CN111757732A - 用于治疗感染性动脉疾病和相关病状的组合物 - Google Patents
用于治疗感染性动脉疾病和相关病状的组合物 Download PDFInfo
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- CN111757732A CN111757732A CN201980006904.6A CN201980006904A CN111757732A CN 111757732 A CN111757732 A CN 111757732A CN 201980006904 A CN201980006904 A CN 201980006904A CN 111757732 A CN111757732 A CN 111757732A
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- Medicinal Preparation (AREA)
Abstract
在替代实施例中，提供用于治疗、改善和预防与感染相关的血管疾病，并且还用于治疗、改善和预防可被这些组合物治疗的受感染因素影响的非血管疾病的药物组合物和方法。在替代实施例中，如本文中提供的组合物和方法所标靶的一种常见病原体是衣原体和嗜衣原体物种，包括肺炎、沙眼和鹦鹉热等可感染人类的物种，包括同样感染人类的肺炎嗜衣原体。在替代实施例中，如本文中提供的组合物和方法所标靶的病原体和所治疗、改善或预防的感染(疾病)包括支原体属、李斯特菌属、钩端螺旋体病、Q热或贝氏考克斯氏体感染；莱姆病或莱姆疏螺旋体病或任何疏螺旋体属感染；以及巴尔通氏体属或巴尔通氏体科感染，包括猫抓病。所述组合物包含至少三种不同的选定抗生素药剂，其中包含利福霉素(如利福布汀)、巨环内酯(如克拉霉素或阿奇霉素)和四环素(如强力霉素)或硝基呋喃(诸如呋喃唑酮)的组合物为较佳的。
Description
技术领域
本发明一般涉及医学和传染病。在替代实施例中，提供用于治疗、改善和预防与感染相关的血管疾病，并且还用于治疗、改善和预防可被这些组合物治疗的受感染因素影响的非血管疾病的药物组合物和方法。在替代实施例中，如本文中提供的组合物和方法所标靶的一种常见病原体是衣原体(Chlamydia)和嗜衣原体(Chlamydophila)物种，包括肺炎(pneumoniae)、沙眼(trachomatis)和鹦鹉热(psittaci)等可感染人类的物种，包括同样感染人类的肺炎嗜衣原体(Chlamydophila pneumoniae)。在替代实施例中，如本文中提供的组合物和方法所标靶的病原体和所治疗、改善或预防的感染(疾病)包括支原体属(Mycoplasma)、李斯特菌属(Listeria)、钩端螺旋体病(Leptospirosis)、Q热(Q fever)或贝氏考克斯氏体(Coxiella burnetii)感染；莱姆病(Lyme disease)或莱姆疏螺旋体病(Lyme borreliosis)或任何疏螺旋体属(Borrelia)感染；以及巴尔通氏体属(Bartonella)或巴尔通氏体科(Bartonellaceae)感染，包括猫抓病。
背景技术
如上所述的非典型感染会感染人体的各个区域，并且通常携带在如单核细胞/巨噬细胞的循环白细胞中。其通常感染细胞内位置，例如，动脉内膜层细胞，引起动脉慢性炎症，随后出现水肿、坏死、泡沫细胞形成，从而导致斑块形成。如冠心病和中风的血管疾病仍然是全世界发病率和死亡率的主要原因所在。特别是在中国，冠心病和外周动脉疾病患者增加人数被描述为具有流行病比例。
冠心病(CAD)和周围血管疾病目前都通过识别和标靶‘风险因素’进行治疗，因为这些风险因素是在没有这些病状的潜在病因的情况下进行治疗的唯一参数。
将肺炎嗜衣原体(Cpn)携带到内膜的巨噬细胞侵入后在血管壁中形成动脉粥样硬化始于可见的泡沫细胞，随后出现水肿或肿胀，之后肌肉细胞受到破坏并坏死，伴随完全成形的斑块突出到搏动的心外膜动脉的内腔中。斑块形成可伴随并发症，如部分斑块破裂和凝血级联反应的局部活化，这可能会使血管部分或完全阻塞。这可能导致被称为‘心肌梗塞’的远端组织/肌肉死亡，并可能伴有严重的疼痛和心律不齐。当这种情况在大脑中发生时，被称为‘缺血性中风’。类似的过程也可能发生在诸如腿部和脚部血管的周围血管中，从而导致其冰冷、疼痛、失去知觉或最终导致脚趾坏死。
血管疾病的常规疗法旨在打开血管腔并防止或逆转血块形成并减少斑块形成。因此，治疗和预防性治疗的目标是风险因素，如高血压、吸烟和血脂异常。
Cpn的治疗是针对一种感染性细菌，所述细菌可以在动脉组织中观察到并由其培养。可与肺炎衣原体(Chlamydia pneumonia)互换的名称肺炎嗜衣原体直到最近才有描述，并已知为可感染多种组织的微生物。其引起社区获得性肺炎、支气管炎、慢性阻塞性呼吸道疾病和哮喘的发生率高达三分之一，并且现已被认为存在于动脉粥样硬化斑块中。因此，Cpn被认为与肺和动脉炎症有因果关系，并且很可能是已知的动脉炎症的病因，所述动脉炎症早于斑块形成并因此引起如冠心病的血管疾病。还已经表明肺炎嗜衣原体Cpn能够使用胆固醇，并且Cpn在其代谢循环中能够产生含有脂质的细胞，并且其因此引起泡沫细胞出现在动脉粥样硬化斑块的形成部位。这更好地解释了血管中胆固醇与脂肪之间的关系以及Cpn的作用，并解释了动脉壁脂质沉积与源于食物的胆固醇和甘油三酯有关的原因。Cpn是专性的细胞内病原体，其在巨噬细胞内以及包括肌肉细胞在内的血管壁细胞内生长。Cpn感染的特征在于感染后细胞内的持久性，并且据估计，成年后约有50％的人群对Cpn呈血清阳性，并且大多数人通常在青少年时期就已通过呼吸道途径得到感染。如沙眼衣原体的相关衣原体感染可引起急性感染，如结膜炎、性传播疾病以及慢性感染，其可导致沙眼、输卵管感染和不孕不育、盆腔炎性疾病和反应性关节炎。对于Cpn，急性感染局限于呼吸道，以肺炎和支气管炎为最常见的病状。由急性或无症状感染引起的慢性后遗症有时不能确切地归因于Cpn。但有越来越多的证据表明，这可能导致使人虚弱的哮喘病甚至致命的心脏病。其还可能引起反应性关节炎、可能的迟发性阿尔茨海默氏病、多发性硬化症以及这些疾病的并发症。
