CN1258381C - 用在痤疮治疗或预防中的肉毒杆菌毒素 - Google Patents
用在痤疮治疗或预防中的肉毒杆菌毒素 Download PDFInfo
- Publication number
- CN1258381C CN1258381C CNB028162455A CN02816245A CN1258381C CN 1258381 C CN1258381 C CN 1258381C CN B028162455 A CNB028162455 A CN B028162455A CN 02816245 A CN02816245 A CN 02816245A CN 1258381 C CN1258381 C CN 1258381C
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- acne
- botulinum toxin
- treatment
- injection
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- A61K38/00—Medicinal preparations containing peptides
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- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
- A61K38/4886—Metalloendopeptidases (3.4.24), e.g. collagenase
- A61K38/4893—Botulinum neurotoxin (3.4.24.69)
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- A61P17/00—Drugs for dermatological disorders
- A61P17/10—Anti-acne agents
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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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Abstract
肉毒杆菌毒素可以用于抑制引起痤疮的事件级联。初步研究结果是出人意料的。不希望受此理论所限,据信肉毒杆菌毒素通过副交感效应达到这种结果,抑制汗腺活动,刺激角化细胞运动,抗炎和可能的抗雄激素效果。肉毒杆菌毒素能够在减少、甚至预防痤疮形成中扮演重要角色。
Description
根据美国35U.S.C.119(e),以及所有国家的可用条约和公约,要求保护2001年7月27日提交的美国临时专利申请系列号60/308,205的利益。
技术领域
本发明涉及寻常痤疮的治疗或预防方法,特别是肉毒杆菌毒素治疗或预防痤疮的用途。
背景技术
寻常痤疮
尽管不至于威胁生命,但寻常痤疮也可以为患病个体带来显著的问题。根据它的严重性和其他因素,顽固性痤疮能够伤害人们的心理,能够给患者增加显著的经济与情绪负担。尽管最近在痤疮疗法中已取得一定的成功,但治疗失败仍然是普遍的,尤其在成年妇女中。尽管很多成人“因成长而不再具有”这种疾病,不过有一些人尽管持续治疗,但在大多数成年期继续患病。不幸的是,目前使用的大多数有效的痤疮药物疗法是全身给药,这种治疗是致畸性的,这对很多妇女而言是一个重要的问题。关于更加局部化的和有效,并且还应具有最少的副作用的痤疮治疗仍然没有满足需要。
痤疮最常见于***,受到若干因素的影响。病理学焦点集中在毛囊皮脂腺上,包括皮脂腺、毛囊(毛孔)和毛发。促进粉刺(白头或黑头)生成的因素包括如下:(1)皮脂产生增加,(2)炎性介质引起真皮和毛囊发炎,(3)毛囊上部区域角化过度和阻塞,和(4)疮疱丙酸杆菌在毛囊内移生。
