Ch75 Dermatological Pharmacology
皮肤病药理学
目录 |
1 Drugs Affecting Hair Growth
影响毛发生长的药物
1.1 Androgenic Alopecia (雄激素性脱发)
雄激素性脱发，通常称为男性和女性型秃发，是 40 岁以上成年人脱发的最常见原因。频率和严重程度随着年龄的增长而增加，一些患者可能在青春期开始。它是一种具有可变表达的遗传性状。在易感毛囊中，二氢睾酮 (DHT) 与雄激素受体结合，激素-受体复合物激活负责将大末端毛囊逐渐转化为小型毳毛囊的基因。雄激素性脱发的治疗旨在减少脱发和维持现有头发（Varothai 和 Bergfeld，2014 年）。
Androgenetic alopecia, commonly known as male and female pattern baldness, is the most common cause of hair loss in adults older than 40 years. The frequency and severity increase with age and may begin during puberty in some patients. It is a genetically inherited trait with variable expression. In susceptible hair follicles, dihydrotestosterone (DHT) binds to the androgen receptor, and the hormone-receptor complex activates the genes responsible for the gradual transformation of large terminal follicles into miniaturized vellus follicles. Treatment of androgenetic alopecia is aimed at reducing hair loss and maintaining existing hair (Varothai and Bergfeld, 2014).
米诺地尔最初是作为抗高血压药开发的，据悉与一些患者的多毛症有关。米诺地尔可增强毛囊大小，使毛干更浓密，并刺激和延长头发周期的生长期，导致头发更长和数量增加。必须继续治疗，否则任何药物诱导的毛发生长都会丢失。磺基转移酶活性升高的患者最有可能对米诺地尔治疗有反应;这可能是将来有用的预测测试（Roberts et al.， 2014）。外用米诺地尔有 2% 溶液和 5% 溶液或泡沫两种形式。可能会发生过敏性和刺激性接触性皮炎，使用药物时应小心，因为毛发生长可能会出现在不良位置。这在停药时是可逆的。应指导患者在使用米诺地尔后洗手。口服低剂量米诺地尔（每天 0.25 – 5 毫克）已超说明书用于治疗雄激素性脱发，推荐剂量为女性每天 0.5 – 2.5 毫克或男性每天 2.5 – 5 毫克。口服小剂量米诺地尔最常见的副作用是多毛症。其他潜在的副作用包括体位性低血压、下肢水肿、心动过速和头痛。
Minoxidil, originally developed as an antihypertensive agent, was noted to be associated with hypertrichosis in some patients. Minoxidil enhances follicular size, resulting in thicker hair shafts, and stimulates and prolongs the anagen phase of the hair cycle, resulting in longer and increased numbers of hair. Treatment must be continued or any drug-induced hair growth will be lost. Patients with increased sulfotransferase enzyme activity are most likely to respond to minoxidil treatment; this may be a useful predictive test in the future (Roberts et al., 2014). Topical minoxidil is available as a 2% solution and a 5% solution or foam. Allergic and irritant contact dermatitis can occur, and care should be taken in applying the drug because hair growth may emerge in undesirable locations. This is reversible on stopping the drug. Patients should be instructed to wash their hands after applying minoxidil. Oral low-dose minoxidil (0.25 – 5 mg daily) has been used off label for androgenic alopecia with recommended dosages of 0.5 – 2.5 mg daily in females or 2.5 – 5 mg daily in males. The most common side effect with oral low-dose minoxidil is hypertrichosis. Additional potential side effects include postural hypotension, lower extremity edema, tachycardia, and headache.