同菌属的其它成员一样，Cpn在传染性、代谢上惰性的基本体(EB)和非传染性代谢活性的网状体(RD)之间具有特征性的两相生命周期。EB被内化到病原体修饰的吞噬体中，避免了溶酶体的破坏。这被称为包裹体，并且Cpn进入非繁殖性生长状态的这种能力通常称为持久性或休眠性。并非所有感染Cpn的人都患有血管疾病或哮喘，但是微生物的恢复率介于动脉粥样硬化组织部位的20％至60％之间，而进行连续组织学切片处理时，其回收率则高达100％。所述生物尚未从正常血管组织中恢复。已经开发出动物模型，在所述模型中以加速方式在感染Cpn后形成动脉粥样硬化斑块。
已经尝试了多种疗法，但一般来说，仅使用了单一疗法，即给患者使用了一种抗生素。阿奇霉素已被使用并显示出一定的益处，但这并没有持续。使用罗红霉素也有益处。四环素已被用作单一疗法，但并没有临床益处，并且从那时起，已发现抑菌四环素可以将代谢活跃的网状体(RB)转化成代谢不活跃的基本体(EB)，其在代谢上是惰性的，并且受抗生素的影响较小。
由于处于休眠形式，使用单一的抗生素治疗Cpn最多难于根除，其有可能在世界上的大量人口中造成严重的不良后果，而且许多抗生素会产生耐药性感染，而这实际上不可能成为任何有效的疗法。在许多情况下，发生的是抑制而不是根除，并且在撤除抗生素后，被抑制的病原体可能会重新活化并产生耐药菌株。
可以使用某些细胞因子，抗生素并通过剥夺某些营养物质在体外建立持续的衣原体感染。这也可能在体内发生。当去除生长抑制因子时，作为呈非典型形式的网状体(RB)的异常体可以恢复正常。持续性Cpn感染的特征在于大RB形式的形成以及EB的缺失。因此，在产生营养应激条件的细胞环境中，Cpn生物体陷入‘持续状态’。持续状态的存在会导致所述个体的免疫系统呈现一致状态，并可能导致潜在的有害免疫影响，例如慢性关节炎和动脉炎症。反复感染也可能引起与持续感染相似的影响。去除各种抗生素(特别是青霉素、环丙沙星(Ciprofloxacin)或氧氟沙星(Ofloxacin))可引起持久性感染明显减少，并使持久性衣原体变成传染性EB，其更易于治疗，并为更好地根除打开了大门。及时开始和停止某些此类抗生素的循环会改善复原为可治疗状态。
关于联合使用抗生素的教导很少。但是，使用体外敏感性测试与体内临床结果无关，因此不应再使用这种方法。敏感性仍应进行测试，但在慢性长期感染中，至少应结合三种抗菌剂，以尝试防止形成广泛的耐药性。因此，需要一种更好的方法来治疗与上述Cpn和其它感染相关的疾病。还需要用抗生素的组合有效地治疗初始感染，以防止其进入慢性阶段，从而导致疾病持续发展和细菌耐药性增强。
发明内容
在替代实施例中，提供药物组合物、调配物或制品，其包含选自由以下组成的组的至少三种不同的抗生素：
(a)
(i)大环内酯类(例如阿奇霉素(azithromycin)、克拉霉素(clarithromycin)、红霉素、非达霉素(fidaxomicin)、泰利霉素(telithromycin))、喹诺酮(quinolone)(例如氟喹诺酮(fluoroquinolone))、氯霉素(例如PENTAMYCETINTM、CHLOROMYCETINTM)、头孢菌素(cephalosporin)、硝唑尼特(nitazoxanide)(例如ALINIATM、NIZONIDETM)、呋喃唑酮(furazolidone)(例如FUROXONETM、DEPENDAL-MTM)、林可霉素(lincomycin)或克林霉素(clindamycin)(例如CLEOCINTM、CLINACINTM)、氨基糖苷(例如链霉素)、碳青霉烯类(carbapenem)(例如亚胺培南(imipenem)、美罗培南(meropenem)、厄他培南(ertapenem)、多利培南(doripenem)、帕尼培南(panipenem)或倍他米隆(betamipron)、比阿培南(biapenem)、替比培南(tebipenem))，糖肽(例如万古霉素(vancomycin)、替考拉宁(teicoplanin)、特拉万星(telavancin)、拉莫宁(ramoplanin)、德卡拉宁(decaplanin))、甘氨四环素(例如替加环素(tigecycline))、链阳菌素类(例如奎奴普汀(quinupristin)/达福普汀(dalfopristin)、普那霉素(pristinamycin)、维吉霉素(virginiamycin))、利福霉素(例如利福平(rifampicin)(或立复霉素(rifampin))、利福布汀(rifabutin)、利福喷丁(rifapentine)、利福拉齐(rifalazil)、利福昔明(rifaximin)、利福霉素SV(或AEMCOLOTM))、安沙霉素(ansamycin)(例如曲线链菌素(streptovaricin)、格尔德霉素(geldanamycin)、利福霉素)、磺酰胺(例如磺胺二甲氧嘧啶(sulfadimethoxine)、磺胺甲氧哒嗪(sulfamethoxypyridazine)、磺胺对甲氧嘧啶(sulfametoxydiazine)、磺胺多辛(sulfadoxine)、磺胺甲氧吡嗪(sulfametopyrazine)、泰瑞夫塔(terephtyl))、恶唑烷酮(oxazolidinone)(例如2-恶唑烷酮、利奈唑胺(linezolid)、泊斯唑胺(posizolid)、特地唑胺(tedizolid)、雷德唑胺(radezolid)、环丝氨酸(cycloserine))和/或硝基咪唑(例如甲硝唑(metronidazole)、替硝唑(tinidazole)、尼莫拉唑(nimorazole)、迪美唑(dimetridazole)、普雷托麦迪(pretomanid)、奥硝唑(ornidazole)、米甲唑(megazol)、阿扎硝唑(azanidazole))；或
