CN101304750A - 用于治疗肉芽肿性酒糟鼻的阿奇霉素 - Google Patents
用于治疗肉芽肿性酒糟鼻的阿奇霉素 Download PDFInfo
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Abstract
阿奇霉素全身性给药至少两个星期对减轻肉芽肿性酒糟鼻的体征和症状是有效的，肉芽肿性酒糟鼻是酒糟鼻的一种变型，通常对除肉芽肿性酒糟鼻之外的各型酒糟鼻有效的治疗方案没有有利的反应。
Description
技术领域
本发明属于疾病的药理学治疗领域。特别地，本发明属于肉芽肿性酒糟鼻的药理学治疗领域。
背景技术
酒糟鼻(rosacea)，也称为酒糟鼻性痤疮，是面部皮肤的慢性皮炎。其特征是持续性红斑并通常有毛细血管扩张，急性期有水肿、丘疹和脓疱。据说在美国，酒糟鼻影响大约一千四百万人，并且在敏感个体中多种因素包括日光接触、高温环境、酒精和多种其它食物以及收敛剂的皮肤施用都引发酒糟鼻或使其恶化。
酒糟鼻的治疗包括避免引发或加剧引发因素以及局部和内服药物施用。多种类型的药物用于治疗酒糟鼻，经常联合使用。已经表明痤疮产品例如过氧化苯甲酰、免疫抑制剂例如他克莫司以及类维生素A例如异维A酸在酒糟鼻治疗中有效。已证明在酒糟鼻治疗中有效的局部抗生素药物是甲硝唑，即METROGEL
(Galderma Laboratories，Fort Worth，TX，USA)。用于治疗酒糟鼻的全身性抗生素包括克林霉素、红霉素、四环素、米诺环素、强力霉素、克拉霉素和阿奇霉素。阿奇霉素治疗酒糟鼻以250mg/日的水平给药约5日，通常第1日施以500mg的负荷剂量。
肉芽肿性酒糟鼻是酒糟鼻的一种变型，在脸部迎面区中间和侧面以及周期性发生不连续的丘疹。在组织学上，肉芽肿性酒糟鼻中的丘疹，典型地是坚硬的并且颜色从黄棕色到红色范围内变化，是非干酪化上皮样细胞肉芽肿。这些肉芽肿在其它形式的酒糟鼻中没有发现。因为肉芽肿的存在，因此关于肉芽肿性酒糟鼻是否真是酒糟鼻的变型，或者其是否是一种独立的疾病或另一种皮肤肉芽肿性病症的变型，已存在一些问题。参见，例如Kaur等，“Granulomatous Rosacea：Is it a variant of lupus miliaris disseminatusfaciei？″，Indian Journal of Dermatology，Venereology，and Leprology，69(7)：58-60(2003)。
已证明肉芽肿性酒糟鼻是一种难以治疗的疾病。大多数对其它各种酒糟鼻亚型有效的治疗在肉芽肿性酒糟鼻的治疗中是无效的。非常需要用于肉芽肿性酒糟鼻的有效治疗。
发明内容
已经令人惊奇地发现全身性给药阿奇霉素几个星期或更长时间在治疗肉芽肿性酒糟鼻的体征(sign)和症状中是有效的。
本发明是一种治疗患有肉芽肿性酒糟鼻体征和症状的个体中所述体征和症状的方法，其通过以足够改善个体肉芽肿性酒糟鼻体征和症状的剂量和时间对所述个体进行全身性给药阿奇霉素。
用于本发明的方法的阿奇霉素可以是阿奇霉素的任何形式。所述形式包括非晶体和晶体阿奇霉素。阿奇霉素晶体形式包括二水合物和一水合物形式。
治疗肉芽肿性酒糟鼻的阿奇霉素的给药是全身性的。所述全身性给药包括肠道和肠胃外给药途径。适于本发明的方法的全身性给药的实例包括注射，例如静脉内、肌内和皮下注射，以及口服给药，例如通过吞服片剂或胶囊剂，包括速释和延缓释放片剂和胶囊剂。
