异维A酸介绍

异维A酸属于维甲酸类药物,于1979年首次应用于重度痤疮患者。口服异维A酸能作用于痤疮发病的所有病理生理因素,是治疗重度痤疮的标准方法,也是目前治疗痤疮的最有效的方法。异维A酸应和富含脂肪的食物同服[1],以提高其利用率,疗程视皮损消退情况和服用剂量而定,通常推荐为15-20周[2],小剂量使用时疗程可能超过六个月。

适应症状包括[3-6]:严重的结节囊肿型痤疮;其他治疗方法效果不好的中、重度痤疮;有瘢痕或有形成倾向的痤疮;频繁复发的痤疮;有快速疗效需求的少数轻、中度痤疮;暴发性痤疮和聚合性痤疮等变异型痤疮等。 不过需要注意的是,异维A酸的显著疗效也伴随着很多副作用,它有明确的致畸作用,也可能引起其他一些严重的不良反应。一般情况下,异维A酸也不能与其他药物同时应用[7]

How Accutane (isotretinoin) Works

异维A酸作用于痤疮发病的4个关键病理生理环节:

  • 1.显著缩小皮脂腺(35%-58%),并减少皮脂的分泌(可降低80%左右)[8-9]
  •  
  • 2.改善毛囊的厌氧环境,从而减少痤疮丙酸杆菌的繁殖;
  •  
  • 3.调节毛囊皮脂腺导管的过度角化,从而减少毛囊阻塞[10]
  •  
  • 4.具有抗炎作用[10]

对于30%左右的患者,使用异维A酸的第一个月,可能会出现痤疮加重的情况,不过持续使用后情况就会明显好转[11]。95%左右的患者在完成一个疗程后,痤疮症状会部分或完全治愈[12]。另外,研究表明,采用异维A酸治疗的复发率约为33%,这个时候可以进行第二个疗程治疗[7,9,12-17]。复发率与服用剂量有关[13],累计剂量达到100-120mg/kg的患者治疗效果最好,复发率也最低。剂量减少,痤疮也往往更易复发。每日的服用剂量取决于患者的体重,一般为0.5-2mg/kg/d[15]

低剂量或间歇给药:对于轻到中度的痤疮患者,低剂量服用异维A酸,可以获得长期疗效,不良反应也相应少些[18-20]。对于比较严重的情况,长期低剂量服用异维A酸(直到累计剂量达到120mg/kg)也可以提供长时间治疗,并显著减少不良反应的发生[21]。对于间歇性用药,即每月仅第一个周服用异维A酸,对于多数患者疗效会大大降低[19-22]

