Crisaborole is a novel, nonsteroidal, topical anti-inflammatory ointment, and inhibits overactive PDE4 to reduce the local inflammation.Studies showed that inflammatory cells from patients with atopic dermatitis (AD) had subnormal cAMP levels due to increased PDE4 activity, and increased production of inflammatory cytokines.A literature search was conducted using Medline with the key word Crisaborole.Its pharmacological effects, pharmacodynamics, pharmacokinetics, clinical assessment of the treatment of atopic dermatitis, dosage, safety and drug interactions were reviewed in this paper.
美国皮肤病学会(American Academy of Dermatology,AAD)推荐特应性皮炎(atopic dermatitis,AD)患者的治疗,首先是局部使用增湿剂,如果症状持续,局部用糖皮质激素(topical corticosteroids,TCS)或者钙调神经磷酸酶抑制剂(topical calcineurin inhibitors,TCI)。尽管短期局部使用这些药物具有很好的耐受性,但长期局部使用TCS可能引起表皮和全身不良反应[1,2],导致局部毛细血管扩张、皮纹、紫癜、毛发增生、色素沉着和口周皮肤炎等不良反应,甚至可能引起肾上腺抑制、生长发育迟缓、高血压、高血糖、胰岛素抵抗和白内障等其他系统并发症。长期局部使用TCI具有潜在的发生恶性肿瘤的危险[3]。尤其是在儿童无法发挥其最佳疗效。
CARROLL CL,BALKRISHNANR,FELDMAN SR,et al.The burden of atopic dermatitis:impact on the patient,family,and society[J].Pediatr Dermatol,2005,22(3):192-199.
Abstract Abstract: Atopic dermatitis is a common disease of increasing prevalence. Affected individuals must cope with a significant psychosocial burden, in addition to dealing with the medical aspects of the disease. Furthermore, because this is primarily a disease of childhood, family members, especially parents, are also affected by the condition. Individuals and family members are burdened with time-consuming treatment regimens for the disease, as well as dietary and household changes. The financial impact of atopic dermatitis on families can also be great. Moreover, the cost to society is significant, with estimates ranging from less than $100 to more than $2000 per patient per year. It is estimated that the direct cost of atopic dermatitis in the United States alone is almost $1 billion per year. Reducing the onus of this disease must take into account the full breadth of its burden. Targeting parents and caregivers with education and psychosocial support can decrease family and personal burden, which in turn may decrease the cost of treating the condition because of better medical, psychosocial, and family outcomes.
EICHENFIELD LF,TOM WL,BERGER TG,et al.Guidelines of care for the management of atopic dermatitis section 2.Management and treatment of atopic dermatitis with topical therapies[J].J Am Acad Dermatol,2014,71(1):116-132.
Atopic dermatitis is a common and chronic, pruritic inflammatory skin condition that can affect all age groups. This evidence-based guideline addresses important clinical questions that arise in its management. In this second of 4 sections, treatment of atopic dermatitis with nonpharmacologic interventions and pharmacologic topical therapies are reviewed. Where possible, suggestions on dosing and monitoring are given based on available evidence.
This parameter was developed by the Joint Task Force on Practice Parameters, representing the American Academy of Allergy, Asthma & Immunology (AAAAI); the American College of Allergy, Asthma & Immunology (ACAAI); and the Joint Council of Allergy, Asthma and Immunology. The AAAAI and the ACAAI have jointly accepted responsibility for establishing "Atopic dermatitis: a practice parameter update 2012.'' This is a complete and comprehensive document at the current time. The medical environment is a changing environment, and not all recommendations will be appropriate for all patients. Because this document incorporated the efforts of many participants, no single individual, including those who served on the Joint Task Force, is authorized to provide an official AAAAI or ACAAI interpretation of these practice parameters. Any request for information about or an interpretation of these practice parameters by the AAAAI or ACAAI should be directed to the Executive Offices of the AAAAI, the ACAAI, and the Joint Council of Allergy, Asthma & Immunology. These parameters are not designed for use by pharmaceutical companies in drug promotion. Published practice parameters of the Joint Task Force on Practice Parameters for Allergy & Immunology are available online at http://www.jcaai.org. (J Allergy Clin Immunol 2013;131:295-9.)