根据本发明的方法使用的阿奇霉素的剂量是有效改善患有肉芽肿性酒糟鼻的个体的肉芽肿性酒糟鼻体征和症状的剂量。典型地，给药的日剂量是100至1000mg阿奇霉素。优选地，日剂量在150mg至750mg之间。最优选地，最多约500mg的日剂量，例如在175至350mg之间。
另一种给药法是隔日给药法，其中患者隔日接受250mg至1000mg之间的剂量，优选隔日250mg至750mg，最优选以隔日计约500mg。如果需要，可在初始时间的日剂量给药阿奇霉素后使用隔日给药法。
在本发明下，其它给药法也是可能的，包括每周一次剂量，其中每周总剂量以等于在上述日剂量下每周将给药的总量提供。例如，阿奇霉素的典型周剂量可以是700mg至7000mg，作为单次周剂量给药。给药方案中的其它变化也是可能的，例如通过每周给药2或3剂以提供相同周量的阿奇霉素。
另一种给药方案为周期治疗。周期治疗指给药一段时间例如一个星期后，然后一段时间的休息期(没有给药阿奇霉素)，休息期的时间通常与给药期的时间相同，例如一个星期。然后重复给药和休息周期。如此，对于一个星期给药/一个星期休息的周期，总的治疗持续时间可以少至2个周期或多至13个周期，如果需要甚至更多。另一种优选治疗周期是一个月治疗和一个月的休息期，其中在一个月的治疗中在每个星期中使用如上所描述的给药方案中的任何一种。
使用阿奇霉素改善肉芽肿性酒糟鼻体征和症状的治疗持续时间根据个体病症的严重程度以及个体对阿奇霉素治疗的反应不同而改变。优选地，阿奇霉素给药至少两个星期，优选四个星期或更长，更优选至少两个月。通常治疗应该持续到直至观察到临床显著的清除为止。根据本发明，阿奇霉素的治疗可以持续6个月或甚至更长时间。
此外，在使用如上所述的用阿奇霉素起始治疗之后个体的肉芽肿性酒糟鼻恶化的情况下，根据本发明可以使用另外的治疗方案把疾病带回可控制情况下。
如果需要，阿奇霉素可以与其它辅助药物和治疗方法相结合用于患有肉芽肿性酒糟鼻体征和症状的个体。所述辅助药物的实例包括激素例如性激素如雌激素、类维生素A如异维A酸以及其它局部药物例如壬二酸(azaleic acid)(FINACEA
，Intendis，Montville，NJ)、10％磺胺醋酰钠加5％硫(ROSACCream with Sunscreens，Stiefel Laboratories，Coral Gables，FL)和/或甲硝唑(METROGEL
，Galderma Laboratories，Fort Worth，TX)。已知的在治疗除肉芽肿性酒糟鼻之外的酒糟鼻形式中有效的局部和/或全身性药物可以与阿奇霉素联合用药。
本发明的方法尤其适于治疗对其它治疗没有有利反应或仅有低于期望的有利反应的肉芽肿性酒糟鼻病例。上述不成功的治疗包括用阿奇霉素之外的抗生素的治疗，包括抗真菌药物例如盐酸萘替芬(NAFTIN
，Merz，Pharmaceuticals，Greensboro，NC)，以及用阿奇霉素治疗短于2个星期。
本发明的方法以下列非限制性实施例进一步例示。
实施例1
一位34岁的西班牙女性患者表现出严重的炎症性扩散面部肉芽肿性酒糟鼻。所述病症已经存在6年。以前使用的抗生素强力霉素治疗没有改善。
她开始口服日剂量500mg的阿奇霉素和雌激素诺孕酯/乙炔雌二醇(ORTHO TRI-CYCLEN
，Ortho-McNeil Pharmaceutical，Raritan，NJ)。在开始阿奇霉素治疗后9个星期，患者症状大大改善，表现为仅剩最小的面部红斑并且没有残余炎性损害。此时，阿奇霉素剂量减为隔日500mg并且每日局部施用壬二酸。在两个月以后的随访检查时患者保持无疵瑕(clear)。继续治疗并在另外6至8个星期进行预期的随访检查。