  1. Del Rosso, JQ. "Face to face with oral isotretinoin: a closer look at the spectrum of therapeutic outcomes and why some patients need repeated courses." The Journal of Clinical and Aesthetic Dermatology. 2012; 5(11): 17-24.
  2. Ganceviciene R and Zouboulis CC. "Isotretinoin: State of the art treatment for acne vulgaris." Journal of the German Society of Dermatology. 2009; 8 Suppl. 1: S47-S59.
  3. Dreno B, et al. "An expert view on the treatment of acne with systemic antibiotics and/or oral isotretinoin in the light of the new European recommendations." European Journal of Dermatology. 2006; 16(5): 565-71.
  4. Chen K, et al. "Oral isotretinoin: an analysis of its utilization in a managed care organization." Journal of Managed Care Pharmacy. 2002; 8(4): 272-7.
  5. Wysowski DK, Swann J and Vega A. "Use of isotretinoin (Accutane) in the United States: Rapid increase from 1992 through 2000." Journal of the American Academy of Dermatology. 2002; 46(4): 505-9.
  6. Rigopoulos D, Larios G and Katsambas AD. "The role of isotretinoin in acne therapy: Why not as first-line therapy? Facts and controversies." Clinics in Dermatology. 2010; 28(1): 24-30.
  7. Dhir R, et al. "Oral isotretinoin is as effective as a combination of oral isotretinoin and topical anti-acne agents in nodulocystic acne." Indian Journal of Dermatology, Venereology and Leprology. 2008; 74(2): 187.
  8. Nelson AM, et al. "13-cis-retinoic acid induces apoptosis and cell cycle arrest in human SEB-1 sebocytes." Journal of Investigative Dermatology. 2006; 126(10): 2178-89.
  9. Plewig G, et al. "Low dose isotretinoin combined with tretinoin is effective to correct abnormalities in acne." Journal of the German Society of Dermatology. 2004; 2(1): 31-45.
  10. Ellis CN and Krach KJ. "Uses and complications of isotretinoin therapy." Journal of American Academy of Dermatology. 2001; 45(5): S150-7.
  11. Demircay Z, Kus S and Sur H. "Predictive factors for acne flare during isotretinoin treatment." European Journal of Dermatology. 2008; 18(4): 452-456.
  12. Mandekou-Lefaki I, et al. "Low-dose schema of isotretinoin in acne vulgaris." International Journal of Clinical Pharmacological Research. 2003; 23(2-3): 41-6.
  13. Ng PP and Goh CL. "Treatment outcome of acne vulgaris with oral isotretinoin in 89 patients." International Journal of Dermatology. 1999; 38(3): 213-6.
  14. Quereux G, et al. "Prospective study of risk factors of relapse after treatment of acne with oral isotretinoin." Dermatology. 2006; 212(2): 168-76.
  15. Haryati I and Jacinto SS. "Profile of acne patients in the Philippines requiring a second course of isotretinoin." International Journal of Dermatology. 2005; 44(12): 999-1001.
  16. Akman A, et al. "Treatment of acne vulgaris with intermittent and conventional isotretinoin: a randomized, controlled multicenter study." Archives of Dermatological Research. 2007; 299(10): 467-73.
  17. Morales-Cardona CA and Sanchez-Vanegas G. "Acne relapse rate and predictors of relapse following treatment with oral isotretinoin." Actas Dermo-Sifiliograficas. 2013; 104(1): 61-6.
  18. Rademaker M, Wishart JM and Birchall NM. "Isotretinoin 5 mg daily for low-grade adult acne vulgaris – a placebo-controlled, randomized double blind study." Journal of the European Academy of Dermatology and Venereology. 2013; [ahead of print].
  19. Boyraz N and Mustak PK. "Comparison of the efficacies of intermittent and continuous low-dose isotretinoin regimens in the treatment of moderate acne vulgaris." International Journal of Dermatology. 2013; [ahead of print].
  20. Borghi A, et al "Low-cumulative dose isotretinoin treatment in mild-to-moderate acne: Efficacy in achieving stable remission." Journal of the American Academy of Dermatology. 2011; 25(9): 1094-1098.
  21. Rasi A, et al. "Efficacy of fixed daily 20 mg of isotretinoin in moderate to severe scar prone acne." Advanced Biomedical Research. 2014; 3: 103.
  22. Lee JW, et al. "Effectiveness of conventional, low-dose and intermittent oral isotretinoin in the treatment of acne: A randomized, controlled comparative study." British Journal of Dermatology. 2011; 164(6): 1369-1375.
  23. 中国痤疮治疗指南专家组. 中国痤疮治疗指南(2014修订版). 临床皮肤科杂志. 2015;44(1): 52-57.

服用异维A酸是一种系统疗法,作用于全身。在发挥显著的疗效的同时,也伴随着诸多副作用,80%以上的患者都出现过不良反应[1]。临床试验中多数不良反应是轻到中度的,并且具有可逆性,停药后会逐渐恢复,但也有一些较为严重并且长期存在的情况。有相关数据证实的副作用如下:

Accutane side effects

肝酶升高

又名肝中毒,临床研究发现15%的病例出现了此症状。[3,28]

胰腺炎

临床研究中属于罕见病例。

呼吸道症状

支气管痉挛、呼吸道感染、声音改变。[8]

唇干

临床研究表明92%的患者会出现唇干的症状。[3.8]

皮肤干燥

又名干燥症,临床研究表明57%的患者会出现此症状。[3,7,8]

流鼻血

临床研究中30%的患者出现过此症状。[8]

皮疹(包括湿疹)