***是以循环中的雄激素水平增加为标志的,特别是硫酸脱氢表雄甾酮(DHEAS)。增加了的雄激素水平被认为可导致皮脂腺扩大,增加皮脂产生。尽管大多数痤疮患者具有正常的激素水平,不过有理由推断皮脂产生的增加在痤疮中扮演重要角色。例如,在皮脂产生的速率和痤疮的严重性之间存在相互关系。另外,痤疮患者通常产生亚油酸缺乏的皮脂,这是异常角化作用和毛囊阻塞的潜在原因。
响应于增加的皮脂水平,疮疱丙酸杆菌—一种革兰氏阳性、厌氧性类白喉杆菌——经常在皮脂毛囊内移生。疮疱丙酸杆菌使痤疮恶化是因为它充当嗜中性白细胞(白细胞的一种类型,也称多形核白细胞或PMN)的化学趋化剂。嗜中性白细胞摄取疮疱丙酸杆菌,与此同时释放各种破坏毛囊壁的水解酶。所释放的毛囊内容物然后侵入真皮,导致炎性反应,表现为脓疱、红斑样丘疹或结节。在另一途径中,疮疱丙酸杆菌可以水解甘油三酯为游离脂肪酸,这也增加炎症和毛囊阻塞。疮疱丙酸杆菌还可以活化免疫***的补体成分,这也引起毛囊阻塞。
毛囊衬有鳞状上皮,这层细胞与皮肤表面相延续。在有痤疮倾向的个体中,细胞从该衬层脱落经常受阻,这也许是由于细胞内粘连水平增加,促进了细胞的保留。所保留的细胞能够阻塞毛囊,导致粉刺。这种脱落受抑制的确切原因是未知的,但是它可能涉及表皮分化中的异常或异常的皮脂组成(例如亚油酸缺乏)。
也已经证明,增加了的皮脂水平能够刺激角化细胞,导致白介素-1的释放,这继而能够导致毛囊角化过度。
在这些并不互相排斥的导致痤疮的途径中,最终共有的途径是毛囊阻塞。
目前的痤疮疗法
目前所用的痤疮疗法针对痤疮级联的各个方面。最常用的疗法可能是局部用过氧化苯甲酰,它具有抗菌效果,并且也可以减少游离脂肪酸,导致炎症和毛囊阻塞的减少。
局部和全身用抗生素已经用于定向疮疱丙酸杆菌。为此已经使用的抗生素包括红霉素、四环素、克林霉素和多西环素。可以预测,抗生素的长期使用经常引起耐药性疮疱丙酸杆菌菌株的形成。
局部和全身用视黄醛衍生物(维生素A衍生物)已经用于使毛囊角化作用恢复正常,减少毛囊阻塞和破裂。全身用异维A酸(AccutaneTM)对痤疮是非常有效的,不幸的是它具有严重的副作用,最主要是致畸性。局部用视黄醛衍生物包括维A酸(Retin-ATM),它的化学结构与异维A酸相似。
本领域在治疗痤疮中的现状例如总结在下列两篇综述文章中:D.Krowchuk,″Managing Acne in Adolescents,″PediatricDermatology,vol.47,pp.841-857(2000);和B.Johnson et al.,″Use of Systemic Agents in the Treatment of Acne Vulgaris,″American Family Physician,vol.62,pp.1823-1830,1835-1836(2000)。
在更好地理解多种原因之后,痤疮疗法也取得一定进展。大多数治疗致力于使角蛋白产生恢复正常(例如通过视黄醛衍生物的使用),或者致力于控制细菌移生。就发明人所知,现有技术中没有治疗涉及影响汗腺产生或角化细胞运动,二者都是引起痤疮的毛囊阻塞的因素。
肉毒杆菌毒素和药理学
肉毒杆菌是一种厌氧菌,产生七种具有相似神经毒性的毒素,但是它们在抗原性上是不同的:血清型A至G。这些毒素是有力的神经麻痹剂,抑制神经肌肉接合处和神经腺体接合处的乙酰胆碱的释放。参见M.F.Brin,″Botulinum toxin:Chemistry,Pharmacology,Toxicity,and Immunology,″Muscle and Nerve Supp.6,pp.S146-S168(1997);和I.Kinkelin et al.,″Effective Treatmentof Frontal Hyperhidrosis with botulinum toxin A,″Brit.J.Dermatol.,vol.143,pp.824-827(2000)。
乙酰胆碱的合成和贮存都不受肉毒杆菌毒素的影响。因此,它的效果是暂时的。肉毒杆菌毒素穿透内含体膜,进入细胞质,在那里阻滞乙酰胆碱的分泌。肉毒杆菌毒素还似乎具有抗炎效果。肉毒杆菌毒素对腺体功能的效果研究已经观察到它的效果发生在副交感胆碱能神经的突触前膜。
