tacrolimus and Dermatitis--Atopic

Atopic dermatitis is a prevalent condition in children and can be effectively managed with medications such as topical calcineurin inhibitors (pimecrolimus or tacrolimus). A key unresolved safety concern is whether use of topical calcineurin inhibitors is associated with cancer. We systematically reviewed the risk of cancer in patients with atopic dermatitis exposed to topical calcineurin inhibitors.. As part of the 2022 American Academy of Allergy, Asthma and Immunology and American College of Allergy, Asthma and Immunology Joint Task Force on Practice Parameters atopic dermatitis guidelines, we searched MEDLINE, Embase, the Latin American and Caribbean Health Sciences Literature database, the Índice Bibliográfico Espanhol de Ciências da Saúde database, the Global Resource of Eczema Trials database, WHO's International Clinical Trials Registry Platform, the US Food and Drug Administration database, the European Medicines Agency database, company registers, and relevant citations from inception to June 6, 2022. We included randomised controlled trials and comparative and non-comparative non-randomised studies in any language addressing cancer risk in patients with atopic dermatitis using topical calcineurin inhibitors. We excluded split-body studies and studies with less than 3 weeks of follow-up. Paired reviewers independently screened records, extracted data, and assessed risk of bias in duplicate. We used Bayesian models to estimate the probability for cancer due to topical calcineurin inhibitor exposure and the GRADE approach to determine the certainty of the evidence. Patients, advocacy groups, and care providers set a priori thresholds of important effects. This study is registered with Open Science Framework, https://osf.io/v4bfc.. We identified and analysed 110 unique studies (52 randomised controlled trials and 69 non-randomised studies [11 were non-randomised study extensions of randomised controlled trials]) including 3·4 million patients followed up for a mean of 11 months (range 0·7-120). The absolute risk of any cancer with topical calcineurin inhibitor exposure was not different from controls (absolute risk 4·70 per 1000 with topical calcineurin inhibitors vs 4·56 per 1000 without; odds ratio 1·03 [95% credible interval 0·94-1·11]; moderate certainty). For all age groups and using data from observational studies and randomised controlled trials, the use of pimecrolimus (OR 1·05 [95% credible interval 0·94-1·15]) or tacrolimus (0·99 [0·89-1·09]) is likely to have had little to no association with cancer compared with no topical calcineurin inhibitor exposure. For pimecrolimus versus tacrolimus, the finding was similar (0·95 [95% credible interval 0·83-1·07]). Findings were similar in infants, children, and adults, and robust to trial sequential, subgroup, and sensitivity analyses.. Among individuals with atopic dermatitis, moderate-certainty evidence shows that topical calcineurin inhibitors do not increase the risk of cancer. These findings support the safe use of topical calcineurin inhibitors in the optimal treatment of patients with atopic dermatitis.. American Academy of Allergy, Asthma and Immunology and American College of Allergy, Asthma and Immunology via the Joint Task Force on Practice Parameters.

Topics: Adult; Asthma; Bayes Theorem; Calcineurin Inhibitors; Child; Dermatitis, Atopic; Humans; Hypersensitivity; Infant; Neoplasms; Randomized Controlled Trials as Topic; Tacrolimus

Topical corticosteroids (TCS) are a mainstay of treatment for atopic dermatitis (AD). There are shared physician and patient concerns that TCS use can result in skin atrophy and systemic absorption. The clinical use of topical calcineurin inhibitors (TCI) for AD is relatively limited despite evidence that TCI are safe and effective. Understanding the differences in efficacy and adverse effects between TCS and TCI can help shape prescription practices to the benefit of patients. The objective of this review is to characterize the difference in efficacy and adverse effects between TCS and TCI. A review of the literature between 2002 and 2022 was performed using the PubMed, EMBASE, and Cochrane Library databases. Ten studies comparing TCS of varying potencies with TCI approved for AD treatment were included in the review. Outcome measures were qualified using percent reductions on the modified Eczema Area and Severity Index score and decreases in physician's global evaluation of AD severity. Tacrolimus had statistically significant (P < .05) improvement in disease severity compared with TCS in 4 of the 5 studies that compared tacrolimus with weak TCS. The data suggest greater treatment efficacy of tacrolimus over weak TCS, and inferior efficacy of pimecrolimus (TCI) compared with both tacrolimus and weak TCS. It is difficult to draw conclusions between moderate, potent, and very potent TCS and TCI due to the small number of available studies. TCI can improve disease severity, especially on thin or intertriginous skin regions most vulnerable to adverse events with TCS treatment, and their use may help overcome adherence issues due to patient bias against TCS.

Topics: Calcineurin Inhibitors; Dermatitis, Atopic; Dermatologic Agents; Glucocorticoids; Humans; Tacrolimus; Treatment Outcome

New topical agents have been developed for the treatment of atopic dermatitis (AD) in recent years. This systematic review is intended to synthesize the clinical trial literature and concisely report the updated safety and adverse effects of topical medications used to treat atopic dermatitis in children.. A systematic search of Cochrane Library, Embase, PubMed and ClinicalTrials.gov from inception to March 2022 was conducted for trials of topical medications used to treat AD in patients <18 years (PROSPERO #CRD42022315355). Included records were limited to English-language publications and studies of ≥3 weeks duration. Phase 1 studies and those that lacked separate paediatric safety reporting were excluded.. A total of 5005 records were screened; 75 records met inclusion criteria with 15 845 paediatric patients treated with tacrolimus, 12 851 treated with pimecrolimus, 3539 with topical corticosteroid (TCS), 700 with crisaborole and 202 with delgocitinib. Safety data was well reported in tacrolimus trials with the most frequently reported adverse events being burning sensation, pruritus and cutaneous infections. Two longitudinal cohort studies were included, one for tacrolimus and one for pimecrolimus, which found no significant increased risk of malignancy with topical calcineurin inhibitor (TCI) use in children. Skin atrophy was identified as an adverse event in TCS trials, which other medications did not. Systemic adverse events for the medications were largely common childhood ailments.. Data discussed here support the use of steroid-sparing medications (tacrolimus, pimecrolimus, crisaborole, delgocitinib) as safe options with minimal adverse events for managing paediatric AD, although a larger number of TCI studies reported burning and pruritus compared to TCS studies. TCS was the only medication class associated with reports of skin atrophy in this review. The tolerability of these adverse events should be considered when treating young children. This review was limited to English-language publications and the variable safety reporting of trial investigators. Many newer medications were not included due to pooled adult and paediatric safety data that did not meet inclusion criteria.

Topics: Adult; Calcineurin Inhibitors; Child; Child, Preschool; Dermatitis, Atopic; Dermatologic Agents; Humans; Longitudinal Studies; Pruritus; Tacrolimus; Treatment Outcome

Provide a review of atopic dermatitis management, focusing on optimizing topical therapy, creating a stepwise approach for treatment plans, and providing guidance on when to start systemic therapy.. PubMed search of articles in the English language regarding atopic dermatitis in all ages.. Articles on the subject matter were selected and reviewed.. Topical corticosteroids are the first-line treatment for managing atopic dermatitis. Topical nonsteroidal agents, calcineurin inhibitors, crisaborole, and recently, ruxolitinib, which cause no cutaneous atrophy, are options for reducing the use of topical corticosteroids, including on sensitive sites. Emerging topical agents are in clinical trials. Proactive management, with continued application 2 to 3 times weekly of a midpotency topical corticosteroid or tacrolimus, may maintain control for clear (or almost clear) localized sites of dermatitis that rapidly recur when topical anti-inflammatory medication is stopped. If topical therapy alone cannot control disease and quality of life is impacted, reevaluation to confirm the diagnosis, manage comorbid conditions, address compliance and patient-specific concerns, and optimize topical therapy must be undertaken before deciding to advance to systemic medication. Dupilumab, an interleukin-4 receptor inhibitor, has become first-line systemic therapy given its efficacy and safety, allowing long-term treatment without laboratory monitoring. Other biologics and Janus kinase inhibitors are emerging as alternatives that could eliminate the need for immunosuppressants with their higher risks.. Several options are now available for topical treatment. A stepwise approach is needed to consider alternative therapies and diagnoses before advancing to systemic treatment, but the safety of newer immunomodulators will lower the threshold for more aggressive intervention.

Topics: Administration, Topical; Calcineurin Inhibitors; Dermatitis, Atopic; Dermatologic Agents; Glucocorticoids; Humans; Quality of Life; Tacrolimus

This is an abridged edition of English version of the Clinical Practice Guidelines for the Management of Atopic Dermatitis 2021. Atopic dermatitis (AD) is a disease characterized by relapsing eczema with pruritus as a primary lesion. In Japan, from the perspective of evidence-based medicine, the current strategies for the treatment of AD consist of three primary measures: (i) use of topical corticosteroids, tacrolimus ointment, and delgocitinib ointment as the main treatment of the inflammation; (ii) topical application of emollients to treat the cutaneous barrier dysfunction; and (iii) avoidance of apparent exacerbating factors, psychological counseling, and advice about daily life. In the present revised guidelines, the description about three new drugs, namely, dupilumab, delgocitinib, and baricitinib, has been added. The guidelines present recommendations to review clinical research articles, evaluate the balance between the advantages and disadvantages of medical activities, and optimize medical activity-related patient outcomes with respect to several important points requiring decision-making in clinical practice.

Topics: Dermatitis, Atopic; Emollients; Glucocorticoids; Humans; Japan; Ointments; Tacrolimus

The goal of a treatment regimen for atopic dermatitis is to reach and maintain a state where the patient exhibits mild symptoms or an absence of symptoms, and the patient should not experience disturbance during daily activities. The basis of a treatment regimen for atopic dermatitis is topical therapy, and currently there exist topical corticosteroids, tacrolimus and delgocitinib. Using these, proactive therapy is performed as maintenance therapy after remission induction therapy. However, in cases of moderate to severe atopic dermatitis, topical drugs alone cannot induce remission and systemic therapies such as cyclosporin, ultraviolet therapy, and dupilumab should be used in combination. In particular, dupilumab has many advantages such as high efficacy, relatively few adverse reactions, and ease of use in elderly patients with severe atopic dermatitis. In this review, we present a treatment algorithm for atopic dermatitis that emphasizes the importance of maintaining remission after induction of remission, and summarizes the characteristics of current medication therapy for atopic dermatitis in Japan.

Topics: Aged; Cyclosporine; Dermatitis, Atopic; Humans; Japan; Tacrolimus; Treatment Outcome

Atopic dermatitis (AD) is a chronic and relapsing, inflammatory skin disease characterized by impaired skin barrier function and immune system dysregulation that results in dryness, skin microbiome dysbiosis and intense pruritus. It is highly heterogeneous, and its management is demanding. Patients with AD are at greater risk of comorbidities such as attention-deficit hyperactivity disorder as well as other atopic diseases. Early-onset AD cases typically improve or resolve in late childhood; however, it is proposed that the prevalence of persistent or adult-onset AD is higher than previously thought. Basic therapy consists of emollient application and trigger avoidance, and when insufficient, topical corticosteroids (TCS) are the first-line treatment. However, corticophobia/steroid aversion and TCS side-effects, particularly on sensitive skin areas, lead to low compliance and insufficient disease control. Several long- and short-term randomized controlled and daily practice studies have demonstrated that topical calcineurin inhibitors, such as pimecrolimus, have similar anti-inflammatory effects to low-to-medium strength TCS, reduce pruritus and improve the quality of life of patients. In addition, pimecrolimus does not cause skin atrophy, is steroid-sparing and has a good safety profile, with no evidence for an increased risk of malignancies or skin infections. In general, pimecrolimus cream is well-accepted and well-tolerated, encouraging patient adherence and leading to its use by many physicians as a preferred therapy for children and sensitive skin areas.

Topics: Adult; Calcineurin Inhibitors; Child; Dermatitis, Atopic; Humans; Quality of Life; Tacrolimus; Treatment Outcome

The topical calcineurin inhibitors (TCIs) tacrolimus and pimecrolimus have been used widely as corticosteroid-sparing agents in treating various cutaneous diseases. However, the association between TCIs and risk of malignancy remains controversial. By systematic review and meta-analysis, we aimed to investigate the association between TCIs and lymphoma. Eligible studies in online databases were identified from the date of inception to August 30, 2020. To assess the outcome of TCI-related risk of lymphoma, analysis of cohort studies comparing the incidence of lymphoma with and without treatment with TCIs was performed. Furthermore, the subgroup analyses of Hodgkin lymphoma and non-Hodgkin lymphoma were also conducted. The pooled results revealed that using topical tacrolimus (RR 1.68, 95 % CI 1.39-2.04) or pimecrolimus (RR 1.40, 95 % CI 1.13-1.74) significantly increased the risk of lymphoma. TCI users also showed higher incidence of lymphoma in the range of 0.02-0.09 %, compared to that of 0.02-0.06 % in the control group. Additionally, subgroup analyses showed both tacrolimus (RR 1.89; 95 % CI 1.53-2.32) and pimecrolimus (RR 1.38; 95 % CI 1.09-1.74) had significantly higher risk of non-Hodgkin lymphoma, but no increased risk of Hodgkin lymphoma. In conclusion, TCI-exposed patients have a significantly increased risk of lymphoma, especially non-Hodgkin lymphoma.

Topics: Administration, Topical; Calcineurin Inhibitors; Dermatitis, Atopic; Hodgkin Disease; Humans; Lymphoma; Tacrolimus

Atopic dermatitis (AD) is perhaps the most common inflammatory skin disorder worldwide, with an increasing incidence in developed countries. The mainstay treatment for patients with AD is topical therapies, which are used not only by the mild patients but also by the moderate-to-severe patients, in conjunction with systemic treatment. While topical steroids and calcineurin antagonists are widely used, these are associated with long-term cutaneous adverse effects (AEs) or a black box warning, preventing their chronic use. Areas covered: The aim of this review is to provide a comprehensive overview of new and upcoming topical therapies currently in development and undergoing clinical trials, as well as their safety and efficacy profiles, and discuss current topicals used in the management of AD. Expert opinion: AD is a heterogeneous disease with complex pathophysiology. Treatments available to date for AD provide disease control; however, patients struggle to find an optimized therapeutic regimen they may use long term and without severe effects. Novel therapies are currently under investigation, with the hope of shifting the paradigm of AD management from symptom control to disease eradication.

Topics: Administration, Topical; Animals; Calcineurin Inhibitors; Clinical Trials as Topic; Dermatitis, Atopic; Expert Testimony; Humans; Immunosuppressive Agents; Skin; Tacrolimus

More than 15 years have passed since the clinical launch of topical tacrolimus for the treatment of atopic dermatitis. Its efficacy and safety have been clearly demonstrated in many global and domestic short-term and long-term clinical trials. Although the prolonged external application of steroids causes many adverse reactions including cutaneous atrophy, no such reactions occur with the use of topical tacrolimus. Therefore, the therapeutic guidelines recommend a combined topical treatment with tacrolimus and steroids. Tacrolimus is a potent immunosuppressant. However, recent studies have revealed its diverse action on the cardinal pathomechanisms of atopic dermatitis. In this review, we summarize the mechanistic role of tacrolimus in various aspects of allergic inflammation including mast cell activation, innate allergic response, pruritus, sensory nerve activation, and skin barrier dysfunction.

Topics: Administration, Topical; Animals; Cytokines; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Pruritus; Skin; Tacrolimus; Treatment Outcome

Atopic dermatitis (AD) requires long-term management, mainly with topical anti-inflammatory agents. Topical corticosteroids (TCS) and tacrolimus ointment (TAC-O) are recommended as first-line treatments for AD. However, the long-term use of TCS is limited by cutaneous adverse events such as skin atrophy. For TAC-O, Japanese and US labelings were updated in 2003 and 2006, respectively, to include a boxed warning about a theoretical risk of skin cancer and lymphoma in patients treated with topical calcineurin inhibitors. However, TAC-O has been used worldwide for longer than 15 years to treat adult and pediatric patients with AD. Available data suggest that TAC-O is effective and well tolerated, and can improve quality of life. TAC-O has successfully been used in the proactive management of AD consisting of long-term intermittent use to prevent, delay or reduce the occurrence of AD flares. Systemic drug absorption after TAC-O application is negligible and unlikely to result in systemic immunosuppression. There is currently no strong evidence of an increased rate of malignancy in treated patients, and observational data from postmarketing surveillance studies have shown no safety concerns. In the absence of robust evidence, the warning about the carcinogenic potential in the Japanese labeling for TAC-O does not appear justified and should be reconsidered. This mitigation of description would allow adult and pediatric patients with AD to receive the effective treatment more appropriately.

Topics: Administration, Cutaneous; Adult; Atrophy; Calcineurin Inhibitors; Child; Dermatitis, Atopic; Dermatologic Agents; Glucocorticoids; Humans; Ointments; Skin; Skin Neoplasms; Tacrolimus; Treatment Outcome

Atopic dermatitis (AD) is a common inflammatory skin disease in both adults and children. Whilst topical calcineurin inhibitors (TCIs), tacrolimus ointment and pimecrolimus cream, have proven efficacy for the treatment of AD, it is important to involve experts to obtain their opinion on its optimal treatment.. Using a modified Delphi approach, this project aimed to generate consensus amongst experts on the use of TCIs in the treatment of AD, with a focus on the differentiation between tacrolimus and pimecrolimus.. Six expert dermatologists from different European countries participated in this project based on their experience with AD and its treatment, which was evaluated by literature analysis and expert opinion. Consensus amongst the experts was generated using a modified Delphi approach, consisting of three distinct phases, during which a web meeting (June 2017), two online rounds of blinded Delphi voting (July-September 2017) and a face-to-face meeting (November 2017) were conducted. The consensus statements concerned two main topics: (i) Background of AD; and (ii) TCIs in AD. Hot topics in the treatment of AD not supported by meta-analysis, clinical trials or large observational studies were also discussed based on clinical experience.. In total, 25 consensus statements were defined and validated: eight statements on the general background of AD and 17 statements on the use of TCIs in AD, including their mechanism of action and therapeutic indications in AD, efficacy in adult and paediatric AD patients, pharmacokinetics, incidence of adverse events and safety concerns. Hot topics on the use of TCIs for the treatment of AD included cream vs. ointment, dosages, TCIs contact allergy, burning sensation management, superinfection and vaccination concerns.. Topical calcineurin inhibitors are a suitable therapy for AD, and selection of the specific TCI should be based on factors which differentiate tacrolimus from pimecrolimus.

Topics: Calcineurin Inhibitors; Consensus; Delphi Technique; Dermatitis, Atopic; Humans; Tacrolimus

The guidelines for the treatment of atopic dermatitis (AD) issued by the Japanese Dermatological Association (JDA), which are basically designed for dermatologists, were first prepared in 2000 and revised in 2016. The guidelines for AD of the Japanese Society of Allergology (JSA), which are basically designed for allergologists, including internists, otorhinolaryngologists, ophthalmologists, and dermatologists, were first prepared in 2009 and revised in 2014. In this article, I review the definition, pathophysiology, etiology, epidemiology, diagnosis, severity classification, examination for diagnosis and severity assessment, and treatments for AD in Japan according to these two guidelines for AD (JDA and JSA). Based on the definition and diagnostic criteria for AD of the JDA, patients meeting three basic criteria, 1) pruritus, 2) typical morphology and distribution of the eczema, and 3) chronic or chronically relapsing course, are regarded as having AD. Treatment measures for AD basically consist of drug therapy, skin care, and elimination of exacerbating factors. Drugs that potently reduce AD-related inflammation in the skin are topical corticosteroids and tacrolimus. It is most important to promptly and accurately reduce inflammation related to AD by using these topical anti-inflammatory drugs. Proactive therapy refers to a treatment method in which, after inducing remission, a topical corticosteroid or tacrolimus ointment is intermittently applied to the skin in addition to skin care with moisturizers in order to maintain remission.

Topics: Administration, Topical; Adrenal Cortex Hormones; Allergy and Immunology; Dermatitis, Atopic; Humans; Japan; Ointments; Practice Guidelines as Topic; Societies, Medical; Tacrolimus

Topics: Administration, Topical; Animals; Antigens, Dermatophagoides; Child; Child, Preschool; Cyclosporine; Dermatitis, Atopic; Desensitization, Immunologic; Eczema; Edema; Humans; Immunoglobulin E; Male; Pyroglyphidae; Tacrolimus

Atopic dermatitis (AD) is a distressing dermatological disease, which is highly prevalent during infancy, can persist into later life and requires long-term management with anti-inflammatory compounds. The introduction of the topical calcineurin inhibitors (TCIs), tacrolimus and pimecrolimus, more than 10 yr ago was a major breakthrough for the topical anti-inflammatory treatment of AD. Pimecrolimus 1% is approved for second-line use in children (≥2 yr old) and adults with mild-to-moderate AD. The age restriction was emphasized in a boxed warning added by the FDA in January 2006, which also highlights the lack of long-term safety data and the theoretical risk of skin malignancy and lymphoma. Since then, pimecrolimus has been extensively investigated in short- and long-term studies including over 4000 infants (<2 yr old). These studies showed that pimecrolimus effectively treats AD in infants, with sustained improvement with long-term intermittent use. Unlike topical corticosteroids, long-term TCI use does not carry the risks of skin atrophy, impaired epidermal barrier function or enhanced percutaneous absorption, and so is suitable for AD treatment especially in sensitive skin areas. Most importantly, the studies of pimecrolimus in infants provided no evidence for systemic immunosuppression, and a comprehensive body of evidence from clinical studies, post-marketing surveillance and epidemiological investigations does not support potential safety concerns. In conclusion, the authors consider that the labelling restrictions regarding the use of pimecrolimus in infants are no longer justified and recommend that the validity of the boxed warning for TCIs should be reconsidered.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Child, Preschool; Consensus; Dermatitis, Atopic; Humans; Infant; Practice Guidelines as Topic; Tacrolimus

There is controversy regarding a potential increased risk of lymphoma in patients with atopic dermatitis (AD).. To assess the risk of lymphoma and the role of topical treatments in patients with AD.. A systematic literature search and a separate meta-analysis were performed on case control and cohort studies.. Of the 3979 articles retrieved, 24 references met the inclusion criteria. In cohort studies, the risk of lymphoma was slightly increased, with a relative risk (RR) of 1.43 (95% confidence interval [CI], 1.12-1.81). In case control studies, no significant increased risk of lymphoma was found, with an odds ratio (OR) of 1.18 (95% CI, 0.94-1.47). Severity of AD was a significant risk factor. Highly potent topical steroids were associated with an increased risk of lymphoma. For topical calcineurin inhibitors (TCIs), a significant association between tacrolimus and mostly skin lymphoma was found in 1 study.. Confusion between severe AD and cutaneous T-cell lymphoma may account for part of the increased risk of lymphoma in patients with AD.. This systematic literature review shows a slightly increased risk of lymphoma in patients with AD. Severity of AD appears to be a significant risk factor. The role of topical steroids and TCIs is unlikely to be significant.

Topics: Administration, Topical; Adrenal Cortex Hormones; Age Distribution; Calcineurin Inhibitors; Comorbidity; Dermatitis, Atopic; Female; Humans; Immunosuppressive Agents; Incidence; Lymphoma, T-Cell, Cutaneous; Male; Prognosis; Risk Assessment; Severity of Illness Index; Sex Distribution; Skin Neoplasms; Tacrolimus

Using a network meta-analysis, we aimed to compare the efficacy and safety of tacrolimus and pimecrolimus as treatment options for children with atopic dermatitis (AD).. Randomized controlled studies with a modified Jadad score >3 using tacrolimus or pimecrolimus in pediatric patients with AD were studied.. Out of 163 articles, 19 studies enrolling a total of 6,413 pediatric patients were selected. Pooled analysis revealed that tacrolimus 0.03% or 0.1% and pimecrolimus 1% were better at reducing eczema compared with vehicles. No significance was found between tacrolimus and pimecrolimus in improving the severity of eczema. More patients tended to withdraw in the vehicle groups compared to the tacrolimus and pimecrolimus groups. No significant difference existed between total adverse events and withdrawals in the tacrolimus and pimecrolimus groups.. Pimecrolimus was similar to tacrolimus in both efficacy and safety for AD in children, but both were better than vehicles.

Topics: Adolescent; Child; Child, Preschool; Dermatitis, Atopic; Humans; Infant; Randomized Controlled Trials as Topic; Tacrolimus

Atopic dermatitis (AD) (or atopic eczema) is a chronic inflammatory skin condition that affects children and adults and has an important impact on quality of life. Topical corticosteroids (TCS) are the first-line therapy for this condition; however, they can be associated with significant adverse effects when used chronically. Tacrolimus ointment (in its 2 manufactured strengths of 0.1% and 0.03%) might be an alternative treatment. Tacrolimus, together with pimecrolimus, are drugs called topical calcineurin inhibitors (TCIs).. To assess the efficacy and safety of topical tacrolimus for moderate and severe atopic dermatitis compared with other active treatments.. We searched the following databases up to 3 June 2015: the Cochrane Skin Group Specialised Register, CENTRAL in the Cochrane Library (Issue 5, 2015), MEDLINE (from 1946), EMBASE (from 1974), LILACS (from 1982), and the Global Resource of Eczema Trials (GREAT database). We searched six trials registers and checked the bibliographies of included studies for further references to relevant trials. We contacted specialists in the field for unpublished data.A separate search for adverse effects of topical tacrolimus was undertaken in MEDLINE and EMBASE on 30 July 2013. We also scrutinised the U.S. Food and Drug Administration (FDA) websites for adverse effects information.. All randomised controlled trials (RCTs) of participants with moderate to severe atopic dermatitis (both children and adults) using topical tacrolimus at any dose, course duration, and follow-up time compared with other active treatments.. Two authors independently screened and examined the full text of selected studies for compliance with eligibility criteria, risk of bias, and data extraction. Our three prespecified primary outcomes were physician's assessment, participant's self-assessment of improvement, and adverse effects. Our secondary outcomes included assessment of improvement of the disease by validated or objective measures, such as SCORAD (SCORing Atopic Dermatitis), the EASI (Eczema Area and Severity Index), and BSA (Body Surface Area) scores.. We included 20 studies, with 5885 participants. The variability of drug doses, outcomes, and follow-up periods made it difficult to carry out meta-analyses.A single trial showed that tacrolimus 0.1% was better than low-potency TCS by the physician's assessment (risk ratio (RR) 3.09, 95% confidence interval (CI) 2.14 to 4.45, 1 study, n = 371, moderate-quality evidence). It was also marginally better than low-potency TCS on face and neck areas and moderate-potency TCS on the trunk and extremities by the physician's assessment (RR 1.32, 95% CI 1.17 to 1.49, 1 study, n = 972, moderate level of evidence) and for some of the secondary outcomes. Compared with pimecrolimus 1%, people treated with tacrolimus were almost twice as likely to improve by the physician's assessment (RR 1.80, 95% CI 1.34 to 2.42, 2 studies, n = 506, moderate quality of evidence). Compared with the lower concentration of 0.03%, the tacrolimus 0.1% formulation reduced the risk of not having an improvement by 18% as evaluated by the physician's assessment (RR 0.82, 95% CI 0.72 to 0.92, 6 studies, n = 1640, high-quality evidence). Tacrolimus 0.1% compared with moderate-to-potent TCS showed no difference by the physician's assessment, and 2 secondary outcomes (1 study, 377 participants) and a marginal benefit favouring tacrolimus 0.1% was found by the participant's assessment (RR 1.21, 95% CI 1.13 to 1.29, 1 study, n = 974, low quality of evidence) and SCORAD.Based on data from 2 trials, tacrolimus 0.03% was superior to mild TCS for the physician's assessment (RR 2.58, 95% CI 1.96 to 3.38, 2 studies, n = 790, moderate-quality evidence) and the participant's self-assessment (RR 1.64, 95% CI 1.41 to 1.90, 1 study, n = 416, moderate quality of evidence). One trial showed moderate benefit of tacrolimus 0.03% compared with pimecrolimus 1% on the physician's assessment (RR 1.42, 95% CI 1.02 to 1.98, 1 study, n = 139, low-quality evidence), but the effects were equivocal when evaluating BSA. In the comparison of tacrolimus 0.03% with moderate-to-potent corticosteroids, no difference was found in most of the outcomes measured (including physician's and participant's assessment and also for the secondary outcomes), but in two studies, a marginal benefit favouring the corticosteroid group was found for the EASI and BSA scores.Burning was more frequent in those using calcineurin inhibitors than those using corticosteroid tacrolimus 0.03% (RR 2.48, 95% CI 1.96 to 3.14, 5 studies, 1883 participants, high. Tacrolimus 0.1% was better than low-potency corticosteroids, pimecrolimus 1%, and tacrolimus 0.03%. Results were equivocal when comparing both dose formulations to moderate-to-potent corticosteroids. Tacrolimus 0.03% was superior to mild corticosteroids and pimecrolimus. Both tacrolimus formulations seemed to be safe, and no evidence was found to support the possible increased risk of malignancies or skin atrophy with their use. The reliability and strength of the evidence was limited by the lack of data; thus, findings of this review should be interpreted with caution. We did not evaluate costs.