临床研究中,异维A酸的使用可能会使湿疹恶化。[7-8]另外,也有罕见面部红疹的报道。[10]脱发

少数患者会在短期内出现脱发症状。[7-8]

唇炎

唇部出现炎症。[8]

荨麻疹

少数病例中出现过敏症状,包括荨麻疹。[7-8]

秃头症

表现为头皮脱发,也可能发生在身体其它长毛发的部位,有少数病例的报道。[7]

女性多毛症

有少数女性出现多毛症的报道。

指甲异常

有极罕见的指甲异常的报道。

睑黄疣

又称睑黄色瘤,表现为眼睑皮肤出现淡黄色扁平疣状隆起。关于此不良反应有罕见病例的报道。

其他不良反应还包括口干、晒伤敏感性增加、皮肤瘀斑、牙龈出血、牙龈牙。

出生缺陷

异维A酸有明确的致畸作用[2],会导致严重的出生缺陷,包括颅骨、眼、耳、面部畸形,中枢神经系统、心血管、胸腺、甲状旁腺发育异常,甚至死亡。因此,妊娠或即将妊娠的女性禁用,育龄期妇女或其配偶在开始服用异维A酸治疗前3个月、治疗期间及停药后3个月内应采用有效的避孕措施。

月经紊乱

肌肉疼痛

又名肌痛,临床研究中,15%-50%的病例出现了此症状。[7,8,14,19,20]

腰痛

临床研究中,30%的病例出现了此症状。

关节痛

临床研究中,15%-35%的病例出现了此症状。[7,8,13-16]

骨质增生

临床研究中,10%的病例出现了此症状。[8,11]

肌腱炎

肌腱出现炎症反应。[7,8]

关节炎

关节出现暂时的炎症和功能障碍。[8,15]

急性关节炎

临床研究中,罕见病例会出现此种症状。[14,17,18]

骨骼、肌腱、韧带钙化

即骨骼、肌腱、韧带因为钙盐沉积而硬化。[11]临床研究中,仅在高剂量、长期服用(数年)异维A酸的情况下会出现此不良反应。[12]

横纹肌溶解症

临床研究中,有罕见横纹肌溶解的报道。[8]

头痛

临床研究中,10%-28%的病例出现此症状。[9,29]

视觉问题

明确的副作用包括:睑板腺分泌异常、角膜混浊、角膜炎、夜间视力下降、睑板腺萎缩、视力下降、近视、眼干、畏光、眼畸形(出生缺陷)。[7,8]

可能的副作用包括:色觉下降(可逆)、夜间视力永久丧失、干眼症。[3,9,7,8]

颅内压升高

临床研究中,有罕见颅内压升高的报道。[8]

神经症状

包括头昏、困倦、头痛、失眠、嗜睡、心神不安、神经质、感觉异常、癫痫、中风、昏厥、无力。临床研究中,16-29%的病例出现此类症状。[8]

抑郁

异维A酸与抑郁或自杀的关联系尚不明确,需要进一步的研究。

脑供血不足

即脑缺血,临床研究中,极罕见的病例会出现此症状。[23]

听觉障碍

有导致听觉障碍的报道,并且治疗结束后仍可能持续。[8]

严重过敏反应

临床研究中,有罕见过敏反应的报道。[8]

白细胞减少

白细胞计数减少,包括严重中性粒细胞减少症及罕见的粒细胞缺乏症。[26]

炎症性肠病/回肠炎/结肠炎

炎症性肠病(IBD)和回肠炎经常与异维A酸联系在一起,不过临床研究中尚未发现此种相关性。而溃疡性结肠炎和异维A酸的使用在临床研究中呈现出了些许关联性。[27-28,30-32]

肛裂和直肠出血

有罕见此类症状的报道。

血液检查异常

血脂升高、胆固醇升高、转氨酶升高。临床研究中,出现这三种症状的病例分别为44%、31%以及11%。[8,24,25]

粒细胞缺乏症

临床研究中,有罕见粒细胞缺乏症的报道。

贫血

血液中铁含量降低。

维生素水平较低

研究表明,伴随有血清叶酸[34]和维生素E[35]水平的降低。


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