肉毒杆菌毒素A(由Allergan销售的Botox(Irvine,California)和由Ipsen Limited销售的Dysport(Maidenhead,Berkshire,United Kingdom))已经用于某些治疗目的,既作用于神经腺体接合处也作用于神经肌肉接合处。它的暂时性神经肌肉阻滞作用已经见于大量以前的应用,包括治疗斜视、偏头痛、弛缓不能、半面痉挛、皱缩和痉挛性发音困难。注射剂已被证实对这些用途而言是安全有效的,仅有微小的副作用,例如局部肿胀和附近肌肉的瞬间虚弱。肉毒杆菌毒素A和B据报道在使用它们的患者中可被良好地耐受。
皮内用肉毒杆菌毒素A已经成为主要的疗法,用于腋下、手掌、腹腔丛和前额多汗(发汗过多),以及用于味觉性发汗(弗莱氏综合征)。还已经显示它是黑利氏病手术的有效替代选择,该疾病是一种良性家族性天疱疮,主要影响腹股沟和腋窝(高湿性部位)。
研究已经发现肉毒杆菌毒素A在人类组织中没有长期效果。组织学研究已经发现作为疗法的结果,没有神经纤维变性,也没有汗腺萎缩。在接受肉毒杆菌毒素A注射的患者中不到5%见到抗肉毒杆菌毒素A抗体。也没有报道响应于肉毒杆菌毒素A注射的过敏情况。
肉毒杆菌毒素B(由Elan Pharmaceuticals销售的MyoblocTM和NeuroBlocTM(Dublin,Ireland))已被FDA批准用于治疗颈肌张力障碍患者。
全部七种肉毒杆菌毒素血清型(A至G)在商业上都可从Metabiologics,Inc.(Madison,Wisconsin)获得。
神经肌肉接合处阻滞
第一次报道的肉毒杆菌毒素A的临床应用是20世纪70年代它在斜视治疗中的应用。注射小外眼肌导致肌肉重新排列,校直球状体,在有些情况下提高视力校正。随后,肉毒杆菌毒素A已经在治疗学上用于若干其他目的,既有功能性的也有美容性的。它已被证实有效治疗局灶性张力障碍、痉挛性张力障碍、睑痉挛、半面痉挛、斜颈和颈肌张力障碍。最近它也已用在面部整形手术中,尤其是治疗皱缩(皱纹)
1990年报道了肉毒杆菌毒素A在能动与不能动的脑瘫患者中的应用,也就是说通过向不同的肌肉群注射以治疗痉挛性双侧瘫痪。例如,针对内毒杆菌毒素A对四肢张力障碍和痉挛状态的效果所进行的双盲、安慰剂对照的研究已经发现显著的主观以及客观益处。
American Academy of Ophthalmology、American Academy ofNeurology、American Academy of Otolaryngology和NationalInstitutes of Health都已发布过支持肉毒杆菌毒素A对多种临床病症的治疗功效的报告。已经采用肉毒杆菌毒素A治疗的病症有睑痉挛、斜视、颈肌张力障碍、痉挛性斜颈、皱缩、半面痉挛、面部痉挛、痉挛性发音困难、局灶性手张力障碍、功能亢进性面部皱纹、弗莱氏综合征、多汗症、成人痉挛状态、脑瘫痉挛状态的附助治疗、口下颌张力障碍和其他张力障碍。
神经腺体接合处阻滞
肉毒杆菌毒素A作为抗胆碱能剂对神经腺体接合处的效果研究尚不及对神经肌肉接合处研究的那么广泛。检查皮内肉毒杆菌毒素对局灶性多汗症的效果的研究发现,在3至7天内,注射部位的发汗完全消失。没有报道不利效果,在随后五个月内也不存在多汗症的临床复发。一般参见I.Kinkelin et al.,″Effective Treatment of FrontalHyperhidrosis with botulinum toxin A,″Brit.J.Dermatol.,vol.143,pp.824-827(2000)。
味觉性发汗是另一种神经腺体功能障碍,肉毒杆菌毒素A已被证实对其有效。味觉性发汗(或弗莱氏综合征)是一种无能性障碍,在进食期间颊部皮肤大量出汗。该综合征经常发生在腮腺切除术后,可能是由于再生中的副交感神经纤维的错误指示,使面部汗腺衰弱。皮内肉毒杆菌毒素A据报道显著减少或预防发汗达六个月以上,在任何患者中都没有面部虚弱的临床证据。
注射到下颌下腺中的肉毒杆菌毒素A已报道显著减少由刺激舌神经所致的唾液分泌。所减少的唾液分泌是暂时性的,并且似乎对腺泡细胞没有直接毒性。参见D.Suskind et al.,″Clinical study ofbotulinum A toxin in the treatment of sialorrhea in childrenwith cerebral palsy,″Laryngoscope,vol.112,pp.73-81(2002)。