Topics: Administration, Topical; Calcineurin Inhibitors; Dermatitis, Atopic; Dermatologic Agents; Humans; Randomized Controlled Trials as Topic; Tacrolimus

Topics: Administration, Topical; Adrenal Cortex Hormones; Anti-Allergic Agents; Baths; Cholestasis, Intrahepatic; Cyclosporins; Dermatitis, Atopic; Diagnosis, Differential; Female; Histamine Antagonists; Humans; Immunosuppressive Agents; Pemphigoid Gestationis; Pregnancy; Pregnancy Complications; Prurigo; Pruritus; Skin; Tacrolimus

New knowledge on the pathogenesis of atopic dermatitis (AD) gives us new treatment options. This review emphasizes long-term treatment results.. This study includes basic pathogenic factors in AD and presents present and future treatment options. Topical corticosteroids treat the inflammation effectively short term. Topical calcineurin inhibitors (TCIs) show better benefit/risk ratio in long-term treatment. For topical treatment, an effective maintenance treatment results in optimal control of the AD. Of systemic immunosuppressive treatments, efficacy has been shown with azathioprine, ciclosporin, methotrexate and mycophenolate-free sodium. With these compounds, the treatment outcome was ~ 50% improvement in clinical signs compared with baseline. New treatments under study include systemic compounds, which suppress the T helper type 2 cells. The importance of adherence to treatment is often overlooked, although it has a major impact on treatment outcome. For the present review, PubMed was used as a primary source.. Combination of future T(H)2-specific systemic treatment with optimal topical treatment with TCI, especially tacrolimus ointment, could help to completely control the skin inflammation in AD. The ultimate goal is to control AD completely, which should help to control the atopic airway disease as well.

Topics: Administration, Topical; Adrenal Cortex Hormones; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Long-Term Care; Maintenance Chemotherapy; Medication Adherence; Tacrolimus; Treatment Outcome

Topical calcineurin inhibitors (TCIs), commercially available since 2000-2001, are the first and only topical medications approved for chronic treatment of atopic dermatitis (AD) in pediatric patients and remain a welcomed alternative to topical corticosteroids. In January 2006, the US Food and Drug Administration (FDA) issued a boxed warning requirement based on a theoretical risk of malignancy (including lymphoma) with TCI use. However, in the years since, analyses of epidemiologic and clinical data have failed to demonstrate a causal relationship between TCI use and malignancy or lymphoma risk, especially for pimecrolimus cream. In fact, the observed number of malignancies and lymphomas observed both in post-marketing surveillance and reported to the FDA using its adverse events reporting system is much lower among TCI-exposed patients than the expected number for the general population. Furthermore, among children enrolled in post-marketing pediatric registry studies for both tacrolimus and pimecrolimus followed for up to 5.5 years [10,724 patient-years (PY)] or 6.5 years (16,219 PY), respectively, the observed number of malignancies and lymphomas is very low and similar to the number expected for a sample of similar size in the general population. In addition to reporting these comparative malignancy and lymphoma data, this article provides a historical overview of the boxed warning requirement and critically evaluates the preclinical, clinical, and epidemiological evidence that has thus far failed to substantiate a relationship between TCI use and malignancy. The authors also provide practical clinical advice for optimizing AD management and patient care in the context of the boxed warning.

Topics: Advertising; Animals; Calcineurin Inhibitors; Dermatitis, Atopic; Drug Labeling; Evidence-Based Medicine; Humans; Immunosuppressive Agents; Lymphoma; Risk Factors; Tacrolimus; United States; United States Food and Drug Administration

Pimecrolimus , a calcineurin inhibitor, is a non-steroidal treatment option in patients aged ≥ 2 years with mild-to-moderate atopic eczema (AE). It was approved as a viable therapeutic option by the FDA in 2001 and in the European Union a year later in 2002. Calcineurin inhibitors inhibit the synthesis of inflammatory cytokines released from T cells and mast cells. In contrast to corticosteroids, calcineurin inhibitors act specifically on proinflammatory cells. Pimecrolimus shows comparative efficacy to mild topical corticosteroids and a special antipruritic effect. Furthermore, examinations of the systemic absorption of pimecrolimus implicated no systemic immunosuppression. In 2006, the FDA set a black box warning in the packaging materials of pimecrolimus alluding to the risk of skin malignancy or lymphomas due to theoretical consideration.. The authors provide a review of pimecrolimus as a treatment for AE. Specifically, the authors present the pharmacokinetic and pharmacodynamic information on pimecrolimus and also review its efficacy. The authors also discuss pimecrolimus' safety and tolerability profile.. Pimecrolimus represents a valuable part of active and proactive therapy in AE. That being said, the long-term safety of topical calcineurin inhibitors remains to be investigated. Given the results from experimental photocarcinogenicity studies, effective sun protection should be employed during the therapy, although an increased risk for skin malignancies and lymphomas was not found in recent studies. Pimecrolimus should be considered as an alternative therapeutic approach in AE treatment management going along with a corticoid-sparing effect.

Topics: Calcineurin; Dermatitis, Atopic; Dermatologic Agents; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Enzyme Inhibitors; Humans; Randomized Controlled Trials as Topic; Skin; Tacrolimus

Topics: Administration, Oral; Administration, Topical; Adrenal Cortex Hormones; Anti-Allergic Agents; Cyclosporins; Dermatitis, Atopic; Drug Administration Schedule; Histamine Antagonists; Humans; Immunosuppressive Agents; Ointments; Practice Guidelines as Topic; Tacrolimus; Time Factors

Atopic dermatitis is a common chronic skin disorder whose management is complex. Topical corticosteroids have been the mainstay of atopic dermatitis treatment for more than 50 years but have multiple side effects. Topical calcineurin inhibitors including tacrolimus and pimecrolimus are safe and efficacious in atopic dermatitis. In 2005 the FDA issued "black box" warnings for pimecrolimus cream and tacrolimus ointment because of potential safety risks, including skin cancers and lymphomas. However, these concerns are not supported by current data. Topical calcineurin inhibitors are particularly indicated for treating patients with atopic dermatitis in whom topical corticosteroid therapy cannot be employed or may cause irreversible side effects. They can be used advantageously in problem zones. A novel regimen of proactive treatment has been shown to prevent, delay and reduce exacerbations of atopic dermatitis. Therapy with topical calcineurin inhibitors should be managed by an experienced specialist and each patient should receive proper education on how to use them and what possible unwanted effects may be expected.

Topics: Administration, Topical; Calcineurin Inhibitors; Dermatitis, Atopic; Dose-Response Relationship, Drug; Humans; Hyperalgesia; Immunosuppressive Agents; Risk Factors; Tacrolimus

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by extreme pruritis and lichenified papules and plaques that may begin in or persist into adulthood. Topical corticosteroids are first-line prescription therapy for AD; they are efficacious and have a well established safety profile. The topical calcineurin inhibitors tacrolimus and pimecrolimus were approved by the US FDA in 2000 and 2001, respectively, as second-line topical therapy for AD. This review evaluates the available studies on the comparative effectiveness, safety, cost, and impact on quality of life of topical corticosteroids and topical calcineurin inhibitors for the treatment of adult AD. Tacrolimus was found to be as effective as class III-V topical corticosteroids for AD of the trunk and extremities, and more effective than low-potency class VI or VII corticosteroids for AD of the face or neck. Pimecrolimus was less effective than both tacrolimus and low-potency topical corticosteroids for moderate to severe AD. The short-term safety studies found that, compared with topical corticosteroid-treated adults, patients treated with topical calcineurin inhibitors had an increased frequency of application-site reactions, an equivalent infection risk, and a decreased risk of skin atrophy. The long-term safety of topical calcineurin inhibitors remains under investigation. Currently published studies that evaluated the comparative cost and quality-of-life effects compared tacrolimus with less potent topical corticosteroids despite the availability of equivalent potency corticosteroids. Further cost and quality-of-life studies are needed that compare topical calcineurin inhibitors with stronger classes of topical corticosteroids over longer time periods. The available clinical trials data do not suggest an efficacy advantage for topical calcineurin inhibitors over topical corticosteroids in adults with AD of the trunk and extremities, and there is not yet adequate evidence to support topical calcineurin inhibitors as first-line therapy for adult AD.

Topics: Administration, Cutaneous; Adult; Calcineurin Inhibitors; Comparative Effectiveness Research; Cost-Benefit Analysis; Dermatitis, Atopic; Glucocorticoids; Humans; Immunosuppressive Agents; Quality of Life; Tacrolimus

Topical calcineurin inhibitors have proved to be suitable for the treatment of AD. We conducted a meta-analysis comparing efficacy and tolerance of tacrolimus with pimecrolimus in treatment of AD. According to our meta-analysis, tacrolimus 0.1% was more effective than pimecrolimus 1% in adult patients (week 3: risk ratio [RR] 0.55, 95% confidence interval [CI] 0.42-0.73), and tacrolimus (a combination of 0.03% and 0.1%) was also more effective than pimecrolimus 1% in pediatric patients (week 6/end of study: RR 0.76, 95% CI 0.63-0.92). Regardless of age or illness severity, tacrolimus 0.1% had higher efficacy than pimecrolimus 1% in the treatment of AD (week 3: RR 0.55, 95% CI 0.42-0.72). In adult patients, tacrolimus 0.1% had more adverse events than pimecrolimus 1% (RR 1.30, 95% CI 1.02-1.66), but the incidence of adverse events between tacrolimus 0.1% (or 0.03%) and pimecrolimus 1% was not significantly different in pediatric patients. No matter whether the patients were adult or pediatric, more pimecrolimus-treated patients withdrew from the trials because of a lack of efficacy. Regardless of age and illness severity, more pimecrolimus 1%-treated patients withdrew from the trials because of a lack of efficacy, compared with tacrolimus 0.1% (or 0.03%)-treated patients. More pimecrolimus-treated pediatric patients withdrew from the trials because of adverse events (RR 0.26, 95% CI 0.1-0.68). More pimecrolimus 1%-treated patients withdrew from the trials because of adverse events, compared with tacrolimus 0.03%-treated patients, regardless of age (RR 0.1, 95% CI 0.02-0.53). In conclusion, tacrolimus ointment has higher efficacy and better tolerance than pimecrolimus cream in treatment of AD.

Topics: Administration, Topical; Adult; Calcineurin Inhibitors; Child; Dermatitis, Atopic; Humans; Tacrolimus; Treatment Outcome

Atopic dermatitis, also known as atopic eczema, is a chronic pruritic skin condition affecting approximately 17.8 million persons in the United States. It can lead to significant morbidity. A simplified version of the U.K. Working Party's Diagnostic Criteria can help make the diagnosis. Asking about the presence and frequency of symptoms can allow physicians to grade the severity of the disease and response to treatment. Management consists of relieving symptoms and lengthening time between flare-ups. Regular, liberal use of emollients is recommended. The primary pharmacologic treatment is topical corticosteroids. Twice-daily or more frequent application has not been shown to be more effective than once-daily application. A maintenance regimen of topical corticosteroids may reduce relapse rates in patients who have recurrent moderate to severe atopic dermatitis. Pimecrolimus and tacrolimus are calcineurin inhibitors that are recommended as second-line treatment for persons with moderate to severe atopic dermatitis and who are at risk of atrophy from topical corticosteroids. Although the U.S. Food and Drug Administration has issued a boxed warning about a possible link between these medications and skin malignancies and lymphoma, studies have not demonstrated a clear link. Topical and oral antibiotics may be used to treat secondary bacterial infections, but are not effective in preventing atopic dermatitis flare-ups. The effectiveness of alternative therapies, such as Chinese herbal preparations, homeopathy, hypnotherapy/biofeedback, and massage therapy, has not been established.

Topics: Adrenal Cortex Hormones; Anti-Bacterial Agents; Bacterial Infections; Calcineurin Inhibitors; Cicatrix; Complementary Therapies; Dermatitis, Atopic; Dermatologic Agents; Diagnosis, Differential; Dose-Response Relationship, Drug; Emollients; Histamine Antagonists; Humans; Phototherapy; Pruritus; Skin; Tacrolimus

Long-term low-level topical anti-inflammatory therapy has been suggested as a new paradigm in the treatment of atopic eczema (AE).. To determine the efficacy and tolerability of topical corticosteroids and calcineurin inhibitors for flare prevention in AE.. Systematic review of randomized controlled trials reporting efficacy of topical corticosteroids and/or topical calcineurin inhibitors for flare prevention in AE. Identification of relevant articles by systematic electronic searches (Cochrane Library, Medline) supplemented by hand search. Primary efficacy endpoint: proportion of participants experiencing at least one flare during proactive anti-inflammatory treatment. Relative risks (RRs) and corresponding 95% confidence intervals (CIs) were calculated and pooled by pharmaceutical agent using random-effects meta-analysis. Sensitivity analysis included meta-regression to explore the influence of study-specific covariates.. Nine articles reporting on eight vehicle-controlled trials were included. Three, four and one trial(s) evaluated proactive therapy with topical tacrolimus, fluticasone propionate and methylprednisolone aceponate, respectively. Each agent under study was more efficacious to prevent flares than vehicle. Meta-analysis suggested that topical fluticasone propionate (RR 0·46, 95% CI 0·38-0·55) may be more efficacious to prevent disease flares than topical tacrolimus (RR 0·78, 95% CI 0·60-1·00). Meta-regression indicated robustness of these findings. Proactive anti-inflammatory therapy was generally well tolerated. The trials identified, however, do not allow firm conclusions about long-term safety.. Vehicle-controlled trials indicate efficacy of proactive treatment with tacrolimus, fluticasone propionate and methylprednisolone aceponate to prevent AE flares. Indirect evidence from vehicle-controlled trials suggests that twice weekly application of the potent topical corticosteroid fluticasone propionate may be more efficacious to prevent AE flares than tacrolimus ointment. Head to head trials should be conducted to confirm these results. Future studies are also needed to evaluate the long-term safety of proactive treatment of AE.

Topics: Administration, Topical; Adrenal Cortex Hormones; Age Factors; Androstadienes; Calcineurin Inhibitors; Dermatitis, Atopic; Dermatologic Agents; Female; Fluticasone; Humans; Immunosuppressive Agents; Male; Methylprednisolone; Randomized Controlled Trials as Topic; Tacrolimus

Atopic dermatitis (AD) is a common, chronic inflammatory dermatosis with a prevalence of 7-21% in school-aged children. Childhood AD has a profound impact on the social, personal, emotional, and financial perspectives of families. For the last half-century, topical corticosteroids of different potencies have been the mainstay of topical therapy. In recent years, two topical calcineurin inhibitors (TCIs), tacrolimus and pimecrolimus, have become available for the treatment of AD. Both tacrolimus and pimecrolimus have been extensively evaluated in the management of pediatric AD. Trials comparing them with placebo, topical corticosteroids, and each other have shown them to be effective and safe for continuous short-term use, and for noncontinuous use for up to 4 years. Long-term safety of TCIs is not known as they have been in clinical use for less than a decade.

Topics: Administration, Cutaneous; Animals; Calcineurin Inhibitors; Child; Dermatitis, Atopic; Dermatologic Agents; Glucocorticoids; Humans; Immunosuppressive Agents; Tacrolimus

Cases of lymphoma or cutaneous cancer have been observed following use of topical calcineurin inhibitors (TCIs), but it is unclear whether TCI use increases cancer risk. We used published literature to assess the extent to which atopic dermatitis (AD) or TCI use is associated with lymphoma, melanoma, basal cell carcinoma and squamous cell carcinoma. We searched the literature and summarized the results of all studies that provided data on the absolute or relative frequency of any malignancy among patients with AD or eczema or among patients using TCIs. The relative risk for all lymphoma in broad populations of AD or eczema ranged from 0·7 to 1·8. Available data on lymphoma following TCI use were inconsistent and insufficient to draw a conclusion about the causal role of TCIs. We found no evidence indicating that melanoma or nonmelanoma skin cancer is associated with TCI use. A bias analysis showed that cutaneous T-cell lymphomas initially misdiagnosed and treated as AD would lead to overestimation of the association between TCI use and lymphoma. However, there are only sparse data on specific malignancies among TCI-treated patients. The short duration of typical TCI exposure hinders conclusions about longer exposure. There is insufficient evidence in the epidemiological literature to infer whether TCIs do or do not cause malignancy.

Topics: Administration, Topical; Calcineurin Inhibitors; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Dermatitis, Atopic; Dermatologic Agents; Humans; Lymphoma; Melanoma; Risk Factors; Skin Neoplasms; Tacrolimus

A systematic review and meta-analysis was conducted to determine the efficacy and tolerability of tacrolimus ointment for the treatment of atopic dermatitis (AD) compared with topical corticosteroids.. Electronic searches were performed in Medline, Embase and the Cochrane Library, as well as relevant conference proceedings. Two researchers independently selected trials investigating the efficacy and/or safety of tacrolimus ointment in the treatment of AD. No language restrictions were applied. Relevant outcome data from included trials were extracted by two independent reviewers. Direct meta-analysis to calculate relative risks (RR) (95% confidence intervals (CIs)) was conducted on dichotomous efficacy/safety outcomes of interest.. Seventeen trials comparing tacrolimus ointment with topical corticosteroids in both paediatric (n = 2328) and adult (n = 2849) patients were identified. No studies comparing tacrolimus ointment with class IV topical corticosteroids were identified. Tacrolimus 0.1% ointment was found to be of similar efficacy to class I/II and class III topical corticosteroids. In three individual trials (comparing tacrolimus 0.1% ointment to a topical corticosteroid), evaluation of the Physician's Global Evaluation of Clinical Response (PGECR) resulted in RRs of 0.95 (95% CI 0.78-1.16), 3.09 (95% CI 2.14-4.45) and 1.35 (95% CI 0.86-2.12), where values above one favour tacrolimus ointment. With the exception that tacrolimus ointment caused more skin burning than comparator treatments (tacrolimus 0.03% versus a class III topical corticosteroid, the RR was 3.00 (95% CI 1.21-7.43) in favour of the corticosteroid), no significant differences with regards to side-effects and withdrawals due to AEs were found. Quality of life data were reported in two studies. While one study reported greater improvements in tacrolimus-treated adult patients compared with topical steroids, the second reported greater improvements in paediatric patients treated with steroids compared with tacrolimus ointment.. The current review and meta-analysis showed tacrolimus ointment to be of similar efficacy to corticosteroids. The interpretation of available data is limited by heterogeneity in outcome measures between trials. Further trials are needed to assess the impact of treatments on patient reported outcomes.

Topics: Administration, Cutaneous; Adrenal Cortex Hormones; Adult; Dermatitis, Atopic; Dermatologic Agents; Humans; Immunosuppressive Agents; Ointments; Randomized Controlled Trials as Topic; Tacrolimus; Treatment Outcome

There have been many new developments in therapeutic modalities for the treatment of pediatric dermatological diseases in the past year. Advances in the treatment of atopic dermatitis, psoriasis, infantile hemangiomas and dystrophic epidermolysis bullosa will be discussed. The following review will update the reader on these exciting new possibilities for patient care and future directions for research to improve the lives of children suffering from skin diseases.. This review will discuss recent articles describing the use of topical tacrolimus for maintenance of remission in atopic dermatitis, utility of nurse educators in atopic dermatitis, safety and efficacy of etanercept for the treatment of psoriasis in children, narrow band ultraviolet B phototherapy for atopic dermatitis and psoriasis, use of topical timolol for infantile hemangiomas and bone marrow transplantation for dystrophic epidermolysis bullosa.. There are many new interesting, potentially useful therapeutic modalities emerging in pediatric dermatology. New treatments for atopic dermatitis, psoriasis, infantile hemangiomas and dystrophic epidermolysis bullosa are reviewed.

Topics: Adrenergic beta-Antagonists; Child; Dermatitis, Atopic; Epidermolysis Bullosa Dystrophica; Etanercept; Hemangioma; Humans; Immunoglobulin G; Immunosuppressive Agents; Pediatrics; Psoriasis; Receptors, Tumor Necrosis Factor; Skin Diseases; Skin Neoplasms; Tacrolimus; Timolol; Ultraviolet Therapy; Vitamin D; Vitamins

This review summarizes clinically important findings from systematic reviews indexed in bibliographical databases between August 2007 and August 2008 that dealt with disease prevention (six reviews) and treatment of atopic eczema (seven reviews). Regarding disease prevention, two independent systematic reviews found some clinical trial evidence that ingestion of probiotics by mothers during pregnancy might reduce the incidence of subsequent eczema. Another review failed to find any clear benefit of prebiotics in eczema prevention. Although furry pets are often cited as causing allergic disease, a systematic review of observational studies found no evidence that exposure to cats or dogs at birth increases eczema risk. One very large review of studies of breastfeeding found some evidence of a protective effect on eczema risk, although all the studies were limited by their observational nature. A German group has attempted an overview of eczema prevention studies with a view to informing national guidelines. In terms of eczema treatment, two systematic reviews have confirmed the efficacy of topical tacrolimus ointment. Another review of 31 trials confirms the efficacy of topical pimecrolimus, although many of those trials were vehicle controlled, which limits their clinical utility. A review of 23 studies of desensitization therapy for allergic diseases found some evidence of benefit for eczema, which needs to be explored further. Despite the popularity of antistaphylococcal therapies for eczema, a Cochrane Review of 21 trials failed to show any clear benefit for any of the therapies for infected or clinically noninfected eczema. Another Cochrane Review dealt with dietary exclusions for people with eczema and found little evidence to support any dietary exclusion, apart from avoidance of eggs in infants with suspected egg allergy supported by evidence of sensitization. A review of 13 studies of probiotics for treating established eczema did not show convincing evidence of a clinically worthwhile benefit, an observation that has been substantiated in a subsequent Cochrane Review.

Topics: Administration, Cutaneous; Adrenal Cortex Hormones; Animals; Anti-Infective Agents; Breast Feeding; Cats; Dermatitis, Atopic; Dermatologic Agents; Desensitization, Immunologic; Diet; Dogs; Female; Humans; Immunosuppressive Agents; Male; Pets; Prebiotics; Probiotics; Randomized Controlled Trials as Topic; Risk Factors; Tacrolimus

Two new topical immunomodulators, pimecrolimus cream and tacrolimus ointment for atopic dermatitis (AD) in pediatric patients, have provided alternatives to topical corticosteroids without the associated adverse events.. To evaluate the efficacy and safety of tacrolimus ointment and pimecrolimus cream for the treatment of AD in pediatric patients.. MEDLINE, Embase, the CNKI and Cochrane Library databases were searched up to December 2008. Additional data sources were manual searches of abstract proceedings and personal contact with investigators and pharmaceutical companies. Two investigators assessed the quality of trials with unified tables independently. Disagreements on validity assessment were resolved through discussion or consultation with the third author. Quality analysis of methodology was evaluated according to the Jadad scale, including randomization, blinding and patients' discontinuation.. Twenty trials involving 6288 infants and children with AD met the inclusion criteria. More patients using tacrolimus had a good response than those in control groups including vehicle, 1% hydrocortisone acetate and 1% pimecrolimus, the corresponding OR were (4.56; 95%CI: 2.80 to 7.44), (3.92; 95% CI: 2.96 to 5.20) and (1.58; 95% CI: 1.18 to 2.12). The effect difference between 0.03% tacrolimus and 0.1% tacrolimus ointments was not statistically significant (OR = 0.90; 95% CI: 0.55 to 1.48). The incidence of adverse events of tacrolimus ointment or pimecrolimus cream was similar to the vehicle. The major adverse events were burning and pruritus.. Both tacrolimus ointment and pimecrolimus cream are safe and effective in the treatment of AD in pediatric patients. Tacrolimus ointments were superior to pimecrolimus cream.

Topics: Administration, Topical; Adolescent; Adrenal Cortex Hormones; Calcineurin; Calcineurin Inhibitors; Child; Child, Preschool; Dermatitis, Atopic; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Ointments; Randomized Controlled Trials as Topic; Severity of Illness Index; Tacrolimus; Treatment Outcome

Persistent pruritus, or itch, is one of the earliest symptoms of atopic dermatitis (AD). When pruritus is untreated, the incessant scratching response by the patient can increase the inflammatory response, resulting in aggravation of disease symptoms and severity, increasing flares and worsening patient quality of life. Therefore, it is essential that pruritus be treated effectively, rapidly and safely for optimal management of AD. In this article, the authors review clinical trials using tacrolimus ointment, a topical calcineurin inhibitor, to treat adult and pediatric patients with AD over a wide range of disease severity focusing on its efficacy in rapidly reducing pruritus. Furthermore, the authors evaluate trials in which tacrolimus ointment was directly compared with topical corticosteroids, the mainstay of AD treatment, and pimecrolimus cream, another topical calcineurin inhibitor, as well as long-term safety trials in which patients applied tacrolimus ointment for extended periods.

Topics: Administration, Cutaneous; Adolescent; Adult; Calcineurin Inhibitors; Child; Child, Preschool; Clinical Trials as Topic; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Ointments; Pruritus; Quality of Life; Severity of Illness Index; Tacrolimus

Topical tacrolimus and pimecrolimus are indicated for treatment of atopic dermatitis, but they have been studied in many off-label uses. Double-blind and open studies have shown favorable results with topical tacrolimus and pimecrolimus in oral lichen planus. In 1 study of oral lichen planus, blood tacrolimus was detected in 54% of patients, but there were no signs of systemic toxicity. Double-blind and open studies of vitiligo have shown favorable results with tacrolimus in combination with excimer laser, especially for lesions over bony prominences and on extremities. Similarly, double-blind studies of vitiligo have shown favorable results when pimecrolimus is combined with narrow-band UVB, especially for facial lesions. Double-blind and open studies of psoriasis have shown favorable results for tacrolimus and pimecrolimus, especially for inverse psoriasis. Topical calcineurin inhibitors have been effective in many other cutaneous disorders, and further studies would help clarify their roles.

Topics: Administration, Cutaneous; Calcineurin Inhibitors; Child; Child, Preschool; Crohn Disease; Dermatitis, Atopic; Dermatologic Agents; Double-Blind Method; Female; Humans; Lichen Planus, Oral; Lupus Erythematosus, Cutaneous; Male; Off-Label Use; Psoriasis; Rosacea; Skin Diseases; Tacrolimus; Therapies, Investigational; Vitiligo

This review summarizes clinically important findings from nine systematic reviews of the causes, treatment and prevention of atopic eczema (AE) published between August 2008 and August 2009. Two systematic reviews concluded that there is a strong and consistent association between filaggrin (FLG) mutations and development of eczema. The associations between FLG mutations and atopic sensitization, rhinitis and asthma are weaker than between FLG mutations and eczema, especially if those who also have eczema are excluded. The relationship between transforming growth factor levels in breast milk and eczema development is still unclear. A further systematic review found no strong evidence of a protective effect of exclusive breastfeeding for at least 3 months against eczema, even in those with a positive family history of atopy. Based on a systematic review and meta-analysis of six randomized controlled trials, supplementation with omega-3 and omega-6 oils is unlikely to play an important role in the primary prevention of eczema or allergic diseases in general. There is little evidence to support dietary restrictions of certain foods in unselected children with AE. There is also little evidence to suggest a clinically useful benefit from using probiotics in patients with established eczema. A systematic review of topical pimecrolimus and tacrolimus added little additional information to previous reviews, and did not provide any new data on long-term safety. Both of these drugs work in AE, and may reduce flares and usage of topical corticosteroids; however, there is still uncertainty about how they compare with topical corticosteroids.