YOSIPOVITCHG,PAPOIU AD.What causes itch in atopic dermatitis?[R].Curr Allergy Asthma Rep,2008,8(4):306-311.
[本文引用:1]
[5]
BARNES KC.An update on the genetics of atopic dermatitis.Scratching the surface in 2009[J].J Allergy Clin Immunol,2010,125(1):16-29.
A genetic basis for atopic dermatitis (AD) has long been recognized. Historic documents allude to family history of disease as a risk factor. Before characterization of the human genome, heritability studies combined with family-based linkage studies supported the definition of AD as a complex trait in that interactions between genes and environmental factors and the interplay between multiple genes contribute to disease manifestation. A summary of more than 100 published reports on genetic association studies through mid-2009 implicates 81 genes, in 46 of which at least 1 positive association with AD has been demonstrated. Of these, the gene encoding filaggrin (FLG) has been most consistently replicated. Most candidate gene studies to date have focused on adaptive and innate immune response genes, but there is increasing interest in skin barrier dysfunction genes. This review examines the methods that have been used to identify susceptibility genes for AD and how the underlying pathology of this disease has been used to select candidate genes. Current challenges and the potential effect of new technologies are discussed.
LEUNG DY.New insights into atopic dermatitis.role of skin barrier and immune dysregulation[J].Allergol Int,2013,62(2):151-161 .
Atopic dermatitis (AD) is a chronic inflammatory skin disease that is often associated with the development of food allergy and asthma. New insights into AD reveals an important role for structural abnormalities in the epidermis resulting in a leaky epithelial barrier as well as chronic immune activation that contribute to the pathophysiology of this common skin disease. Patients with AD have a predisposition to colonization or infection by microbial organisms, most notably Staphylococcus aureus and herpes simplex virus (HSV). Measures directed at healing and protecting the skin barrier and controlling the immune activation are needed for effective management of AD. Early intervention may improve outcomes for AD as well as reduce the systemic allergen sensitization that may lead to associated allergic diseases in other organs.
HANIFIN JM,CHAN SC,CHENG JB,et al.Type 4 phosphodiesterase inhibitors have clinical and in vitro anti-inflammatory effects in atopic dermatitis[J].J Invest Dermatol,1996,107(1):51-56.
Abstract Increased cyclic AMP-phosphodiesterase activity in peripheral blood leukocytes is associated with the immune and inflammatory hyperreactivity that characterizes atopic dermatitis. Atopic phosphodiesterase has high sensitivity to a variety of enzyme inhibitors, suggesting an increased therapeutic advantage. The objective of this study was to use in vitro assays to identify a potent phosphodiesterase inhibitor and then to investigate its effectiveness in treating atopic dermatitis. Leukocyte enzyme activity was measured by radioenzyme assay, whereas prostaglandin E2 and interleukins 10 (IL-10) and 4 (IL-4) were measured in 24-h culture supernatants of mononuclear leukocytes by immunoassays. The effect of a topical phosphodiesterase inhibitor on atopic dermatitis lesional skin was assessed by double-blind, paired comparisons of active drug and placebo ointments applied to symmetrically involved sites over a 28-d period. Using in vitro, assays, we demonstrated the ability of selective high-potency phosphodiesterase inhibitors to reduce prostaglandin E2, IL-10, and IL-4 production in atopic mononuclear leukocyte cultures. We selected the Type 4 phosphodiesterase inhibitor, CP80,633, based on its inhibitory potency, for clinical testing by topical, bilateral paired comparisons in 20 patients with atopic dermatitis and demonstrated significant reductions of all inflammatory parameters. Phosphodiesterase inhibitors modulate several pathways contributing to the exaggerated immune and inflammatory responses, which characterize atopic dermatitis. This in vivo demonstration of anti-inflammatory efficacy may provide a useful alternative to the over-reliance on corticosteroid therapy in atopic disease.
ZANE LT,CHANDAS,JARNAGINK,et al.Crisaborole and its potential role in treating atopic dermatitis:overview of early clinicalstudies[J].Immunotherapy,2016,8(8):853-866.