犬研究也已显示一种受副交感控制的现象,血管舒缩性鼻溢对局部用肉毒杆菌毒素A有反应。
肉毒杆菌毒素A对神经肌肉接合处的作用的持续时间似乎可达约三个月,而在腺体水平上持续效果可能更长。肉毒杆菌毒素A已经使味觉性发汗患者产生无汗症达12个月以上。作用持续时间差异的原因是不确定的。假说包括神经肌肉突触中SNAP-25(被肉毒杆菌毒素裂解的蛋白质)的重新合成速率更高、肌肉纤维的轴索萌芽与连续性重新分布的面积比腺体组织更高。
就发明人所知,以前尚没有提示肉毒杆菌毒素可能用于痤疮的治疗或预防。
发明内容
我们已经发现,肉毒杆菌毒素可以用于抑制引起痤疮的事件级联。利用肉毒杆菌毒素A所进行的初步研究结果是戏剧性的。不希望受此理论所限,据信肉毒杆菌毒素通过副交感效应达到这种结果,抑制汗腺活动,刺激角化细胞运动。有关的抗炎和抗雄激素效果也可能有助于此。根据需要,治疗可以定期反复进行,以抑制痤疮的复发,通常间隔在约3个月与6个月之间,优选约每4个月一次。
不希望受此理论所限,我们相信肉毒杆菌毒素通过至少三种不同的途径抑制痤疮的形成。第一,肉毒杆菌毒素抑制汗腺发汗。通过减少疮疱丙酸杆菌的生长,减少出汗可以在临床上改善痤疮。因而,肉毒杆菌毒素减少出汗的能力引起痤疮减少。第二,毛囊因角化细胞而阻塞是各种引起痤疮的途径中最终的共有途径。角化细胞运动受大剂量烟碱乙酰胆碱受体刺激的抑制。通过抑制乙酰胆碱的释放,肉毒杆菌毒素可以间接增加角化细胞的移行,从而减少毛囊阻塞。第三,雄激素在***的大量释放是已知的痤疮诱因,研究已经显示雄激素增加乙酰胆碱受体的数量。有趣的是,雄激素受体见于毛囊皮脂腺导管角化细胞上,它们对毛囊阻塞而言是重要的。因而我们相信,在***雄激素增加毛囊皮脂腺角化细胞上的乙酰胆碱受体数量,通过增加了的乙酰胆碱刺激引起角化细胞运动的进一步抑制。通过抑制乙酰胆碱的释放,肉毒杆菌毒素减少毛囊皮脂腺角化细胞上的乙酰胆碱受体数量,从而通过减少了的乙酰胆碱刺激增加角化细胞运动。另外,肉毒杆菌毒素可能具有抗炎效果。
具体实施方式
实施例1
“病例指标”是一名处于生命后二十年的高加索妇女,她自从***就患有严重的囊性痤疮。在皮内肉毒杆菌毒素A注射之后,痤疮完全消除。另一名健康妇女试用若干在先的药物治疗痤疮,包括安体舒通和三个疗程的异维A酸,没有消除。
在最初的肉毒杆菌毒素A注射之后,她的前额完全痊愈,而以前遍布深度的囊性损伤。
她现在接受肉毒杆菌毒素A注射,在前额、下颌和颊/鼻唇皱褶部位,大约每六个月一次。约六个月后,囊肿开始复发。它们在注射后约一周消除。注射部位彼此间距大约1.5cm,每一注射位点的剂量为约2.5U。
她的身体检查现在显示她是皮肤白皙光滑的吸引人的金发美女。她的面神经是完整的,她的额肌仅有轻微至中等的虚弱。她表示肉毒杆菌毒素A注射和所致痤疮的消除已对她的生活产生突出的影响,既有社会上的也有心理上的。
皮肤病学家已经确认这名患者的病症有实质性改善。
实施例2
一名高加索妇女在她生命的前三十年出现严重的囊性痤疮,始于***,并且对传统治疗没有反应。她已经因痤疮而留下严重的疤痕。肉毒杆菌毒素A的注射是在背部进行的。在一周内,注射区域痤疮有实质性减少,一个月后,丘疹和脓疱有显著减少。在注射结束时可以见到明显的界线,在周围存在活动的损伤,始于距离注射地带约1cm。总计使用了86单位的肉毒杆菌毒素A,每一注射位点2.5单位,注射部位彼此间隔约2-3cm。
皮肤病学家已经确认这名患者的病症有实质性改善。改善持续约五个月,之后恢复瘙痒和丘疹。
实施例3
一名20岁高加索男性自从***患有严重的囊性痤疮,遍及他的面、颈、胸和背部。他以前接受过两个疗程的异维A酸以及多个疗程的全身与局部用抗生素治疗,都没有消除他的痤疮。他的唯一其他显著的医学问题是克隆氏结肠炎。向他的背部注射总计162U肉毒杆菌毒素A,存在痤疮的其他部位则没有注射。一周后经过治疗的部位有实质性清除,三周后几乎完全清除。相反,未经治疗的部位(即面、颈和胸)则没有改善。
皮肤病学家已经确认这名患者的病症有实质性改善。在随访观察期间清除效果持续五个月。
尽管在初步实验中接受肉毒杆菌毒素治疗测试的患者数量很少,只有三名,不过这些患者100%见到戏剧性的改善,他们都患有对常规治疗没有响应的顽固性痤疮。随后还进行了小规模的临床研究,下面报道结果。