(ii)利福拉齐、利福布汀(例如MYCOBUTINTM)、奥米加南(omiganan)(或奥米加南五盐酸盐)、雷德唑胺(radezolid)(RX-1741)、特地佐利(torezolid)、RWJ-416457、头孢比普(ceftobiprole)(或ZEVTERATM、MABELIOTM)、硝基呋喃(例如硝呋烯腙(difurazone)、呋喃唑酮(furazolidone)、硝呋福林(nifurfoline)、硝呋齐特(nifuroxazide)、硝呋喹唑(nifurquinazol))、异烟肼(例如HYDRATM、HYZYDTM、ISOVITTM)、头孢洛林(ceftaroline)(例如头孢洛林酯(ceftaroline fosamil)或TEFLAROTM、ZINFOROTM)、艾拉普林(iclaprim)、加雷沙星(garenoxacin)、喹红霉素(例如RESTANZATM)和/或泰利霉素(例如KETEKTM)(大环内酯类的一部分)、强力霉素、替加环素(例如TYGACILTM)、米诺环素(例如MINOCINTM、AKAMINTM)和/或四环素(例如SUMYCINTM)；或，
(iii)(i)和(ii)的组合；
(b)(a)的药物组合物、调配物或制品，其还包含至少四种抗生素，并且任选地，甲硝唑(例如FLAGYLTM、METROTM)、替硝唑(例如FASIGYNTM、SIMPLOTANTM、TINDAMAXTM)、奥硝唑(ornidazole)(例如XYNORTM)、塞克硝唑(secnidazole)(例如FLAGENTYL、SINDOSETM、SECNITML、SOLOSECTM)、罗红霉素(roxithromycin)、强力霉素(例如DORYXTM、DOXYHEXALTM、DOXYLINTM)、米诺环素(例如，MINOCINTM、MINOMYCINTM、AKAMINTM)、克拉霉素(例如BIAXINTM)和/或硝基咪唑(例如甲硝唑、替硝唑、尼莫拉唑、迪美唑、普雷托麦迪、奥硝唑、米甲唑、阿扎硝唑)为所述至少一种第四种抗生素，
并且任选地，所述硝基咪唑调配用于给药，以循环呈服药2周并停药2周。
在替代实施例中，至少三种不同的抗生素包含：
(a)利福平、阿奇霉素和莫西沙星(moxifloxacin)，其任选地呈渐升剂量(或调配用于渐升剂量方案)；
(b)至少包含利福布汀、克拉霉素或阿奇霉素；
(c)至少包含利福布汀和米诺环素；
(d)至少包含利福布汀和阿奇霉素；
(e)至少包含利福布汀和克拉霉素；或
(f)包含利福布汀、阿奇霉素和米诺环素。
在替代实施例中，提供一种药物组合物、调配物或制品，其包含：
(a)至少三种不同的抗生素，其选自由以下组成的组：
(i)大环内酯类(例如阿奇霉素、克拉霉素、红霉素、非达霉素、泰利霉素)、喹诺酮(例如氟喹诺酮)、氯霉素(例如PENTAMYCETINTM、CHLOROMYCETINTM)、头孢菌素、硝唑尼特(例如ALINIATM、NIZONIDETM)、呋喃唑酮(例如FUROXONETM、DEPENDAL-MTM)、林可霉素或克林霉素(例如CLEOCINTM、CLINACINTM)、氨基糖苷(例如链霉素)、碳青霉烯类(例如亚胺培南、美罗培南、厄他培南、多利培南、帕尼培南或倍他米隆、比阿培南、替比培南)，糖肽(例如万古霉素、替考拉宁、特拉万星、拉莫宁、德卡拉宁)、甘氨四环素(例如替加环素)、链阳菌素类(例如奎奴普汀/达福普汀、普那霉素、维吉霉素)、利福霉素(例如利福平(或立复霉素)、利福布汀、利福喷丁、利福拉齐、利福昔明、利福霉素SV(或AEMCOLOTM))、安沙霉素(例如曲线链菌素、格尔德霉素、利福霉素)、磺酰胺(例如磺胺二甲氧嘧啶、磺胺甲氧哒嗪、磺胺对甲氧嘧啶、磺胺多辛、磺胺甲氧吡嗪、泰瑞夫塔)、恶唑烷酮(例如2-恶唑烷酮、利奈唑胺、泊斯唑胺、特地唑胺、雷德唑胺、环丝氨酸)和/或硝基咪唑(例如甲硝唑、替硝唑、尼莫拉唑、迪美唑、普雷托麦迪、奥硝唑、米甲唑、阿扎硝唑)；或
(ii)利福拉齐、利福布汀(例如MYCOBUTINTM)、奥米加南(或奥米加南五盐酸盐)、雷德唑胺(RX-1741)、特地佐利、RWJ-416457、头孢比普(或ZEVTERATM、MABELIOTM)、硝基呋喃(例如硝呋烯腙、呋喃唑酮、硝呋福林、硝呋齐特、硝呋喹唑)、异烟肼(例如HYDRATM、HYZYDTM、ISOVITTM)、头孢洛林(例如头孢洛林酯或TEFLAROTM、ZINFOROTM)、艾拉普林、加雷沙星、喹红霉素(例如RESTANZATM)和/或泰利霉素(例如KETEKTM)(大环内酯类的一部分)、强力霉素、替加环素(例如TYGACILTM)、米诺环素(例如MINOCINTM、AKAMINTM)和/或四环素(例如SUMYCINTM)；或，
(iii)(i)和(ii)的组合；或
(b)(a)的药物组合物、调配物或制品，其还包含至少一种第四抗生素，并且任选地，甲硝唑(例如FLAGYLTM、METROTM)、替硝唑(例如FASIGYNTM、SIMPLOTANTM、TINDAMAXTM)、奥硝唑(例如XYNORTM)、塞克硝唑(例如FLAGENTYL、SINDOSETM、SECNITML、SOLOSECTM)、罗红霉素、强力霉素(例如DORYXTM、DOXYHEXALTM、DOXYLINTM)、米诺环素(例如，MINOCINTM、MINOMYCINTM、AKAMINTM)、克拉霉素(例如BIAXINTM)和/或硝基咪唑(例如甲硝唑、替硝唑、尼莫拉唑、迪美唑、普雷托麦迪、奥硝唑、米甲唑、阿扎硝唑)为所述至少第四抗生素，