Atopic dermatitis (AD), a chronic, relapsing, inflammatory skin disease that is characterized by intense pruritus and eczematous lesions with up to 90% of patients presenting with mild to moderate disease. Current topical treatments for AD have not changed in over 15 years and are associated with safety concerns. In AD, overactivity of phosphodiesterase 4 (PDE4), leads to inflammation and disease exacerbation. Crisaborole Topical Ointment, 2%, is a novel, nonsteroidal, topical anti-inflammatory PDE4 inhibitor currently being investigated for the treatment of mild to moderate AD. Preliminary studies in children and adults demonstrated favorable efficacy and safety profiles. Crisaborole may represent an anti-inflammatory option that safely minimizes the symptoms and severity of AD and that can be used for both acute and long-term management.
MOUSTAFAF,FELDMAN SR.A review of phosphodiesterase-inhibition and the potential role for phosphodiesterase 4-inhibitors in clinical dermatology[J].Dermatol Online J,2014,20(5):22608.
Phosphodiesterase inhibitors are commonly used drugs. Specific phosphodiesterase inhibitors with anti-inflammatory properties are being assessed as dermatological treatments.To describe important aspects of phosphodiesterase inhibition and the safety and efficacy of 2 phosphodiesterase- 4 inhibitors being studied for the treatment of dermatologic diseasesWe did a non-systematic analysis of literature on phosphodiesterase inhibition followed by a review of published information on apremilast and topical AN2728 and their use for psoriasis and atopic dermatitis.Apremilast and topical AN2728 have modest efficacy in treatment of psoriasis. Apremilast achieved PASI-75 scores ranging from 24-33%. In phase 2 studies, AN2728 had modest efficacy for psoriasis (40% of patients achieved a 2 grade improvement as assessed by the Overall target Plaque Severity Score). In phase 2 studies of AN2728 use in atopic dermatitis, subjects achieved a 71% improvement from baseline Atopic Dermatitis Severity Index. In all studies, most adverse effects were minimal. The limitations of this paper are the limited number of published studies, the lack of long-term data, and the lack of head -to - head trials directly comparing phosphodiesterase inhibitors with other treatments.Phosphodiesterase inhibitors constitute a widely used class of drugs that may see growing use for inflammatory dermatologic diseases.
JARNAGINK,CHANDAS,CORONADOD,et al.Crisaborole topical ointment,2%:a nonsteroidal,topical,anti-inflammatory phosphodiesterase 4 inhibitor in clinical development for the treatment of atopic dermatitis[J].J Drugs Dermatol,2016,15(4):390-396.
[本文引用:1]
[11]
BAUMERW,HOPPMANNJ,RUNDFELDTC,et al.Highly selective phosphodiesterase 4 inhibitors for the treatment of allergic skin diseases and psoriasis[J].Allergy Drug Targets,2007,6(1):17-26.
The phosphodiesterase (PDE) 4 is the predominant cyclic AMP degrading enzyme in a variety of inflammatory cells including eosinophils, neutrophils, macrophages, T cells and monocytes. In addition, this enzyme is expressed in non-immune cells such as keratinocytes and fibroblasts. Highly selective PDE4 inhibitors are currently under evaluation for the treatment of asthma and/or chronic obstructive pulmonary disease. Due to the broad anti-inflammatory/immunomodulatory action of PDE4 inhibitors, it has been proposed that PDE4 inhibitors might also be efficacious for skin disorders such as atopic dermatitis. Consequently, PDE4 inhibitors including cilomilast and AWD 12-281 have been tested in several models of allergic and irritant skin inflammation. These PDE4 inhibitors displayed strong anti-inflammatory action in models of allergic contact dermatitis in mice, in the arachidonic acid induced skin inflammation in mice and in ovalbumin sensitised guinea pigs. The determination of cytokines in skin homogenates revealed that both Th1 as well as Th2 cytokines are suppressed by PDE4 inhibitors, indicating an anti-inflammatory activity in both the Th2 dominated acute phase as well as the Th1 dominated chronic phase of atopic dermatitis. Due to the suppression of Th1 cytokines, activity can also be expected in psoriasis. <br/> Results of early clinical trials with both topically (cipamfylline, CP80,633) and systemically (CC-10004) active PDE4 inhibitors demonstrated efficacy in atopic dermatitis and in the case of CC-10004, also in psoriasis. AWD 12-281 (GW 842470) is currently under clinical evaluation for the topical treatment of atopic dermatitis. Results concerning clinical efficacy of this potent and selective PDE4 inhibitor are anxiously awaited. <br/> <br/>
FREUND YR,AKAMAT,ALLEY MR,et al.Boron-based phosphodiesterase inhibitors show novel binding of boron to PDE4 bimetal center[J].FEBS Lett,2012,586(19):3410-3414.