Topics: Breast Feeding; Dermatitis, Atopic; Fatty Acids, Omega-3; Fatty Acids, Omega-6; Filaggrin Proteins; Humans; Immunosuppressive Agents; Intermediate Filament Proteins; Milk, Human; Mutation; Probiotics; Tacrolimus; Transforming Growth Factor beta

Atopic dermatitis, a chronic disease seen by allergist-immunologists, has both dermatologic and ocular manifestations. The ocular component is often disproportionately higher than the dermatologic disease. Even if skin abnormalities seem well controlled, these patients require ophthalmic evaluation. Atopic keratoconjunctivitis in atopic dermatitis patients is characterized by acute exacerbations and requires maintenance therapy for long-term control. Future studies will continue to emphasize the use of steroid-sparing, immunomodulating agents that have the potential to provide long-lasting anti-inflammatory control with a more favorable side-effect profile.

Topics: Adrenal Cortex Hormones; Animals; Blepharitis; Cyclosporine; Dermatitis, Atopic; Humans; Immunomodulation; Keratoconjunctivitis; Risk Factors; Tacrolimus

This review will focus on the diagnostic features of atopic keratoconjunctivitis (AKC), its relationship to atopic dermatitis, the immunopathogenesis, and therapy, and will include strategies used for the management of severe disease unresponsive to conventional therapy.. Recent research has demonstrated the importance of various cytokines (IL-33), proteins (thymic stromal lymphopoetin) and effector cells (conjunctival epithelial cells, eosinophils and basophils) in the pathogenesis of chronic ocular inflammation. Current evidence supports the use of tacrolimus and cyclosporin A, topically or systemically, as well tolerated and effective steroid sparing agents.. Recalcitrant AKC may be a blinding condition. Understanding the immunopathogenesis of atopic dermatitis and AKC has already influenced therapy and is essential to the development of future immunomodulatory treatments. The successful management of AKC requires the use of topical cromones, antihistamines and calcineurin inhibitors. Severely affected patients also require systemic immunosuppressive therapy. The current challenge is to find more specific topical and systemic immunomodulatory therapies with a better side-effect profile.

Topics: Basophils; Conjunctivitis, Allergic; Cyclosporine; Cytokines; Dermatitis, Atopic; Drug Resistance; Eosinophils; Epithelial Cells; Humans; Interleukin-33; Interleukins; Keratoconjunctivitis; Tacrolimus; Thymic Stromal Lymphopoietin

Topics: Administration, Topical; Adrenal Cortex Hormones; Anti-Allergic Agents; Child; Child, Preschool; Cyclosporins; Dermatitis, Atopic; Diet Therapy; Histamine Antagonists; Humans; Infant; Tacrolimus

To build a critical appraisal of the available literature to evaluate the effectiveness of topical calcineurin inhibitors in treatment of atopic dermatitis (AD), in comparison to topical corticosteroids (TCs) and/or placebo.. systematic review and meta-analysis.. electronic search of MEDLINE Pubmed along the last 10 years (1997-2006).. randomized control trials of TCIs reporting efficacy outcomes, in comparison to TCs or vehicle (placebo) or both.. of 210 articles, 19 studies were included, 10 for tacrolimus and 9 for pimecrolimus, involving 7378 patients of whom 2771 applied tacrolimus, 1783 applied pimecrolimus, and 2824 were controls. Both drugs were significantly more effective than a vehicle. However, two long-term trials comparing demonstrated the value of pimecrolimus in reduction of flares and steroid-sparing effect after 6 months. Compared to TCs, both 0.1% and 0.03% tacrolimus ointments were as effective as moderate potency TCs, and more effective than a combined steroid regimen. Tacrolimus was more effective than mild TCs.. TCIs in AD are more effective than placebo. Although less effective than TCs, pimecrolimus has its value in long-term maintenance and as a steroid-sparing agent in AD, whenever used early enough, at first appearance of erythema and/or itching. In treatment of moderate to severe AD, topical tacrolimus is as effective as moderately potent TCs, and more effective than mild preparations. Chronic AD lesions of the face and flexures are the most justified indication for topical calcineurin inhibitors.

Topics: Adrenal Cortex Hormones; Calcineurin Inhibitors; Dermatitis, Atopic; Enzyme Inhibitors; Humans; Immunosuppressive Agents; Tacrolimus

Tacrolimus ointment has shown efficacy as monotherapy in both short- and long-term studies in atopic dermatitis. Absorption of tacrolimus after topical application is dependent on the barrier function of the skin. Absorption through the intact epidermis is very low and eczematic skin a little higher. In comparison to systemic tacrolimus used for prevention and treatment of rejection after organ transplantation, the bioavailability of topical tacrolimus in patients with atopic dermatitis is between 3 and 4%. Long-term safety studies of up to 4 years have not shown adverse events associated with systemic use of immunosuppressive agents, that is, increased risk of infections, lymphomas or skin cancers. Despite these findings, many physicians remain concerned about possible long-term malignancies associated with long-term treatment with a topical calcineurin inhibitor.. To identify in the published literature possible long-term safety issues associated with topical tacrolimus treatment.. PubMed was used to identify studies of atopic dermatitis therapy in which tacrolimus ointment was used for at least 6 months. We evaluated the safety data available from these studies. In addition, some safety data were evaluated from clinical follow-up of our own patients who have used tacrolimus ointment intermittently for up to 14 years.. During a follow-up period of 4 years in clinical studies, no increased risk of infections or cancer was associated with long-term use of tacrolimus ointment. Only short-term adverse events were detected. They included increased burning and stinging of the skin, and a temporary increase in skin infections. No signs of immunosuppression were observed after 1 - 4 years of intermittent treatment with tacrolimus ointment.

Topics: Administration, Topical; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Ointments; Skin Diseases; Skin Neoplasms; Tacrolimus

Topics: Dermatitis, Atopic; Humans; Immunosuppressive Agents; Ointments; Tacrolimus

This review considers randomized trials of topical calcineurin inhibitors in atopic dermatitis that have included quality-of-life (QOL) data. Relatively few trials were identified and several different QOL measures have been used, partly because trial subjects included adults, children, and the parents of affected infants. Tacrolimus 0.1% and 0.03% ointment and pimecrolimus 1% cream were found to be superior to vehicle treatment in terms of QOL for active AD. In adults, tacrolimus 0.1% ointment provided a greater improvement in QOL than the 0.03% strength. Pimecrolimus 1% cream was superior to vehicle treatment for flare prevention in the studies that contained QOL outcomes but no data are available for tacrolimus ointment in this regard. QOL data comparing topical calcineurin inhibitors with other active treatments such as topical corticosteroids are sparse and it would be useful for future randomized trials to include QOL measures as a primary outcome.

Topics: Administration, Cutaneous; Adult; Calcineurin Inhibitors; Child; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Infant; Quality of Life; Tacrolimus; Treatment Outcome

Pimecrolimus is a non-steroidal immunosuppressant derived from ascomycin. This drug inhibits the action of calcineurin phosphatase and blocks the production of inflammatory substances that are thought to be important in causing skin lesions in inflammatory diseases. Pimecrolimus 1% cream (Elidel, Novartis Pharma, East Hanover, NJ, USA) was approved in the European Union, the United States and Japan as second-line therapy for the short- term and non-continuous chronic treatment of mild to moderate atopic dermatitis in non-immunocompromised adults and children aged 2 years and older, who have failed to respond adequately to other topical prescription treatments, or when those treatments are not advisable. This topical immunomodulator has also an enormous potential as topical treatment for numerous inflammatory skin diseases like psoriasis and vitiligo. Recently, some authors reported its efficacy in the treatment of skin manifestations of Lupus erytematosus.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Calcineurin Inhibitors; Dermatitis, Atopic; Dermatologic Agents; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Lymphocyte Activation; Molecular Structure; Pain; Psoriasis; T-Lymphocytes; Tacrolimus; Vitiligo

Repeated courses of potent topical corticosteroids and maintenance therapy with moderately potent topical corticosteroids are frequently needed to treat various forms of vulvar dermatoses, which are often characterized by an abnormal proliferation or activation of T lymphocytes. Because such therapeutic regimen is associated with an increased risk of potential side effects, particularly skin atrophy, an anti-inflammatory alternative to topical corticosteroids is desirable. The two non-steroid topical calcineurin inhibitors pimecrolimus and tacrolimus are immunomodulators that block the release of inflammatory cytokines from T lymphocytes in the skin while promoting cutaneous innate host defences. They are currently approved in Europe and in the United States of America as second-line anti-inflammatory agents for the treatment of atopic dermatitis. We provide a comprehensive summary of existing case reports, series of cases, and open-label prospective studies concerning the use of topical pimecrolimus and tacrolimus for the treatment of anogenital lichen sclerosus, genital lichen planus, vulvar lichen simplex chronicus and related pruritic vulvar dermatoses (chronic vulvar pruritus and allergic contact dermatitis of the vulva). The available data suggest that both topical calcineurin inhibitors may be effective and well tolerated in these vulvar dermatoses, although topical pimecrolimus may exhibit a better long-term tolerability profile. Being devoid of steroid-related side effects, they may represent a useful second-line therapeutic option for patients who are intolerant of, or resistant to topical corticosteroids. Controlled clinical trials and comparative studies are warranted to substantiate the promising findings summarized in this review.

Topics: Administration, Cutaneous; Adult; Aged; Aged, 80 and over; Calcineurin Inhibitors; Child; Dermatitis, Atopic; Female; Humans; Middle Aged; Skin Diseases; Tacrolimus; Vulvar Diseases

Pimecrolimus has been approved for more than five years for the treatment of atopic dermatitis in Germany. An important difference in the safety profile of this drug compared with topical corticosteroids is the lack of potential side effects which are often observed upon prolonged use of topical corticosteroids (skin atrophy, steroid-induced rosacea or perioral dermatitis). Even after prolonged use in sensitive skin areas, no tolerance to this drug is induced, in contrast to that seen with topical corticosteroids. The most common side effect of pimecrolimus is burning. Placebo-controlled studies suggest that pimecrolimus is associated with a slightly increased incidence of herpes simplex infections. Compared with topical corticosteroids, pimecrolimus does not increase the overall incidence of skin infections (including recurrent herpes simplex infections). So far, clinical studies with pimecrolimus have not shown any evidence of an increased risk of malignancy. The analysis of spontaneously reported adverse events has also not shown any evidence of malignancy caused by pimecrolimus. This corresponds with the results of a case-control study from a large U.S. database. According to the German guidelines on atopic dermatitis, topical calcineurin inhibitors are indicated when topical corticosteroids are not indicated or when an anticipated lengthy treatment course would lead to inevitable side effects. On sensitive areas such as face, intertriginous regions and scalp, they are preferred as first-line choice over topical corticosteroids

Topics: Administration, Topical; Anti-Inflammatory Agents, Non-Steroidal; Dermatitis, Atopic; Drug Eruptions; Humans; Risk Assessment; Tacrolimus

This article reviews if local immunosuppression of atopic dermatitis is associated with an increased risk of cancer - as implicated by a warning issued by the FDA and EMEA health authorities because systemic immunosuppression of transplanted patients leads to a significant increase of non-melanoma skin cancer and lymphoma. So far, no studies support that the use of topical immunosuppression increases the risk of local or systemic cancer.

Topics: Administration, Topical; Adult; Child; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Lymphoma; Risk Factors; Skin Neoplasms; Tacrolimus

Topical pimecrolimus 1% cream (Elidel) [hereafter referred to as topical pimecrolimus] is a nonsteroidal alternative in the treatment of pediatric atopic dermatitis. In vehicle-controlled, short-term, continuous-use trials in pediatric patients with mild to moderate atopic dermatitis, topical pimecrolimus was effective in treating disease symptoms. Topical pimecrolimus was effective in preventing disease flares and reducing the need for topical corticosteroids in longer term, intermittent-use trials. In addition, topical pimecrolimus was associated with improvements in the health-related quality of life (HR-QOL) of pediatric patients with atopic dermatitis and their parents. In vehicle-controlled trials, topical pimecrolimus was generally as well tolerated as vehicle. Topical pimecrolimus showed similar efficacy to topical tacrolimus 0.03% ointment (hereafter topical tacrolimus) in a short-term, continuous-use trial and the two agents had a generally similar tolerability profile. Although comparative data between topical pimecrolimus and topical corticosteroids are lacking in pediatric patients, and the long-term tolerability (beyond 1-2 years) of topical pimecrolimus is yet to be established, topical pimecrolimus is a useful agent in the management of pediatric patients with mild to moderate atopic dermatitis who do not achieve satisfactory treatment with other topical pharmacologic treatments, including topical corticosteroids.

Topics: Administration, Topical; Animals; Child; Dermatitis, Atopic; Drug-Related Side Effects and Adverse Reactions; Humans; Quality of Life; Tacrolimus

This review summarizes clinically important findings from 19 systematic reviews published between January 2006 and August 2007 on the topic of atopic eczema (AE). The evidence suggests that avoidance of allergenic foods during pregnancy or the use of hydrolyzed or soy formula milks does not prevent eczema. Delayed introduction of solids may decrease eczema risk. Asthma typically develops in around a third of children with eczema, and wheezing in early infancy is a predictor of risk. Established topical corticosteroids such as betamethasone should be used just once daily. Topical tacrolimus and pimecrolimus can be used for people who become dependent on topical corticosteroids, especially on sensitive sites such as the face. Wet wraps are useful in secondary care for inducing remission in a child, but they are not a treatment for mild eczema and they should not be used long term. Oral ciclosporin can be used for inducing a remission in severe eczema, and azathioprine can be considered for maintenance treatment. Narrowband ultraviolet (UV)B phototherapy can be used for chronic AE, and UVA1 may be useful for acute eczema. There is little convincing evidence of a clinical benefit with evening primrose oil for eczema, but there is some good new evidence that educational support to eczema families is beneficial. Future trials need to be larger, and include active comparators, patient-reported outcomes and longer-term aspects of disease control. They should be better reported, and registered on a public clinical trials register.

Topics: Administration, Topical; Child; Child, Preschool; Dermatitis, Atopic; Emollients; Glucocorticoids; Humans; Immunosuppressive Agents; Tacrolimus; Ultraviolet Rays

Topics: Administration, Oral; Administration, Topical; Anti-Allergic Agents; Dermatitis, Atopic; Glucocorticoids; Histamine Antagonists; Humans; Immunosuppressive Agents; Practice Guidelines as Topic; Severity of Illness Index; Tacrolimus

Pimecrolimus (SDZ ASM 981), nonsteroid anty-inflammatory ackomycin-derived drug has more and more indications in dermatology. It has been recommended in therapy of atopic and contact dermatitis at the beginning. Nowadays pimecrolimus is used in the treatment of seborrhoic dermatitis, post-steroidal rosacea, bullous diseases etc. News reporting higher incidence of skin cancers after pimecrolimus application has not been proved clinically. The common use of mentioned medication forced us to detailed analysis of references concerning that problem.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Causality; Comorbidity; Dermatitis, Atopic; Dermatitis, Contact; Dermatologic Agents; Humans; Incidence; Skin Neoplasms; Tacrolimus

Atopic dermatitis (AD) is a common, chronic skin disorder characterized by itch and dry skin, which can develop into pruritic red plaques that ooze when scratched. AD flares often occur in anatomic areas where the skin is naturally thin (the face, neck, and intertriginous zones). Such regions, especially the face, are also areas of sensitive skin and need special consideration when being treated.. This article will briefly review the concepts of thin and sensitive skin and discuss the treatment of AD in such areas.. The MEDLINE database was searched for English-language articles published that contained the text terms atopic dermatitis, sensitive skin, treatment, topical corticosteroids, or topical calcineurin inhibitors. Articles that pertained to the safety and efficacy of various treatments were selected for further review.. Topical corticosteroids (TCSs) are effective for the treatment of AD in thin and sensitive skin areas, but their use is limited due to adverse events, such as skin thinning, and the potential for impairing the skin barrier. Topical calcineurin inhibitors (TCIs) also provide effective AD treatment without impairing the skin barrier or inducing skin thinning. Although TCIs may be associated with a higher incidence of application-site reactions such as pruritus and skin burning, these symptoms are typically transient and mild to moderate in nature.. This analysis focused primarily on relatively recent key trials evaluating the treatment of AD in sensitive skin; due to the limited number of controlled trials evaluating TCS agents, consensus statements and comprehensive review articles were used for most of the information pertaining to this therapeutic option.. Although both TCSs and TCIs have a place in a long-term, comprehensive treatment strategy for AD, TCIs may have a particular use in thin and sensitive skin areas.

Topics: Administration, Cutaneous; Adrenal Cortex Hormones; Calcineurin Inhibitors; Dermatitis, Atopic; Dermatologic Agents; Drug Hypersensitivity; Female; Humans; Immunosuppressive Agents; Male; Skin; Tacrolimus

Atopic dermatitis is a chronic inflammatory skin disease characterized by recurrent intense pruritus and a distinctive distribution of skin lesions. The topical calcineurin inhibitors tacrolimus and pimecrolimus were approved in the USA, as an ointment and a cream, respectively, for the treatment of atopic dermatitis in 2000 and 2001, respectively. In 2005, the Pediatric Advisory Committee of the US FDA implemented a 'black box' warning for tacrolimus ointment and pimecrolimus cream due to the lack of long-term safety data and the potential risk of the development of malignancies. This article focuses on the safety aspects of these agents by discussing the findings from preclinical and clinical studies and postmarketing reports with regard to malignancies occurring after the use of tacrolimus ointment and pimecrolimus cream.

Topics: Administration, Cutaneous; Adverse Drug Reaction Reporting Systems; Animals; Calcineurin Inhibitors; Child; Clinical Trials as Topic; Dermatitis, Atopic; Drug Evaluation, Preclinical; Drug Labeling; Humans; Immunosuppressive Agents; Neoplasms; Tacrolimus; United States; United States Food and Drug Administration

Safety concerns related to systemic immunosuppressive therapy have raised questions regarding systemic exposure to topically applied tacrolimus.. To summarise all currently available information on the pharmacokinetics of tacrolimus ointment and to compare it with the pharmacokinetics of systemic use of tacrolimus.. Low and highly variable systemic exposure has been shown in pharmacokinetic studies of tacrolimus ointment performed in patients (adults and children) with moderate to severe atopic dermatitis. Patients with larger treatment areas tended to have higher exposure to the drug, but there was no evidence of systemic accumulation. Overall, 96, 92 and 97% of the blood samples assayed contained tacrolimus concentrations below 1 ng/ml, and 23, 17 and 20% of samples were below 0.025 ng/ml (the lower limit of quantification) in adults, children aged 6-12 and infants aged 3-24 months, respectively.. Although tacrolimus applied topically is absorbed systemically, the overall exposure as measured by the area under the curve (AUC)0-24 is low and highly variable. The extent of systemic exposure is higher in patients with larger treatment areas, but even in patients with up to 75% of the body surface area treated, the systemic exposure is substantially lower than that measured in transplant patients. Systemic exposure to tacrolimus tends to decrease as the skin lesions heal and there is no evidence of systemic accumulation despite repeated applications of ointment. The tacrolimus ointment was efficacious and well-tolerated.

Topics: Administration, Cutaneous; Administration, Oral; Adult; Area Under Curve; Child; Child, Preschool; Dermatitis, Atopic; Graft Rejection; Graft vs Host Disease; Humans; Immunosuppressive Agents; Infant; Intestinal Absorption; Ointments; Skin Absorption; Tacrolimus

Topical treatment with tacrolimus is more effective than the placebo and the low potency corticosteroids in the treatment of atopic dermatitis (AD) in both adults and children while it has a similar potency as some topical corticosteroids of medium potency. Since it was put on the market, more evidence has been accumulating to make our previous statements and it has been demonstrated to have greater effectivity than topical pimecrolimus and oral cyclosporine. It is a safe drug and its side effects are of little importance. Specifically no side effects have been demonstrated due to its systemic absorption nor has there been any increase in skin infections. The most frequent side effect is burning sensation or increased pruritus in the area where the product is applied. It is more frequent if the lesions treated are very acute and is generally transitory, not causing the treatment to be discontinued. Furthermore, with the current information, it cannot be associated to an increase of any type of neoplasms.

Topics: Adrenal Cortex Hormones; Adult; Child; Clinical Trials as Topic; Cost-Benefit Analysis; Cyclosporine; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Meta-Analysis as Topic; Middle Aged; Neoplasms; Pruritus; Retrospective Studies; Spain; Tacrolimus; Young Adult

More than five years have passed since tacrolimus (Protopic) has been put on the market in Spain. This is sufficient time to reevaluate the successes and failures that this product has had after the great expectations created prior to the time when it was put on the market based on its extensive experimentation in clinical trials and very encouraging results. It is also time to reconsider the future of the indications and uses of tacrolimus, to reconsider our personal experiences with it and to offer answers to the new questions that have arisen after five years of using the product. Tacrolimus was sold for topical use in the treatment of atopic dermatitis. Since atopic dermatitis (AD) is a disease that affects children more frequently, tacrolimus is a product oriented directly toward use in children. This entails some added concerns. In this article, we review the most relevant findings that have arisen in the last five years in regards to the treatment of AD with tacrolimus in children.

Topics: Adolescent; Adrenal Cortex Hormones; Age Factors; Calcineurin Inhibitors; Child; Child, Preschool; Clinical Trials as Topic; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Infant; Lymphoma; Retrospective Studies; Skin Neoplasms; Spain; Tacrolimus

In this article there were regarded the most frequent side effects that appear in the patients who have been treated with topical tacrolimus, and the association between topical tacrolimus and the development of tumors is unfolded. The irritation in the site of application of the tacrolimus can manifiest as pruritus, sensation of burning and/or eritema located to the area of the application. It is the most frequent side effect, independently of the duration of the study. The cutaneous infections, especially the viral ones, tend to be more numerous in patients with atopic dermatitis that receive topic tacrolimus. After reviewing the medical literature one concludes that nowadays there doesn t exist scientific evidence of an increase of skin cancer, lymphomas or systemic immunosuppression in those patients that use or have used topical tacrolimus. Nevertheless, it is not possible to exclude the possibility that there appear cutaneous and/or systemic long-term side effects.

Topics: Administration, Cutaneous; Animals; Calcineurin Inhibitors; Clinical Trials as Topic; Dermatitis, Atopic; Flushing; Humans; Immunosuppressive Agents; Neoplasms; Neoplasms, Experimental; Organ Transplantation; Postoperative Complications; Pruritus; Retrospective Studies; Skin Absorption; Skin Diseases, Viral; Spain; Tacrolimus

Topics: Child; Dermatitis, Atopic; Dermatologic Agents; Humans; Ointments; Tacrolimus

Over the past 30 yr, the prevalence of atopic dermatitis (AD) has increased significantly in the general population. Given this increased burden of disease, more AD will be seen in civilian and military aviators. This article reviews the clinical aspects of AD with a focus on the aeromedical implications of the disease. The diagnosis of AD is mainly clinical. Treatment options are numerous, although topical corticosteroids are generally the mainstay of treatment. The new immunomodulators are options for treatment of AD and have advantages and disadvantages when compared with topical corticosteroids. These immunomodulators are discussed in detail with an emphasis on their mechanism of action, efficacy, side effect profile, and possible risks. The implications of AD in aviators and safety of flight are reviewed. Interference of the wearing of cockpit equipment, use of systemic or topical medications, and AD's association with the other diseases of atopy all contribute to whether an aviator is qualified to fly. Environmental triggers, such as temperature changes, sweating, humidity, bathing frequency, contact with irritating substances, and stress may exacerbate the aviator's disease. Special consideration should be given to the severity of their disease, the treatment the aviator requires, and the environment he or she will be working and living in before giving aeromedical clearance. Finally, the policies of each military service and experiences in civil aviation are discussed.

Topics: Administration, Topical; Adrenal Cortex Hormones; Aerospace Medicine; Aviation; Dermatitis, Atopic; Female; Humans; Immunosuppressive Agents; Male; Tacrolimus

Pimecrolimus, yet another intriguing local immunomodulator, has been approved for use in atopic dermatitis in individuals of more then 2 years of age. However, its indications are now being extended to include a variety of inflammatory dermatoses, which are identified in the current article with a proviso that their use should be considered only as an alternative when conventional modalities have failed.

Topics: Administration, Cutaneous; Clinical Trials as Topic; Dermatitis, Atopic; Humans; Immunologic Factors; Tacrolimus

Tacrolimus ointment is a nonsteroid treatment for atopic dermatitis which is both effective and has a minimal side-effect profile. However, some clinicians may be reluctant to use tacrolimus ointment due to the "unknown risks", meaning those that have not been uncovered in human studies conducted thus far. Therefore, the available animal data regarding the "unknown risks" of topical tacrolimus therapy are reviewed, and a discussion of the interpretation of this available but limited data is presented.. Some of the fear on the part of clinicians regarding the use of topical tacrolimus may come from the results of animal studies which showed an increase in lymphoma and UV-induced skin cancer after treatment with topical tacrolimus in animal models of carcinogenesis. However, rigorous assessment of these studies suggest that it is somewhat likely that these represent a species-specific response to tacrolimus in an animal already predisposed to tumor formation, and therefore may not be relevant in assessing the possibility of an increased human health risk.. Animal and human studies suggest that topical tacrolimus is a safe alternative to topical steroids, with the major known adverse effect being a transient burning sensation, compared with the known adverse effects of topical steroids, including long-lasting ones. Therefore, in the opinion of the authors, currently available data, including animal studies, does not suggest that "unknown risks" of topical tacrolimus need be any more concerning than the known side-effects of the topical steroids.

Topics: Administration, Topical; Animals; Dermatitis, Atopic; Drug-Related Side Effects and Adverse Reactions; Humans; Immunosuppressive Agents; Lymphoma; Skin Absorption; Skin Neoplasms; Tacrolimus; Ultraviolet Rays

Combination of suplatast tosilate with tacrolimus ointment was reported to reduce the dose of tacrolimus ointment with maintained treatment efficacy for refractory facial erythema in atopic dermatitis (AD), however these were only case-controlled studies and the number of cases was not sufficiently large. Thus, the efficacy of a combination therapy of tacrolimus ointment and suplatast tosilate for treating AD including refractory facial erythema was investigated using a method of meta-analysis on the basis of published papers collected by database search.. We searched the literature on the efficacy of a combination of topical tacrolimus and suplatast tosilate for refractory facial erythema in patients with adult atopic dermatitis, and related data were collected for meta-analysis.. Our meta-analysis study showed that suplatast/tacrolimus combination therapy revealed better improvement in skin symptom scores and significantly decreased the dose of tacrolimus compared with topical tacrolimus monotherapy. In addition, a significantly greater number of patients could stop using tacrolimus ointment by using the combination with suplatast tosilate than by tacrolimus monotherapy for refractory facial erythema.. The combination therapy with suplatast tosilate decreased the effective dosage of tacrolimus ointment supporting use of the combination therapy for refractory facial erythema.

Topics: Adult; Anti-Allergic Agents; Arylsulfonates; Dermatitis, Atopic; Drug Therapy, Combination; Erythema; Face; Female; Humans; Immunosuppressive Agents; Male; Sulfonium Compounds; Tacrolimus; Treatment Outcome

Atopic dermatitis is a chronic, highly pruritic, and frequently recurring inflammatory skin disease that can be burdensome to affected individuals as well as to their family members, the health care system, and society as a whole. Immunomodulatory agents, such as topical corticosteroids and topical calcineurin inhibitors (TCIs), target the underlying immunopathology of atopic dermatitis and are the foundation of pharmacologic treatment for disease exacerbations. Recent recommendations from the United States Food and Drug Administration prompted the addition of a black-box warning and medication guide for tacrolimus ointment and pimecrolimus cream (both TCIs). The recommendations were based on a theoretical risk of malignancy derived from safety profiles, animal data, and reported cases of malignancy from clinical trials and postmarketing safety surveillance of oral calcineurin inhibitors. We know of no data that suggest that TCI use increases the risk of malignancy. Several dermatologic associations have issued statements supporting the safety of TCIs, and independent oncology experts have concluded that reported lymphomas were not related to TCI use. The black-box warning added to the TCI prescribing information also states that no causal link has been established. Effective treatment of atopic dermatitis can help alleviate the burden this disease imposes, and TCIs remain important treatment options.