并且任选地，所述硝基咪唑调配用于给药，以循环呈服药2周并停药2周。
在替代实施例中，至少三种不同的抗生素包含克拉霉素、利福布汀和呋喃唑酮。或者，至少三种抗生素包含利福布汀、阿奇霉素和强力霉素。利福布汀、阿奇霉素和强力霉素可与维生素D合并使用。
在替代实施例中，药物组合物、调配物或制品还包含：(a)维生素E、生育三烯酚、天然生育酚或生育色原烷醇、维生素D或其任何组合，其中任选地，维生素D调配用于以每天至多约5000至20,000单位的剂量使用，任选地获得约150至375nmol/l的血液含量；(b)青霉胺或DEPENTM或CUPRIMINETM；(c)乙酰半胱氨酸或N-乙酰半胱氨酸(NAC)，或ACETADOTETM、FLUIMUCILTM、MUCOMYST；或(d)(a)至(c)的任何组合。在替代实施例中，维生素D需要以高于预期的剂量使用，如在患者中所显示，例如，以每天约5000至20,000单位的剂量达到接近约200至375nmol/l的正常范围上限的血液含量。这些含量是无毒的，为了使毒性发生，需要达到要高得多的含量才行。
在替代实施例中，药物组合物、调配物或制品还包含：选自以下的药剂：用于管理冠状动脉和其它血管疾病的其它药物、增强对根除细胞内病原体至关重要的宿主防御机制的其它药物；选择性和非选择性环氧合酶抑制剂；其它抗血小板药物；β受体阻滞剂；抗心律失常药；钙通道阻滞剂；其它抗凝血药物；硝酸盐药物和HMG-Coa还原酶抑制剂；选自以下的免疫应答调节剂：细胞因子；菌落刺激因子；肿瘤坏死因子α和β；干扰素α、β和γ；结合于巨噬细胞和淋巴细胞表面受体的肽：模拟细胞因子的糖蛋白；和其它介体分子；泼尼松和相关类固醇；硫唑嘌呤(azathioprine)；霉酚酸酯(mofetil mycofenolate)和相关嘌呤拮抗剂；环磷酰胺和相关烷基化剂；甲氨蝶呤和相关叶酸拮抗剂；沙利度胺(thalidomide)；氯喹(chloroquine)和相关抗疟化合物；左旋咪唑(levamisole)；环孢菌素A；雷帕霉素(rapamycin)和/或FK506。
在替代实施例中，药物组合物、调配物或制品调配用于肠胃外或肠内递送或用于口服递送，任选地在胶囊、片剂、凝胶片或溶液或液体中或以气雾剂形式递送，其中任选地，至少三种不同的抗生素，或至少两种抗生素，或所有活性剂在一种调配物中，任选地呈胶囊、片剂、凝胶片或溶液或液体。
在替代实施例中，制品是植入物。
在替代实施例中，提供用于抑制将肺炎嗜衣原体(Cpn)携带到动脉内膜的巨噬细胞入侵后在动脉血管壁中形成动脉粥样硬化的方法，或用于治疗、改善和预防以下疾病的方法：
-与感染相关的血管疾病，
-受感染物影响的非血管疾病，
-由衣原体或嗜衣原体物种引起的病症或病状，包括肺炎、沙眼和鹦鹉热等可感染人类的物种，包括肺炎嗜衣原体，
-由以下引起的疾病或病状：支原体属、李斯特菌属、钩端螺旋体病、Q热或贝氏考克斯氏体感染；莱姆病或莱姆疏螺旋体病或任何疏螺旋体属(Borrelia)感染；以及巴尔通氏体属或巴尔通氏体科感染，包括猫抓病，
-动脉炎症、动脉粥样硬化或动脉泡沫细胞，
-慢性关节炎，或
-阿尔茨海默氏病或痴呆，其中任选地，所述痴呆是血管性痴呆、路易体性痴呆、或额颞叶性痴呆、或因正常压力脑积水、帕金森氏病痴呆、梅毒或克-雅氏病(Creutzfeldt-Jakob disease)导致或引起的痴呆，
所述方法包括向有需要的个体给予如本文中提供的药物组合物、调配物或制品。
在替代实施例中，所述方法进一步包含给予以下物质：
(a)维生素E或生育三烯酚或等效物(任选地包含维生素E或生育色原烷醇，其呈天然生育酚或生育三烯酚)，其任选地以循环方式添加，任选地介于每天至每周投药之间；和/或
(b)维生素D，其任选地被给予直到正常含量的上限，任选地以每天至少约5,000至约20,000单位的剂量给予，任选地直到达到还能够杀死细胞内感染物并降低所述细胞内感染物，任选地巨噬细胞中的肺炎嗜衣原体的细胞内持久性的含量。
在所述方法的替代实施例中，药物组合物或调配物肠胃外或肠内或口服，任选地在胶囊、片剂、凝胶片或溶液或液体中或以气雾剂形式给予，其中任选地，至少三种不同抗生素，或至少两种抗生素，或所有活性剂在一种制剂中，任选地呈胶囊、片剂、凝胶片或溶液或液体，并且任选地，将每种活性剂调配成单独制品，任选地将每种活性剂调配成单独的胶囊、片剂、凝胶片、溶液或液体。
在替代实施例中，提供如本文中提供的药物组合物、调配物或制品的用途，其用于抑制将肺炎嗜衣原体(Cpn)携带到动脉内膜的巨噬细胞入侵后在动脉血管壁中形成动脉粥样硬化，或用于治疗、改善和预防以下疾病：
-与感染相关的血管疾病，
-受感染物影响的非血管疾病，
-由衣原体或嗜衣原体物种引起的病症或病状，包括肺炎、沙眼和鹦鹉热等可感染人类的物种，包括肺炎嗜衣原体，
-由以下引起的疾病或病状：支原体属、李斯特菌属、钩端螺旋体病、Q热或贝氏考克斯氏体感染；莱姆病或莱姆疏螺旋体病或任何疏螺旋体属感染；以及巴尔通氏体属或巴尔通氏体科感染，包括猫抓病，
-动脉炎症、动脉粥样硬化或动脉泡沫细胞，
-慢性关节炎，或
-阿尔茨海默氏病或痴呆，其中任选地，所述痴呆是血管性痴呆、路易体性痴呆、或额颞叶性痴呆、或因正常压力脑积水、帕金森氏病痴呆、梅毒或克-雅氏病导致或引起的痴呆。
在替代实施例中，提供如本文中提供的药物组合物、制剂、制品，其用于抑制将肺炎嗜衣原体(Cpn)携带到动脉内膜的巨噬细胞入侵后在动脉血管壁中形成动脉粥样硬化，或用于治疗、改善和预防以下疾病：