We have used boron-based molecules to create novel, competitive, reversible inhibitors of phosphodiesterase 4 (PDE4). The co-crystal structure reveals a binding configuration which is unique compared to classical catechol PDE4 inhibitors, with boron binding to the activated water in the bimetal center. These phenoxybenzoxaboroles can be optimized to generate submicromolar potency enzyme inhibitors, which inhibit TNF, IL-5 and IL-10 activities in vitro and show safety and efficacy for topical treatment of human psoriasis. They provide a valuable new route for creating novel potent anti-PDE4 inhibitors.
PALLER AS,TOM WL,LEBWOHL MG,et al.Efficacy and safety of crisaboroleointment,a novel,nonsteroidalphosphodiesterase 4 (PDE4) inhibitorfor the topical treatment ofatopic dermatitis (AD)in children and adults[J].J Am Acad Dermatol,2016,75(3):494-503.
Additional topical treatments for atopic dermatitis (AD) are needed that provide relief while minimizing risks. We sought to assess the efficacy and safety of crisaborole ointment, a phosphodiesterase 4 inhibitor, in two phase III AD studies (AD-301:NCT02118766; AD-302:NCT02118792). Two identically designed, vehicle-controlled, double-blind studies enrolled and randomly assigned (2:1, crisaborole:vehicle) patients aged 202years or older with an Investigator's Static Global Assessment (ISGA) score of mild or moderate for twice-daily application for 2802days. The primary end point was ISGA score at day 29 of clear (0)/almost clear (1) with 2-grade or greater improvement from baseline. Additional analyses included time to success in ISGA score, percentage of patients achieving clear/almost clear, reduction in severity of AD signs, and time to improvement in pruritus. More crisaborole- than vehicle-treated patients achieved ISGA score success (clear/almost clear with ≥2-grade improvement; AD-301: 32.8% vs 25.4%,P=02.038; AD-302: 31.4% vs 18.0%,P<02.001), with a greater percentage with clear/almost clear (51.7% vs 40.6%,P=02.005; 48.5% vs 29.7%,P<02.001). Crisaborole-treated patients achieved success in ISGA score and improvement in pruritus earlier than those treated with vehicle (bothP≤02.001). Treatment-related adverse events were infrequent and mild to moderate in severity. Short study duration was a limitation. Crisaborole demonstrated a favorable safety profile and improvement in all measures of02efficacy, including overall disease severity, pruritus, and other signs of AD.
BLUME-PEYTAVIU,METZM.Atopic dermatitis in children:management of pruritus[J].J Eur Acad Dermatol Venereol,2012,26(Suppl 6):2-8.
Children with chronic atopic dermatitis (AD)-related itch require a comprehensive treatment approach that addresses the underlying cause of pruritus, as well as symptoms and complications that extend beyond the physical domain. In small children and infants, the short-term complications of quality of life disturbance and sleep dysfunction are closely associated with the course of adolescent development. In addition, the physical damage that results from uncontrolled pruritus and scratching can lead to disease chronification. Therefore, the rapid relief of acute pruritic flares, followed by the long-term maintenance of symptom-free skin, should be prioritized in AD treatment, in an effort to avoid the emotional, social and physical chronic manifestations described above. Alleviation of AD symptoms with fourth-generation topical anti-inflammatory agents like methylprednisolone aceponate is an appropriate choice of therapy for children and infants, due to its optimized therapeutic index and versatility in formulation. Especially in AD, supplemental disease management education should be considered, to address the psycho-social needs of children (and their families) suffering from pruritus.