Topics: Animals; Calcineurin Inhibitors; Clinical Trials as Topic; Dermatitis, Atopic; Dermatologic Agents; Humans; Immunosuppressive Agents; Lymphoma; Product Surveillance, Postmarketing; Tacrolimus

The topical immunomodulators tacrolimus and pimecrolimus were approved for the treatment of atopic dermatitis in 2000 and 2001, respectively. However, on 20 January 2006, the US FDA approved a 'black box' warning for these agents because of concerns regarding a possible link to development of malignancy. These concerns were based upon the known mechanism of action of this drug class, the results of animal studies, and case reports. This article provides an overview of the data that led to the approval by the FDA of a 'black box' warning and concludes that physicians, patients, and caregivers should feel confident about using tacrolimus and pimecrolimus for atopic dermatitis so long as they follow the FDA guidelines.

Topics: Administration, Topical; Animals; Carcinogenicity Tests; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Lymphoma; Models, Animal; Skin Neoplasms; Tacrolimus; Ultraviolet Rays

Tacrolimus ointment is a topical calcineurin inhibitor (TCI) that was developed specifically for the treatment of atopic dermatitis (AD). It is one of the most extensively tested dermatological products, with more than 19 000 patients (including approximately 7600 children) having participated in the tacrolimus ointment clinical development programme. Recent regulatory reviews have focused on the potential risk of malignancy with TCIs, based on their mode of action and the effects of systemic tacrolimus when given to transplant recipients. Studies have shown, however, that the systemic absorption of tacrolimus when applied topically is very low, with blood concentrations being below the level of quantification in most patients. Moreover, TCIs are not associated with a decrease in immunocompetence in the skin and there is no increase in the incidence of infections with long-term treatment. More than 5.4 million prescriptions for tacrolimus ointment have been issued worldwide, with no evidence of an increased risk of malignancy in adults or children compared with the general population. Similarly, epidemiological studies have failed to demonstrate an increased incidence of skin cancer in patients using TCIs. The most common adverse events (AEs) that occur with tacrolimus ointment treatment are transient application-site reactions, such as burning or pruritus. These complications are related to disease severity, and decrease in frequency over time as AD improves. The incidence of nonapplication-site AEs does not increase with long-term treatment, and most such events occurring in clinical trials were considered to be unrelated to therapy. Although it is important that clinicians are aware of the recent changes in product labelling, extensive clinical trials continue to show that tacrolimus ointment is well tolerated, and is generally an effective therapy for suitable patients with AD.

Topics: Administration, Topical; Dermatitis, Atopic; Dermatologic Agents; Humans; Immunosuppressive Agents; Ointments; Skin Neoplasms; Tacrolimus; Treatment Outcome

Atopic eczema is a chronic inflammatory skin disorder with a relapsing and remitting course. For many decades,topical corticosteroids have been the mainstay therapy for atopic dermatitis. After the introduction of calcineurin inhibitors as a corticosteroid-free alternative, there were high expectations. After the black box warning from the FDA regarding the potential theoretical risk for developing neoplasia under treatment with calcineurin inhibitors, patients and physicians became uncertain about its safety, regardless of the fact that current scientific data do not support increased concern for risk of malignancy.

Topics: Administration, Topical; Adult; Animals; Calcineurin Inhibitors; Child; Dermatitis, Atopic; Enzyme Inhibitors; Humans; Immunosuppressive Agents; Infant; Lymphoma; Product Surveillance, Postmarketing; Skin Neoplasms; Tacrolimus

Atopic eczema is predominantly a disease of children and infants, and is often a significant burden for both the sufferer and the family. Pimecrolimus cream 1% (Elidel) is a topical calcineurin inhibitor that has been developed for the treatment of inflammatory skin diseases. When applied twice daily, pimecrolimus has been shown to be effective and well tolerated in paediatric patients with mild to moderate atopic eczema, and appears to be particularly suitable for use on the face, the neck and skin folds. Reduction of pruritus or erythema can be seen within 48 hours of initiating treatment, and when used at the first signs or symptoms of recurrence, pimecrolimus can significantly reduce the incidence of flares and the amount of topical corticosteroid used. Long-term pimecrolimus therapy shows that the initial reduction of disease severity (Eczema Area and Severity Index) is sustained and that most patients have minimal residual disease at 2 years. The most common application-site reaction is a mild to moderate, transient, warm/burning sensation occurring in approximately 10% of patients. Blood concentrations of pimecrolimus following topical administration remain low in all patients. Currently there is no evidence for systemic adverse events, immune suppression or alterations in the vaccine response, after short-term or prolonged treatment. In conclusion, pimecrolimus is an effective treatment option for the short-term treatment and long-term control of atopic eczema in paediatric patients.

Topics: Administration, Cutaneous; Adolescent; Animals; Body Size; Calcineurin Inhibitors; Child; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Infant; Infections; Severity of Illness Index; Skin; Skin Diseases, Infectious; Tacrolimus

In approximately 60% of patients atopic eczema starts in early childhood and persists throughout adolescence. The inadequate treatment of adult patients with recurrent flaring atopic eczema is associated with poor symptom control and diminished quality of life. The prolonged continuous use of topical corticosteroids is not advocated because of the risk of local and systemic adverse events. Pimecrolimus cream 1% (Elidel) is an alternative to topical corticosteroids, particularly for delicate skin, e.g. face and other sensitive skin areas, because it has no atrophogenic potential. The results from clinical trials in adult patients demonstrate that intermittent treatment with pimecrolimus relieves the acute symptoms of atopic eczema and improves disease control and quality of life in the long term.

Topics: Administration, Cutaneous; Adult; Calcineurin Inhibitors; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Quality of Life; Severity of Illness Index; Skin; Skin Absorption; Tacrolimus

In this report, we review the data on the safety and tolerability of pimecrolimus cream 1% (Elidel) from clinical trials and post-marketing surveillance in patients with atopic dermatitis. These data demonstrate that topically applied pimecrolimus is minimally absorbed through the skin and has a favourable safety margin. The most common treatment-related adverse events are transient local reactions, particularly skin burning (16.1 and 12.9 events per 1,000 patient-months of follow-up in adults and children, respectively). When compared to the vehicle, the use of pimecrolimus cream 1% is associated with an increased incidence of herpes simplex virus infections in children (relative risk: 2.5; 95% confidence interval: 1.2-5.8; p = 0.017). However, pimecrolimus cream 1% does not increase the incidence of any skin infection in comparison with moderately potent topical corticosteroids and lacks other corticosteroid-related side effects such as skin atrophy. While cases of malignancy have been reported in patients who have used pimecrolimus cream 1%, there is no clinical evidence to establish that treatment with pimecrolimus cream 1% increases the risk of malignancy.

Topics: Administration, Cutaneous; Animals; Calcineurin Inhibitors; Clinical Trials as Topic; Dermatitis, Atopic; Glucocorticoids; Humans; Immunosuppressive Agents; Neoplasms; Product Surveillance, Postmarketing; Skin Absorption; Skin Diseases, Infectious; Tacrolimus

Atopic eczema (AE) is a multifactorial skin disease caused by a variety of factors such as genetic conditions, alterated skin structure, immunologic deviations and environmental factors, among others. There are two main subtypes of AE, i.e. the IgE-associated ("atopic eczema") and the non-IgE-associated type ("nonatopic eczema") with different prognosis concerning the development of respiratory diseases ("atopy march"). Recently, it was demonstrated that Filaggrin (=filament-aggregating protein, FL) is a major gene for atopic eczema. Filaggrin binds to and aggregates the keratin cytoskeleton in the epidermis. Homozygous FLG mutation leads to complete loss of filaggrin expression in skin. Half or more of children with moderate to severe AE carry FLG mutations. Moreover, filaggrin loss-of-function mutations predispose to phenotypes involved in the atopy march. The altered skin structure and a deficiency in antimicrobial peptides favour colonization with Staphylococcus aureus and yeasts (Malassezia sp.). Sensitization to the yeast occurs almost exclusively in AE patients. S. aureus enterotoxins with superantigenic activity stimulate activation of T cells and macrophages. So far, AE skin lesions are orchestrated by the local tissue expression of proinflammatory cytokines and chemokines with activation of T lymphocytes, dendritic cells, macrophages, keratinocytes, mast cells, and eosinophils which lead to the skin inflammatory responses. From the therapeutic point of view, besides emollients and local corticosteroids, topic immunomodulatory drugs (tacrolimus and pimecrolimus) have substantially improved the treatment of AE.

Topics: Dermatitis, Atopic; Filaggrin Proteins; Genetic Predisposition to Disease; Humans; Hypersensitivity, Immediate; Immunosuppressive Agents; Intermediate Filament Proteins; Mutation; Phenotype; Tacrolimus

Pimecrolimus is a calcineurin inhibitor developed for the topical treatment of atopic dermatitis. During the clinical development of 1% pimecrolimus cream, 1133 patients 3 to 23 months of age with mild to severe atopic dermatitis were treated for up to 2 years. The objective of this review is to discuss the safety and tolerability of 1% pimecrolimus cream among infants, on the basis of the combined results from all studies (4 pharmacokinetic studies and 6 clinical trials) conducted among these patients. Pimecrolimus blood concentrations measured for 35 patients were consistently low (< or =1 ng/mL in >80% of samples), irrespective of the disease severity and extent, and remained low during intermittent treatment for up to 1 year. The level of systemic exposure to pimecrolimus among infants was comparable to that observed for older pediatric patients enrolled in the same studies and treated in the same way with 1% pimecrolimus cream, which indicated that young pediatric patients are not at higher risk of significant percutaneous absorption of topically applied pimecrolimus, despite their large skin surface area/body mass ratio. The 6 clinical trials included a total of 1098 infants, who were treated for periods ranging from 4 weeks to 2 years. Most of these patients (60%) had moderate to severe disease at baseline. The most frequently reported adverse events were common childhood disorders such as nasopharyngitis, pyrexia, upper respiratory tract infections, ear infections, and bronchitis. During the double-blind (DB) studies or DB phases of studies, the incidence rates for the most frequently reported adverse events were similar for patients who received 1% pimecrolimus cream and patients who received the vehicle, except for the incidence of teething, which was higher among the pimecrolimus-treated infants (relative risk: 2.02; 95% confidence interval: 1.32-3.27). Treatment with 1% pimecrolimus cream was not associated with an increase in the overall incidence of nonskin infections, compared with the vehicle (relative risk: 1.015; 95% confidence interval: 0.88-1.18). The incidence density (ID) rates for total bacterial, fungal, parasitic, and viral skin infections during the DB studies or DB phases of studies were comparable for patients treated with 1% pimecrolimus cream and patients who received the vehicle. The ID rate of herpes simplex virus infections was 0.8 cases per 1000 patient-months of follow-up monitoring among patients treated with 1% pimecro

Topics: Calcineurin Inhibitors; Dermatitis, Atopic; Dermatologic Agents; Humans; Infant; Tacrolimus

Topics: Administration, Topical; Calcineurin Inhibitors; Clinical Trials as Topic; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Neoplasms; Risk Factors; Safety; Tacrolimus; United States; United States Food and Drug Administration

Netherton syndrome is a rare disorder inherited in an autosomal recessive pattern consisting of ichthyosiform dermatosis, hair shaft abnormalities (trichorrhexis invaginata), and an atopic diathesis. Patients with Netherton syndrome have been found to have a mutation on chromosome 5q32 in a gene named SPINK5 (serine protease inhibitor, Kazal type-5), which encodes an inhibitor of serine proteases called LEKTI. We report a female patient with previously undiagnosed Netherton syndrome who presented to participate in a clinical research trial investigating the benefit of topical tacrolimus 0.03% ointment [Protopic (Fujisawa Pharmaceutical Co. Ltd., Japan)] for the treatment of atopic dermatitis. This patient was confirmed to have a gene mutation in SPINK5. Current literature suggests a relative contraindication for use of topical tacrolimus in patients with Netherton syndrome owing to concern for increased systemic absorption of the drug. Our patient was not able to tolerate topical tacrolimus owing to local irritation, and did not derive any benefit from therapy. Though rare, when evaluating patients with a possible diagnosis of atopic dermatitis, an index of suspicion for Netherton Syndrome must be maintained. History and overall clinical findings, especially in regards to examination of the hair, will aid in diagnosis.

Topics: Child, Preschool; Dermatitis, Atopic; Female; Humans; Ichthyosiform Erythroderma, Congenital; Immunosuppressive Agents; Tacrolimus; Treatment Outcome

Topical calcineurin inhibitors (pimecrolimus, Elidel, East Hanover, NJ; and tacrolimus, Protopic, Tokyo, Japan) have been approved for the use in atopic dermatitis since the year 2000. These compounds represent a relatively safe class of topical anti-inflammatory, nonsteroidal therapy. However, in January of 2006, the US Food and Drug Administration issued a black box warning on these compounds about possible concerns of increased long-term malignancy risk due to systemic immunosuppression. To date, studies from clinical trials, systemic absorption, and post-marketing surveillance show no evidence for this systemic immunosuppression or increased risk for any malignancy.

Topics: Calcineurin Inhibitors; Dermatitis, Atopic; Dermatologic Agents; Drug-Related Side Effects and Adverse Reactions; Immunosuppression Therapy; Immunosuppressive Agents; Neoplasms; Tacrolimus; Time Factors; United States; United States Food and Drug Administration

Topics: Administration, Topical; Adult; Adverse Drug Reaction Reporting Systems; Allergy and Immunology; Attitude of Health Personnel; Attitude to Health; Causality; Child; Dermatitis, Atopic; Drug Labeling; Fear; Humans; Lymphoma; Lymphoproliferative Disorders; Neoplasms; Patient Acceptance of Health Care; Patients; Physicians; Quality of Life; Skin Neoplasms; Societies, Medical; Tacrolimus

Tacrolimus ointment is an effective treatment for atopic dermatitis. As a calcineurin inhibitor, it works through the FK-binding protein, inhibiting calcineurin and preventing dephosphorylation of nuclear factor of activated T cells (NFAT). Systemic absorption from the drug is minimal, allowing a favorable safety profile. In head-to-head clinical trials with pimecrolimus, tacrolimus proved to be a more effective treatment. Tacrolimus ointment has also been compared to standard topical cortico-steroid treatments and is equally effective if not superior to several topical steroids. Overall, tacrolimus ointment is a safe and effective treatment for atopic dermatitis and can be used as an adjunctive treatment to standard management with topical corticosteroids.

Topics: Calcineurin; Calcineurin Inhibitors; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Ointments; Phosphorylation; Tacrolimus; Treatment Outcome

To review the role of calcineurin inhibitors in the treatment of allergic dermatitis, focusing on mechanisms of action, efficacy and topical and systemic adverse effects.. Articles written in English and published in MEDLINE using the following keywords: pimecrolimus, tacrolimus, calcineurin inhibitors. Original articles that presented controlled and open studies for assessing efficacy, tolerability and adverse effects were selected. Review articles and case series were also evaluated; the latter was only considered for assessing adverse effects. The official websites of the Food and Drug Administration and of manufacturers of calcineurin inhibitors were also used.. The data showed that calcineurin inhibitors are efficient in the treatment of mild to severe atopic dermatitis, leading to improvement in symptoms, reduction in number of attacks and need of topical corticotherapy. Calcineurin inhibitors have good tolerability and few topical adverse effects. To date, there has been no evidence to support higher prevalence of neoplasia in patients using these drugs; however, an adequate pharmacovigilance system has been set up to assess this aspect.. Calcineurin inhibitors, which are a new drug class in the treatment of allergic dermatitis, are efficient, well tolerated and have few adverse effects. Calcineurin inhibitors should always be used according to recommended guidelines, and patients should always be followed by the physician during and after their administration.

Topics: Adult; Calcineurin Inhibitors; Child; Dermatitis, Atopic; Dermatologic Agents; Drug Tolerance; Humans; Immunosuppressive Agents; Interleukins; Severity of Illness Index; Tacrolimus

Tacrolimus (FK506) ointment is widely used in the treatment of patients with atopic dermatitis. The drug exerts its action by down-regulating antigen-specific T-cell activities and associated proinflammatory cytokine production. A number of clinical studies have evaluated the efficacy and safety of 0.1% tacrolimus ointment compared with vehicle or topical corticosteroids in adult patients with atopic dermatitis. These studies have suggested that topical tacrolimus has a rapid onset of action and exerts sustained therapeutic effects, with an efficacy similar to that of moderate to potent topical corticosteroids, but without causing skin atrophy. Two phase III randomised, controlled clinical trials have been conducted in Japanese adult patients with atopic dermatitis to compare the efficacy and safety of topical 0.1% tacrolimus with topical corticosteroid ointments. In the first study, patients with moderate or severe atopic dermatitis on the trunk and extremities were randomised to 3 weeks of treatment with topical 0.1% tacrolimus or the mid-potency topical corticosteroid 0.12% betamethasone valerate. Over 90% of the patients in each study group experienced at least a moderate improvement at the end of the study. In the second study, patients with moderate or severe atopic dermatitis on the head or neck were randomised to 1 week of treatment with 0.1% tacrolimus or the mild-potency corticosteroid 0.1% alclometasone dipropionate. Significantly greater improvements in individual symptom scores were observed with topical tacrolimus compared with alclometasone dipropionate, with overall global improvement at 1 week being statistically superior with tacrolimus. Furthermore, in a long-term open-label study involving 568 patients, at least a moderate global improvement in symptoms was observed in 85% of patients at 6 weeks, increasing to 91% at both 26 weeks and 52 weeks; this rate was maintained throughout the 2-year duration of the study. 0.1% tacrolimus ointment was considered to be safe in the majority of patients. The most prevalent adverse reactions were local application site irritations, which generally resolved with continued therapy. In summary, these findings suggest that 0.1% tacrolimus ointment is an effective and safe nonsteroidal alternative therapy for adult patients with atopic dermatitis.

Topics: Adult; Anti-Inflammatory Agents; Dermatitis, Atopic; Double-Blind Method; Humans; Hydrocortisone; Immunosuppressive Agents; Japan; Ointments; Randomized Controlled Trials as Topic; Tacrolimus; Treatment Outcome

Topics: Administration, Topical; Animals; Anti-Allergic Agents; Anti-Inflammatory Agents; Antipruritics; Dermatitis, Atopic; Drug Design; Forecasting; Glucocorticoids; Histamine H1 Antagonists; Humans; Immunosuppressive Agents; NF-kappa B; Oligodeoxyribonucleotides; Tacrolimus

Topics: Administration, Topical; Dermatitis, Atopic; Evidence-Based Medicine; Glucocorticoids; Humans; Immunosuppressive Agents; Ointments; Patient Compliance; Patient Education as Topic; Tacrolimus

Atopic dermatitis (AD) is a pruritic and inflammatory skin disease affecting at least 28 million people in the United States. During an AD flare, the skin becomes inflamed and intensely pruritic. A "major flare" is characterized by persistent or uncontrollable pruritus, intense erythema, extensive excoriation, and potential oozing and crusting. The overall goal of AD treatment is to minimize the frequency and severity of disease flares. Long-term management involves multiple treatment strategies, including identifying and eliminating triggers, routine moisturization, antipruritic therapy, and use of topical anti-inflammatory agents (topical corticosteroids and topical calcineurin inhibitors). Pimecrolimus cream 1% is a topical calcineurin inhibitor developed specifically for patients with AD.. The aim of this review was to assess the current literature (clinical trials and postapproval studies) on the efficacy and safety of pimecrolimus cream 1% in the treatment of AD.. A literature search was performed using the National Library of Medicine (MEDLINE), EMBASE, International Pharmaceutical Abstracts, Current Contents, and SciSearch databases (1980-2006) with the search term pimecrolimus. Selected studies comprised randomized, vehicle-controlled trials of topical pimecrolimus cream 1%, focused on efficacy and safety, and complied with the pimecrolimus cream 1% indication (study participants were aged >or=2 years with mild to moderate AD).. When used in appropriately identified pediatric and adult patients with mild to moderate AD, pimecrolimus cream 1% improved the signs and symptoms of AD and delayed time to a major flare. The most commonly seen adverse events in clinical trials were application-site reactions (10.4%-14.5%) and nasopharyngitis (10.1%-28.9%), headache (13.9%-23.0%), cough (11.6%-19.3%), pyrexia (7.5%-15.4%), influenza (3.0%-14.6%), and bronchitis (0.4%-13.2%), which overall were not significantly different from patients treated with vehicle cream. Pimecrolimus cream 1% was not associated with skin atrophy (supporting its use on sensitive areas of the skin such as the face, neck, and skinfolds). In addition, a review of the literature identified no reports of cumulative irritation or photosensitivity potential, no substantial increases in the incidence of common bacterial and viral skin infections compared with vehicle cream (placebo), and no effects on the systemic immune system, including delayed-type hypersensitivity.. Pimecrolimus cream 1% is a valuable treatment option for mild to moderate AD in adults and children aged >or=2 years.

Topics: Administration, Cutaneous; Clinical Trials as Topic; Dermatitis, Atopic; Dermatologic Agents; Diagnosis, Differential; Humans; Ointments; Tacrolimus

For a long time, therapeutic strategies of atopic dermatitis (AD) have been dominated by the application of local or systemic steroids or other immunosuppressive agents, which have been limited by their potential for unwanted local or systemic side effects. Recently, the use of a new generation of topical nonsteroidal, immunomodulatory drugs has revolutionized the therapeutic options of this often recalcitrant allergic-inflammatory skin disease. Research work has focused on the identification of the exact mode of action and the immune specificities of the so-called 'topical immunomodulators' (TIMs) such as tacrolimus and pimecrolimus in AD. In addition to the previous findings about the mode of action of TIMs on T cells, other target cells of TIMs such as keratinocytes, mast cells, eosinophils and dendritic cells have been identified recently as potential therapeutic targets. In this overview, we provide a research update about the anti-inflammatory and anti-allergic properties of TIMs on effector cells of AD that may be involved in the complex pathophysiology of AD.

Topics: Acute Disease; Dendritic Cells; Dermatitis, Atopic; Humans; Immunosuppressive Agents; T-Lymphocyte Subsets; Tacrolimus

To determine the efficacy and tolerability of topical pimecrolimus and tacrolimus compared with other treatments for atopic dermatitis.. Systematic review and meta-analysis.. Electronic searches of the Cochrane Library, Medline, and Embase.. Randomised controlled trials of topical pimecrolimus or tacrolimus reporting efficacy outcomes or tolerability.. investigators' global assessment of response; patients' global assessment of response; proportions of patients with flares of atopic dermatitis; and improvements in quality of life. Tolerability: overall rates of withdrawal; withdrawal due to adverse events; and proportions of patients with burning of the skin and skin infections.. 4186 of 6897 participants in 25 randomised controlled trials received pimecrolimus or tacrolimus. Both drugs were significantly more effective than a vehicle control. Tacrolimus 0.1% was as effective as potent topical corticosteroids at three weeks and more effective than combined treatment with hydrocortisone butyrate 0.1% (potent used on trunk) plus hydrocortisone acetate 1% (weak used on face) at 12 weeks (number needed to treat (NNT) = 6). Tacrolimus 0.1% was also more effective than hydrocortisone acetate 1% (NNT = 4). In comparison, tacrolimus 0.03% was more effective than hydrocortisone acetate 1% (NNT = 5) but less effective than hydrocortisone butyrate 0.1% (NNT = -8). Direct comparisons of tacrolimus 0.03% and tacrolimus 0.1% consistently favoured the higher strength formulation, but efficacy differed significantly between the two strengths only after 12 weeks' treatment (rate ratio 0.80, 95% confidence interval 0.65 to 0.99). Pimecrolimus was far less effective than betamethasone valerate 0.1% (NNT = -3 at three weeks). Pimecrolimus and tacrolimus caused significantly more skin burning than topical corticosteroids. Rates of skin infections in any of the comparisons did not differ.. Both topical pimecrolimus and topical tacrolimus are more effective than placebo treatments for atopic dermatitis, but in the absence of studies that show long term safety gains, any advantage over topical corticosteroids is unclear. Topical tacrolimus is similar to potent topical corticosteroids and may have a place for long term use in patients with resistant atopic dermatitis on sites where side effects from topical corticosteroids might develop quickly. In the absence of key comparisons with mild corticosteroids, the clinical need for topical pimecrolimus is unclear. The usefulness of either treatment in patients who have failed to respond adequately to topical corticosteroids is also unclear.

Topics: Administration, Topical; Adult; Child; Dermatitis, Atopic; Dermatologic Agents; Humans; Ointments; Patient Compliance; Quality of Life; Randomized Controlled Trials as Topic; Tacrolimus; Treatment Outcome

Topics: Administration, Oral; Administration, Topical; Adrenal Cortex Hormones; Allergens; Anti-Infective Agents; Calcineurin Inhibitors; Child; Child, Preschool; Clinical Protocols; Dermatitis, Atopic; Dermatologic Agents; Drug Therapy, Combination; Histamine H1 Antagonists; Humans; Immunosuppressive Agents; Infant; Patient Education as Topic; Phototherapy; Skin Care; Tacrolimus

Approximately 10-20% of infants in industrialized countries experience atopic dermatitis. In recent decades topical corticosteroids have been the first-choice therapy for treatment of flares. However, this form of therapy may induce skin atrophy, especially after application to facial lesions or with long-term use. Thus, development of new anti-inflammatory topical agents for the treatment of childhood atopic dermatitis was needed. The topical calcineurin inhibitors tacrolimus and pimecrolimus have an effect on various cells of the cutaneous immune system, specifically on T cells, by inhibiting the phosphatase calcineurin and preventing the transcription of proinflammatory cytokines. In several clinical studies of children and adults with atopic dermatitis, topical calcineurin inhibitors were found to be effective both on the face and the trunk and extremities, in both short- and long-term treatment regimens. Tachyphylaxis or rebound were not observed. In most patients an improvement of their eczema occurred during the first week of treatment, as measured by subjective and objective clinical signs of atopic dermatitis. Treatment significantly reduced the incidence of flares and the need for corticosteroids in children and adults. Treatment success, commonly defined as 'excellent improvement' or 'clearing of all lesions', was observed in more than one-third of all children treated with 0.03% or 0.1% tacrolimus or 1% pimecrolimus. Topical application of pimecrolimus and tacrolimus does not lead to significant blood concentrations of these agents in the majority of children with atopic dermatitis, and any increase in blood concentrations decreases after a few days of therapy. No changes in laboratory parameters were observed in short- and long-term studies in patients with atopic dermatitis. The most common adverse effect following the application of topical calcineurin inhibitors is mild to moderate symptoms of irritation such as burning, erythema and pruritus, which occurred in up to 20% of all children treated with tacrolimus and 10% of children treated with pimecrolimus, and usually faded after a few days. In contrast to topical corticosteroids, calcineurin inhibitors do not induce skin atrophy, even after long-term use. Topical calcineurin inhibitors have been proven to be effective and have a good safety profile during short-term and long-term use for up to 1 year with pimecrolimus and up to 4 years with tacrolimus. Given the lack of extensive experien

Topics: Administration, Topical; Calcineurin Inhibitors; Child; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Tacrolimus

Tacrolimus ointment (Protopic) is a topically applied macrolide lactone immunomodulator effective in the treatment of atopic dermatitis. Its mechanism of action primarily involves calcineurin inhibition, which interrupts cytokine gene expression and leads to the downregulation of T-cell activity. Tacrolimus ointment (0.03% and 0.1% for adults and 0.03% for children) is an effective treatment for atopic dermatitis of the trunk and limbs, as well as sensitive skin areas such as the face. Its efficacy is similar to or greater than that of hydrocortisone acetate 1%, hydrocortisone butyrate 0.1% and betamethsone valerate 0.12% ointments and pimecrolimus 1% cream. Systemic absorption of tacrolimus from the ointment is minimal, and adverse events, which are mostly associated with the application site and include skin burning and pruritus, tend to resolve early in treatment. Unlike topical corticosteroids, tacrolimus ointment is not associated with skin atrophy, and it is a well tolerated treatment for adults or children with atopic dermatitis, particularly when long-term treatment is indicated or the face or skin-fold regions are involved.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Ointments; Skin Diseases; Tacrolimus

The prevalence of atopic dermatitis is increasing, and more than 50% of children with atopic dermatitis go on to develop asthma and allergies. A better understanding of the underlying immune abnormalities of this complex chronic relapsing skin disease is needed. Although the optimal treatment approach remains to be defined, several recent studies suggest a rationale for using topical calcineurin inhibitors as early intervention and adding topical corticosteroids as rescue therapy if needed.

Topics: Adrenal Cortex Hormones; Bacterial Toxins; Child; Child, Preschool; Dermatitis, Atopic; Exanthema; Humans; Ointments; Pruritus; Tacrolimus

Topical calcineurin inhibitors, also called topical immunomodulators or downregulators, represent an innovative class of non-steroidal anti-inflammatory agents. Pimecrolimus 1% cream (Elidel) is one representative drug available for the treatment of atopic dermatitis. Unlike topical steroids, this drug does not affect collagen synthesis and does not alter the dendritic cell functions and the barrier function of the skin.