实施例4
进行小规模的临床研究,以检查真皮内肉毒杆菌毒素A(BotoxTM)注射在成人寻常痤疮损伤的预防或减少中的临床益处。直至本申请的提交之日,本研究仍在进行,但是取得了一些初步结果。用在本研究中的方案如下:
该研究是一项开放标记的、预测性的、单中心的、引导性研究。有十五名受试者参与该研究。全部得到受试者的同意。
合格标准
合格标准如下:
准入标准
1、男性或女性。
2、由最初的问卷调查确定健康状况一般良好。
3、愿意接受临床检查和面与背部照相。
4、诊断为顽固性痤疮(对常规疗法无响应,包括全身用抗生素)。
5、妊娠测试阴性(女性)。
6、参加研究的15名受试者至少有10名患有前额或背部囊性痤疮(至少一半必须在前额)。
7、高达5名受试者患有前额或背部非囊性炎性痤疮(至少3名必须在前额)。
8、个体必须愿意充当无治疗对照组。15名受试者中有3名被安排在无治疗组(至少2名来自囊性组,1名来自非囊性组)。
9、能够理解研究的要求,签署知情同意书。
10、在每次面部检查之前,愿意除去面部化妆不少于30分钟。
排除标准
1、在基线之前已经开始用***或避孕丸治疗12周或以下的女性。
2、患有任何可能干扰痤疮诊断或评价的皮肤病的受试者。
3、最近参加调查性药物研究或者已经在基线访问30天内参加过一次的受试者。
4、患有失控性代谢疾病的个体,例如糖尿病、高血压、甲状腺机能亢进或甲状腺机能减退,这是由健康问卷调查来确定的。
5、已知妊娠的、哺乳的或者计划在后面六(6)个月内怀孕的妇女,这是由最初的问卷来确定的。
6、对肉毒杆菌毒素A有***反应或过敏的个体。
7、有对治疗的合作性差、无顺应性历史或者在以前的临床研究中不可靠历史的个体。
8、有重症肌无力或Eaton Lambert病历史的个体。
9、在最近1.5个月内抗生素使用有变化的个体。
10、正在接受氨基苷、抗胆碱酯酶、硫酸镁和其他干扰神经肌肉传递的药物或产物的个体。
11、已经接受过或者接触过肉毒杆菌毒素A治疗的个体。
基于医疗历史和研究前面试与检查的发现,由研究人员决定允许加入研究的个体。预期每名受试者完成全部研究过程。
研究的进行
方法
访问1-筛选
未来的受试者完成一份健康/合格性问卷调查、照相发布表、保密协议和知情同意书。检查有资格的人的面部和背部囊性或炎性痤疮的存在。
如合格标准所述,十五名有资格的受试者加入研究,在1-3天内恢复至基线水平。
基于痤疮的位置(前额或背部),将受试者分入治疗组。治疗每名受试者的前额或背部,但不是二个部位都治疗。在访问1和2之间发生治疗组的随机化(在筛选全部个体和加入全部受试者之后)。
访问2-基线
受试者在资格访问1-3天后返回诊所。治疗组和对照组的受试者都完成一份注射前问卷调查。
由经过培训的临床工作人员计数试验部位的丘疹、脓疱、开放的粉刺、封闭的粉刺和囊肿。工作人员还评估损伤的红斑和凸起,以及周围皮肤的干性和油性。对试验部位拍摄单一的交叉极化照片。
在注射之前将局部麻醉霜涂在试验部位上。由研究人员在前额进行BotoxTM注射,相邻注射点之间的距离为1.5至2cm。对照患者仅被注射盐水。在距离眉毛1.5cm内没有进行注射,以防止上睑下垂。与治疗皱纹的肉毒杆菌毒素注射相比,注射的皮内性质预期可减少肌肉虚弱的可能性。按相似的间隔进行背部注射,这依赖于个体的痤疮分布。向每一区域注射大约2.5-3个小鼠单位的BotoxTM,另见M.Naumann etal.,″Focal Hyperhidrosis:Effective Treatment withIntracutaneous Botulism Toxin,″Arch.Dermatol.,vol.134,pp.301-304(1998);和M.Naumann et al.,″Treatment of GustatorySweating with Botulism Toxin,″Ann.Neurol.,vol.42,pp.973-975(1997)。稀释比为3个单位每0.05cc,等于1.66cc每100单位肉毒杆菌毒素A。前额的剂量上限为80单位,背部的剂量上限为125单位。受试者在接受注射后留在诊所观察30分钟。继续受试者目前的痤疮治疗方案。