-与感染相关的血管疾病，
-受感染物影响的非血管疾病，
-由衣原体或嗜衣原体物种引起的病症或病状，包括肺炎、沙眼和鹦鹉热等可感染人类的物种，包括肺炎嗜衣原体，
-由以下引起的疾病或病状：支原体属、李斯特菌属、钩端螺旋体病、Q热或贝氏考克斯氏体感染；莱姆病或莱姆疏螺旋体病或任何疏螺旋体属感染；以及巴尔通氏体属或巴尔通氏体科感染，包括猫抓病，
-动脉炎症、动脉粥样硬化或动脉泡沫细胞，
-慢性关节炎，或
-阿尔茨海默氏病或痴呆，其中任选地，所述痴呆是血管性痴呆、路易体性痴呆、或额颞叶性痴呆、或因正常压力脑积水、帕金森氏病痴呆、梅毒或克-雅氏病导致或引起的痴呆。
在本说明书中阐述了本发明的一个或多个示例性实施例的细节。根据说明书和权利要求书，本发明的其它特征、目的和优点将变得显而易见。
本文引用的所有出版物、专利、专利申请出于所有目的通过引用明确地并入本文。
在替代实施例中，提供根据技术方案1至5中任一项所述的药物组合物、调配物或制品的用途，其用于制造供用于抑制将肺炎嗜衣原体(Cpn)携带到动脉内膜的巨噬细胞入侵后在动脉血管壁上形成动脉粥样硬化，或供用于治疗、改善和预防以下疾病的药物：
-与感染相关的血管疾病，
-受感染物影响的非血管疾病，
-由衣原体或嗜衣原体物种引起的病症或病状，包括肺炎、沙眼和鹦鹉热等可感染人类的物种，包括肺炎嗜衣原体，
-由以下引起的疾病或病状：支原体属、李斯特菌属、钩端螺旋体病、Q热或贝氏考克斯氏体感染；莱姆病或莱姆疏螺旋体病或任何疏螺旋体属感染；以及巴尔通氏体属或巴尔通氏体科感染，包括猫抓病，
-动脉炎症、动脉粥样硬化或动脉泡沫细胞，
-慢性关节炎，或
-阿尔茨海默氏病或痴呆，其中任选地，所述痴呆是血管性痴呆、路易体性痴呆、或额颞叶性痴呆、或因正常压力脑积水、帕金森氏病痴呆、梅毒或克-雅氏病导致或引起的痴呆。
具体实施方式
在替代实施例中，提供用于治疗、改善和预防与感染相关的血管疾病，并且还用于治疗、改善和预防可被这些组合物治疗的受感染因素影响的非血管疾病的药物组合物和方法。在替代实施例中，如本文中提供的组合物和方法所标靶的一种常见病原体是衣原体和嗜衣原体物种，包括肺炎、沙眼和鹦鹉热等可感染人类的物种，包括同样感染人类的肺炎嗜衣原体。在替代实施例中，如本文中提供的组合物和方法所标靶的病原体和所治疗、改善或预防的感染(疾病)包括支原体属、李斯特菌属、钩端螺旋体病、Q热或贝氏考克斯氏体感染；莱姆病或莱姆疏螺旋体病(Lyme borreliosis)或任何疏螺旋体属感染；以及巴尔通氏体属或巴尔通氏体科感染，包括猫抓病。
在替代实施例中，本文提供用于治疗、改善和预防衣原体感染的血管并发症以及由此类感染引起或加重的病症的方法和药物组合物。此类疾病包括哮喘、慢性阻塞性肺疾病、痴呆、泌尿和妇科粘膜衣原体感染。
在替代实施例中，提供用于在需要这种治疗或预防的患者中治疗、改善或预防与衣原体感染(包括肺炎嗜衣原体(Cpn))或如上文所列的其它感染所导致的与感染相关的病状或疾病的方法。
在替代实施例中，如本文中提供的组合物和方法包含或包含向个体(例如患者或动物)给予有效量的至少三种不同的抗生素，所述抗生素选自由以下组成的组：大环内酯类、喹诺酮类、氯霉素、头孢菌素、硝唑尼特、呋喃唑酮、林可霉素、氨基糖苷、碳青霉烯类、糖肽、甘氨四环素、异烟肼、链阳菌素类、利福霉素/安沙霉素、磺酰胺、恶唑烷酮、硝基呋喃和硝基咪唑。
如本文中提供的替代实施例、组合物和方法包含或包含对个体(例如，患者或动物)给予有效量的至少三种不同的抗生素，所述抗生素选自由以下组成的组：克拉霉素、利福布汀和呋喃唑酮。或者，至少三种抗生素包含利福布汀、阿奇霉素和强力霉素。利福布汀、阿奇霉素和强力霉素可与维生素D合并使用。
在替代实施例中，如本文中提供的组合物和方法包含或包含对个体(例如患者或动物)施用有效量的至少三种不同的抗生素，所述抗生素选自由以下组成的组：利福拉齐、利福布汀、奥米加南、雷德唑胺(RX-1741)、特地佐利、RWJ-416457、头孢比普、头孢洛林、艾拉普林、加雷沙星、喹红霉素和/或泰利霉素(大环内酯类的一部分)、替加环素、米诺环素和四环素。
替加环素是一种新型甘氨酰环素，但其仍然是四环素衍生物，对肺炎嗜衣原体(Cpn)具有良好的活性。称为酮内酯的一类新大环内酯类衍生物(其中包括泰利霉素)往往具有与克拉霉素所具有的活性相似的高活性，但某些分离物比其它分离物更敏感。如本文中提供的组合物和方法中使用的最具活性的大环内酯类是喹红霉素。在替代实施例中，如本文中提供的组合物和方法中使用的其它抗Cpn药物和其它抗感染物药物包括万古霉素、庆大霉素、利福昔明、氨苄青霉素(ampicillin)、链霉素、甲氧苄啶/磺胺甲恶唑。在替代实施例中，可以使用的新型肽去甲酰基酶抑制剂包括NVP-PDF386/ABT/773和Des/喹诺酮/BMS/284756。这些是在Cpn治疗中出现的强大的新型抗菌剂。
在替代实施例中，如本文中提供的三药方案包含利福平、阿奇霉素和莫西沙星，任选地呈渐升剂量，这是本发明人观察到的允许用所述组合物治疗而没有副作用的一种特征。在替代实施例中，如本文中提供的三药疗法包含利福布汀和克拉霉素。
在替代实施例中，提供通过给予至少三种以上列出的抗微生物剂来治疗、改善或预防个体(例如患者或动物)的先前或当前的Cpn感染或上述其它感染的方法。
在替代实施例中，为了防止形成Cpn的持久形式，将介于第二每天到每周之间以循环方式添加补充维生素E或生育三烯酚；并且其可以包含维生素E或生育色原烷醇，其呈天然生育酚或生育三烯酚。维生素E衍生物的添加可以显著减少人体异常发育，从而加速人体淋巴细胞中衣原体的破坏。
