外用他克莫司和吡美莫司治疗红斑狼疮皮肤损害的研究进展

他克莫司和吡美莫司是两种新的钙调神经磷酸酶抑制剂,皮肤红斑狼疮的免疫源性的病因假说提示了他克莫司和吡美莫司有效的可能.临床报道他克莫司和吡美莫司治疗红斑狼疮皮肤损害有一定疗效.     

外用吡美莫司治疗18岁以下特应性皮炎患者的Meta分析

目的 评价外用吡美莫司治疗儿童-婴儿特应性皮炎的疗效和安全性。方法 计算机检索Cochrane图书馆（2010年第2期）、Medline（1966～2010）、Embase（1974～2010）和CBM（1978～2010.6）、CNKI（1980～2010.6）等数据库,纳入所有外用吡美莫司与安慰剂或外用糖皮质激素或外用他克莫司的随机对照试验,由2组研究者（每组3人）独立提取资料与评价质量,用RevMan5.0软件统计分析。结果 共纳入16个研究,5076例儿科患者,均为高质量研究。Meta分析治疗有效率,结果显示：1%吡美莫司无论短期疗程和长期疗程均优于安慰剂（P值均小于0.01）,1%吡美莫司与0.03%他克莫司比较疗效无差别（P值均大于0.05）,但不如0.1%他克莫司有效（P=0.01）。所有研究均未发现严重的不良反应。最常见的不良反应是皮肤刺激和烧灼感。结论 外用吡美莫司治疗儿童-婴儿特应性皮炎有效安全,能改善IGA评分、瘙痒评分及PIQoL-AD评分。尚不清楚与TCs的疗效相比有无优势,故需进行更多的RCT。     

外用吡美莫司治疗特应性皮炎的系统评价

【摘要】目的 评价外用吡美莫司治疗特应性皮炎的疗效和安全性。方法 计算机检索Cochrane图书馆（2007年第2期）,Medline（1966～2007）,Embase（1974～ 2007）和中国生物医学文献数据库（CBM, 1978～2007）,收集所有外用吡美莫司与赋形剂或外用糖皮质激素制剂或外用他克莫司制剂的随机对照试验（RCT）,由两名评价人员独立提取资料与评价质量,用RevMan软件统计分析。结果 共纳入16篇RCT,包括4241例患者,均为高质量研究。对IGA治疗成功率的Meta分析结果显示：0. 1%吡美莫司与赋形剂比较,OR合并=2.87 [95% CI(2.21,3.73), P <0.001]。0. 1%吡美莫司与0.1%戊酸倍他米松比较, OR=0.15 [95% CI(0.05,0.47), P <0.001 ]。0. 1%吡美莫司与0. 03%他克莫司比较, OR合并=0.74 [ 95% CI(0.39,1.37) ,P=0.33 ]。所有研究均未发现严重的不良反应。结论 外用吡美莫司治特应性皮炎比赋形剂有效,而不如外用强效糖皮质激素有效。0. 1%吡美莫司与0. 03%他克莫司疗效相同。吡美莫司对湿疹面积和严重程度指数评分、瘙痒程度评分、生活质量相关评分均有明显改善。     

茶多酚、吡美莫司、他克莫司外用对莫诺苯宗诱导白癜风样模型小鼠的疗效比较

目的 探讨茶多酚、吡美莫司、他克莫司对莫诺苯宗诱导的白癜风样模型小鼠的疗效差异。 方法 45%莫诺苯宗诱导C57BL/6三周龄雌小鼠脱色,建立白癜风样动物模型。并研究他克莫司、吡美莫司、茶多酚对白癜风样模型小鼠脱色的治疗效果。通过肉眼观察毛发脱色及脱色面积,实验结束后取非用药部位脱色皮肤行组织学检查,HE染色检测淋巴细胞浸润情况,共聚焦激光扫描显微镜（RCM）观察小鼠皮肤的黑素和黑素细胞,免疫荧光检测CD8+ T细胞 。 结果 模型组小鼠在用药部位及非用药部位均有脱色现象。他克莫司组、吡美莫司组、茶多酚组小鼠脱色减少,出现时间晚和面积指数均较模型组低;且用药部位脱色斑局部淋巴细胞和CD8+ T细胞浸润减少。其中他克莫司组疗效优于其他组。 结论 他克莫司、吡美莫司、茶多酚对白癜风样模型小鼠均有疗效。     