The burden of atopic dermatitis:impact on the patient,family,and society
1
2005
... 美国皮肤病学会(American Academy of Dermatology,AAD)推荐特应性皮炎(atopic dermatitis,AD)患者的治疗,首先是局部使用增湿剂,如果症状持续,局部用糖皮质激素(topical corticosteroids,TCS)或者钙调神经磷酸酶抑制剂(topical calcineurin inhibitors,TCI).尽管短期局部使用这些药物具有很好的耐受性,但长期局部使用TCS可能引起表皮和全身不良反应[1,2],导致局部毛细血管扩张、皮纹、紫癜、毛发增生、色素沉着和口周皮肤炎等不良反应,甚至可能引起肾上腺抑制、生长发育迟缓、高血压、高血糖、胰岛素抵抗和白内障等其他系统并发症.长期局部使用TCI具有潜在的发生恶性肿瘤的危险[3].尤其是在儿童无法发挥其最佳疗效. ...
Guidelines of care for the management of atopic dermatitis section 2.Management and treatment of atopic dermatitis with topical therapies
1
2014
... 美国皮肤病学会(American Academy of Dermatology,AAD)推荐特应性皮炎(atopic dermatitis,AD)患者的治疗,首先是局部使用增湿剂,如果症状持续,局部用糖皮质激素(topical corticosteroids,TCS)或者钙调神经磷酸酶抑制剂(topical calcineurin inhibitors,TCI).尽管短期局部使用这些药物具有很好的耐受性,但长期局部使用TCS可能引起表皮和全身不良反应[1,2],导致局部毛细血管扩张、皮纹、紫癜、毛发增生、色素沉着和口周皮肤炎等不良反应,甚至可能引起肾上腺抑制、生长发育迟缓、高血压、高血糖、胰岛素抵抗和白内障等其他系统并发症.长期局部使用TCI具有潜在的发生恶性肿瘤的危险[3].尤其是在儿童无法发挥其最佳疗效. ...
Atopic dermatitis:a practiceparameter update 2012
1
2013
... 美国皮肤病学会(American Academy of Dermatology,AAD)推荐特应性皮炎(atopic dermatitis,AD)患者的治疗,首先是局部使用增湿剂,如果症状持续,局部用糖皮质激素(topical corticosteroids,TCS)或者钙调神经磷酸酶抑制剂(topical calcineurin inhibitors,TCI).尽管短期局部使用这些药物具有很好的耐受性,但长期局部使用TCS可能引起表皮和全身不良反应[1,2],导致局部毛细血管扩张、皮纹、紫癜、毛发增生、色素沉着和口周皮肤炎等不良反应,甚至可能引起肾上腺抑制、生长发育迟缓、高血压、高血糖、胰岛素抵抗和白内障等其他系统并发症.长期局部使用TCI具有潜在的发生恶性肿瘤的危险[3].尤其是在儿童无法发挥其最佳疗效. ...
Crisaborole topical ointment,2%:a nonsteroidal,topical,anti-inflammatory phosphodiesterase 4 inhibitor in clinical development for the treatment of atopic dermatitis
Efficacy and safety of crisaboroleointment,a novel,nonsteroidalphosphodiesterase 4 (PDE4) inhibitorfor the topical treatment ofatopic dermatitis (AD)in children and adults
1
2016
... 在美国进行的两项设计相同的多中心、随机、双盲、安慰药对照Ⅲ期临床研究(AD-301,AD-302)[13],评价了患者使用crisaborole治疗轻中度AD的疗效和安全性.两项研究共入选患者1522例,均>2岁.患者被随机分为治疗组和安慰药组,人数比2:1.其中,AD-301研究有47个研究中心,治疗组和安慰药组分别纳入受试者503例和256例.AD-302有42个研究中心,两组分别纳入受试者513例和250例.患者年龄分布及基线ISGA见表1.AD诊断依据Hanifin和Rajka34标准,通过研究者静态总体评分表(Investigator’s Static Global Assessment,ISGA) 见表2,将皮炎累及超过身体表面积5%的患者分为轻度(2)或中度(3).最近28 d使用过生物治疗或者全身糖皮质激素,或者14 d内使用过TCS或者TCI的患者不能参加该研究.患者应无皮肤感染,允许患者在治疗前使用吸入糖皮质激素、抗组胺药和局部维甲酸类药物治疗非AD.两项研究和两组之间基本资料和疾病严重程度无明显统计学差异. ...
Atopic dermatitis in children:management of pruritus
, 封宇飞