Topics: Calcineurin Inhibitors; Dermatitis, Atopic; Dermatologic Agents; Humans; Molecular Structure; Tacrolimus

Atopic dermatitis is a chronic inflammatory skin disease with a relapsing course. Topical corticosteroids are the usual treatment of atopic dermatitis. Long-term use of topical corticosteroids may lead to local side effects, such as skin atrophy, and systemic side effects, such as induction of hypothalamus-pituitary-adrenal axis suppression. Tacrolimus and pimecrolimus are new topical immunosuppressive drugs known as topical immunomodulators (TIMs). Clinical efficacy of these drugs has been demonstrated in various long- and short-term placebo-controlled studies. The efficacy oftacrolimus is comparable to a class 2 dermatocorticosteroid and the efficacy of pimecrolimus is comparable to a class 1 dermatocorticosteroid. A major advantage of the use of TIMs is that they do not result in skin atrophy. Tacrolimus may cause local irritation, which mostly disappears after 2 weeks. Little is known about the long-term safety of TIMs. It is expected that TIMs will have an important role in the treatment of mild to moderate atopic dermatitis. Combined treatment with dermatocorticosteroids and TIMs needs further investigation. For patients with severe atopic dermatitis, the addition of TIMs to oral immunosuppressive drugs, such as cyclosporin, may allow for dose reductions of oral medication.

Topics: Administration, Topical; Dermatitis, Atopic; Dermatologic Agents; Humans; Immunosuppressive Agents; Ointments; Tacrolimus; Treatment Outcome

The use of topical immunosuppressors during treatment of atopic dermatitis is an important innovation that reinforces the therapeutic arsenal in this chronic disease in children. Two products have been studied in depth: tacrolimus, which exists in pomade form at a concentration of 0.1 and 0.03% under the trademark Protopic. It is the 0.03% concentration that has been studied in children and obtained official indication in children aged over 2. Pimecrolimus marketed under the trademark Elidel in the form of a 1% cream has also been studied in depth and obtained European marketing authorisation for prescription in children aged over 2. Unfortunately it is not yet available in France, although it is marketed in nearly all countries worldwide. These products decrease the production of cytokines by the T-cell lymphocytes when stimulated by the antigen. This effect is produced by the inhibition of calcineurine. The clinical efficacy of these two products has been demonstrated in many studies in the United States and in Europe. Short term efficacy has been demonstrated in comparisons versus a placebo or versus grade 2 or 3 corticosteroids. Longer term studies (6 months to one year) have confirmed the efficacy. Short-term tolerance to these new treatments has been shown, although, as with any new product, the long-term results are unknown. Nevertheless, tolerance studies after more than 4 years' use exist. The side effects most often reported are local, erythema-like at the start of treatment with burning and pruritus. There has been no significant increase in the number of bacterial and viral infections compared with control groups. Doubt remains regarding viral infections of herpetic origin, notably Kaposi-Juliusberg's disease, although no significant difference has been observed compared with the placebo-treated. No systemic impact has been reported with these two products or inhibition of the effect of vaccinations made in infants or children. However, care should be taken: not to use the products in patients with a history of Kaposi-Juliusberg's disease and any contact with a patient exhibiting herpes should be avoided; the photoprotection measures should be respected as instructed in the patient insert for the use of tacrolimus.

Topics: Administration, Topical; Child; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Tacrolimus

Topics: Adrenal Cortex Hormones; Anti-Infective Agents; Child; Clinical Trials as Topic; Cromolyn Sodium; Dermatitis, Atopic; Histamine H1 Antagonists; Humans; Immunosuppressive Agents; Tacrolimus

Tacrolimus is one of the newer immunosuppressants that act by inhibiting T-cell activation and cytokine release. It is approved for the treatment of atopic dermatitis, and its safety and efficacy have been extensively studied in large-scale randomized controlled trials and open-label studies worldwide involving over 12,000 patients and up to 3 years of follow-up. Since its introduction, anecdotal reports and case series have found topical tacrolimus also to be effective and well tolerated in patients with a variety of other skin disorders, including other types of eczema, papulosquamous disorders, disorders of cornification, rosacea, other inflammatory skin conditions, vesiculobullous diseases, vitiligo, connective-tissue diseases, graft-versus-host disease, and follicular disorders. This paper reviews the currently available evidence on the use of topical tacrolimus for these conditions, as well as its safety profile and cost-effectiveness. Tacrolimus does appear to offer a safe and efficacious alternative that minimizes the need for topical glucocorticoids and does not cause skin atrophy. However, the risk of systemic absorption is increased with generalized disruption of the skin barrier. Further large-scale studies are needed to clarify the efficacy of topical tacrolimus in a variety of conditions for which anecdotal reports of success exist, especially in regard to different racial groups and in comparison to (as well as in combination with) other existing therapies. Long-term safety data should continue to be monitored and reported.

Topics: Administration, Cutaneous; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Randomized Controlled Trials as Topic; Tacrolimus

Atopic dermatitis (AD) is an inflammatory, immunologically mediated skin disease characterized by a T helper type 2 cell-predominant phenotype initially with additional acquisition of T helper type 1 cell phenotype during the chronic eczematous phase. Compelling evidence presented here suggests that two types of dendritic cells (DC), myeloid DC (mDC) and plasmacytoid DC (pDC), are important in the pathogenesis of AD.. We reviewed the current literature and summarized key information about the role of mDC and pDC in the pathogenesis of AD.. Langerhans cells and inflammatory dendritic epidermal cells, which bear the high-affinity receptor for immunoglobulin E on their cell surface, are hypothesized to contribute to the pathogenesis of AD. pDC, Which play an important role in the defence against viral infections, have also been shown to express high-affinity receptor for immunoglobulin E.. Immunoglobulin E receptor-bearing mDC and pDC subtypes in the blood and the skin of patients with AD are of critical immunologic importance in the complex pathophysiologic network of AD. Targeting mDC and pDC subtypes may lead to effective new therapies for the management of AD.

Topics: Chemokines; Cytokines; Dendritic Cells; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Receptors, IgE; Skin; Tacrolimus

To consider the effectiveness and cost-effectiveness of pimecrolimus for mild to moderate atopic eczema and tacrolimus for moderate to severe atopic eczema compared with current standard treatment in adults and children.. Electronic databases. Experts and the manufacturers of these agents were also approached for information.. The systematic review was carried out using standard methodological guidelines and a stringent quality assessment strategy. A state transition (Markov) model was developed to estimate cost--utility of tacrolimus and pimecrolimus separately, compared with current standard practice with topical corticosteroids, (a) as first-line treatment and (b) as second-line treatment. Pimecrolimus was also compared to emollients only.. The pimecrolimus trial reports were of varying quality; however when compared with a placebo (emollient), pimecrolimus was found to be more effective and to provide quality of life improvements. There is very little evidence available about pimecrolimus compared with topical corticosteroids. Compared with a placebo (emollient), both 0.03% and 0.1% tacrolimus were found to be more effective. Compared with a mild corticosteroid, 0.03% tacrolimus is more effective in children as measured by a 90% or better improvement in the Physician's Global Evaluation (PGE). Compared with potent topical corticosteroids, no significant difference in effectiveness is seen with 0.1% tacrolimus as measured by a 75% or greater improvement in the PGE. Minor application site adverse effects are common with tacrolimus. However, this did not lead to increased rates of withdrawal from treatment in trial populations. The PenTag economic model demonstrates a large degree of uncertainty, which was explored in both deterministic and stochastic analyses. This is the case for the cost-effectiveness of pimecrolimus and tacrolimus in first- or second-line use compared with topical steroids. In all cases immunosuppressant regimes were estimated to be more costly than alternatives and differences in benefits to be small and subject to considerable uncertainty.. There is limited evidence from a small number of randomised controlled trials (RCTs) that pimecrolimus is more effective than placebo treatment in controlling mild to moderate atopic eczema. Although greater than for pimecrolimus, the evidence base for tacrolimus in moderate to severe atopic eczema is also limited. At both 0.1% and 0.03% potencies, tacrolimus appears to be more effective than the placebo treatment and mild topical corticosteroids. However, these are not the most clinically relevant comparators. Compared with potent topical corticosteroids, no significant difference was shown. Short-term adverse effects with both immunosuppressants are relatively common, but appear to be mild. Experience of long-term use of the agents is lacking so the risk of rare but serious adverse effects remains unknown. No conclusions can be confidently drawn about the cost-effectiveness of pimecrolimus or tacrolimus compared with active topical corticosteroid comparators. Areas for further research should focus on the effectiveness and safety of the treatments through good-quality RCTs and further economic analysis.

Topics: Adrenal Cortex Hormones; Adult; Child; Cost-Benefit Analysis; Dermatitis, Atopic; Dermatologic Agents; Emollients; Humans; Immunosuppressive Agents; Markov Chains; Randomized Controlled Trials as Topic; Tacrolimus

Pimecrolimus is a calcineurin inhibitor developed for the topical therapy of inflammatory skin diseases, particularly atopic dermatitis (AD). Pimecrolimus selectively targets T cells and mast cells. Pimecrolimus inhibits T-cell proliferation, as well as production and release of interleukin-2 (IL-2), IL-4, interferon-gamma and tumour necrosis factor-alpha. Moreover, pimecrolimus inhibits mast cell degranulation. In contrast to tacrolimus, pimecrolimus has no effects on the differentiation, maturation and functions of dendritic cells. In contrast to corticosteroids, pimecrolimus does not affect endothelial cells and fibroblasts and does not induce skin atrophy. Given the low capacity of pimecrolimus to permeate through the skin, it has a very low risk of systemic exposure and subsequent systemic side-effects. In different randomised controlled trials, topical pimecrolimus as cream 1% (Elidel) has been shown to be effective, well tolerated and safe in both adults and children with mild to moderate AD. In addition, pimecrolimus has been successfully used in inflammatory skin diseases other than AD, including seborrheic dermatitis, intertriginous psoriasis, lichen planus and cutaneous lupus erythematosus.

Topics: Dermatitis; Dermatitis, Atopic; Hand Dermatoses; Humans; Immunosuppressive Agents; Ointments; Psoriasis; Skin Absorption; Tacrolimus

Topics: Administration, Topical; Cost-Benefit Analysis; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Tacrolimus

Atopic dermatitis (AD) is a chronic or chronically relapsing inflammatory skin condition that primarily affects children. Topical corticosteroids have been the mainstay of treatment since the late 1950s. While providing excellent short-term efficacy, topical corticosteroid usage is limited by potential adverse effects, including impairment of the function and viability of Langerhans cells/dendritic cells. The recently introduced topical calcineurin inhibitors pimecrolimus cream 1% (Elidel) and tacrolimus ointment 0.03 and 0.1% (Protopic) exhibit a more selective mechanism of action and do not affect Langerhans cells/dendritic cells. For the immune system of young children 'learning' to mount a balanced Th1/Th2 response, this selective effect has particular benefits. In clinical experience, topical calcineurin inhibitors have been shown to be a safe and effective alternative to topical corticosteroids in almost 7 million patients (>5 million on pimecrolimus; >1.7 million on tacrolimus). Topical pimecrolimus is primarily used in children with mild and moderate AD, whereas tacrolimus is used preferentially in more severe cases. None of the topical calcineurin inhibitors have been associated with systemic immunosuppression-related malignancies known to occur following long-term sustained systemic immunosuppression with oral immunosuppressants (e.g., tacrolimus, cyclosporine A, and corticosteroids) in transplant patients. Preclinical and clinical data suggest a greater skin selectivity and larger safety margin for topical pimecrolimus.

Topics: Administration, Topical; Animals; Calcineurin Inhibitors; Dermatitis, Atopic; Disease Models, Animal; Female; Humans; Immunosuppressive Agents; Male; Ointments; Prognosis; Randomized Controlled Trials as Topic; Rats; Risk Assessment; Severity of Illness Index; Tacrolimus; Treatment Outcome

Topical Calcineurin Inhibitors (TCIs) used for the treatment of atopic eczema modify the immune regulatory function of the skin and may have the potential to enhance immunosuppressive ultraviolet (UV) effects. Current recommendations on UV protection in eczema patients treated with PCIs are inconsistent and have given rise to uncertainty and anxiety in patients. Therefore, the European Dermatology Forum (EDF) developed a position statement which reviews critically the available data with regard to the problem, especially analysing and commenting the limitations of rodent models for the human situation. There is no conclusive evidence from rodent trials to indicate that long-term application of TCIs is photococarcinogenic. There is a need for further studies to investigate the validity of mouse models as well as long-term cohort studies in patients using TCIs. Available data suggest that long-term application of TCIs is safe, that there is no evidence of increased skin cancer risk and that it is ethical to treat patients with TCIs when indicated.

Topics: Administration, Topical; Animals; Calcineurin Inhibitors; Cocarcinogenesis; Dermatitis, Atopic; Disease Models, Animal; Humans; Immunosuppressive Agents; Mice; Neoplasms, Radiation-Induced; Skin Neoplasms; Tacrolimus; Ultraviolet Rays

Atopic dermatitis is a highly pruritic inflammatory disorder of the skin characterized by onset in infancy or childhood and a chronically relapsing course. Mainstay treatments are emollients and topical corticosteroids, but the latter are limited by side-effects from longterm use. Pimecrolimus is an ascomycin macrolactam derivative and a calcineurin inhibitor that targets T-cell activation but does not inhibit antigen-presenting cells in the skin. In multiple clinical trials comprising more than 19,000 patients, pimecrolimus cream has been shown to be very effective in suppressing atopic dermatitis and to have an excellent safety profile. This has also been shown in long-term studies (>2 years) and by postmarketing experience.

Topics: Clinical Trials as Topic; Dermatitis, Atopic; Dermatologic Agents; Humans; Tacrolimus

Pimecrolimus (SDZ ASM 981, Elidel ) is an ascomycin macrolactam derivative and a cell-selective inhibitor of inflammatory cytokines specifically developed to treat inflammatory skin diseases. Pimecrolimus combines high anti-inflammatory activity in the skin with a low potential to impair systemic immune reactions. Multi-centre studies have proved the efficacy and safety of pimecrolimus cream in patients with atopic dermatitis (AD) and confirmed that it is suitable for short-term treatment and long-term management of AD in adults, children and infants as young as 3 months. Topical application in humans is not associated with the atrophogenic side effects observed with corticosteroids. Pimecrolimus blood levels remained consistently low after repeated topical application and no clinically relevant drug-related systemic adverse events have been reported among the 8000 patients treated in clinical trials so far. Short-term, Phase I/II and Phase II trials of pimecrolimus administered orally in psoriasis and AD have shown that this drug is highly effective in a dose-dependent manner in patients with these diseases and has high safety profile. This finding is confirmed by pharmacogenomic blood analysis. Available data thus indicates that pimecrolimus, in both the cream and oral formulations, may represent a new option for the treatment of inflammatory skin diseases.

Topics: Administration, Cutaneous; Administration, Oral; Animals; Anti-Inflammatory Agents, Non-Steroidal; Clinical Trials as Topic; Dermatitis, Atopic; Disease Models, Animal; Humans; Psoriasis; Tacrolimus

Topics: Administration, Topical; Adult; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Male; Molluscum Contagiosum; Tacrolimus

Common pediatric skin conditions such as infantile atopic dermatitis, vitiligo, hemangiomas of infancy, warts, and molluscum contagiosum do not always respond to standard therapy. In some settings pediatricians will use "off-label" medications if the benefit-to-risk ratio is favorable. This article reviews important literature from the past year related to "off-label" immune-based treatment of skin disease, using the topical immunomodulators tacrolimus, pimecrolimus, and imiquimod, as well as intravenous Ig.. The topical immunomodulators tacrolimus and pimecrolimus have been embraced by pediatricians as long awaited alternatives for treating atopic dermatitis in children 2 years of age and older. Their unique appeal as nonsteroidal topical agents with good safety profiles has led to their frequent use for unapproved indications. A number of recent publications detail their use in infantile atopic dermatitis in children as young as 3 months of age, as well as use in other conditions such as vitiligo. Imiquimod, another topical immunomodulator, approved for genital wart treatment in adults, has also been examined for "off-label" pediatric use in nongenital warts, molluscum contagiosum, hemangiomas of infancy, and basal cell carcinoma. Finally, "off-label" use of intravenous Ig has been evaluated for the life-threatening dermatoses Stevens-Johnson syndrome and toxic epidermal necrolysis.. In the absence of larger controlled trials, pediatricians must consider the cumulative weight of smaller studies with their personal experience when assessing any role for "off label" therapy. The recent literature reviewed herein will facilitate such assessments of the non-steroid topical immune modifiers tacrolimus, pimecrolimus, and imiquimod as well as intravenous immunoglobulin.

Topics: Adjuvants, Immunologic; Aminoquinolines; Child; Clinical Trials as Topic; Dermatitis, Atopic; Hemangioma; Humans; Imiquimod; Immunoglobulins; Immunologic Factors; Immunosuppressive Agents; Infant; Molluscum Contagiosum; Skin; Skin Diseases; Stevens-Johnson Syndrome; Tacrolimus; Vitiligo; Warts

To summarize success rates of the topical calcineurin inhibitors tacrolimus and pimecrolimus in treating atopic dermatitis.. Randomized controlled trials (RCTs) comparing either drug to themselves (i.e. dose-ranging studies), each other, the vehicle (or placebo), or corticosteroids were obtained from Medline, EMBASE, and Cochrane databases. Two reviewers identified studies and extracted data, a third reviewer adjudicated disagreements. Outcomes included success, as defined by 90%, 75%, or 50% reductions from baseline in Eczema Area and Severity Index (EASI) scores or equivalent at 1, 3, 6, and 12 months, and also the difference between drug and vehicle (placebo). Rates were combined using a random effects meta-analytic model.. Of 180 articles identified, 165 were rejected (142 not RCTs/inappropriate outcome, 23 inappropriate/unextractable data). We included 15 articles reporting on 16 trials (nine tacrolimus and seven pimecrolimus trials) involving a total of 5301 patients, of whom 2107 received tacrolimus, 1225 received pimecrolimus and 1969 patients were controls. Tacrolimus reduced EASI scores by 65.6% at 1 month and 73.0% at 3 months; pimecrolimus reduced scores by 61.5% at 1 month, 60.3% at 6 months, and 61.9% at 12 months. When the difference in EASI score reductions were compared between active drug and placebo, tacrolimus success was 51.5% above placebo at 1 month and pimecrolimus was 45.9% higher at 1 month, 24.9% at 6 months, and 16.1% at 12 months.. Success rates for tacrolimus and pimecrolimus were statistically similar. However, tacrolimus rates were consistently higher numerically than those for pimecrolimus, and tacrolimus was used in patients with more severe disease. A head-to-head RCT is required to determine if true differences exist between these drugs.

Topics: Administration, Cutaneous; Calcineurin Inhibitors; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Randomized Controlled Trials as Topic; Severity of Illness Index; Tacrolimus

Atopic dermatitis (AD) is a common eczematous skin condition; as many as 10-17 percent of all children are affected, and 35-60 percent of affected patients manifest symptoms manifest during the first year of life. Treatment principles for AD in young children involve conservative measures such as avoidance of hot water and environmental irritants, combined with liberal use of emollients after bathing. Low potency topical corticosteroids (TCS) are the current standard of therapy for AD in young children, reserving mid- and high-potency TCS for severe disease. However, complications of long-term use of TCS include skin atrophy, stria formation, telangiectasia, hypopigmentation, secondary infections, steroid acne, allergic contact dermatitis, and miliaria. The pediatric population is also at increased risk for systemic absorption because of their high ratio of skin surface to body mass. Systemic absorption may result in hypothalamic-pituitary-adrenal axis suppression and ultimately growth retardation. Although most topical and systemic corticosteroids are not approved by the Food and Drug Administration for use in children less than 2 years of age, conservative treatment often fails in this age group and frequently patients are treated with TCS, antibiotics, and antihistamines.

Topics: Administration, Cutaneous; Adrenal Cortex Hormones; Anti-Bacterial Agents; Dermatitis, Atopic; Dose-Response Relationship, Drug; Drug Evaluation; Drug Utilization Review; Emollients; Female; Histamine H1 Antagonists; Humans; Immunosuppressive Agents; Infant; Male; Ointments; Pain; Pruritus; Retrospective Studies; Tacrolimus; Treatment Outcome

Atopic Dermatitis (AD) is a common cutaneous inflammatory disease. Recent estimates of prevalence in United States school children range from 10-20%. Topical treatment of AD is unsatisfactory. Now two new topical agents, tacrolimus and pimecrolimus, are revolutionizing the treatment of AD. Here we review AD as well as these breakthrough therapies.

Topics: Dermatitis, Atopic; Dermatologic Agents; Humans; Immunosuppressive Agents; Tacrolimus

Topical tacrolimus (FK506, Protopic) has been developed and marketed for the treatment of atopic dermatitis (AD). Tacrolimus works as an inhibitor of calcineurin, which creates a downregulation of the inflammatory cascade. Numerous trials have shown the efficacy and safety of tacrolimus in treating AD in both adults and children. Additionally, comparison data with other medications commonly used for AD, such as topical steroids and pimecrolimus, show improved efficacy of tacrolimus. A comprehensive review of the off-label uses of tacrolimus in other dermatoses, including psoriasis, lichen planus and seborrhoeic dermatitis, is provided. The efficacy of tacrolimus in treating these diseases is based on Phase IV clinical trials and on case reports or series in the literature. Overall, tacrolimus has proven to be a safe and useful topical therapy for many inflammatory dermatological conditions, with AD being the principal indication.

Topics: Adult; Calcineurin Inhibitors; Child; Clinical Trials as Topic; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Ointments; Skin Diseases; Tacrolimus

Topical therapy of atopic dermatitis should incorporate an understanding of the underlying immune abnormalities of this complex chronic skin disease. Avoidance of irritants and proven allergens, skin hydration, and use of emollients and anti-inflammatory therapy help maintain a normal skin barrier. Topical calcineurin inhibitors have been added to the topical treatment armamentarium. Although the optimal treatment approach remains to be defined, several studies suggest the use of topical calcineurin inhibitors as early intervention therapy and topical corticosteroids as rescue therapy.

Topics: Administration, Topical; Adrenal Cortex Hormones; Calcineurin Inhibitors; Clinical Trials as Topic; Dermatitis, Atopic; Humans; Tacrolimus

Tacrolimus and pimecrolimus are new macrolactam immunomodulators which were developed for the treatment of inflammatory skin diseases, mainly atopic dermatitis. In this article, we review the pharmacologic properties of the drugs, their side effects, and their clinical uses.

Topics: Administration, Cutaneous; Dermatitis, Atopic; Dermatologic Agents; Humans; Immunosuppressive Agents; Tacrolimus

For more than five decades, topical corticosteroids and emollients have been the mainstay of therapy for atopic dermatitis. However, the potential for side-effects limits the clinical utility of corticosteroids in providing long-term disease control. With a unique mode of action that differs from that of corticosteroids, the steroid-free topical calcineurin inhibitors (TCIs), tacrolimus ointment and pimecrolimus cream, provide skin-selective treatment that targets key factors involved in the pathogenesis of this chronic disease. An extensive series of clinical trials involving more than 16,000 patients with predominantly moderate to severe atopic dermatitis in tacrolimus studies and over 2000 patients with primarily mild to moderate disease in pimecrolimus studies has shown that both TCIs provide effective and well-tolerated treatment for atopic dermatitis. Randomized controlled trials have demonstrated that tacrolimus is superior to conventional hydrocortisone-based regimens and does not cause skin atrophy or other steroidal side-effects. Both tacrolimus and pimecrolimus prevent disease flares and provide progressive and sustained disease improvement with long-term therapy. These and other clinical benefits of TCIs are discussed, together with the safety profiles of tacrolimus and pimecrolimus and their use in clinical practice. In addition, this review summarizes findings from the many trials carried out with these agents and outlines how TCIs can provide long-term treatment and control of a chronic skin disease that may persist for years.

Topics: Administration, Topical; Adrenal Cortex Hormones; Calcineurin Inhibitors; Clinical Trials as Topic; Cost-Benefit Analysis; Dermatitis, Atopic; Dermatologic Agents; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Ointments; Patient Selection; Tacrolimus; Treatment Outcome

Pimecrolimus is the most recent member of calcineurin inhibitors available for the therapy for inflammatory skin diseases. It targets T-cells and mast cells and inhibits the production and release of cytokines and other inflammatory mediators, as well as the expression of signals essential for the activation of inflammatory T-lymphocytes. Pimecrolimus has a cell-selective mode of action. In contrast to corticosteroids, it does not affect, e.g., Langerhans'cells/dendritic cells (LC/DC), as demonstrated in vitro with human monocyte-derived DC and in vivo with epidermal LC in mice, nor human primary fibroblasts. As shown in vitro with human skin and by comparison of clinical pharmacokinetic data from patients with atopic dermatitis, pimecrolimus permeates less through skin than tacrolimus and much less than corticosteroids. It, thus, has a lower potential for transcutaneous resorption after topical administration, resulting in a lower risk of systemic effects. Pimecrolimus has high anti-inflammatory activity in animal models of skin inflammation, including a model reflecting neurogenic inflammation, but a more favourable balance of anti-inflammatory vs. immunosuppressive activity than tacrolimus. Pimecrolimus does not affect sensitization in a murine model of allergic contact dermatitis and has a lower potency in various models of immunosuppression after systemic administration, compared to tacrolimus. In conclusion, the results of preclinical studies show that pimecrolimus has a selective pharmacological profile, suited for effective and safe treatment for inflammatory skin diseases.

Topics: Animals; Anti-Inflammatory Agents; Child; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Inflammation; Risk; Skin; Skin Diseases; T-Lymphocytes; Tacrolimus; Time Factors

Within the last decade, healthcare providers have had a larger selection of effective novel topical immunomodulatory agents to treat many dermatologic conditions. Novel mechanisms of action of newer topical agents have facilitated differentiation from well-established topical agents such as corticosteroids and 5-fluorouracil. Further, because of a growing understanding of the immune mechanisms within the skin, the opportunity has arisen to use the body's immune system to effectively treat many dermatologic conditions, such as condyloma acuminata, actinic keratosis, basal cell carcinoma, and atopic dermatitis, while maintaining a favorable safety profile. Imiquimod 5% cream, an immune response modifier, is safe and effective in the treatment of condyloma acuminata, actinic keratosis, and primary superficial basal cell carcinoma (sBCC). Pimecrolimus cream 1% and tacrolimus ointment (0.1% and 0.03%) are safe and effective in the treatment of atopic dermatitis. This review highlights newer data on approved and investigational indications for these topical immunomodulatory agents.

Topics: Adjuvants, Immunologic; Administration, Topical; Aminoquinolines; Condylomata Acuminata; Dermatitis, Atopic; Dermatitis, Seborrheic; Humans; Hutchinson's Melanotic Freckle; Imiquimod; Keratosis; Melanoma; Membrane Glycoproteins; Receptors, Cell Surface; Skin Diseases; Skin Diseases, Viral; Skin Neoplasms; Tacrolimus; Toll-Like Receptors

Immune response modifiers (IRMs) are agents that target the body's immune system (i.e., cytokines, receptors, and inflammatory cells) to combat disease. Topical IRM therapies, which encompass both proinflammatory and immunosuppressive therapeutics, have been used to successfully treat a number of dermatologic conditions. Proinflammatory treatments include Toll-like receptor agonists (e.g., imiquimod 5% cream) and interferon (e.g., interferon-alpha) therapies, which have been used in the treatment of external genital warts, basal cell carcinoma, and other dermatologic diseases. Immunosuppressive therapies include topical and intralesional corticosteroids, anti-tumor necrosis factor agents (e.g., infliximab and etanercept), and anti-CD4+ T-cell agents, including calcineurin inhibitors and mycophenolate. These agents have been used to treat a number of conditions, including atopic and seborrheic dermatitis and psoriasis. This article reviews the mechanism of action of IRMs and the application of IRMs in several dermatologic diseases.