实施例2
一位70岁的高加索男性患者主述“面部皮疹”。体检时，该患者具有颧骨部位红斑，在鼻、脸颊、前额以及躯干上伴随大丘疹。还报告有睑缘炎。他开始口服先锋霉素。一个月以后，患者病情恶化，在面部两侧伴随加重的脓疱和痛性节结。对右颌进行活检，病理学显示“化脓性和肉芽肿性毛囊炎”。开始用双氯西林(dicloxicillin)治疗。六个星期后，随访观察到患者病情持续严重至恶化，增加萘替芬乳膏。
次日，患者求诊不同的皮肤科医生，其诊断为肉芽肿性酒糟鼻。开始每日500mg的剂量口服阿奇霉素，同时每日局部施用10％磺胺醋酰钠加5％硫的乳膏以及甲硝唑乳膏。在阿奇霉素治疗开始六个星期后再次评价患者，此时具有可最低限度地查觉到的残余红斑和丘疹。继续治疗，只是阿奇霉素减少到隔日500mg。两个月后再次评价患者，没有残余酒糟鼻的证据。终止阿奇霉素用药。
实施例3
一位59岁妇女表现面部皮疹。诊查显示在她的前额、发迹、眶下区域和鼻部位有片状红斑和一些脓疱和丘疹。做出肉芽肿性酒糟鼻的临床诊断。开始使用各种局部药物进行治疗，所述药物包括甲硝唑凝胶Elidel
(吡美莫司，Novartis Pharmaceuticals Corp.，New York，NY)、2.4％氢化可的松以及地奈德乳膏。这些局部治疗进行了几个月的时间，并且是无效的。然后试用每日两次口服500mg四环素，但是患者的病症对该治疗无反应。
在这些不成功治疗之后，对患者进行活检，并且活检证实肉芽肿性酒糟鼻的诊断。接着试用的治疗是每日两次口服100mg强力霉素。该治疗也是不成功的。Klaron洗剂(10％磺胺醋酰钠，Dermik Laboratories，Berwyn，PA)也未能改善患者的病症。然后患者开始以20mg/日的起始剂量使用Accutane(Hoffman-LaRoche Inc.，Nutley，NJ)，随后提高到40mg/日，然后是60mg/日。即使在较高剂量的Accutane
下，患者病症也没有改善。
后来开始用阿奇霉素作为唯一治疗进行治疗，每日250mg的剂量口服给药三个星期。患者的病症经历了显著的改善，她的脸部清洁了，并且在阿奇霉素治疗停止后，她仍没有再发生肉芽肿性酒糟鼻。
本文描述的本发明的进一步修改、应用和施用对于本领域技术人员而言是清楚的。意在于所附的权利要求书中包含这些修改。
Claims (9)
1.一种用于改善肉芽肿性酒糟鼻体征和症状的方法，其包括以有效改善个体肉芽肿性酒糟鼻体征和症状的剂量和时间对患有肉芽肿性酒糟鼻的个体进行全身性给药阿奇霉素。
2.权利要求1的方法，其中每日给药阿奇霉素至少两个星期。
3.权利要求1的方法，其中每日或隔日给药阿奇霉素至少两个星期。
4.权利要求1的方法，其中阿奇霉素的剂量为100mg/日至1000mg/日。
5.权利要求1的方法，其中通过口服给药阿奇霉素。
6.权利要求1的方法，其中将阿奇霉素与给药一种或多种已知在治疗除肉芽肿性酒糟鼻以外的酒糟鼻类型中有效的局部药物联合给药。
7.权利要求6的方法，其中所述局部药物选自激素、类维生素A、壬二酸、10％磺胺醋酰钠加5％硫和甲硝唑。
8.权利要求1的方法，其中阿奇霉素作为唯一治疗在肉芽肿性酒糟鼻的治疗中给药。
9.权利要求1的方法，其中在给药一种或多种除阿奇霉素之外的药物不成功治疗肉芽肿性酒糟鼻之后，开始用阿奇霉素治疗。
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