外用钙调磷酸酶抑制剂对非特应性皮炎性皮肤病的治疗

外用糖皮质激素是许多炎症性皮肤病的主要治疗手段，长期应用可能产生皮肤萎缩等不良反应。近年来出现了一类可以替代糖皮质激素的大环内酯类免疫调节剂，是子囊霉素衍生物，属于皮肤外用的钙调磷酸酶抑制剂，日前国内上市的有他克莫司软膏和吡美莫司乳膏。他克莫司（Tacrolimus，商品名Protopic，普特彼）是从日本发现的链霉菌tsukubaens中提取的，分子量为822kd，外用制剂包括0．03％和0．1％的软膏。     

皮肤型红斑狼疮的治疗现状

皮肤型红斑狼疮是红斑狼疮病谱中相对较轻的一型,治疗上有别于系统性红斑狼疮,目前尚无固定的治疗模式。局部外用糖皮质激素是广泛采用的治疗手段之一,对各种皮肤型红斑狼疮均有效。较新型的外用制剂如他克莫司及吡美莫司,主要用于治疗对糖皮质激素和常规药物无效的皮肤型红斑狼疮。对外用药物治疗无效的皮损,可选择皮损内注射糖皮质激素,以快速发挥抗炎和免疫抑制作用。细胞毒药物和沙利度胺主要治疗复发或难治性皮肤型红斑狼疮。激光及光疗也能有效改善皮肤型红斑狼疮的皮损。     

色素障碍性皮肤病

进行期白癜风皮损周围黑素细胞的抗原递呈细胞相关表型的测定及其临床意义;复方卡力孜然酊联合窄谱中波紫外线治疗白癜风临床疗效观察;他克莫司软膏治疗白癜风的临床疗效观察;外用吡美莫司治疗白癜风的进展（综述）;他克莫司软膏治疗面颈部白癜风疗效观察;     

钙调磷酸酶抑制剂治疗银屑病研究进展

钙调磷酸酶抑制剂可阻断钙调磷酸酶的信号通路,抑制T细胞的活化,以往主要作为免疫抑制剂用于器官移植后的免疫调节治疗.近年的研究发现其对一些炎症性皮肤病,如银屑病和特应性皮炎等同样有效,外用疗效接近糖皮质激素却不会导致皮肤萎缩,他克莫司软膏和吡美莫司乳膏有望成为外用糖皮质激素在银屑病治疗中的替代药物.概述几种钙调磷酸酶抑制剂治疗银屑病的临床疗效、作用机制以及其不良反应.     

吡美莫司在特应性皮炎中的应用

吡美莫司是目前治疗特应性皮炎的一个新选择,多项临床试验表明,外用吡美莫司治疗特应性皮炎安全有效。与外用糖皮质激素相比,外用吡美莫司不会引起皮肤萎缩,可以安全用于面颈部及皱褶部;透皮吸收少,未见系统不良反应;早期间歇外用毗美莫司可以明显减少特应性皮炎的严重发作,延长缓解期。     

308nm准分子激光治疗白癜风概述

白癜风治疗方法较多,308 nm准分子激光凭借起效快、疗效高及副作用小等优势而迅速应用于临床。其治疗白癜风的作用机制不清,可能通过诱导皮损处浸润的淋巴细胞凋亡而取得疗效。联合外用他克莫司软膏或吡美莫司乳膏治疗白癜风效果比单独应用308 nm准分子激光更为显著。     

Role of Topical Calcineurin Inhibitors in the Treatment of Seborrheic Dermatitis

Seborrheic dermatitis (SD) is characterized by erythematous pruritic patches and plaques with greasy scale that occur in sebaceous areas. It is common, affecting up to 3% of the population. Past treatments have relied on a wide variety of anti-inflammatory and antifungal agents, but corticosteroids have limited use because of long-term adverse effects. Topical calcineurin inhibitors provide a safe alternative for the treatment of SD, as these drugs block the inflammatory cascade involved in the disease process and pose no risk of skin atrophy. Studies of topical pimecrolimus and tacrolimus in the treatment of SD have found that improvement occurred within 2 weeks, and if SD recurred after stopping treatment, it was significantly less severe. There have been no studies of the comparative efficacy of pimecrolimus versus tacrolimus for the treatment of SD. Common adverse effects of mild burning and irritation have been associated with the use of both of these agents. Safety profile studies are limited to studies of atopic dermatitis, which show no increase in infection rate, photocarcinogenicity, or signs of immunosuppression in patients using topical calcineurin inhibitors for long-term treatment. This article reviews the clinical trials of pimecrolimus and tacrolimus in the treatment of SD, focusing on efficacy and safety.     