非那雄胺抑制 5α-还原酶的 II 型同工酶，5α-还原酶是将睾酮转化为 DHT 的酶（见第 49 章），存在于毛囊中。与非秃顶区域相比，头皮的秃顶区域与 DHT 水平升高和毛囊较小有关。口服非那雄胺 (1 mg/d) 在 2 年内不同程度地增加男性的头发生长。非那雄胺被批准仅用于男性，但已被超说明书用于女性型脱发（Varothai 和 Bergfeld，2014 年）。非那雄胺在女性中的使用受到其致畸性的限制。孕妇不应接触该药物，因为有可能诱发男性胎儿生殖器异常。非那雄胺的不良反应包括下降、勃起功能障碍、射精障碍和射精量减少。有上市后监测报告称，停药后持续性功能障碍。与米诺地尔一样，停用非那雄胺后，新的头发生长会丢失。度他雄胺 (0.5 mg/d) 是一种 I 型和 II 型同工酶 5α-还原酶抑制剂的组合，具有相似或更高的疗效，但副作用可能更常见（Varothai 和 Bergfeld，2014 年）。
Finasteride inhibits the type II isozyme of 5α-reductase, the enzyme that converts testosterone to DHT (see Chapter 49) and that is found in hair follicles. Balding areas of the scalp are associated with increased DHT levels and smaller hair follicles than nonbalding areas. Orally administered finasteride (1 mg/day) variably increases hair growth in men over a 2-year period. Finasteride is approved for use only in men but has been used off label for female pattern hair loss (Varothai and Bergfeld, 2014). Finasteride use in women is limited by its teratogenicity. Pregnant women should not be exposed to the drug because of the potential for inducing genital abnormalities in male fetuses. Adverse effects of finasteride include decreased libido, erectile dysfunction, ejaculation disorder, and decreased ejaculate volume. There have been postmarketing surveillance reports of persistent sexual dysfunction after stopping the medication. As with minoxidil, new hair growth will be lost when finasteride is discontinued. Dutasteride (0.5 mg/day) is a combined type I and type II isozyme 5α-reductase inhibitor that has similar or greater efficacy, but side effects may be more common (Varothai and Bergfeld, 2014).
螺内酯是一种醛固酮拮抗剂和保留 K+ 的利尿剂;它还具有抗雄激素活性。它用于女性型脱发，剂量为 50 至 200 毫克/天（Varothai 和 Bergfeld，2014 年）。有生育潜力的女性不应在没有可靠避孕措施的情况下接受螺内酯治疗，因为螺内酯可导致男性胎儿女性化。
Spironolactone is an aldosterone antagonist and K+-sparing diuretic; it also has antiandrogen activity. It is used off label for female pattern alopecia at dosages of 50 to 200 mg/day (Varothai and Bergfeld, 2014). Women of reproductive potential should not receive spironolactone without reliable contraception because spironolactone can cause feminization of a male fetus.
1.2 Other Agents
1.2.1 Eflornithine (依氟鸟氨酸)
Eflornithine is an inhibitor of ornithine decarboxylase (ODC) that is approved for the reduction of excessive and unwanted facial hair in women. ODC is the rate-limiting enzyme in the synthesis of polyamines, which are important in cellular migration, differentiation, and proliferation. Levels of ODC activity are higher in proliferating cells, such as in follicular matrix cells in anagen phase, and inhibiting ODC decreases hair growth. Eflornithine 13.9% cream is applied twice daily and is intended to be used along with the patient’s preferred hair removal method to slow hair regrowth.
依氟鸟氨酸是鸟氨酸脱羧酶 （ODC） 的抑制剂，被批准用于减少女性过多和不需要的面部毛发。ODC 是多胺合成中的限速酶，在细胞迁移、分化和增殖中很重要。在增殖细胞中，例如在生长期的滤泡基质细胞中，ODC 活性水平较高，抑制 ODC 会减慢毛发生长。依氟鸟氨酸 13.9% 乳膏每天使用两次，旨在与患者首选的脱毛方法一起使用，以减缓毛发再生。
1.2.2 Bimatoprost (比马前列素)
Bimatoprost is a prostaglandin analogue approved for topical treatment of hypotrichosis of the eyelashes by increasing their growth, including length, thickness, and darkness. The prostaglandin-mediated increase in eyelash growth was serendipitously noted during the use of intraocular prostaglandin analogues for glaucoma. The proposed mechanism of eyelash growth is by an increase in the fraction of hairs in, and the duration of, the anagen phase. Increased pigmentation of the hairs is thought to occur due to stimulation of melanin production without an increase in the number of melanocytes. Importantly, brown pigmentation of the iris and eyelid skin may occur, and the increased iris pigmentation may be permanent.