Topics: Adjuvants, Immunologic; Alefacept; Aminoquinolines; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Calcineurin Inhibitors; CD11 Antigens; Dermatitis, Atopic; Glucocorticoids; Humans; Imiquimod; Interferons; Membrane Glycoproteins; Mycophenolic Acid; Psoriasis; Receptors, Cell Surface; Recombinant Fusion Proteins; Skin Diseases; Tacrolimus; Toll-Like Receptors

Pimecrolimus (Elidel) is a topically active, nonsteroid, calcineurin inhibitor that has shown efficacy in controlling symptoms of atopic dermatitis in adult and pediatric patients. Topical pimecrolimus 1% cream is approved in the US for the short-term and intermittent long-term treatment of mild-to-moderate atopic dermatitis in non-immunocompromised patients aged >/=2 years who do not respond well to, or may have adverse effects with, conventional treatments. Pimecrolimus 1% cream is an effective and well tolerated treatment for atopic dermatitis in infants, children, adolescents, and adults. Pimecrolimus is effective at reducing the incidence of disease flares and, thus, the need for rescue treatment with topical corticosteroids. The drug also improves the health-related quality of life (HR-QOL) of children and adolescents, and improves the QOL of parents of children with atopic dermatitis. Furthermore, pimecrolimus does not cause skin atrophy, a problem commonly associated with topical corticosteroids, and is not associated with clinically relevant systemic adverse events. Thus, topical pimecrolimus 1% cream is an effective treatment option for the management of mild-to-moderate atopic dermatitis.

Topics: Administration, Cutaneous; Calcineurin Inhibitors; Dermatitis, Atopic; Dermatologic Agents; Humans; Peptidylprolyl Isomerase; Randomized Controlled Trials as Topic; Tacrolimus; Treatment Outcome

To review epidemiologic correlations between asthma and atopic dermatitis (AD), identify common features in disease pathophysiology, and review steps involved in the development of asthma therapy guidelines to assess the appropriateness of a similar process and approach for AD.. A 7-member panel representing specialists in dermatology, allergy, asthma, immunology, and pediatrics from around the United States convened to review the current literature and evolving data on AD. Participants presented reviews to the panel on the epidemiology of asthma and AD, the genetic predisposition to allergic disease, the current understanding of the immunopathophysiology of AD, interrelationships between the pathologic pathways of asthma and AD, evolving treatment concepts and options in AD, and the applicability of the asthma treatment model and how it may be adapted for guideline development for AD. Commentary and criticism were recorded for use in document preparation.. There are clear epidemiologic parallels in asthma and AD. Importantly, AD frequently is the first manifestation of an atopic diathesis, which occurs in genetically predisposed individuals and also includes asthma and allergic rhinitis. Up to 80% of children with AD will eventually develop allergic rhinitis or asthma later in childhood. This classic "atopic triad" has numerous pathophysiologic elements in common, including cyclic nucleotide regulatory abnormalities, immune cell alterations, and inflammatory mediators and allergic triggers. New therapeutic options that target underlying immune mechanisms are available, and their place among treatments for AD is becoming established. Guidelines of care have been developed for asthma. The panel noted that the National Institutes of Health/National Heart, Lung, and Blood Institute guidelines for diagnosis and management of asthma, first issued in 1991, had a tremendous positive impact on many aspects of asthma treatment. It not only created a heightened awareness that asthma is a disease of chronic inflammation, but it also provided unified approaches for therapy and opened new areas of basic science and clinical research. In addition, the guidelines spurred interactions among physicians of various specialties and stimulated a great quantity of research in asthma therapy. It is anticipated that AD therapy guidelines would have similar positive outcomes.. The panel concluded that, on the basis of current information and evolving therapeutic options, a clear rationale exists to support AD guideline development. The many parallels between AD and asthma suggest that processes and approaches used for the asthma therapy guidelines would be appropriate for AD.

Topics: Administration, Topical; Adolescent; Adrenal Cortex Hormones; Adult; Anti-Inflammatory Agents; Asthma; Child; Child, Preschool; Comorbidity; Dermatitis, Atopic; Glucocorticoids; Humans; Infant; Practice Guidelines as Topic; Tacrolimus; United States

During the past year there have been significant advances in our understanding of the mechanisms underlying allergic skin diseases. This article reviews some of these advances in atopic dermatitis and urticaria. The introduction of a new class of topical anti-inflammatory medications, topical calcineurin inhibitors, has significantly increased our treatment options and led to a rethinking of potential management approaches in atopic dermatitis.

Topics: Administration, Topical; Anti-Inflammatory Agents, Non-Steroidal; Calcineurin Inhibitors; Dermatitis, Atopic; Humans; Immunosuppressive Agents; T-Lymphocytes; Tacrolimus; Urticaria

Topical corticosteroids (TCC) have significantly shaped dermatological therapy for five decades. A few months ago the TCC were joined by competition, the topical inhibitors of calcineurin (TIC), wrongly termed topical immunomodulators. The present paper reviews the pharmacological effects and clinical efficacy of TIC, compares the risks, benefits and costs of those two groups of topical drugs and develops a position on the use of TIC. While TIC have ushered in a new era of topical anti-inflammatory therapy, the age of TCC is far from over.

Topics: Acute Disease; Administration, Topical; Anti-Inflammatory Agents; Calcineurin Inhibitors; Cyclosporins; Dermatitis, Atopic; Eczema; Facial Dermatoses; Glucocorticoids; Humans; Immunosuppressive Agents; Neurodermatitis; Psoriasis; Pyoderma Gangrenosum; Risk Factors; Skin Diseases; Tacrolimus

Topics: Administration, Topical; Chemotherapy, Adjuvant; Clinical Trials as Topic; Dermatitis, Atopic; Dermatologic Agents; Humans; Immunosuppressive Agents; Practice Guidelines as Topic; Tacrolimus

The clinical experience with topical calcineurin inhibitors in the field is still rudimentary, if compared to our knowledge of topical corticosteroids. This is especially true for the long-term effects. The systemic transcutaneous absorption that occurs during the therapy of atopic dermatitis is quantitatively irrelevant. However, in the setting of permanent disruption of the skin barrier, as may be encountered in rare Genodermatoses, but as well in cases that do not respond to therapy, continued treatment my result in clinically relevant blood levels. Side effects of topical calcineurin inhibitors may be separated into two groups, i.e. local intolerance reactions, and skin infections. While the typical burning sensation of the newly treated skin is ephemeral, local alcohol intolerance, albeit less frequent, will persist throughout the treatment period. Regarding skin infections, Eczema herpeticatum seems to be the only serious complication; adequate preventive will further reduce the risk of this rare complication.

Topics: Administration, Topical; Calcineurin Inhibitors; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Randomized Controlled Trials as Topic; Skin Absorption; Tacrolimus

Pimecrolimus inhibits some specific steps of the Th1 and Th2 immune reactions. It belongs to the class of ascomycin macrolactams. The topical drug formulation targets cutaneous inflammation, more particularly lymphocytes and mast cells without impairing systemic immunosurveillance. Topical applications are indicated for treating atopic dermatitis. In this indication, it represents an alternative or an adjuvant drug to topical corticosteroids. The treatment of other dermatoses could also benefit from pimecrolimus.

Topics: Administration, Cutaneous; Calcineurin Inhibitors; Dermatitis, Atopic; Dermatologic Agents; Humans; Peptidylprolyl Isomerase; Tacrolimus

The management of atopic dermatitis is set for a major shift with the introduction of the first new topical treatment for the condition in 40 years--the non-steroidal topical immunomodulator tacrolimus (Protopic). Backed by strong clinical data, tacrolimus ointment is a valuable addition to topical steroids in the management of moderate-to-severe atopic dermatitis.

Topics: Administration, Topical; Adrenal Cortex Hormones; Dermatitis, Atopic; Dermatologic Agents; Dose-Response Relationship, Drug; Humans; Ointments; Tacrolimus; Treatment Outcome

Elidel is a steroid-free cream containing a 1% strength of the topical immunomodulator pimecrolimus. Elidel was specifically developed as a treatment for atopic dermatitis (AD) and is approved for use in children as young as 2 years of age. The production of inflammatory cytokines by activated T cells in skin is thought to play an important role in the pathogenesis of AD. Elidel potently suppresses cytokine production by dermal T cells without significantly impairing systemic immune responses. Elidel does not cause steroid-associated local effects, such as dermal atrophy, striae, or telangiectasia. In randomized controlled clinical studies, twice-daily application of Elidel was shown to significantly improve the signs and symptoms of AD in infants, children, and adults. The clinical effect of Elidel on pruritus, the most troublesome symptom of AD, can be observed within 1 week of therapy and is maintained for the duration of treatment. Elidel is well tolerated; the risk of application-site reactions, such as itching or burning, is comparable with that of the vehicle. Adverse effects were generally mild in patients receiving Elidel and occurred at rates comparable with those in patients receiving vehicle treatment. In a 1-year study, Elidel significantly reduced the incidence of flares when used at the first signs and symptoms of acute AD. As a result, overall corticosteroid use to treat flares was significantly lower in patients using Elidel for early intervention.

Topics: Administration, Oral; Adolescent; Adult; Animals; Anti-Inflammatory Agents, Non-Steroidal; Child; Child, Preschool; Dermatitis, Atopic; Dermatologic Agents; Drug Evaluation; Humans; Infant; Tacrolimus

Pimecrolimus (pronounced pi-me-kro-ly-mus) cream (Elidel--Novartis) is a new topical immunosuppressant licensed for the treatment of patients aged 2 years or over with mild or moderate atopic dermatitis. It is the second topical treatment in this class, the first being tacrolimus ointment (Protopic--Fujisawa) which we reviewed in October 2002. Pimecrolimus is the first such treatment to be licensed for first-line use in atopic dermatitis. It can be used either as short-term treatment for actively inflamed lesions, or as intermittent long-term treatment to prevent the progression of early symptoms and signs to flares. The company claims that "when used at the first sign of redness and itch" pimecrolimus cream is "the only treatment clinically proven to prevent progression to flare", and that many people using it have "eliminated or reduced steroid use". Here, we consider the place of pimecrolimus cream in the management of atopic dermatitis.

Topics: Administration, Cutaneous; Adolescent; Adult; Child; Child, Preschool; Dermatitis, Atopic; Dermatologic Agents; Dose-Response Relationship, Drug; Double-Blind Method; Humans; Immunosuppressive Agents; Infant; Ointments; Randomized Controlled Trials as Topic; Secondary Prevention; Tacrolimus; Time Factors

Pimecrolimus (Elidel) is a novel cell-selective inhibitor of inflammatory cytokines that has specifically been developed for the treatment of inflammatory skin diseases due to its favourable skin selective pharmacological profile. Therapeutic efficacy and safety of pimecrolimus cream 1% has been established in the short-term treatment and the long-term management of atopic eczema in clinical studies in adults, children and infants. It rapidly relieves pruritus, and redness and swelling disappear or are only mild in up to 70% of pimecrolimus treated patients during the first three weeks. When applied at the first signs and symptoms of atopic eczema, pimecrolimus has proven to prevent flare progression and to provide superior long-term disease control compared with a conventional treatment, based on reactive use of corticosteroids. Pimecrolimus cream 1% is well tolerated, even on sensitive areas such as the face and neck. Blood concentrations remain low, even when extensive body areas are treated and no clinically significant systemic effects have been observed during short- or long-term clinical studies with pimecrolimus.

Topics: Administration, Cutaneous; Adolescent; Adult; Animals; Anti-Inflammatory Agents, Non-Steroidal; Child; Child, Preschool; Dermatitis, Atopic; Dose-Response Relationship, Drug; Double-Blind Method; Humans; Immunosuppressive Agents; Infant; Mice; Models, Animal; Randomized Controlled Trials as Topic; Severity of Illness Index; Swine; Tacrolimus; Treatment Outcome

Atopic dermatitis (AD), often called eczema, is a disease characterized by intense pruritus, erythema, dry skin, and inflammation. Pimecrolimus is a novel steroid-free treatment for AD. Consistently positive results have been found with pimecrolimus treatment in infants, children/adolescents, and adults. Its safety record is excellent, and studies have found no clinically relevant drug-related systemic adverse events. In this article, we first review atopic dermatitis and conventional treatment strategies. We then discuss various aspects of pimecrolimus, including pharmacologic properties, toxicology, short- and long-term studies, and safety and adverse events. Finally, we propose a new steroid-sparing treatment strategy for AD.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Dermatitis, Atopic; Humans; Quality of Life; Tacrolimus; Treatment Outcome

Atopic eczema is one of the most common chronic inflammatory skin diseases, with a prevalence of at least 10% in children and 0.5-1% in adults. The disease shows a drastically increasing tendency. This article provides an overview of the pathophysiology, pathomechanisms, prevention, and treatment of atopic eczema. We present a therapeutic concept that integrates all aspects of the complex pathophysiology that is a prerequisite for individualized and successful treatment. This is based on intervention in the pathophysiology of atopic eczema and elimination of exogenous provocation factors. Particular attention is given to unconventional therapy options such as phytotherapy, which are attracting patients in many countries, and possible effects, side effects, and interactions with other drugs are discussed.

Topics: Adjuvants, Immunologic; Dermatitis, Atopic; Humans; Phytotherapy; Plant Extracts; Plants, Medicinal; Tacrolimus

Pimecrolimus (SDZ ASM 981), an ascomycin derivative, is one of the new classes of immunomodulating macrolactams and was specifically developed for the treatment of inflammatory skin diseases. The interest in pimecrolimus has been substantial because of its significant anti-inflammatory activity and immunomodulatory capabilities and its low systemic immunosuppressive potential. The mechanism of action of pimecrolimus is the blockage of T cell activation. Pimecrolimus (like all ascomycins) is an immunophilin ligand, which binds specifically to the cytosolic receptor, immunophilin macrophilin-12. This pimecrolimus-macrophilin complex effectively inhibits the protein phosphatase calcineurin, by preventing calcineurin from dephosphorylating the nuclear factor of activated T cells (NF-AT), a transcription factor. This results in the blockage of signal transduction pathways in T cells and the inhibition of the synthesis of inflammatory cytokines, specifically Th1- and Th2-type cytokines. Pimecrolimus has also been shown to prevent the release of cytokines and pro-inflammatory mediators from mast cells. Several studies have evaluated the effectiveness of pimecrolimus as a treatment for skin diseases. In animal models of allergic contact dermatitis, topical pimecrolimus was found to be effective. In human studies of allergic contact dermatitis pimecrolimus demonstrated significantly more efficacy than the control treatment. As well, the effectiveness of pimecrolimus 0.6% cream was comparable to 0.1% betamethasone-17-valerate; however, pimecrolimus was not associated with any of the side effects characteristic of a topical steroid. Topical application of pimecrolimus is not associated with skin atrophy. Pimecrolimus is effective and safe in both children and adults with atopic dermatitis. When pimecrolimus 1% cream has been applied to adult atopics, improvement has been observed as early as the first week, with a 72% reduction in severity after 3 weeks. Pharmacokinetic studies have shown very low blood levels of pimecrolimus following topical application, with no accumulation after repeated applications. Following application of pimecrolimus cream occasional transient irritation may be experienced at the application site. Similar results have also been found in children aged 3 months and older following application of pimecrolimus 1% cream. Topical pimecrolimus in psoriasis appears to exhibit a dose-dependent therapeutic effect under semi-occlusive conditions. Pime

Topics: Administration, Oral; Administration, Topical; Adult; Animals; Child, Preschool; Controlled Clinical Trials as Topic; Dermatitis, Allergic Contact; Dermatitis, Atopic; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Middle Aged; Psoriasis; Swine; Tacrolimus; Treatment Outcome

The incidence of atopic diseases, including atopic dermatitis, allergic rhinitis, and asthma, has increased in developed countries over the past several decades. These diseases comprise a large component of general pediatric practice. This review will highlight some of the recent advances in understanding the pathogenesis and natural history of these diseases, as well as the current approaches to the treatment of children with atopic diseases.. Recent studies have identified multiple risk factors for the development and progression of atopic diseases. As a result, much research is focused on identifying therapies that can be initiated at a young age to prevent disease progression. New treatment options have become available in recent years, such as topical immunomodulators for atopic dermatitis, leukotriene antagonists for seasonal allergic rhinitis, and alpha-immunoglobulin E therapy for asthma. The importance of viewing allergic rhinitis and asthma as disorders of a single airway has been emphasized. Finally, an update on the national asthma guidelines was recently released in an effort to promote optimal asthma care.. This review summarizes many of the recent advances in the diagnosis and treatment of atopic diseases in children. Although not intended to be a comprehensive review of this broad field, it provides a framework for appreciating the complexity of these diseases and for effectively managing them.

Topics: Acetates; Adrenergic beta-Agonists; Animals; Asthma; Child; Cyclopropanes; Dermatitis, Atopic; Environmental Exposure; Feces; Genetic Predisposition to Disease; Hepatitis A Virus Cellular Receptor 1; Hepatitis A Virus Cellular Receptor 2; Humans; Hypersensitivity, Immediate; Immunosuppressive Agents; Leukotriene Antagonists; Membrane Proteins; Mice; Quinolines; Receptors, Virus; Skin; Sulfides; T-Lymphocytes; Tacrolimus

Many patients with atopic dermatitis feel that their treatment is ineffective and 25% may be noncompliant with treatments involving corticosteroids. Developing safe and effective pharmacologic alternatives to steroids has presented a challenge to physicians and drug researchers. A new class of nonsteroid immunomodulators, topical calcineurin inhibitors, overcome some of the difficulties and concerns associated with steroid use. The introduction of new drug therapies reinforces the importance of dermatology nursing in managing atopic dermatitis.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Calcineurin Inhibitors; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Tacrolimus

Tacrolimus ointment is the first of a new class of non-steroidal topical immunomodulators indicated for the treatment of atopic dermatitis. Topical tacrolimus has been subject to an extensive clinical development program involving more than 16,000 patients. A clinical trial program, including vehicle-controlled studies, short- and long-term comparative studies and long-term safety studies, has investigated tacrolimus 0.1% and 0.03% ointment for the treatment of atopic dermatitis in adults and children aged 24 months and older. Tacrolimus monotherapy is rapidly effective, resulting in clinical improvements within three days of starting therapy, and produces a progressive increase in efficacy that is sustained during long-term treatment. Tacrolimus treats the signs and symptoms of atopic dermatitis, reduces the incidence of flares, and offers the potential for long-term disease control. No major safety concerns have been reported to date. Tacrolimus ointment is generally well tolerated, the primary adverse events being mild to moderate and transient application-site reactions: skin burning, pruritus and erythema. Tacrolimus ointment is a significant advance in dermatology and provides physicians with an alternative to conventional topical corticosteroid therapy.

Topics: Adolescent; Adult; Child; Child, Preschool; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Ointments; Tacrolimus

Topical inhibitors of calcineurin--tacrolimus and pimecrolimus have recently been approved in the treatment of atopic dermatitis. These are the first topical immunosuppressants other than glucocorticosteroids, awaited in dermatology since approximately 50 years. Both medications present similar mechanism of action, good therapeutic and safety profiles and should be considered as important factors in the treatment of atopic dermatitis.

Topics: Dermatitis, Atopic; Humans; Immunosuppressive Agents; Tacrolimus

Topics: Administration, Topical; Adrenal Cortex Hormones; Anti-Bacterial Agents; Dermatitis, Atopic; Drugs, Chinese Herbal; Emollients; Humans; Immunosuppressive Agents; Referral and Consultation; Tacrolimus

This article aims to review the literature on the use of tacrolimus in dermatology. We tried to focus on the local application of tacrolimus. The local application of tacrolimus is known to be effective for several skin diseases, especially atopic dermatitis. Since the major action site of tacrolimus is activated T-lymphocytes, the drug showed efficiency mostly in inflammatory dermatological diseases including psoriasis, lichen planus, alopecia areata and pyoderma gangrenosum. Tacrolimus lacks most of side effects of local steroids and seems to have better results for short and long term application. We presume that tacrolimus will be widely used on skin diseases, especially when it becomes less expensive.

Topics: Dermatitis, Atopic; Humans; Immunosuppressive Agents; Lymphocyte Activation; Skin Diseases; T-Lymphocytes; Tacrolimus

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.

Topics: Adjuvants, Immunologic; Administration, Topical; Anti-Inflammatory Agents, Non-Steroidal; Dermatitis, Atopic; Humans; Tacrolimus; Treatment Outcome

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

Topics: Administration, Topical; Anti-Inflammatory Agents, Non-Steroidal; Dermatitis, Atopic; Humans; Severity of Illness Index; Tacrolimus; Treatment Outcome

Topics: Adjuvants, Immunologic; Administration, Topical; Clinical Trials as Topic; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Tacrolimus

Atopic dermatitis is a chronic inflammatory skin disease characterized by severe pruritus, typical morphology and distribution of skin lesions, and personal and family history of atopy. The management of atopic dermatitis is directed at preventing the inflammation, itch, and secondary lesions. Therapy relies on general management measures, anti-inflammatory agents, antiprurites, antibiotics, and immunosuppressants. Treatment options for patients with severe or longstanding disease, extensive body surface area involvement of facial lesions are limited. Tacrolimus ointment is the first in the class of topical immunomodulators that has been formulated for the treatment of atopic dermatitis in children (2 to 15 years of age) and adult patients. The mechanism of action of tacrolimus in atopic dermatitis seems to involve T-cells, Langerhans cells, mast cells and basophiles. Experimental evidence suggests that tacrolimus inhibits T-lymphocytes activation by binding to an intracellular protein, FKBP-12. This binding phenomenon inhibits the ability of calcineurin to activate the promotor region of the gene for IL-2, IL-3, IL-4, IL-5, interferon gamma, tumor necrosis factor alpha, and granulocyte macrophage colony-stimulating factor, all of which participate in the early immune response and play a role in the pathogenesis of atopic dermatitis. Tacrolimus ointment is not atrophogenic, and is associated with minimal systemic absorption. There were no consistent changes in any laboratory variable during topical tacrolimus therapy. The most common adverse events associated with its use were transient skin burning and pruritus at the site of application. Tacrolimus ointment is safe and efficacious therapy for the treatment of pediatric and adult patients with atopic dermatitis on all skin regions including the face, neck and intertriginous areas. An overview is given of tacrolimus in atopic dermatitis.

Topics: Dermatitis, Atopic; Humans; Immunosuppressive Agents; Ointments; Tacrolimus

Tacrolimus is a potent inhibitor of immune mechanisms. It belongs to the macrolactam group. It inhibits the release of both Th1 and Th2 cytokines. It proves to be efficacious after topical application in the treatment of atopic dermatitis. In this indication, tacrolimus challenges topical corticosteroids. Irritation risks are present. The local immuno-depression can boost disseminated infections including herpes. The risk to promote photocarcinogenesis on the long term, and that bound to chronic resorption remain theoretical concerns that have not been assessed so far.

Topics: Administration, Cutaneous; Dermatitis, Atopic; Drug Tolerance; Humans; Immunosuppressive Agents; Risk Factors; Skin Absorption; Tacrolimus; Th1 Cells; Th2 Cells; Treatment Outcome

Conventional treatment of atopic dermatitis includes the regular, frequent use of emollients, and intermittent application of topical corticosteroids to control acute 'flares'. [symbol: see text] Tacrolimus (pronounced ta-kro-li-mus), which is available for systemic use for the prevention of organ rejection following allogenic liver and kidney transplantation, is now formulated as an immunosuppressant ointment (Protopic-Fujisawa). This is licensed for use in adults and children aged 2 years and over with moderate to severe atopic dermatitis inadequately responsive to conventional therapy. Promotion states that, in these groups, tacrolimus is "at least as effective as topical steroids" and "without the potential side effects of conventional therapy". Here we consider the place of tacrolimus ointment in the management of atopic dermatitis.

Topics: Administration, Cutaneous; Adult; Child; Dermatitis, Atopic; Dermatologic Agents; Humans; Immunosuppressive Agents; Ointments; Tacrolimus; Treatment Outcome

There is a paucity of randomized, controlled therapy studies of the extraintestinal manifestations of inflammatory bowel disease (IBD). Most current therapeutic approaches are empiric or based on approaches to therapy in other settings. In the past year anecdotal evidence has emerged for the use of therapies that neutralize tumor necrosis factor-a in both ankylosing spondylitis and the dermatologic extraintestinal manifestations. Topical tacrolimus has also emerged as a potentially useful therapy for dermatologic manifestations. Finally, patients with IBD occasionally become transplant recipients. One study reported worsening IBD after orthotopic liver transplantation for primary sclerosing cholangitis, and another reported the benefit of renal transplantation in amyloidosis-induced renal failure.

Topics: Antibodies, Monoclonal; Cholangitis, Sclerosing; Dermatitis, Atopic; Drug Combinations; Gastrointestinal Agents; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Infliximab; Myocarditis; Osteoporosis; Psoriasis; Pyoderma Gangrenosum; Tacrolimus; Treatment Outcome; Tumor Necrosis Factor-alpha; Vitamin D

Atopic dermatitis is a common problem affecting up to 10 percent of all children. The mainstays of therapy have been oral antihistamines, topical emollients, topical doxepin, and topical corticosteroids. Side effects associated with higher potency topical corticosteroids have limited their use in children and for facial areas. Tacrolimus (Protopic) is an immunosuppressive agent typically used systemically in transplant patients. Used topically, it has been found to be effective in treating moderate to severe atopic dermatitis without causing the atrophy that might occur with prolonged use of topical corticosteroids. Tacrolimus works equally well in children and adults, with more than two thirds of both groups having an improvement of greater than 50 percent. Despite its potency, very little of the medication is systemically absorbed, and absorption decreases as the atopic dermatitis resolves. The main side effects are burning and itching, but these also decrease with improvement of the atopic dermatitis.

Topics: Administration, Cutaneous; Clinical Trials as Topic; Dermatitis, Atopic; Dermatologic Agents; Humans; Immunosuppressive Agents; Tacrolimus

Chronic antiinflammatory treatment is required in autoimmunologic dermatoses. Tacrolimus ointment (Protopic) an inhibitor of calcineurin, is the first topical nonsteroidal immunosuppressant for the last 50 years. Pimecrolimus (ASM 981), a newer calcineurin inhibitor developed for atopic dermatitis treatment has the same mode of action and altered skin penetration profile as takrolimus. Their structure, mechanism of immunosuppressive action, efficacy and safety in atopic dermatitis and other inflammatory dermatitides was described in this article. The attention was paid to systemic and in topical treatment, their intact and injured skin penetration profile, optimal doses, costs and perspectives of broad use of these drugs in dermatology were described.

Topics: Administration, Topical; Calcineurin Inhibitors; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Ointments; Tacrolimus

Tacrolimus ointment, a topical inhibitor of the phosphatase calcineurin, has recently been approved in the United States for use in the treatment of atopic dermatitis. It is the first topical immune suppressant that is not one of the hydrocortisone derivatives, important allies in dermatology for nearly 50 years. Although tacrolimus is less able to penetrate thick skin than glucocorticoids, it does not cause dermal atrophy, an important advantage over the hydrocortisone class. Pimecrolimus (ASM 981), a newer calcineurin inhibitor closely related to tacrolimus, is also being developed for atopic dermatitis therapy. Pimecrolimus has an altered skin penetration profile but the same mechanism of action as tacrolimus. In this review we chronicle the discovery of the calcineurin inhibitors, their presumed evolutionary role as a bacterial "smart bomb" against fungi, molecular and cellular mechanisms of action in the immune system, systemic and topical side effects, efficacy in atopic dermatitis, and future applications within the specialty of dermatology. Particular attention is given to the issues of systemic absorption of tacrolimus, the conditions in which absorption can become a concern, efficacy relative to glucocorticoids, and the choice of 0.03% or 0.1% tacrolimus ointment for use in adults and children.