在替代实施例中，组合物和方法还包含通过每天摄入至少5,000-20,000单位直至达到还能够杀死Cpn并降低细胞内感染物的细胞内持久性的水平，将维生素D添加到正常含量的上限。
在替代实施例中，如甲硝唑、替硝唑、奥硝唑和塞克硝唑的硝基咪唑的循环也防止抗性细胞内网状体(RB)形成，并且可以插入到三种抗生素的循环方案中作为第四抗生素，或甲硝唑、替硝唑、奥硝唑、塞克硝唑、罗红霉素、多西环素、米诺环素、克拉霉素或硝基咪唑可为如本文中提供的药物组合物、调配物或制品中的第四抗生素。
在替代实施例中，如本文中提供的三种药物方案包含利福平、阿奇霉素和莫西沙星，任选地避免使用四环素，因为其可以抑制基本体的产生。
在替代实施例中，如本文中提供的组合物和方法用于阿尔茨海默氏病或痴呆，其中任选地，痴呆为血管性痴呆、路易体痴呆或额颞叶性痴呆，或因正常压力脑积水，帕金森氏病痴呆、梅毒或克雅氏病导致或引起的痴呆；并且所述组合物和方法可以包含使用：硝基咪唑、罗红霉素、多西环素、米诺环素、克拉霉素或米诺环素和克拉霉素，任选地与维生素E和/或维生素D组合，其任选地呈循环方式，或任选地两周中的一周包括硝基咪唑，或两周服药并两周停药，以允许形成易感肺炎嗜衣原体(Cpn)体。
已经描述了本发明的多个实施例。然而，可以理解的是，在不脱离本发明的精神和范围的情况下可以进行各种修改。因此，其它实施例在所附权利要求书的范围内。
实例
实例1：
一名50岁男性患者，其患有70％左前降支(LAD)动脉阻塞，伴随压力测试呈阳性并且经甲氧基异丁基异腈(sestamibi)扫描，血流量减少，其标准心脏治疗失败。其开始用三种抗生素(克拉霉素、利福布汀和呋喃唑酮)进行治疗。三个月的治疗之后，所述患者报告心绞痛得到完全缓解，并且6个月时进行的甲氧基异丁基异腈测试显示血流量明显改善。
实例2：
一位63岁的女性，甲氧基异丁基异腈测试呈阳性，并且流向远端心外膜动脉的血流量减少，开始用三种不同的抗生素进行治疗并补充10,000单位维生素D。在利福布汀、阿奇霉素和强力霉素加维生素D组合使用3个月时，所述患者报告有明显的临床改善，并且甲氧基异丁基异腈扫描结果也得到了改善。
Claims (13)
1.一种药物组合物、调配物或制品，其包含：
(a)至少三种不同的抗生素，其选自由以下组成的组：
(i)大环内酯类(例如阿奇霉素(azithromycin)、克拉霉素(clarithromycin)、红霉素、非达霉素(fidaxomicin)、泰利霉素(telithromycin))、喹诺酮(quinolone)(例如氟喹诺酮(fluoroquinolone))、氯霉素(例如PENTAMYCETINTM、CHLOROMYCETINTM)、头孢菌素(cephalosporin)、硝唑尼特(nitazoxanide)(例如ALINIATM、NIZONIDETM)、呋喃唑酮(furazolidone)(例如FUROXONETM、DEPENDAL-MTM)、林可霉素(lincomycin)或克林霉素(clindamycin)(例如CLEOCINTM、CLINACINTM)、氨基糖苷(例如链霉素)、碳青霉烯类(carbapenem)(例如亚胺培南(imipenem)、美罗培南(meropenem)、厄他培南(ertapenem)、多利培南(doripenem)、帕尼培南(panipenem)或倍他米隆(betamipron)、比阿培南(biapenem)、替比培南(tebipenem))，糖肽(例如万古霉素(vancomycin)、替考拉宁(teicoplanin)、特拉万星(telavancin)、拉莫宁(ramoplanin)、德卡拉宁(decaplanin))、甘氨四环素(例如替加环素(tigecycline))、链阳菌素类(例如奎奴普汀(quinupristin)/达福普汀(dalfopristin)、普那霉素(pristinamycin)、维吉霉素(virginiamycin))、利福霉素(例如利福平(rifampicin)(或立复霉素(rifampin))、利福布汀(rifabutin)、利福喷丁(rifapentine)、利福拉齐(rifalazil)、利福昔明(rifaximin)、利福霉素SV(或AEMCOLOTM))、安沙霉素(ansamycin)(例如曲线链菌素(streptovaricin)、格尔德霉素(geldanamycin)、利福霉素)、磺酰胺(例如磺胺二甲氧嘧啶(sulfadimethoxine)、磺胺甲氧哒嗪(sulfamethoxypyridazine)、磺胺对甲氧嘧啶(sulfametoxydiazine)、磺胺多辛(sulfadoxine)、磺胺甲氧吡嗪(sulfametopyrazine)、泰瑞夫塔(terephtyl))、恶唑烷酮(oxazolidinone)(例如2-恶唑烷酮、利奈唑胺(linezolid)、泊斯唑胺(posizolid)、特地唑胺(tedizolid)、雷德唑胺(radezolid)、环丝氨酸(cycloserine))和/或硝基咪唑(例如甲硝唑(metronidazole)、替硝唑(tinidazole)、尼莫拉唑(nimorazole)、迪美唑(dimetridazole)、普雷托麦迪(pretomanid)、奥硝唑(ornidazole)、米甲唑(megazol)、阿扎硝唑(azanidazole))；或