给受试者一份未来访问日历。医师给予每一受试者研究指导,并给他们一份书面副本,供在家里使用。
访问3-7--进一步评价
受试者在处置之后大约1、2、4、8和12周返回诊所(分别为第3、4、5、6和7次访问)。如基线所述在每次访问时进行评价,但是没有给以进一步注射。在每次访问时,受试者完成一份问卷调查;由经过培训的临床工作人员进行痤疮损伤计数,为红斑和凸起分级,为周围皮肤的干性和油性分级。在每一试验部位重复拍摄单一的交叉极化照片。
观察任何副反应。
如果受试者没有能够返回完成预定的检查,那么由工作人员尝试联系该受试者,以确定他是否继续遵守研究指导并继续参与研究。对于受试者的情况要尽可能快地处理,或者由研究人员决定允许他错过研究。错失研究的受试者也记录在案。
实施例5-9
初步结果
正如前面所提到的,本研究在本申请提交之日仍在进行中。下面报道来自已经完成的一部分研究的初步结果。
“背部”组5名受试者在12周后的结果总结在表1中。
表1--“背部”组(n=5)
变量 | 平均基线得分 | 12周后平均得分 | 基线至12周的平均变化 | 基线至12周的平均变化百分比 | 基线至12周平均变化的标准误差 | P(基线至12周的变化)**=统计学显著变化(P<0.05) |
丘疹 | 19.0 | 4.8 | -14.2 | -75% | 5.3 | 0.01** |
脓疱 | 1.8 | 0 | -1.8 | -100% | 2.5 | 0.18 |
开放粉刺 | 5.4 | 1.8 | -3.6 | -90% | 4.4 | 0.14 |
封闭粉刺 | 5.0 | 4.8 | -0.2 | -3% | 1.8 | 0.81 |
囊肿 | 1.2 | 0.6 | -0.6 | -70% | 0.9 | 0.21 |
红斑病损 | 1.8 | 0.9 | -0.9 | -55% | 0.6 | 0.02** |
凸起病损 | 1.6 | 0.8 | -0.8 | -50% | 0.6 | 0.03** |
干性 | 0.2 | 0.0 | -0.2 | -100% | 0.5 | 0.37 |
油性 | 0.2 | 0.2 | 0.0 | 0% | 0.0 | --- |
尽管这些初步结果的样本数较小(n=5),不过在丘疹数量、红斑病损程度和凸起病损程度上见到从基线到12周有统计学显著的减少。在其他三项测量中见到较大的数字差异,这些差异就这种小型样本而言不是统计学显著的,但是随着获得另外的数据而可能变得有统计学显著性:脓疱的数量、开放粉刺的数量和囊肿的数量。同样关于相同样本大小的说明,这些初步结果提示了从这种特定治疗所得在封闭粉刺、干性发生率和油性发生率上存在最小或者没有差异。没有报道副反应、毒性或者副作用。
实施例10--剂量和毒性
一项重要的考虑是恰当剂量的选择。恰当的剂量将通过标准的剂量-响应研究和毒性研究加以确立。因为这种治疗的目标区域与多汗症相似,因此选择相似的剂量进行最初的研究。例如参见M.Naumannetal.,″Focal Hyperhidrosis:Effective Treatment withIntracutaneous Botulism Toxin,″Arch.Dermatol.,vol.134,pp.301-4(1998);和M.Naumann et al.,″Treatment of GustatorySweating with Botulism Toxin,″Ann.Neurol.vol.42,pp.973-975(1997)。似乎还没有研究限定精确的多汗症剂量-响应曲线,不过已经生成了一般性临床指导。参见表2。测量在美国FDA的严格监管下制备的肉毒杆菌毒素A临床制剂,以小鼠单位计。一个小鼠单位1U被定义为肉毒杆菌毒素A经肠胃外注射杀死一组18-20克重雌性Swiss-Weber小鼠中百分之五十的量(LD50)。肉毒杆菌毒素A的使用禁忌症是非常少的(注意:已有报道提示Botox单位的效力是Dysport单位的3-5倍。用在这里所报道的实验中的肉毒杆菌毒素A是Botox;因此,在这两种商业上可得到的肉毒杆菌毒素A制剂效力可能存在差异的程度上,用在本说明书和权利要求书中的“单位”可以参照Botox单位加以解释)。