Topical noncorticosteroid immunomodulation in the treatment of atopic dermatitis

At present, the first-line drugs for treating atopic dermatitis are topical corticosteroids. They are effective when used short-term; however, long-term use of the corticosteroids is associated with suppressive effects on the connective tissue, seen as skin atrophy or resistance to therapy. Currently, two topical noncorticosteroid immunomodulators tacrolimus (FK506) and pimecrolimus (SDZ ASM 981) are under development, or already on the market in some countries for atopic dermatitis. These two compounds show structural similarity. In T lymphocytes they bind to the same cellular receptor, the FK-binding protein (FKBP) or macrophilin-12. Tacrolimus shows a 3-fold greater affinity to FKBP compared with pimecrolimus. The tacrolimus/ pimecrolimus-FKBP complex further binds to calcineurin, an enzyme vital for the early activation of T cells. The consequence of calcineurin binding is a lack of activation of both T helper cell types 1 and 2. Further effects of these compounds have been suggested on other inflammatory cells, such as Langerhans cells and mast cells/basophils. In contrast to corticosteroids, no suppressive effects on connective tissue cells have been observed. Taken together, treatment of inflammation results in healing of the barrier function of the skin. This again results in reduced bioavailability of the drug, as compared with systemic use. Placebo-controlled studies have shown the efficacy of both tacrolimus (at 0.03 and 0.1%) and pimecrolimus (at 0.6 and 1%). The main adverse event in these studies has been a burning sensation and increased pruritus at the site of application. Typically, these adverse events are observed only during the first days of treatment. Long-term safety studies, of up to one year, have not revealed any new adverse events. So far, long-term use of topical noncorticosteroid compounds has not been associated with signs of immune deficiency. Although there is currently no evidence for clinically relevant, prolonged adverse effects, some of these, such as an increased risk of photocarcinogenesis, need to be monitored. There is evidence from tacrolimus studies that monotherapy results in better long-term results when compared with combination therapy with corticosteroids. Tacrolimus and pimecrolimus could replace topical corticosteroids as the first-line treatment of atopic dermatitis.     

Pimecrolimus identifies a common genomic anti-inflammatory profile,is clinically highly effective in psoriasis and is well tolerated

The ascomycin macrolactam pimecrolimus is a novel inflammatory cytokine release inhibitor that so far has not been administered systemically to humans. In this phase I/II randomized double-blind, placebo-controlled, multiple rising dose proof of concept study psoriasis patients were treated with oral pimecrolimus or placebo. Gene profiling identified a common genomic profile with a downregulation of genes associated with inflammation but no changes in gene expression linked to drug-related side-effects. A steady state of pimecrolimus was reached after 5-10 d, Cmax, and area under the curve (0-24) was 54.5 ng per ml and 589.9 ng h per ml, respectively, at steady state at the highest dose. There was clear clinical efficacy in patients receiving 20 mg pimecrolimus twice daily and 30 mg twice daily with a reduction of Psoriasis Area and Severity Index by 60% and 75%, respectively. Histopatho logically and immunopathologically there was a reversion of the psoriatic phenotype towards normal. There were no notable clinical, laboratory, kidney function, or immunologic side-effects. We conclude that pimecrolimus taken orally is highly effective in a concentration-dependent manner in patients with psoriasis and on a short-term basis it is well tolerated and this is confirmed by its pharmacogenomic profile. The latter also indicates that pimecrolimus should be equally effective in other inflammatory skin diseases.     