Topics: Administration, Topical; Adult; Calcineurin; Child; Child, Preschool; Clinical Trials as Topic; Dermatitis, Atopic; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Middle Aged; Risk Assessment; Tacrolimus

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 paediatric 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 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 1.0% cream has shown no potential for skin atrophy, a problem commonly associated with treatment with topical corticosteroids. Pimecrolimus 1.0% cream provides a promising and well tolerated treatment option in the manage

Topics: Administration, Cutaneous; Adolescent; Adult; Child; Child, Preschool; Dermatitis, Atopic; Drug Evaluation; Humans; Immunosuppressive Agents; Infant; Randomized Controlled Trials as Topic; Tacrolimus

The newly developed immunomodulator tacrolimus (FK506) is the first of a new class of agents that have enormous potential to change the way that dermatoses are treated and managed. Tacrolimus has been found to be active in a topical formulation with the latter exerting its effects by acting on the signal transduction pathways inside T cells and inhibiting gene transcription. The result is decreased responsiveness of T cells to antigens. Percutaneous absorption of tacrolimus is higher in diseased skin as opposed to healthy skin and, therefore, the drug will be taken in at progressively lower quantities as lesions heal. There is limited systemic absorption of tacrolimus over the course of therapy. The most extensive experience with tacrolimus has been in treating atopic dermatitis. In numerous trials, tacrolimus ointment 0.03-0.3% has shown to be effective in reducing the symptoms and severity of atopic dermatitis in adults and the paediatric population. Furthermore, there have been no significant toxic effects associated with topical therapy with tacrolimus. The most common complaint is that of local irritation after applying the ointment. This is generally transient and the patient is able to continue with therapy. The other dermatoses where tacrolimus has been used include contact dermatitis, psoriasis and pyoderma gangrenosum.

Topics: Administration, Oral; Administration, Topical; Clinical Trials as Topic; Dermatitis, Atopic; Dermatitis, Contact; Female; Humans; Immunosuppressive Agents; Male; Prognosis; Psoriasis; Skin Absorption; Skin Diseases; Tacrolimus; Treatment Outcome

Tacrolimus (FK-506; Fujisawa Pharmaceutical Co Ltd) and pimecrolimus (SDZ-ASM-981; Novartis AG) are topical immunomodulators, which provide an alternative to glucocorticosteroids for the topical treatment of atopic dermatitis and other inflammatory dermatoses. Both substances form a complex with cytosolic immunophilins. The complex blocks calcineurin and inhibits the transcription of NF-AT-dependent pro-inflammatory cytokine genes. Multicenter, randomized, double-blind clinical trials have shown the efficacy of both substances in atopic dermatitis. We review the physicochemical characteristics, mode of action, pharmacokinetic data, side effects, results of the clincal trials and further indications for tacrolimus and pimecrolimus.

Topics: Adjuvants, Immunologic; Administration, Topical; Dermatitis, Atopic; Humans; Randomized Controlled Trials as Topic; Skin Diseases; Tacrolimus

Tacrolimus ointment, formulated for the treatment of atopic dermatitis, is the first in a class of topical immunomodulators. Its mechanism of action is based on calcineurin inhibition, which results in suppression of antigen-specific T-cell activation and inhibition of inflammatory cytokine release. Animal and human studies have shown that topically applied tacrolimus is minimally absorbed into the systemic circulation, the fraction that is absorbed is extensively distributed, and tacrolimus does not accumulate in tissues following repeated topical application. In addition, tacrolimus ointment is not inherently irritating, sensitizing, phototoxic, or photoallergenic when applied to intact skin. Unlike some topical corticosteroids, tacrolimus ointment does not cause a decrease in collagen synthesis or skin thickness, nor does it produce skin abnormalities or depigmentation. In animal studies, repeated daily application of tacrolimus ointment up to 1 year is associated with dermal findings similar to those following vehicle application (mild to moderate dermal irritation and microscopic findings of acanthosis, hyperkeratosis, and superficial inflammation). In a 52-week study with Yucatan micropigs, no noteworthy macroscopic or microscopic changes (either dermal or systemic) related to the application of tacrolimus ointment (0.03% to 0.3% concentrations) were observed. Tacrolimus ointment was shown to be safe and effective in phase 2 and early phase 3 studies. Significant improvements in atopic dermatitis were observed in the majority of patients treated with tacrolimus ointment. The most common adverse events associated with its use were a transient burning sensation and pruritus at the site of application. Blood tacrolimus concentrations were below the limit of quantitation in most patients.

Topics: Animals; Clinical Trials as Topic; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Ointments; Tacrolimus

Topics: Adjuvants, Immunologic; Administration, Topical; Anti-Inflammatory Agents, Non-Steroidal; Dermatitis, Atopic; Ointments; Tacrolimus

Topics: Administration, Oral; Anti-Infective Agents; Antineoplastic Agents; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Interferon-gamma; Phosphodiesterase Inhibitors; Phototherapy; Tacrolimus

Atopic dermatitis (AD) is thought to be induced by a complex of various allergic reactions and T cells are implicated in its etiology. Since tacrolimus strongly inhibits T cell activation, tacrolimus ointment has been developed as a novel drug for AD throughout the world. Tacrolimus inhibits mast cell and eosinophil activation and antigen presenting activity of Langerhans cells in vitro. In the in vivo experimental animal models of AD, such as contact and spontaneous dermatitis in mice and repeated hapten treated skin inflammation in rats, tacrolimus ointment showed inhibitory activity. In clinical studies with AD patients in Japan, USA and Europe, tacrolimus ointment showed a marked effect. In comparative studies in Japan, it showed the same efficacy as a strong class steroid ointment on eczema at the trunk and extremities and superior efficacy at the face and neck compared to a medium class steroid. The most prominent adverse event is experienced at the local application site with reactions such as a burning sensation and erythema. Systemic side effects were rarely observed. While there is a possibility of skin infections when using tacrolimus, skin atrophy, even after long term treatment, was not observed. Thus tacrolimus ointment could be an efficient alternative to steroid ointment for AD.

Topics: Animals; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Mice; Ointments; Rats; Tacrolimus

The immunomodulatory macrolactams provide an alternative to glucocorticosteroids for the topical treatment of atopic dermatitis and other inflammatory dermatoses. Tacrolimus (FK506), as well as the newer ascomycin derivative ASM 981 (pimecrolimus), penetrate the inflamed epidermis and are suitable for topical therapy. Both substances inhibit the transcription of proinflammatory cytokine genes such as interleukin 2, which are dependent on the nuclear factor NF-AT. They block the catalytic function of calcineurin, which leads to the inhibition of the transport of the cytoplasmic component of NF-AT to the cell nucleus. Multicenter, randomized, double-blind clinical trials with topical formulations have shown the efficacy of both substances in moderate to severe atopic dermatitis. A review is presented of the biochemical and cell biologic properties, mode of action, pharmacokinetic data, side effects, results of the clinical trials, and further indications for tacrolimus and ASM 981, along with an overview of the related substances cyclosporine and sirolimus (rapamycin).

Topics: Administration, Topical; Clinical Trials as Topic; Cyclosporine; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Inflammation; Sirolimus; Skin Diseases; Tacrolimus

Tacrolimus, a macrolide immunomodulator, is believed to control atopic dermatitis by inhibiting T lymphocyte activation, altering cell surface expression on antigen-presenting dendritic cells and modulating the release of inflammatory mediators from skin mast cells and basophils. Tacrolimus ointment penetrates human skin with no systemic accumulation after repeated applications; systemic absorption is generally low, with most patients in clinical trials having blood concentrations of the drug below the limit of quantification. Moderate to severe atopic dermatitis significantly improved (measured using multiple end-points, including > or = 90% improvement in Physician's Global Evaluation of Clinical Response) with tacrolimus 0.03 and 0.1% ointment compared with vehicle in both adult (n = 304 and 328) and pediatric (n = 351) patients in three 12-week, double-blind, randomized, phase III trials. In adults, tacrolimus ointment was effective therapy for the treatment of atopic dermatitis on all skin regions, including the head and neck. The 0.1% concentration was more effective than the 0.03% concentration. Clinical improvement in moderate to severe atopic dermatitis in adult (n = 316) or pediatric (n = 255) patients was seen as early as week 1, and improvement continued and/or was maintained for up to 6 and/or 12 months in long-term studies. The 0.1% formulation was also effective and well tolerated for up to 2 years. Tacrolimus 0.03 and 0.1% ointment was associated with significant quality-of-life benefit in adults, children (aged 5 to 15 years) and toddlers (aged 2 to 4 years) with atopic dermatitis in 12-week phase III trials (n = 985). Skin burning and pruritus were the most common application site adverse events in adult and pediatric patients in short-term and long-term trials. These events were generally of short duration and mild or moderate severity. Cutaneous infections occurred with a similar incidence after treatment with tacrolimus ointment to that seen after vehicle in short-term trials.. Both short- and long-term monotherapy with tacrolimus 0.03 and 0.1% ointment improves moderate to severe atopic dermatitis in adult and pediatric patients. Topical tacrolimus ointment is well tolerated, with the majority of adverse events being localized, transient in nature and of mild or moderate severity. Tacrolimus ointment provides a promising addition to the currently available treatments for atopic dermatitis; it can be used as a short- or long-term intermittent therapy for moderate to severe disease, including disease on the head or neck, in adult (0.1 and 0.03% formulations) and pediatric (0.03% formulation) patients who are not adequately responsive to or are intolerant of conventional treatments.

Topics: Administration, Topical; Age Factors; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Ointments; Pruritus; Quality of Life; Tacrolimus

Tacrolimus (FK506) is a calcineurin inhibitor with potent immunomodulating properties. It has been marketed worldwide since 1993-1994 for the rejection of liver and kidney transplants (Prograf). The pharmacologic properties of tacrolimus resulted in its development as an ointment for the treatment of atopic dermatitis. An outline of nonclinical pharmacology studies that provided a rationale for this development is presented. The key nonclinical toxicology-safety studies that supported clinical efficacy/safety trials are also discussed. Taken collectively, these studies contributed to the marketing approval of 0.03% and 0.1% tacrolimus ointment (Protopic) as a first in class treatment for atopic dermatitis.

Topics: Administration, Cutaneous; Animals; Dermatitis, Atopic; Humans; Immunosuppressive Agents; In Vitro Techniques; Ointments; Tacrolimus; Treatment Outcome

The first topical immunomodulator approved for human use, tacrolimus ointment (Protopic, Fujisawa, Healthcare, Inc, Deerfield, IL), has been shown to be effective and safe in the treatment of children (aged 2 years and older) and adults with atopic dermatitis (AD). Clinical trials conducted worldwide have involved 12,000 patients, with safety and efficacy data available for up to 3 years of treatment. In addition to its beneficial effects in the management of AD, topical tacrolimus has also been reported to be of benefit in other immunologically mediated skin diseases including: hand dermatitis, contact dermatitis, eyelid dermatitis, erosive lichen planus, steroid-induced rosacea, pyoderma gangrenosum, and graft-versus-host disease. This article reviews the clinical experience of topical tacrolimus in the treatment of AD and other skin conditions.

Topics: Administration, Cutaneous; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Randomized Controlled Trials as Topic; Skin Diseases; Tacrolimus; Treatment Outcome

Atopic dermatitis (AD) is one of a family of inflammatory skin diseases (psoriasis, irritant contact dermatitis, and allergic contact dermatitis). Dermal inflammation and production of proinflammatory cytokines by activated T cells is a prominent and defining characteristic in all of these conditions. Corticosteroids, though effective and potent immunosuppressants, are associated with a number of systemic and local adverse effects. The ascomycin derivative pimecrolimus (formerly ASM 981) is a nonsteroid with topical anti-inflammatory activity. Pimecrolimus cream 1% is minimally absorbed into the circulation; thus, it has a low bioavailability-reducing the risk for systemic adverse effects. The efficacy and safety of pimecrolimus cream 1% has been well shown in diverse patient populations with inflammatory skin diseases in several well-controlled trials. Significant and rapid amelioration of the signs and symptoms of AD was established in 3 studies lasting 6 weeks each, evaluating 589 pediatric patients. In a 1-year study, pimecrolimus was applied at the first signs and symptoms of eczema to prevent the progression of AD to flares. Flares were prevented in over 50% of patients who used pimecrolimus cream 1%, reducing or completely eliminating the need for topical corticosteroids during a 1-year treatment period. Results in pimecrolimus studies in chronic irritant hand dermatitis and chronic hand dermatitis of mixed causes indicate potential for use in these important diseases, and further study in these indications is warranted.

Topics: Administration, Cutaneous; Anti-Inflammatory Agents, Non-Steroidal; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Randomized Controlled Trials as Topic; Risk Factors; Tacrolimus; Treatment Outcome

Topical tacrolimus ointment and pimecrolimus cream represent the first members of a new class of medications. Topical immunomodulators have been developed for the treatment of atopic dermatitis. Their superb safety profiles and excellent efficacy as anti-inflammatory agents make them attractive candidates to treat a host of other skin disorders. This article reviews published experiences that use them for psoriasis, seborrheic dermatitis, lichen planus, pyoderma gangrenosum and other diseases. Possible modifications to these compounds and novel untested applications are discussed.

Topics: Administration, Cutaneous; Anti-Inflammatory Agents, Non-Steroidal; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Tacrolimus; Treatment Outcome

Topics: Child; Cystic Fibrosis Transmembrane Conductance Regulator; Dermatitis, Atopic; Genetic Predisposition to Disease; Glucocorticoids; Humans; Hypersensitivity, Immediate; Immunosuppressive Agents; Incidence; Leukotriene Antagonists; Mutation; Rhinitis, Allergic, Seasonal; T-Lymphocytes; Tacrolimus

Tacrolimus and cyclosporin A are potent immunosuppressants that are used systemically to treat several inflammatory skin conditions successfully. They differ in their structure and tacrolimus is 10-100 times more potent than cyclosporin A. They have similar side-effects. They have been used topically in various clinical studies. Topical cyclosporin A is largely ineffective whereas topical tacrolimus is effective in treating atopic dermatitis. Topical tacrolimus has not been studied sufficiently in treating psoriasis although it has been used successfully in allergic contact dermatitis, erosive mucosal lichen planus and pyoderma gangrenosum.

Topics: Adult; Animals; Child; Cytokines; Dermatitis, Atopic; Female; Forecasting; Guinea Pigs; Humans; Immunosuppressive Agents; Male; Mice; Psoriasis; Tacrolimus

Ascomycin derivatives represent a novel class of anti-inflammatory macrolactams currently under development for the treatment of skin diseases. The main biological effect of ascomycins is an inhibition of the synthesis of both Th1 and Th2-type cytokines in target cells. Several compounds are being developed with SDZ ASM 981 being at the most advanced stage. It has high anti-inflammatory activity in animal models of skin inflammation and does not induce skin atrophy. Topical application of SDZ ASM 981 was shown to be effective in atopic dermatitis (AD), allergic contact dermatitis and also in psoriasis under semi-occlusive conditions. In patients with AD, SDZ ASM 981 cream led to consistently low systemic exposure even when applied on large areas of skin. SDZ ASM 981 overcomes the drawbacks of current topical therapies of inflammatory skin diseases as its safety profile is better than that of topical corticosteroids. Studies continue to investigate its efficacy and safety in the treatment of inflammatory skin diseases.

Topics: Adult; Animals; Anti-Inflammatory Agents; Child; Clinical Trials as Topic; Dermatitis, Atopic; Dermatitis, Contact; Dermatologic Agents; Drug Evaluation, Preclinical; Humans; Models, Animal; Rats; Skin Diseases; Tacrolimus

Tacrolimus has been shown to be a powerful suppressor of the immune system. It was introduced into clinical use to prevent allograft rejection and is now routinely used in kidney, liver, and heart transplantation. Recently, 2 double-blind multicenter studies demonstrated the therapeutic efficacy of topical and systemic tacrolimus in the inflammatory skin diseases atopic dermatitis and psoriasis.. MEDLINE was searched for relevant publications and combined with our own clinical, in vitro, and in vivo studies.. All studies dealing with tacrolimus and dermatology were reviewed.. Publications with clinically relevant data were included in this review.. Topical tacrolimus is a safe and effective therapeutic agent that may open a new era in the treatment of inflammatory skin diseases, particularly for patients with atopic dermatitis. Before its full potential in dermatology can be assessed, more clinical experience in treating children and comparison with the criterion standard of anti-inflammatory therapy, glucocorticosteroids, are needed.

Topics: Dermatitis, Atopic; Humans; Immunosuppressive Agents; Psoriasis; Skin Diseases; Tacrolimus

Atopic dermatitis is a chronic, relapsing form of eczema characterized by scaling, itchy, inflamed skin that can be triggered by an interplay of genetic, immunologic, and environmental factors. Immune dysregulation appears to play an important role in the cause of atopic dermatitis. Topical corticosteroid agents have been the mainstay of therapy for atopic dermatitis because of their broad immunomodulatory effects. However, topical corticosteroid agents are not ideal agents because when used over the long term, they may cause cutaneous atrophy and immunosuppression. Systemic corticosteroidal agents, certain antihistiminic agents, systemic cyclosporin, and phototherapy have proven value in treating patients with atopic dermatitis. In the search for a noncorticosteroidal topical agent, tacrolimus stands out as being uniquely suited for this condition. Tacrolimus affects a broad spectrum of inflammatory mediators and processes known to be relevant to atopic dermatitis pathogenesis. Tacrolimus demonstrates good percutaneous penetration and appears to have no potential to cause cutaneous atrophy. There are multiple double-blind, controlled studies demonstrating the safety and efficacy of this agent in treating atopic dermatitis. The agent may be of particular benefit in children, among whom an alternative to the chronic use of corticosteroid agents, either topically or systemically, is highly desirable.

Topics: Administration, Topical; Adrenal Cortex Hormones; Anti-Inflammatory Agents, Non-Steroidal; Dermatitis, Atopic; Humans; Ointments; Tacrolimus

Topics: Administration, Topical; Adult; Child; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Langerhans Cells; Skin; Tacrolimus; Ultraviolet Rays

Topics: Animals; Anti-Bacterial Agents; Carrier Proteins; Cyclosporine; Dermatitis, Atopic; Dermatitis, Contact; Disease Models, Animal; Guinea Pigs; Immunosuppressive Agents; Mice; Polyenes; Receptors, Drug; Receptors, Immunologic; Sirolimus; Swine; Tacrolimus; Tacrolimus Binding Proteins

Atopic dermatitis is a prevalent condition in children and can be effectively managed with medications such as topical calcineurin inhibitors (pimecrolimus or tacrolimus). A key unresolved safety concern is whether use of topical calcineurin inhibitors is associated with cancer. We systematically reviewed the risk of cancer in patients with atopic dermatitis exposed to topical calcineurin inhibitors.. As part of the 2022 American Academy of Allergy, Asthma and Immunology and American College of Allergy, Asthma and Immunology Joint Task Force on Practice Parameters atopic dermatitis guidelines, we searched MEDLINE, Embase, the Latin American and Caribbean Health Sciences Literature database, the Índice Bibliográfico Espanhol de Ciências da Saúde database, the Global Resource of Eczema Trials database, WHO's International Clinical Trials Registry Platform, the US Food and Drug Administration database, the European Medicines Agency database, company registers, and relevant citations from inception to June 6, 2022. We included randomised controlled trials and comparative and non-comparative non-randomised studies in any language addressing cancer risk in patients with atopic dermatitis using topical calcineurin inhibitors. We excluded split-body studies and studies with less than 3 weeks of follow-up. Paired reviewers independently screened records, extracted data, and assessed risk of bias in duplicate. We used Bayesian models to estimate the probability for cancer due to topical calcineurin inhibitor exposure and the GRADE approach to determine the certainty of the evidence. Patients, advocacy groups, and care providers set a priori thresholds of important effects. This study is registered with Open Science Framework, https://osf.io/v4bfc.. We identified and analysed 110 unique studies (52 randomised controlled trials and 69 non-randomised studies [11 were non-randomised study extensions of randomised controlled trials]) including 3·4 million patients followed up for a mean of 11 months (range 0·7-120). The absolute risk of any cancer with topical calcineurin inhibitor exposure was not different from controls (absolute risk 4·70 per 1000 with topical calcineurin inhibitors vs 4·56 per 1000 without; odds ratio 1·03 [95% credible interval 0·94-1·11]; moderate certainty). For all age groups and using data from observational studies and randomised controlled trials, the use of pimecrolimus (OR 1·05 [95% credible interval 0·94-1·15]) or tacrolimus (0·99 [0·89-1·09]) is likely to have had little to no association with cancer compared with no topical calcineurin inhibitor exposure. For pimecrolimus versus tacrolimus, the finding was similar (0·95 [95% credible interval 0·83-1·07]). Findings were similar in infants, children, and adults, and robust to trial sequential, subgroup, and sensitivity analyses.. Among individuals with atopic dermatitis, moderate-certainty evidence shows that topical calcineurin inhibitors do not increase the risk of cancer. These findings support the safe use of topical calcineurin inhibitors in the optimal treatment of patients with atopic dermatitis.. American Academy of Allergy, Asthma and Immunology and American College of Allergy, Asthma and Immunology via the Joint Task Force on Practice Parameters.

Topics: Adult; Asthma; Bayes Theorem; Calcineurin Inhibitors; Child; Dermatitis, Atopic; Humans; Hypersensitivity; Infant; Neoplasms; Randomized Controlled Trials as Topic; Tacrolimus

Topical corticosteroids (TCS), used to treat atopic dermatitis (AD), have been associated with type 2 diabetes and osteoporosis in epidemiological studies, possibly explained by systemic absorption.. We examined whether intensive daily whole-body TCS treatment over 2 weeks followed by twice weekly application for 4 weeks could elicit insulin resistance and increase bone resorption in adults with AD.. A randomized parallel-group double-blind double-dummy non-corticosteroid-based active comparator study design was completed in Copenhagen, Denmark. Thirty-six non-obese, non-diabetic adults with moderate-to-severe AD were randomized to whole-body treatment with betamethasone 17-valerate 0.1% plus a vehicle once daily or tacrolimus 0.1% twice daily after washout. Insulin sensitivity assessed by the hyperinsulinemic-euglycemic clamp combined with tracer infusions and biomarkers of bone formation (P1NP) and resorption (CTX) were evaluated at baseline, after 2 weeks of daily treatment and after further 4 weeks of twice-weekly maintenance treatment.. AD severity improved with both treatments and systemic inflammation was reduced. After 2 weeks, we observed similar increase in peripheral insulin sensitivity with use of betamethasone (n = 18) and tacrolimus (n = 18). Bone resorption biomarker, CTX, was unchanged, while bone formation marker, P1NP, decreased after betamethasone treatment after both 2 and 6 weeks but remained unchanged in the tacrolimus arm.. Whole-body treatment with TCS leads to systemic exposure but appears not to compromise glucose metabolism during short-term use, which may be a result of reduced systemic inflammatory activity. The negative impact on bone formation could be regarded an adverse effect of TCS.

Topics: Adrenal Cortex Hormones; Adult; Betamethasone; Dermatitis, Atopic; Dermatologic Agents; Diabetes Mellitus, Type 2; Double-Blind Method; Glucocorticoids; Homeostasis; Humans; Insulin Resistance; Tacrolimus; Treatment Outcome

Childhood atopic dermatitis (AD) is often followed by other atopic comorbidities such as asthma.. To compare the effectiveness of topical tacrolimus (TAC) and topical corticosteroids (TCSs) and their impact on airway inflammation and bronchial hyperresponsiveness in patients with paediatric AD.. This was a 3-year randomized open-label comparative follow-up study of 152 1-3-year-old children with moderate-to-severe AD (trial registration: EudraCT2012-002412-95). Frequent study visits including clinical examinations, laboratory investigations (total IgE, specific IgEs, blood eosinophils), skin prick and respiratory function tests to assess airway inflammation and bronchial hyperresponsiveness (exhaled nitric oxide, airway responsiveness to exercise and methacholine) were performed.. Changes in eczema parameters at 36 months were similar in the TCS and TAC groups for mean body surface area (BSA) difference 1.4 [95% confidence interval (CI) -1.48 to 4.19); P = 0.12], mean Eczema Area and Severity Index (EASI) difference 0.2 (95% CI -1.38 to 1.82; P = 0.2), mean Investigator's Global Assessment (IGA) difference, 0.3 (95% CI -0.12 to 0.67; P = 0.12) and mean transepidermal water loss (TEWL) difference at the eczema site, -0.3 (95% CI -4.93 to 4.30; P = 0.96) and at the control site, 1.4 (95% CI -0.96 to 3.60, P = 0.19). The control-site TEWL increased more towards the end of follow-up in the TCS vs. TAC group (mean change difference -4.2, 95% CI -8.14 to -0.29; P = 0.04). No significant impact on development of airway inflammation or bronchial hyperresponsiveness occurred in early effective eczema-treatment responders vs. others ('early' vs. 'other' response was defined as the difference in treatment response to airway outcomes in BSA, EASI or IGA at 3 months).. Children with moderate-to-severe AD benefit from long-term treatment with TCS or TAC. There were no significant differences in treatment efficacy. No differences in the impact on airways occurred between early effective treatment responders vs. others.

Topics: Adrenal Cortex Hormones; Child; Child, Preschool; Dermatitis, Atopic; Double-Blind Method; Eczema; Follow-Up Studies; Humans; Immunoglobulin A; Inflammation; Severity of Illness Index; Tacrolimus; Treatment Outcome

Atopic dermatitis (AD) exhibits difference in immune polarization between Caucasians and Asian races due to which an evaluation of the efficacy and safety of Pimecrolimus (PIM) in Asian population is called for. The current study addresses the need. Patients with AD (≥3 months-<12 months of age) were randomized in a 1:1 ratio to either PIM 1% cream or topical corticosteroids (TCS). The primary endpoint was safety. The secondary endpoint was efficacy.. 120 patients were randomized to either PIM 1% or TCS (. PIM showed an early and sustained efficacy in the Chinese sub-population with a substantial corticosteroid-sparing effect in patients with AD.

Topics: Administration, Topical; Dermatitis, Atopic; Dermatologic Agents; East Asian People; Glucocorticoids; Humans; Infant; Skin Cream; Tacrolimus; Treatment Outcome

Recent evidence has suggested that oral antihistamines could have a beneficial role in atopic dermatitis (AD) because of their anti-inflammatory action.. To evaluate the effectiveness of adding an oral second-generation, nonsedating, H1-receptor antihistamine (fexofenadine) to topical treatment in AD.. In this prospective randomized study, 50 patients with a diagnosis of mild to moderate AD were recruited and randomized into two groups: Group A was given appropriate topical treatment (topical tacrolimus 0.03-0.1% ointment once daily along with topical fluticasone propionate 0.05% cream once daily, as well as paraffin-based emollients) combined with oral fexofenadine, while Group B was given appropriate topical treatment only. Both groups received the respective treatments for 8 weeks.. There was no significant difference between the two groups in terms of the SCORing Atopic Dermatitis and the 5-dimensions Itch Scale at any of the time points (Weeks 2, 4 and 8). However, in the fexofenadine group, the level of serum interleukin (IL)-31 decreased significantly from baseline to Week 8 of treatment.. Although we could not conclusively confirm the clinical efficacy of adding oral fexofenadine to topical treatment in AD, serological evaluation indicates that fexofenadine treatment can lead to significant lowering of serum IL-31 levels in patients with AD.

Topics: Administration, Topical; Child; Dermatitis, Atopic; Double-Blind Method; Humans; Interleukins; Prospective Studies; Tacrolimus; Terfenadine; Treatment Outcome

We collected evidence and safety data for topical tacrolimus in small children with atopic dermatitis (AD) and compared the usage with topical corticosteroid.. This was an interim analysis of 75 patients (55% female) at 1 year of an ongoing 3-year randomised open-label comparative follow-up study of topical tacrolimus vs corticosteroid treatment. One- to three-year-old children with moderate-to-severe eczema referred to the Skin and Allergy Hospital in Helsinki, Finland, were enrolled.. Efficacy parameters, the Eczema Area and Severity Index (EASI), Investigator's Global Assessment (IGA), transepidermal water loss (TEWL), eczema area, serum total immunoglobulin E (IgE) and the blood eosinophil count, showed improvement in both groups during the study. However, patients with signs of early sensitisation at baseline (elevated serum total IgE, elevated eosinophil count, positive prick tests or specific IgEs to aero or food allergens) had statistically significantly lower TEWL at the eczema site and a smaller eczema area at 12 months in the tacrolimus group. No severe adverse effects were seen during the treatment.. Children with AD and signs of early sensitisation appeared to benefit more from early tacrolimus than corticosteroid treatment. Small children may need stronger but nevertheless safe ointment options when treating moderate-to-severe AD.