表2
人肉毒杆菌毒素A预期剂量-响应
剂量单位(U)
1U=LD50小鼠=0.04ng
临床功效
1-12U每kg体重,依赖于患者的响应,习惯上最大400U
给药不超过每90天一次;
就有些患者而言更低或更高的剂量可能是适当的
毒性
口服:3,000-250,000U(猴)
肠胃外:39U/kg(猴)
假定:
猴LD50=人LD50
成人LD50=3000U
安全性因子
毒性=40U/kg
基于如上所报道的初步结果,预期在大多数情况下皮内注射应当彼此间距约0.5或1cm至约10cm,优选约1.5至约3cm;每一注射部位的剂量应当是约1U至约10U或20U肉毒杆菌毒素A,优选约2至约3U。这些剂量可以基于个体对注射的响应而异。
肉毒杆菌毒素可以被皮内或皮下注射。作为替代选择,肉毒杆菌毒素可以按相似的剂量肌内注射,特别是当需要同时削弱某些面部肌肉时,例如为了减少皱褶。
作为替代选择,肉毒杆菌毒素可以作为局部或经皮的霜剂、凝胶剂、软膏剂、洗剂、气雾剂或喷雾剂、粉剂、糊剂、固定敷料或其他局部或经皮制剂而施用于皮肤,以提供相似的临床功效。肉毒杆菌毒素的表面用药可以特别有助于改善粉刺性痤疮,这是痤疮的炎性表现,局部用药可以有助于增加吸收。这类局部给药最好根据需要重新配制,然后贮存在冷却条件下,因为它们的货架寿命是有限的。通过调节pH至微酸性,例如约pH 5.6,可以延长货架寿命至数周或更长。局部用载体可以包括用在本领域局部药物治疗中的其他组分,例如本领域已知的消失性(vanishing)载体、保湿剂、润肤剂、化学载体(例如DMSO)和缓冲剂。典型的活性成分浓度可以在5至200U每ml的数量级上,这依赖于吸收速率和毒素血清型。一般而言,浓度应当这样调节,以便有效的给药速率等价于肉毒杆菌毒素的有效注射。超声装置或电生理电流装置、例如离子电渗疗法的使用可以增强局部用毒素的吸收。本领域已知(尽管使用其他化合物治疗其他病症)局部用药的药物能够到达并且在临床上影响汗腺和皮脂腺。例如参见F.Marzulliet al.(Eds.),″Dermatotoxicology and Pharmacology″inAdvances in Modem Toxicology,vol 4,John Wiley and Sons,NewYork(1977)。
在目前商业上可得到的制备物中,肉毒杆菌毒素A是冷冻贮存的;而肉毒杆菌毒素B是在室温下贮存的。
实施例11和12
已经利用两名痤疮患者针对肉毒杆菌毒素A的局部用药进行了初步试验。另外将进行大规模的局部用药试验,以确认何种类型痤疮对局部治疗的响应良好。关于局部治疗,重新配制肉毒杆菌毒素A,浓度为100单位每0.5ml溶剂。对于中背部治疗,溶剂是1.4%聚乙烯醇水溶液,为中性眼用溶液,对于左背部治疗,溶剂是无防腐剂的盐水。将0.2ml或40U溶液施用于6cm x 4cm,贴上TegadermTM达4小时,以避免干扰。结果列在下面。
表3
患者1基线 | 患者1第2周 | 患者1第4周 | 患者2基线 | 患者2第2周 | 患者2第4周 | |
损伤,中背部 | ||||||
丘疹 | 5 | 1 | 0 | 1 | 10 | 2 |
脓疱 | 0 | 0 | 0 | 0 | 0 | 0 |
开放粉刺 | 4 | 1 | 1 | 0 | 0 | 0 |
封闭粉刺 | 0 | 2 | 1 | 11 | 0 | 4 |
结节 | 0 | 0 | 0 | 0 | 0 | 0 |
损伤,左背部 | ||||||
丘疹 | 5 | 3 | 3 | 10 | 5 | 3 |
脓疱 | 2 | 0 | 0 | 0 | 0 | 0 |
开放粉刺 | 0 | 0 | 0 | 0 | 0 | 0 |
封闭粉刺 | 0 | 6 | 2 | 4 | 1 | 2 |
结节 | 0 | 0 | 0 | 0 | 0 | 0 |
这些数据表明在肉毒杆菌毒素的局部用药之后存在痤疮改善的潜在趋势。进一步的研究仍在进行中。由于这些针对局部用药的最初实验中的患者数量少,此时进行统计学分析没有意义。肉毒杆菌毒素治疗痤疮的局部用药最终可以证实是优选的用药方法,因为容易施用,并且容易直接释放药物至患病区域,在那里存在炎症或皮肤紧密接合处的其他破坏。