Low systemic exposure after repeated topical application of Pimecrolimus (Elidel), SD Z ASM 981) in patients with atopic dermatitis

BACKGROUND: Pimecrolimus is a cell-selective inhibitor of inflammatory cytokine release developed specifically for the treatment of inflammatory skin diseases. AIM: The objective of this study was to evaluate blood concentrations and tolerability of pimecrolimus during topical treatment. METHODS: Twelve adult patients with extensive atopic dermatitis were enrolled in an open-label, noncontrolled, pharmacokinetic study. The patients were treated twice daily for 3 weeks with pimecrolimus cream 1% on all lesions. Pimecrolimus blood concentrations were measured at regular time points, and the safety and tolerability were monitored throughout the study. RESULTS: In 78% of the 444 blood samples evaluated, pimecrolimus concentrations remained below the limit of quantitation (0.5 ng/ml). The highest concentration measured was 1.4 ng/ml. There was no indication of drug accumulation. Pimecrolimus was well tolerated locally and systemically. CONCLUSION: The 3-week twice daily treatment with pimecrolimus cream 1% results in consistently low pimecrolimus blood concentrations with no accumulation. Pimecrolimus cream appears suitable for the long-term management of atopic dermatitis.     

Efficacy and safety of pimecrolimus cream 1% in adult patients with vitiligo: Results of a randomized,double‐blind,vehicle‐controlled study

Background: Vitiligo is an acquired, pigmentary skin disorder which is disfiguring and difficult to treat. In an earlier open label study in adult patients with vitiligo, pimecrolimus cream 1% was reported to have similar efficacy as clobetasol propionate 0.05%. We performed a double‐blind, intrapatient comparison of pimecrolimus cream 1% with placebo cream. Patients and methods: Twenty adult Caucasians with symmetrical vitiligo (predominantly on extremities, none in the face) were treated b.i.d. for 6 months left/right with pimecrolimus/vehicle (N = 10) or vehicle/pimecrolimus (N = 10), respectively. Primary efficacy endpoint was the size of the target lesion at month 6 and secondary efficacy endpoint was re‐pigmentation. Results: Treatment with pimecrolimus cream 1% or vehicle resulted in no significant change in mean target lesion size. Modest repigmentation (1–25%) was noted with pimecrolimus at month 2 in 12 of 17 patients (vehicle: 9 of 17 patients). Afterwards, the number of patients who experienced an improvement of pigmentation steadily decreased (3 of 14 patients with pimecrolimus and 2 of 14 with placebo at month 6).Treatment was well tolerated.There were no treatment‐related adverse events, no induction of skin atrophy nor any other application site side effects. Conclusion: In this group of adult patients with symmetrical vitiligo, treatment of body lesions (except face) with pimecrolimus cream 1% could not be shown to be effective.     

Pimecrolimus 1% cream versus betamethasone 17-valerate 0.1% cream in the treatment of facial discoid lupus erythematosus: a double-blind, randomized pilot study

Background.  Discoid lupus erythematosus (DLE) is commonly treated with topical agents, the most important of which are glucocorticosteroids. However, prolonged use of these agents, especially on sensitive areas such as the face, may result in side-effects (e.g. atrophy and telangiectases) by altering collagen synthesis. Therefore, alternative treatments are needed for these patients.
Aim.  To investigate and compare the efficacy of topical pimecrolimus 1% cream and topical betamethasone 17-valerate 0.1% cream on facial lesions of DLE.
Methods.  This was a randomized double-blind pilot study, performed in outpatient clinics of two major referral hospitals. Ten patients aged 20–53 years with moderate to severe DLE of the face were randomized into two groups for 8 weeks of treatment and 8 weeks of follow-up after treatment. In this double-blind study, one group applied pimecrolimus 1% cream twice daily and the other group applied betamethasone valerate 0.1% cream twice daily to facial lesions. Efficacy end-points included a combined score based on evaluation of erythema, infiltration and presence of scale.
Results.  Efficacy end-points showed significant improvement in both groups. A decrease of 86% and 73% in clinical severity scores was obtained for pimecrolimus and betamethasone, respectively ( P  = 0.043). There was no significant difference between the two groups in terms of efficacy ( P  = 0.1). No adverse effect was found at the end of the 8-week trial in any of our patients.
Conclusions.  The efficacy of pimecrolimus 1% cream is comparable with that of betamethasone valerate 0.1% cream in treating facial DLE.     