比马前列素是一种前列腺素类似物，被批准用于局部治疗睫毛少毛症，通过增加睫毛的生长，包括长度、厚度和深色。在使用眼内前列腺素类似物治疗青光眼期间，偶然注意到前列腺素介导的睫毛生长增加。提出的睫毛生长机制是通过增加生长期中的毛发比例和持续时间。毛发色素沉着增加被认为是由于刺激黑色素生成而没有增加黑色素细胞数量的。重要的是，虹膜和眼睑皮肤可能会出现棕色色素沉着，并且虹膜色素沉着增加可能是永久性的。
2 Treatment of Hyperpigmentation
色素过度沉着的治疗
所讨论的药物对表皮内激素或光诱导的色素沉着最有效。它们对真皮内炎症后色素沉着的疗效有限。防晒或避免防晒是任何治疗方案的重要组成部分（Sheth 和 Pandya，2011 年）。
The agents discussed are most effective on hormonally or light-induced pigmentation within the epidermis. They have limited efficacy on postinflammatory pigmentation within the dermis. Sun protection or avoidance is a vital component of any treatment regimen (Sheth and Pandya, 2011).
对苯二酚 （1,4-dihydroxybenzene） 通过抑制酪氨酸酶（黑色素生物合成途径中的初始酶）来减少黑色素细胞色素的产生。此外，它通过产生活性氧自由基导致黑色素体降解和黑色素细胞的破坏。含有 1.5% 至 2% 对苯二酚的制剂可非处方药获得;3% 至 4% 的对苯二酚制剂可通过处方获得。渗透增强剂和防晒成分被添加到一些配方中。提供由 4% 对苯二酚、0.01% 氟轻松和 0.05% 维甲酸组成的组合处方产品。不良反应可能包括皮炎和黄褐斑病。
Hydroquinone (1,4-dihydroxybenzene) decreases melanocyte pigment production by inhibiting tyrosinase, the initial enzyme in the melanin biosynthetic pathway. In addition, it causes degradation of melanosomes and destruction of melanocytes by production of reactive oxygen radicals. Formulations containing 1.5% to 2% hydroquinone are available OTC; 3% to 4% hydroquinone formulations are available by prescription. Penetration enhancers and sunscreen ingredients are added to some formulations. A combination prescription product consisting of hydroquinone 4%, fluocinolone 0.01%, and tretinoin 0.05% is available. Adverse effects may include dermatitis and ochronosis.
壬二酸是一种从糠秕马拉色菌培养物中分离的二羧酸，可抑制酪氨酸酶活性，但不如对苯二酚有效。因为它具有温和的粉刺溶解、抗菌和抗炎特性，它也常用于痤疮和丘疹脓疱性酒渣鼻，尤其是炎症后色素沉着过度的患者。
Azelaic acid, a dicarboxylic acid isolated from cultures of Malassezia furfur, inhibits tyrosinase activity but is less effective than hydroquinone. Because it has mild comedolytic, antimicrobial, and anti-inflammatory properties, it also is often used in acne and papulopustular rosacea, especially in patients with postinflammatory hyperpigmentation.
甲喹醇 （4-hydroxyanisole） 是酪氨酸酶的竞争性抑制剂。它被批准作为 2% 处方产品与 0.01% 维甲酸和维生素 C 联合用于美白皮肤，但目前尚未上市。
Mequinol (4-hydroxyanisole) is a competitive inhibitor of tyrosinase. It was approved as a 2% prescription product in combination with 0.01% tretinoin and vitamin C for skin lightening, but it is not currently commercially available.