实施例13
将进行进一步的II期临床试验,以确认皮内或局部肉毒杆菌毒素A注射能够安全有效地预防或减少成人与***顽固性痤疮的发病率。在II期试验之后,将进行III期试验,均按照适用的法律和条例进行。
本发明人推测,有可能有一部分以前出于其他原因(例如皱褶)已经用肉毒杆菌毒素治疗过的患者也可能偶然作为一种副作用使痤疮得到改善。不过,就发明人所知,以前没有报道提示过这样一种肉毒杆菌毒素治疗副作用的存在,以前也没有任何报道提示过在肉毒杆菌毒素给药与痤疮改善之间存在任何因果关系。
用在本说明书和权利要求书中的肉毒杆菌毒素的“有效量”是足以预防痤疮或者抑制痤疮形成或者减少痤疮水平至临床上显著的程度的量。为此“显著性”被确定在P<0.05水平,或者这类其他统计学显著性量度,这是本领域关于特定实验测定类型所常用的。
尽管如上所报道的初步实验使用肉毒杆菌毒素A,不过不希望受此理论所限,据信其他肉毒杆菌毒素血清型、即肉毒杆菌毒素B、C、D、D、E、F和G也可以用在本发明的方法中治疗或预防痤疮。恰当的剂量和毒性一般将是如上关于肉毒杆菌毒素A所述加以测定的。已有提示说肉毒杆菌毒素C可能具有两种变体,一种具有神经毒性,另一种缺乏这类活性。在任何肉毒杆菌毒素血清型的这类变体确实存在的程度上,所有这类显示抗痤疮活性的变体的应用都被视为属于本发明的范围。
例如,如果患者对特定血清型产生免疫反应,可能需要改变所使用的血清型。剂量和作用持续时间可以因不同血清型而异,一般将按照如上关于血清型A所讨论的实验加以确定。为了减少产生免疫反应的可能性,应当使用关于每名患者的最小有效剂量,成功治疗之间的时间应当尽可能长,并保证没有实质性症状反复。
本说明书所引用的所有参考文献的完整公开内容都结合在此作为参考。不过万一有不可协调的冲突,应当对本说明书加以控制。
Claims (3)
1.肉毒杆菌毒素A制备用于抑制易患寻常痤疮的人的寻常痤疮的药物的用途。
2.肉毒杆菌毒素A制备用于在易患寻常痤疮并且还有至少一个皱褶的一个或多个皮肤区域抑制寻常痤疮及至少一个皱褶的药物的用途。
3.权利要求1或2的用途,其中所述药物为皮内注射、皮下注射、肌内注射或局部用药的剂型。
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WO (1) | WO2003011333A1 (zh) |
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US20050074466A1 (en) | 2005-04-07 |
US7226605B2 (en) | 2007-06-05 |
KR100602308B1 (ko) | 2006-07-18 |
PT1411978E (pt) | 2008-11-28 |
WO2003011333A1 (en) | 2003-02-13 |
KR20040030820A (ko) | 2004-04-09 |
EP1411978A4 (en) | 2005-08-17 |
JP4138651B2 (ja) | 2008-08-27 |
ATE406910T1 (de) | 2008-09-15 |
CA2451923C (en) | 2009-10-20 |
CN1543354A (zh) | 2004-11-03 |
EP1411978A1 (en) | 2004-04-28 |
NZ531389A (en) | 2005-08-26 |
DE60228723D1 (de) | 2008-10-16 |
DK1411978T3 (da) | 2009-01-05 |
CA2451923A1 (en) | 2003-02-13 |
CY1108605T1 (el) | 2014-04-09 |
JP2004538310A (ja) | 2004-12-24 |
EP1411978B1 (en) | 2008-09-03 |
AU2002355730B2 (en) | 2007-09-13 |
ES2312651T3 (es) | 2009-03-01 |
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