Pimecrolimus and narrowband UVB as monotherapy or combination therapy in children and adolescents with atopic dermatitis

Topical pimecrolimus and narrowband ultraviolet B (UVB) are both known to be effective in treating atopic dermatitis. We compared the clinical efficacy of monotherapy with either twice daily topical 1% pimecrolimus cream or twice weekly narrowband UVB, and combination therapy in 26 children and adolescents with moderate to severe atopic dermatitis in a half-side manner for 6 weeks. Twenty-four patients completed the study. Monotherapy and combination therapy notably reduced the scores of the Eczema Area and Severity Index ( p = 0.002) and the severity of pruritus ( p < or = 0.004). There was no significant difference in therapeutic efficacy among the treatment regimens at week 6. In conclusion, because of the lack of short-term additive therapeutic efficacy, concomitant use of pimecrolimus and narrowband UVB is inadvisable in treating moderate to severe atopic dermatitis in children and adolescents.     

Spotlight on topical pimecrolimus in atopic dermatitis

Pimecrolimus (SDZ ASM 981), an ascomycin derivative, is a nonsteroid, has anti-inflammatory activity, and has demonstrated efficacy in reducing symptoms of atopic dermatitis in adult and pediatric patients when applied topically. Compared with vehicle, topical pimecrolimus 1.0% cream was significantly more effective at reducing symptoms of atopic dermatitis, as measured by the Eczema Area and Severity Index (EASI), in infants aged 3 to 23 months, children aged 2 to 17 years, and adults. The median reductions from baseline in the total EASI score in adults after treatment with pimecrolimus 1.0% or corresponding vehicle twice daily for 3 weeks were 47 and 0%, respectively. In infants and children, treatment with pimecrolimus 1.0% twice daily for 6 weeks resulted in significant decreases in mean EASI scores compared with vehicle. The severity of pruritus was significantly reduced in patients of all age groups after topical treatment with pimecrolimus 1.0% cream. Compared with vehicle, the incidence of eczematous flares was also reduced by intermittent long-term use of topical pimecrolimus 1.0% in adults, children and infants. Sixty-one percent of children treated with pimecrolimus for 1 year completed the first 6 months of treatment without experiencing a flare, compared with 35% of patients who received vehicle. Furthermore, the use of topical corticosteroids for the treatment of uncontrolled flares in adults, children and infants was lower in the pimecrolimus groups than in the vehicle groups. Topical pimecrolimus 1.0% cream is well tolerated in atopic dermatitis patients of all age groups. There were no clinically relevant systemic adverse events reported from any of the studies in patients with atopic dermatitis. The most frequently reported adverse events pertained to application site reactions, such as burning and a feeling of warmth. In conclusion, topical pimecrolimus 1.0% cream has shown efficacy in the treatment of mild to moderate atopic dermatitis in infants, children and adults. Although tolerability data concerning infants and children have not yet been published in full, the drug appears to be well tolerated in all age groups, and there have been no reports of clinically relevant systemic adverse events. Furthermore, pimecrolimus has shown no potential for skin atrophy, a problem commonly associated with treatment with topical corticosteroids. Topical pimecrolimus 1.0% provides a promising and well tolerated treatment option in the management of infants, children and adults with mild to moderate atopic dermatitis.     

Efficacy and tolerability of three different doses of oral pimecrolimus in the treatment of moderate to severe atopic dermatitis: a randomized controlled trial

BACKGROUND: Adult atopic dermatitis (AD) can seriously affect quality of life of patients and their families, and patients' disease is frequently not satisfactorily controlled with topical therapy. There is a need for alternatives to topical treatment in patients with moderate to severe AD. OBJECTIVES: To investigate the efficacy and safety of oral pimecrolimus, and to determine the response to three different doses in the treatment of AD. METHODS: In a double-blind, placebo-controlled, parallel-group, dose-finding study, patients with moderate to severe AD were randomized to receive either placebo, or oral pimecrolimus 10, 20 or 30 mg twice daily. The study consisted of a pretreatment phase, a 12-week double-blind treatment phase, and a 12-week post-treatment phase. RESULTS: In total, 103 patients were randomized. A clear, dose-dependent therapeutic effect of pimecrolimus treatment was observed, with a statistically significant onset of efficacy at week 2 and the greatest reduction from baseline of the Eczema Area and Severity Index of 66.6% at week 7 in the 30 mg twice daily dose group. Oral pimecrolimus was well tolerated and there were no signs of nephrotoxicity or the induction of hypertension. CONCLUSIONS: These data demonstrate the clinically relevant efficacy and short-term safety of oral pimecrolimus in adults with moderate to severe AD. Longer-term studies in larger cohorts are now required.