(ii)利福拉齐、利福布汀(例如MYCOBUTINTM)、奥米加南(omiganan)(或奥米加南五盐酸盐)、雷德唑胺(radezolid)(RX-1741)、特地佐利(torezolid)、RWJ-416457、头孢比普(ceftobiprole)(或ZEVTERATM、MABELIOTM)、硝基呋喃(例如硝呋烯腙(difurazone)、呋喃唑酮(furazolidone)、硝呋福林(nifurfoline)、硝呋齐特(nifuroxazide)、硝呋喹唑(nifurquinazol))、异烟肼(例如HYDRATM、HYZYDTM、ISOVITTM)、头孢洛林(ceftaroline)(例如头孢洛林酯(ceftaroline fosamil)或TEFLAROTM、ZINFOROTM)、艾拉普林(iclaprim)、加雷沙星(garenoxacin)、喹红霉素(例如RESTANZATM)和/或泰利霉素(例如KETEKTM)(大环内酯类的一部分)、强力霉素、替加环素(例如TYGACILTM)、米诺环素(例如MINOCINTM、AKAMINTM)和/或四环素(例如SUMYCINTM)；或，
(iii)(i)和(ii)的组合；或
(b)(a)的所述药物组合物、调配物或制品，其还包含至少一种第四抗生素，并且任选地，甲硝唑(例如FLAGYLTM、METROTM)、替硝唑(例如FASIGYNTM、SIMPLOTANTM、TINDAMAXTM)、奥硝唑(ornidazole)(例如XYNORTM)、塞克硝唑(secnidazole)(例如FLAGENTYL、SINDOSETM、SECNITML、SOLOSECTM)、罗红霉素(roxithromycin)、强力霉素(例如DORYXTM、DOXYHEXALTM、DOXYLINTM)、米诺环素(例如，MINOCINTM、MINOMYCINTM、AKAMINTM)、克拉霉素(例如BIAXINTM)和/或硝基咪唑(例如甲硝唑、替硝唑、尼莫拉唑、迪美唑、普雷托麦迪、奥硝唑、米甲唑、阿扎硝唑)为所述至少第四抗生素，
并且任选地，所述硝基咪唑调配用于给药，以循环呈服药2周并停药2周。
2.根据权利要求1所述的药物组合物、调配物或制品，其中所述至少三种不同的抗生素包含：
(a)利福平、阿奇霉素和莫西沙星(moxifloxacin)，其任选地呈渐升剂量(或调配用于渐升剂量方案)；
(b)至少包含利福布汀、克拉霉素或阿奇霉素；
(c)至少包含利福布汀和米诺环素；
(d)至少包含利福布汀和阿奇霉素；
(e)至少包含利福布汀和克拉霉素；或
(f)包含利福布汀、阿奇霉素和米诺环素。
3.根据权利要求1所述的药物组合物、调配物或制品，其中所述至少三种不同的抗生素包含克拉霉素、利福布汀和呋喃唑酮。
4.根据权利要求1所述的药物组合物、调配物或制品，其中至少三种不同的抗生素包含利福布汀、阿奇霉素和强力霉素。
5.根据前述权利要求中任一项所述的药物组合物、调配物或制品，其进一步包含：
(a)维生素E、生育三烯酚、天然生育酚或生育色原烷醇、维生素D或其任何组合，
其中任选地，所述维生素D调配用于以每天至多约5000至20,000单位的剂量使用，任选地获得(达到)约150至375nmol/l的血液含量；
(b)青霉胺或DEPENTM或CUPRIMINETM；
(c)乙酰半胱氨酸或N-乙酰半胱氨酸(NAC)，或ACETADOTETM、FLUIMUCILTM、MUCOMYSTTM；或
(d)(a)至(c)的任何组合。
6.根据前述权利要求中任一项所述的药物组合物、调配物或制品，其进一步包含选自以下的药剂：用于管理冠状动脉和其它血管疾病的其它药物、增强对根除细胞内病原体至关重要的宿主防御机制的其它药物；选择性和非选择性环氧合酶抑制剂；其它抗血小板药物；β受体阻滞剂；抗心律失常药；钙通道阻滞剂；其它抗凝血药物；硝酸盐药物和HMG-Coa还原酶抑制剂；选自以下的免疫应答调节剂：细胞因子；菌落刺激因子；肿瘤坏死因子α和β；干扰素α、β和γ；结合于巨噬细胞和淋巴细胞表面受体的肽：模拟细胞因子的糖蛋白；和其它介体分子；泼尼松和相关类固醇；硫唑嘌呤(azathioprine)；霉酚酸酯(mofetilmycofenolate)和相关嘌呤拮抗剂；环磷酰胺和相关烷基化剂；甲氨蝶呤和相关叶酸拮抗剂；沙利度胺(thalidomide)；氯喹(chloroquine)和相关抗疟化合物；左旋咪唑(levamisole)；环孢菌素A；雷帕霉素(rapamycin)和/或FK506。
7.根据前述权利要求中任一项所述的药物组合物、调配物或制品，其调配用于肠胃外或肠内递送或用于口服递送，任选地在胶囊、片剂、凝胶片或溶液或液体中或以气雾剂形式递送。
其中任选地，所述至少三种不同的抗生素，或至少两种抗生素，或所有活性剂在一种调配物中，任选地呈胶囊、片剂、凝胶片或溶液或液体。
8.一种方法，其用于抑制将肺炎嗜衣原体(Chlamydophila pneumoniae；Cpn)携带到动脉内膜的巨噬细胞入侵后在动脉血管壁中形成动脉粥样硬化，或用于治疗、改善和预防以下疾病：
-与感染相关的血管疾病，
-受感染物影响的非血管疾病，
-由衣原体(Chlamydia)或嗜衣原体(Chlamydophila)物种引起的病症或病状，包括肺炎(pneumoniae)、沙眼(trachomatis)和鹦鹉热(psittaci)等可感染人类的物种，包括肺炎嗜衣原体，
-由以下引起的疾病或病状：支原体属(Mycoplasma)、李斯特菌属(Listeria)、钩端螺旋体病(Leptospirosis)、Q热(Q fever)或贝氏考克斯氏体(Coxiella burnetii)感染；莱姆病(Lyme disease)或莱姆疏螺旋体病(Lyme borreliosis)或任何疏螺旋体属(Borrelia)感染；以及巴尔通氏体属(Bartonella)或巴尔通氏体科(Bartonellaceae)感染，包括猫抓病，
-动脉炎症、动脉粥样硬化或动脉泡沫细胞，
-慢性关节炎，或
-阿尔茨海默氏病或痴呆，其中任选地，所述痴呆是血管性痴呆、路易体性痴呆、或额颞叶性痴呆、或因正常压力脑积水、帕金森氏病痴呆、梅毒或克-雅氏病(Creutzfeldt-Jakobdisease)导致或引起的痴呆，
