC。
3.用于治疗个体中至少部分由选自BCC和嗜麦芽窄食单胞菌的病原体的易感菌株导致的肺部恶化发作中的用途的NAC，所述个体患有还影响下呼吸系统的慢性疾病。
4.权利要求3的NAC，其中所述慢性疾病是囊性纤维化或慢性阻塞性肺疾病。
5.权利要求4的NAC，其中患有慢性疾病的个体是免疫受损和/或住院患者。
6.用于预防受也影响下呼吸系统的慢性疾病侵害的个体中的肺定植中的用途的NAC，通过抑制BCC和/或嗜麦芽窄食单胞菌生物膜的形成来进行。
7.权利要求6的NAC，其中所述慢性疾病是囊性纤维化或慢性阻塞性肺疾病。
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Non-Patent Citations (2)
| Title |
|---|
| FRANCESCO BLASI等: "The effect of N-acetylcysteine on biofilms: Implications for the treatment of respiratory tract infections", 《RESPIRATORY MEDICINE》 * |
| 邹玉明等: "N-乙酰半胱氨酸对呼吸道感染病原菌的抑菌作用及影响因素研究", 《现代预防医学》 * |
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