单苯酮（对苯二酚的单苄醚）会导致永久性色素脱失，不应用于常规激素诱导或炎症后色素沉着过度。批准将 20% 乳膏用于影响至少 50% 以上体表面积的广泛性白癜风的最终色素脱失治疗;它很少使用，目前也没有上市销售。
Monobenzone (monobenzyl ether of hydroquinone) causes permanent depigmentation and should not be used for routine hormonally induced or postinflammatory hyperpigmentation. A 20% cream is approved for final depigmentation therapy of extensive vitiligo affecting at least more than 50% body surface area; it is rarely used and not currently commercially available.
乙醇酸是一种 α-羟基酸，用于化学换肤治疗色素沉着障碍。它被认为通过以 pH 非依赖性方式抑制酪氨酸酶起作用，并通过减少角质形成细胞粘附来引起剥落。可能的副作用是红斑、脱屑和炎症后色素沉着过度。乙醇酸换肤最好用作难治性表皮色素沉着过度患者的辅助治疗和其他局部治疗（Sheth 和 Pandya，2011 年）。
Glycolic acid is an α-hydroxy acid used in chemical peels for disorders of pigmentation. It is thought to work by inhibiting tyrosinase in a pH-independent manner and to cause exfoliation by decreasing keratinocyte adhesion. Potential side effects are erythema, desquamation, and postinflammatory hyperpigmentation. Glycolic acid peels are best used as adjunctive therapy along with other topical therapy in patients with refractory epidermal hyperpigmentation (Sheth and Pandya, 2011).
氨甲环酸是赖氨酸的合成类似物，通过竞争性抑制纤溶酶原向纤溶酶的转化而表现出抗纤维蛋白溶解活性。它被批准用于治疗月经过多或预防拔牙止血缺陷患者的出血。氨甲环酸超说明书用于治疗黄褐斑。紫外线辐射诱导角质形成细胞产生纤溶酶原激活剂，通过纤溶酶、花生四烯酸和成纤维细胞生长因子刺激黑色素细胞导致黑色素生成增加，然后通过血管内皮生长因子刺激增加新生血管形成。氨甲环酸通过抑制纤溶酶原活化来减轻这种紫外线诱导的黑色素生成和新生血管形成。氨甲环酸已局部用作 2% 至 5% 制剂，每天两次或皮内注射，浓度为 4 mg/mL，注射频率从每周一次到每月一次不等。皮内注射最常见的副作用是注射部位灼痛。氨甲环酸已口服，剂量为 250 至 325 毫克，每天两次。最常见的副作用是腹胀或头痛。在全身使用之前，应筛查患者血栓栓塞的危险因素。
Tranexamic acid is a synthetic analogue of lysine that exhibits antifibrinolytic activity by competitively inhibiting transformation of plasminogen to plasmin. It is approved for the treatment of heavy menstrual bleeding or to prevent hemorrhage in patients with hemostatic defects undergoing tooth extraction. Tranexamic acid is used off label for the treatment of melasma. UV radiation induces plasminogen activator production by keratinocytes, which leads to increased melanogenesis through stimulation of melanocytes by plasmin, arachidonic acid, and fibroblast growth factor, and thence to increased neovascularization via vascular endothelial growth factor stimulation. Tranexamic acid mitigates this UV-induced melanogenesis and neovascularization through inhibition of plasminogen activation. Tranexamic acid has been used topically as a 2% to 5% formulation twice daily or intradermally at a concentration of 4 mg/mL with injection frequency ranging from once weekly to once monthly. The most common side effect with intradermal injection was injection site burning. Tranexamic acid has been used orally at a dosage of 250 to 325 mg twice daily. The most common side effect is abdominal bloating or headache. Patients should be screened for thromboembolic risk factors prior to systemic use.