所述方法包括向有需要的个体给予根据前述权利要求中任一项所述的药物组合物、调配物或制品。
9.根据权利要求8所述的方法，其进一步包含给予以下物质：
(a)维生素E或生育三烯酚或等效物(任选地包含维生素E或生育色原烷醇，其呈天然生育酚或生育三烯酚)，其任选地以循环方式添加，任选地介于每天至每周投药之间；和/或
(b)维生素D，其任选地被给予直到正常含量的上限，任选地以每天至少约5,000至约20,000单位的剂量给予，任选地直到达到还能够杀死细胞内感染物并降低所述细胞内感染物，任选地肺炎嗜衣原体的细胞内持久性的含量。
10.根据权利要求8或权利要求9所述的方法，其中所述药物组合物或调配物经肠胃外或肠内或口服，任选地在胶囊、片剂、凝胶片或溶液或液体中或以气雾剂形式给予，
其中任选地，所述至少三种不同的抗生素，或至少两种抗生素，或所有活性剂在一种调配物中，任选地呈胶囊、片剂、凝胶片或溶液或液体，
并且任选地，将每种活性剂调配成单独制品，任选地将每种活性剂调配成单独的胶囊、片剂、凝胶片、溶液或液体。
11.一种根据权利要求1至7中任一项所述的药物组合物、调配物或制品的用途，其用于抑制将肺炎嗜衣原体(Cpn)携带到动脉内膜的巨噬细胞入侵后在动脉血管壁中形成动脉粥样硬化，或用于治疗、改善和预防以下疾病：
-与感染相关的血管疾病，
-受感染物影响的非血管疾病，
-由衣原体或嗜衣原体物种引起的病症或病状，包括肺炎、沙眼和鹦鹉热等可感染人类的物种，包括肺炎嗜衣原体，
-由以下引起的疾病或病状：支原体属、李斯特菌属、钩端螺旋体病、Q热或贝氏考克斯氏体感染；莱姆病或莱姆疏螺旋体病或任何疏螺旋体属感染；以及巴尔通氏体属或巴尔通氏体科感染，包括猫抓病，
-动脉炎症、动脉粥样硬化或动脉泡沫细胞，
-慢性关节炎，或
-阿尔茨海默氏病或痴呆，其中任选地，所述痴呆是血管性痴呆、路易体性痴呆、或额颞叶性痴呆、或因正常压力脑积水、帕金森氏病痴呆、梅毒或克-雅氏病导致或引起的痴呆。
12.根据权利要求1至7中任一项所述的药物组合物、调配物或制品，其用于抑制将肺炎嗜衣原体(Cpn)携带到动脉内膜的巨噬细胞入侵后在动脉血管壁中形成动脉粥样硬化，或用于治疗、改善和预防以下疾病：
-与感染相关的血管疾病，
-受感染物影响的非血管疾病，
-由衣原体或嗜衣原体物种引起的病症或病状，包括肺炎、沙眼和鹦鹉热等可感染人类的物种，包括肺炎嗜衣原体，
-由以下引起的疾病或病状：支原体属、李斯特菌属、钩端螺旋体病、Q热或贝氏考克斯氏体感染；莱姆病或莱姆疏螺旋体病或任何疏螺旋体属感染；以及巴尔通氏体属或巴尔通氏体科感染，包括猫抓病，
-动脉炎症、动脉粥样硬化或动脉泡沫细胞，
-慢性关节炎，或
-阿尔茨海默氏病或痴呆，其中任选地，所述痴呆是血管性痴呆、路易体性痴呆、或额颞叶性痴呆、或因正常压力脑积水、帕金森氏病痴呆、梅毒或克-雅氏病导致或引起的痴呆。
13.一种根据权利要求1至7中任一项所述的药物组合物、调配物或制品的用途，其用于制造供用于抑制将肺炎嗜衣原体(Cpn)携带到动脉内膜的巨噬细胞入侵后在动脉血管壁上形成动脉粥样硬化，或供用于治疗、改善和预防以下疾病的药物：
-与感染相关的血管疾病，
-受感染物影响的非血管疾病，
-由衣原体或嗜衣原体物种引起的病症或病状，包括肺炎、沙眼和鹦鹉热等可感染人类的物种，包括肺炎嗜衣原体，
-由以下引起的疾病或病状：支原体属、李斯特菌属、钩端螺旋体病、Q热或贝氏考克斯氏体感染；莱姆病或莱姆疏螺旋体病或任何疏螺旋体属感染；以及巴尔通氏体属或巴尔通氏体科感染，包括猫抓病，
-动脉炎症、动脉粥样硬化或动脉泡沫细胞，
-慢性关节炎，或
-阿尔茨海默氏病或痴呆，其中任选地，所述痴呆是血管性痴呆、路易体性痴呆、或额颞叶性痴呆、或因正常压力脑积水、帕金森氏病痴呆、梅毒或克-雅氏病导致或引起的痴呆。
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| US6884784B1 (en) * | 1997-05-06 | 2005-04-26 | Vanderbilt University | Diagnosis and management of infection caused by chlamydia |
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| US7628984B2 (en) * | 2005-02-17 | 2009-12-08 | Premier Micronutrient Corporation | Micronutrient formulations for pulmonary and heart health |
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| US6884784B1 (en) * | 1997-05-06 | 2005-04-26 | Vanderbilt University | Diagnosis and management of infection caused by chlamydia |
| WO2000001378A1 (en) * | 1998-06-30 | 2000-01-13 | Karl William Baumgart | Methods and compositions for treatment of disorders associated with chlamydial and similar bacterial infection |
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