Topics: Administration, Topical; Adrenal Cortex Hormones; Child, Preschool; Dermatitis, Atopic; Eczema; Female; Finland; Follow-Up Studies; Humans; Immunosuppressive Agents; Infant; Male; Tacrolimus; Treatment Outcome

There is no consensus on the use of soap in skin care for atopic dermatitis in Japan. Thus, this study aimed to evaluate the efficacy of soap to maintain eczema remission in atopic dermatitis patients during the fall-winter period in Japan.. This assessor-blinded, pragmatic randomized, non-inferiority study enrolled atopic dermatitis patients whose eczema was controlled by regular steroid ointment application less than or equal to 2 days / week (tacrolimus ointment was permitted). For 8 ± 3 weeks, participants washed their upper and lower limbs on one side with soap (soap side) and on the other side with water alone (water side). The primary outcome was an Eczema Area and Severity Index score at week 8 ± 3.. Twenty-nine participants were analyzed. The Eczema Area and Severity Index scores at week 8 ± 3 of the water and soap sides were 0.0 (0.0-0.4) and 0.0 (0.0-0.4), respectively (P = 0.18). The difference between both sides was -0.02 (-0.11-0.08), and the limits of the 95% confidence interval did not reach the prespecified non-inferiority margin. The average Patient-Oriented Eczema Measure score was 1.27 ± 1.7 and 1.32 ± 1.8 for the water and soap sides, respectively (P = 0.92). The total number of additional steroid ointment applications was four (0-20) times and six (0-23) times, respectively (P = 0.98). Participants were categorized according to self-assessments of the usefulness of soap, with 2, 24, and 3 participants in the water-effective, invariant, and soap-effective groups, respectively.. For children with controlled atopic dermatitis, washing with water alone was not inferior to washing with soap for maintaining remission of eczema during the fall-winter period in Japan.

Topics: Child; Child, Preschool; Dermatitis, Atopic; Eczema; Female; Humans; Immunosuppressive Agents; Infant; Japan; Male; Remission Induction; Seasons; Severity of Illness Index; Skin Care; Soaps; Tacrolimus; Treatment Outcome; Water

Topics: Administration, Cutaneous; Calcineurin Inhibitors; Dermatitis, Atopic; Dermatologic Agents; Humans; Tacrolimus; Treatment Outcome

The PETITE study (Sigurgeirsson et al.) aimed to compare safety and efficacy of pimecrolimus 1% cream (PIM) and low-to-medium-potency topical corticosteroids (TCS) in children with mild-to-moderate atopic dermatitis (AD).. Participants of this 5-year drug-company sponsored multicentre, open-label, parallel-group trial were recruited between April 2004 and October 2005. No details are reported regarding the study sites.. Infants aged ≥ 3 to < 12 months with mild-to-moderate AD were randomly assigned in a 1 : 1 ratio to receive either PIM or a low- or medium-potency TCS cream/ointment for 5 years. No information on specific TCS products used was provided. The topical treatment was applied twice daily 'until complete AD clearance or for as long as allowed by the label of the specific TCS', and was reinitiated at the occurrence of first signs and symptoms of AD flares. In the PIM group, exacerbations not controlled by PIM were treated with short-term TCSs.. Adverse events (AEs) and serious AEs (SAEs) were recorded 'during clinic visits'. In a proportion of the patients, various immunological assessments including antibody titres to common vaccine antigens, immunoglobulin levels, B and T lymphocyte cell counts, and T-cell proliferation tests were performed. The children's growth was assessed by measuring height and weight. AD severity was measured using the Investigator Global Assessment (IGA) score and the percentage of the total body surface area affected. No specific information was provided on the number and scheduling of study visits. Primary outcomes were the incidence of AEs 'of primary clinical interest' and those with a crude incidence of ≥ 5% in either treatment group. Secondary outcome was 'long-term efficacy' defined as IGA ≤ 1 at week 3 and year 5.. Patients in the PIM group experienced significantly more AEs [bronchitis (P = 0·02), infected eczema (P ≤ 0·001), impetigo (P = 0·045), nasopharyngitis (P = 0·04)]. No significant differences were seen for the other AEs. The overall incidence of SAEs was slightly higher for PIM (20·5% vs. 17·3%; P = 0·046). The proportion of participants with IGA ≤ 1 at year 5 was 88·7% for PIM and 92·3% for TCS, a success rate difference of 3·6% (95% confidence interval 0·8-6·4) favouring TCS.. Sigurgeirsson et al. conclude that the long-term management of mild-to-moderate AD in children with both TCS and PIM is safe, and that PIM has similar efficacy to TCS. Further, they conclude that their data support the use of PIM as a first-line treatment of mild-to-moderate AD in children.

Topics: Administration, Cutaneous; Dermatitis, Atopic; Dermatologic Agents; Drug Administration Schedule; Female; Humans; Infant; Male; Tacrolimus; Treatment Outcome

Atopic dermatitis (AD) presents a large unmet need for treatments with better safety and efficacy. To facilitate development of topical therapeutics, we need an efficient model for assessing different formulations and concentrations. The "plaque model" has been successfully implemented in patients with psoriasis, another common inflammatory disease, to assess the efficacy of topical treatments. This model has not been validated for AD, which has higher placebo responses and less stable lesions than psoriasis.. We aimed to assess changes in molecular signatures of intrapatient target lesions treated with topical therapeutics.. We enrolled 30 patients with mild-to-moderate AD in a randomized, double-blind, intraindividual comparison of 3 approved agents applied blindly at the investigator site daily for 14 days: pimecrolimus, betamethasone dipropionate, clobetasol propionate, and a vehicle/emollient control. Changes in total sign scores (TSSs), transepidermal water loss, and tissue biomarkers (determined by using RT-PCR and immunohistochemistry) were evaluated.. TSSs showed improvements of 30%, 40%, 68%, and 76% at 2 weeks with vehicle, pimecrolimus, betamethasone, and clobetasol, respectively, with parallel changes in transepidermal water loss (P < .05). Significant differences versus vehicle values were limited to steroids (P < .0001). Steroids (particularly clobetasol) restored epidermal hyperplasia and terminal differentiation versus minimal changes with vehicle or pimecrolimus (P < .001). Levels of cellular infiltrates and cytokines (IL-13, IL-22, and S100As) were similarly reduced only by steroids (P < .001). TSS improvement correlated with changes in hyperplasia, infiltrates, and differentiation markers.. We detected significant clinical and tissue differences between agents, providing a novel approach to study the differential effects of topical formulations using a limited sample size.

Topics: Administration, Topical; Adult; Aged; Anti-Inflammatory Agents; Betamethasone; Biomarkers; Cell Differentiation; Clobetasol; Cytokines; Dermatitis, Atopic; Female; Humans; Hyperplasia; Male; Middle Aged; Placebo Effect; Psoriasis; Skin; Tacrolimus; Young Adult

Atopic dermatitis (AD) is often the first step in the atopic march leading to the development of asthma or allergic rhinitis. The goal of this study was to determine whether early intervention with pimecrolimus limits the atopic march in infants with AD and to evaluate its efficacy and safety.. This was a 3-year double-blind study in which patients were randomized to pimecrolimus or vehicle and then open-label pimecrolimus for a planned further 3 years. Rescue topical corticosteroid was permitted if 3 days of study medication led to no improvement; investigators made decisions on rescue medication until week 14 and caregivers thereafter. Efficacy assessments included disease-free days, Eczema Area and Severity Index, and body surface area affected.. Infants ages 3 to 18 months with recent-onset AD (≤3 months) were observed for a mean of 2.8 years (N = 1,091). No significant differences between pimecrolimus- and placebo-treated groups were found in the percentage of patients with AD who developed asthma (10.7%) or other allergic conditions (allergic rhinitis, 22.4%; food allergy, 15.9%; allergic conjunctivitis, 14.1%; one or more atopic comorbidities, 37.0%) by study end. Allergic rhinitis, food allergy, and having one or more atopic comorbidities (but not asthma or allergic conjunctivitis alone) developed significantly more often in infants with greater AD severity at baseline. Pimecrolimus was significantly more effective than vehicle for AD treatment at week 14. Adverse event incidences were similar.. This longitudinal observation of infants with AD provides evidence of the atopic march. Pimecrolimus was safe and effective in infants with mild to moderate AD.

Topics: Asthma; Comorbidity; Dermatitis, Atopic; Dermatologic Agents; Double-Blind Method; Humans; Infant; Longitudinal Studies; Rhinitis, Allergic; Severity of Illness Index; Tacrolimus; Treatment Outcome

In reactive and proactive therapy of atopic dermatitis a well established agent is tacrolimus, a member of calcineurin inhibitors' family. The clinical safety and efficacy of this drug were evaluated previously in randomized multicenter trials. However, so far in clinical studies the assessment of its action on the skin has been made only on the basis of different scores and scales. We present the 6-month observations of tacrolimus therapy in atopic dermatitis patients monitored with the use of noninvasive techniques like high-frequency ultrasonography and evaporimetry.. The study consisted of 39 patients with AD and their mean age was 26.3 ± 12.8 years. The study lasted 6 months and every 4 weeks patient visited the outpatient clinic (totally 7 visits). The evaluation of disease severity within right antecubital fossa was obtained on the basis of Investigator's Global Assessment (IGA) score. During every control visit noninvasive measurements were carried in the form of HF-USG (with determination of subepidermal low echogenic band, SLEB) and evaporimetry.. 39 patients started the study and 22 of them (54.6%) finished it. Out of 39 patients, 31 (79.5%) received at least 4 week long proactive treatment. We observed statistically significant change of IGA, mean SLEB value and TEWL during underwent therapy. There were also statistically significant differences in mean SLEB and TEWL values between lesional and nonlesional measures.. This report shows the usefulness of HF-USG in monitoring tacrolimus therapy in atopic dermatitis. It is worth emphasizing, that this tool is easily reproducible and allows clinicians to visualize pathologic changes of all skin in vivo. As a noninvasive and independent of subjective judgment method, HF-USG should be included in overall evaluation of atopic dermatitis disease severity together with common scores or scales, especially in the era of evidence based medicine.

Topics: Administration, Topical; Adolescent; Adult; Calcineurin Inhibitors; Child; Dermatitis, Atopic; Drug Monitoring; Female; Humans; Longitudinal Studies; Male; Middle Aged; Reproducibility of Results; Sensitivity and Specificity; Tacrolimus; Treatment Outcome; Ultrasonography; Young Adult

The proactive use of topical anti-inflammatory (TAI) therapy to address subclinical inflammation is an effective, contemporary clinical strategy for the management of atopic dermatitis (AD). The interaction of a proactive TAI dose with the subclinical epidermal barrier defect in AD is yet to be determined. A randomised, observer-blind, functional mechanistic study in 17 subjects with quiescent AD was performed to compare the effect of a twice-weekly dose of betamethasone valerate (0.1%) cream (BMVc), against tacrolimus (0.1%) ointment (TACo) on the biophysical and biological properties of the epidermal barrier. Application of BMVc preserved epidermal barrier function and stratum corneum (SC) integrity, but significantly elevated skin-surface pH with concomitant loss of SC cohesion. By contrast, TACo improved SC integrity, exerted an overall hydrating action, and significantly reduced caseinolytic and trypsin-like protease activity. The differential effects reported support the proactive use of TACo to promote reparation of the subclinical barrier defect in AD.

Topics: Adult; Anti-Inflammatory Agents; Betamethasone Valerate; Calcineurin Inhibitors; Densitometry; Dermatitis, Atopic; Electric Capacitance; Epidermis; Humans; Hydrogen-Ion Concentration; Ointments; Peptide Hydrolases; Single-Blind Method; Skin Cream; Skin Physiological Phenomena; Tacrolimus; Water Loss, Insensible

Atopic dermatitis (AD) primarily affects infants and young children. Although topical corticosteroids (TCSs) are often prescribed, noncorticosteroid treatments are needed because compliance with TCSs is poor due to concerns about their side effects. In this longest and largest intervention study ever conducted in infants with mild-to-moderate AD, pimecrolimus 1% cream (PIM) was compared with TCSs.. A total of 2418 infants were enrolled in this 5-year open-label study. Infants were randomized to PIM (n = 1205; with short-term TCSs for disease flares) or TCSs (n = 1213). The primary objective was to compare safety; the secondary objective was to document PIM's long-term efficacy. Treatment success was defined as an Investigator's Global Assessment score of 0 (clear) or 1 (almost clear).. Both PIM and TCSs had a rapid onset of action with >50% of patients achieving treatment success by week 3. After 5 years, >85% and 95% of patients in each group achieved overall and facial treatment success, respectively. The PIM group required substantially fewer steroid days than the TCS group (7 vs 178). The profile and frequency of adverse events was similar in the 2 groups; in both groups, there was no evidence for impairment of humoral or cellular immunity.. Long-term management of mild-to-moderate AD in infants with PIM or TCSs was safe without any effect on the immune system. PIM was steroid-sparing. The data suggest PIM had similar efficacy to TCS and support the use of PIM as a first-line treatment of mild-to-moderate AD in infants and children.

Topics: Adrenal Cortex Hormones; Child, Preschool; Dermatitis, Atopic; Dermatologic Agents; Dose-Response Relationship, Drug; Drug Therapy, Combination; Humans; Infant; Long-Term Care; Tacrolimus

UR-1505 is a new small molecule with immune modulator properties intended for the topical treatment of inflammatory skin diseases that has shown anti-inflammatory effects in models of skin inflammation. We compared the activity of UR-1505 ointment against its vehicle in the treatment of atopic dermatitis. Secondary objectives included exploring dose response, safety, and local tolerability of UR-1505.. Patients with AD lesions on 2 symmetrical topographic areas (arms, leg, or trunk) were included in this unicenter randomized, double-blind, within-patient, controlled Phase II exploratory trial and received simultaneously 2 different treatments (0.5%, 1%, or 2% UR-1505 and vehicle or 0.1% tacrolimus ointment) once daily during 28 days. The primary efficacy end point was the change from baseline in the Investigator Global Assessment score at Day 28. Secondary end points were percentage of area clearance, local Eczema Area Severity Index (local EASI), and local tolerability. A linear mixed model was used, fitting treatment, body side, and group (treatment at the contralateral side) as fixed factors and the patient as a random effect.. Twenty-eight patients were randomized and 25 patients were included in the per protocol analysis, with 50 evaluable lesions (n = 13 for vehicle, n = 8 for UR-1505 0.5%, n = 9 for 1% UR-1505, n=8 for 2% UR-1505, and n=12 for tacrolimus). The mean Investigator Global Assessment score change from baseline at Day 28 was -1.7 for vehicle, -1.0, -1.2, and -1.5 for 0.5%, 1%, and 2% UR-1505, respectively, and -2.6% for tacrolimus (P = 0.002). No serious nor causal adverse reactions were reported in this study, but patients reported numerous local symptoms after product applications, especially itching, tingling, tightness, and heat/burning sensations at frequencies that were similar for vehicle, 1% UR-1505, and 2% UR-1505; more frequent with 0.5% UR-1505; and lowest for tacrolimus.. This study found that UR-1505 may not be a suitable option for the treatment of atopic dermatitis due to its lack of clinically relevant effect compared with its vehicle and 0.1% tacrolimus ointment.

Topics: Administration, Topical; Adult; Anti-Inflammatory Agents, Non-Steroidal; Dermatitis, Atopic; Dermatologic Agents; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Ointments; Salicylates; Tacrolimus; Treatment Outcome; Young Adult

Atopic dermatitis (AD) is a chronic, inflammatory skin disease in early childhood. Atopic dermatitis is familial disease, often coexists with other atopic diseases with multiple risk factors associated with atopic eczema. The disease is more frequent in urban areas compared with rural areas. Changes in nutrition and a decrease in infant breast-feeding and respiratory allergies are contributory factors for the condition. A Randomized Controlled Trial (RCT) was carried to compare the efficacy and safety of Tacrolimus ointment with a topical corticosteroid reference therapy. A total 60 patients aged between 2 to 10 years, having atopic dermatitis for at least one year and comply Hanifin-Rajka criteria were selected using random number table and allocated into study and control groups through randomization. Study group was treated with topical Tacrolimus 0.03% twice daily for three weeks, while the control group was treated with 1% Hydrocortisone acetate for the same period. Both groups had a washed out phase for 2 weeks with a follow up period of 6 weeks. Eczema Area and Severity lndex (EASI) was assessed at baseline and three weeks after treatment. Efficacy was evaluated at each visit by six clinical signs of atopic dermatitis through measurement of the affected surface area and the EASI score in each of four body regions. Before intervention, in study group mean EASI score was 11.29 with a SD of 2.14, while in control group it was 11.05 with a SD of 2.46. Difference was statistically insignificant (p>0.05). At the end of the treatment, in study group mean EASI score was 4.86 with a SD of 1.01, while in control group it was 7.97 with a SD of 1.80. Statistically high significant difference was observed between EASI scores of two groups before and after the treatment (p<0.001). After getting treatment with Tacrolimus, median reduction of EASI score was 56.07 in study group, while getting treatment with Hydrocortisone, median reduction of EASI score was 27.16. Difference was highly significant (p<0.001). It is evidenced that Tacrolimus ointment (0.03%) acts as an effective as well as safe non-steroidal topical therapy for the treatment of dermatitis in paediatric patients.

Topics: Administration, Cutaneous; Child; Child, Preschool; Dermatitis, Atopic; Double-Blind Method; Female; Humans; Hydrocortisone; Immunosuppressive Agents; Male; Ointments; Tacrolimus; Treatment Outcome

Atopic dermatitis (AD) is an inflammatory skin disease arising as a result of immune system and skin barrier defects. Topical corticosteroids are safe and effective treatments for AD, when used in short courses. Prolonged use is associated with skin barrier damage. Topical calcineurin inhibitors are alternative immune-modulating treatments for AD purported to have no negative effects on the skin barrier.. To compare the effects of betamethasone valerate 0·1% cream (BMVc) and tacrolimus 0·1% ointment (TACo) on the skin barrier.. Twenty volunteers with quiescent AD (no active signs for 6 months) participated in a randomized observer-blind study, wherein BMVc was applied to one forearm and TACo to the other, twice daily for 4 weeks. The biophysical/biological properties of the stratum corneum were assessed before and after treatment. Nine volunteers with active disease and 10 with healthy skin were assessed at untreated sites.. BMVc significantly reduced skin barrier function, integrity and cohesion, and the levels of pyrrolidone carboxylic acid (PCA) and urocanic acid (UCA) towards the subclinical barrier defect observed in patients with AD (nonlesional sites). TACo preserved skin barrier function, integrity, cohesion and PCA and UCA levels, while significantly increasing skin hydration to levels comparable with healthy skin. Both treatments reduced skin surface pH and trypsin-like protease activity, with TACo doing so to a significantly greater degree.. In quiescent AD, 4 weeks of BMVc treatment adversely affected the biophysical properties of the skin and reduced the levels of natural moisturizing factor, whereas TACo improved the condition of the skin barrier.

Topics: Administration, Cutaneous; Betamethasone Valerate; Calcineurin Inhibitors; Dermatitis, Atopic; Glucocorticoids; Humans; Hydrogen-Ion Concentration; Middle Aged; Ointments; Peptide Hydrolases; Skin; Tacrolimus; Water Loss, Insensible

Serum thymus and activation-regulated chemokine (TARC) levels are associated with the disease activity of patients with atopic dermatitis (AD) and sensitively reflect short-term changes in skin conditions. The main treatment for AD is topical agent application.. This study investigated the relationship between serum TARC levels and the dosage of topical agents, including corticosteroids and/or tacrolimus, in patients with AD.. The serum TARC levels of 56 AD patients and the amounts of topical agents prescribed to them were investigated retrospectively. The weekly reduction in serum TARC levels and weekly dosage of topical agents among AD patients were compared and their associations were evaluated.. The dosage of topical agents was closely related to serum TARC levels. One gram of strong rank steroid or the equivalent amount of steroid/tacrolimus is required to reduce serum TARC levels by 9.94 pg/mL weekly in moderate to severe AD patients. Higher initial TARC levels require more topical agent, which results in a more rapid decrease in TARC levels. The serum TARC levels and eosinophil numbers in peripheral blood are significantly correlated.. Serum TARC level improvement and topical agent dosage are strongly correlated. TARC and eosinophil numbers are significantly correlated, but the wider range of TARC levels seems to be clinically more useful for monitoring AD severity. The serum TARC level is a very sensitive biomarker for monitoring the severity and treatment response in AD.

Topics: Administration, Topical; Adolescent; Adrenal Cortex Hormones; Adult; Aged; Biomarkers; Chemokine CCL17; Dermatitis, Atopic; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Ointments; Tacrolimus

Topical steroids are used for the treatment of primary atopic dermatitis (AD); however, their associated risk of serious complications is great due to the presence of vulnerable lesions in young children with AD. Topical calcineurin inhibitors (TCIs) are steroid-free, anti-inflammatory agents used for topical AD therapy. However, their use is prohibited in infants <2 years of age because of their carcinogenic potential. We conducted a randomized, double-blind trial to evaluate the efficacy of TCIs as a secondary AD treatment for children <2 years of age by comparing 1% pimecrolimus cream with 0.05% desonide cream. We performed urinary metabolomics to predict long-term side effects. The 1% pimecrolimus cream displayed similar efficacy and exceptional safety compared with the 0.05% desonide cream. Metabolomics-based long-term toxicity tests effectively predicted long-term side effects using short-term clinical models. This applicable method for the functional interpretation of metabolomics data sets the foundation for future studies involving the prediction of the toxicity and systemic reactions caused by long-term medication administration.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Dermatitis, Atopic; Desonide; Double-Blind Method; Female; Humans; Infant; Male; Metabolomics; Predictive Value of Tests; Skin Cream; Tacrolimus; Time Factors

Atopic dermatitis (AD) is a chronic, relapsing skin disorder, which is characterized by intense pruritus, skin dryness and concomitant epidermal barrier dysfunction. The basic therapy involves the application of anti-inflammatory topical drugs like; glucocorticosteroids and calcineurin inhibitors. Phototherapy in AD is regarded as an additional form of treatment. The latest invention, ultraviolet A1-UVA1 phototherapy (340-400 nm), was introduced to the treatment of AD by Krutmann et al in 1992. It appears that the main mode of action of UVA1 phototherapy in AD is through activation of apoptosis of T lymphocytes. Additionally, new studies show that UVA1 can also inhibit the activity of calcineurin phosphatase, similarly to calcineurin inhibitors such as cyclosporin A or tacrolimus. The aim of this study is to, for the first time, compare the efficacy of medium dose UVA1 phototherapy and tacrolimus ointment in patients with moderate-severe AD.. This study involved 20 AD patients. Half of the patients were treated with UVA1 phototherapy, while another 10 participants were treated with the application of tacrolimus ointment. The severity of the disease progress was assessed on the basis of EASI score (Eczema Area Severity Index). Moreover, the clinical condition of patients was assessed using non-invasive techniques such as measurement of transepidermal water loss - TEWL and skin capacitance, as well as high-frequency ultrasonography (20 MHz).. This study described above confirmed the beneficial influence of both therapies on the course of moderate-severe AD. Tacrolimus induced a greater reduction in TEWL, while phototherapy caused the reduction of subepidermal low echogenic band-SLEB within sites affected with pathological lesions.. Both tacrolimus and phototherapy treatment seemed to significantly reduce EASI.

Topics: Administration, Topical; Adult; Apoptosis; Dermatitis, Atopic; Female; Humans; Male; T-Lymphocytes; Tacrolimus; Treatment Outcome; Ultrasonography; Ultraviolet Therapy

The skin barrier plays a crucial role in the pathophysiology of atopic dermatitis. The quality of the skin barrier can be assessed using a new semi-quantitative method to measure intercellular lipid lamellae. This procedure was used to evaluate the influence of the topical application of the calcineurin inhibitor tacrolimus 0.1% ointment (Protopic®) versus mometasone furoate cream (Ecural®) on the quality of the skin barrier.. 20 adult patients with active atopic dermatitis (SCORAD 10-63) were included in an open, non-interventional study. Lesions on their forearms were treated twice daily over 10 days with either tacrolimus 0.1% ointment or mometasone furoate cream. At the beginning and the end of the treatment period, SCORAD, TEWL and skin hydration were determined and the intercellular lipids were measured using transmission electron microscopy.. The SCORAD improved in both groups nearly to the same extent, whereas TEWL and skin hydration improved significantly only in the tacrolimus group. Using the semi-quantitative analysis of intercellular lipid length per 1,000 nm(2) intercellular space, a twofold increase for mometasone furoate cream and a fourfold increase for tacrolimus 0.1% ointment were determined.. In addition to its known antiinflammatory effect, tacrolimus 0.1% ointment leads also to a measurable increase of the lipids of the skin barrier in patients with atopic dermatitis, exceeding the effect of mometasone furoate cream.

Topics: Administration, Topical; Adult; Anti-Allergic Agents; Anti-Inflammatory Agents; Dermatitis, Atopic; Epidermis; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Mometasone Furoate; Ointments; Pregnadienediols; Skin Absorption; Skin Cream; Tacrolimus; Treatment Outcome

Patients with atopic dermatitis (AD) have an epidermal barrier dysfunction, which allows invasion of allergens to occur. Stratum corneum skin barrier is formed by corneocytes and extracellular lipids extruded from the epidermal lamellar bodies. In a controlled, randomized, double-blinded, right-left comparison study we investigated the effect of pimecrolimus (PIM) cream compared with triamcinolone acetonide cream (TA) on the skin barrier in 15 patients with symmetrical elbow lesions of AD. In punch biopsies, before and after treatment, skin lipid bilayer and lamellar body structure were examined by transmission electron microscopy (TEM). Partial Eczema Area and Severity Index (pEASi), stratum corneum hydration, and transepidermal water loss (TEWL) were monitored on days 1, 8 and 22. The pEASi was significantly more improved with TA compared with PIM, whereas stratum corneum hydration was slightly more improved after treatment with PIM. The TEM revealed a strong reduction in lamellar bodies in lesional skin of AD; only 32% of the lamellar bodies were normal. A significantly higher number of normal lamellar bodies was found after 3 weeks of treatment with PIM (58%; p < 0.005). An increase in lamellar bodies also occurred with TA treatment (46%; p < 0.05); however, significantly less than with PIM (p < 0.05). Clinical score and TEWL were more improved after treatment with TA, whereas the lamellar bodies were more normal after treatment with PIM.

Topics: Administration, Cutaneous; Adult; Biopsy; Dermatitis, Atopic; Dermatologic Agents; Double-Blind Method; Epidermis; Female; Germany; Glucocorticoids; Humans; Male; Microscopy, Electron, Transmission; Middle Aged; Severity of Illness Index; Skin Cream; Tacrolimus; Time Factors; Treatment Outcome; Triamcinolone Acetonide; Water Loss, Insensible; Young Adult

Pruritus ani (PA) is defined as intense chronic itching affecting perianal skin.. We aimed to determine the efficacy of topical tacrolimus treatment in atopic dermatitis (AD) patients who have PA.. The study included 32 patients with AD who were suffering PA. Patients were randomized into two groups. In total, 16 patients used 0.03% tacrolimus ointment and 16 patients used vaseline as placebo. All groups applied topical treatments to their perianal area twice daily for 4 weeks. The treatments were then reversed for 4 weeks after a 2 weeks wash out period.. In total, 32 patients with AD who had refractory anal itching were enrolled in this study. None of the patients had obtained successful results with previous treatments. There was a statistically significant decrease in the recorded EASI, DLQI and itching scores for the tacrolimus group compared to the placebo group at weeks 4 and 6 of treatment (p < 0.05).. Topical tacrolimus treatment was well tolerated and effective in controlling persistent PA in AD patients.

Topics: Administration, Topical; Adolescent; Adult; Antipruritics; Dermatitis, Atopic; Emollients; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Petrolatum; Pruritus Ani; Tacrolimus; Young Adult

Pimecrolimus cream 1% is approved for mild to moderate atopic dermatitis in children older than two years of age and adults. Tacrolimus ointment 0.03% is approved for moderate to severe atopic dermatitis in the patient population between two to seventeen years of age and Tacrolimus 0.1% ointment for moderate to severe atopic dermatitis in patients 18 years of age and older. However, beyond safety and efficacy, the delivery system or vehicle used in topical treatment formulations is equally important in affecting patient satisfaction, tolerability, and subsequent treatment compliance and hence clinical resolution of active disease.

Topics: Administration, Topical; Adolescent; Adult; Calcineurin Inhibitors; Dermatitis, Atopic; Female; Humans; Immunosuppressive Agents; Male; Ointments; Patient Compliance; Patient Preference; Patient Satisfaction; Pilot Projects; Quality of Life; Tacrolimus; Young Adult

Immunosuppressive therapy is the main postoperative treatment for keratoplasty, but there are considerable differences in protocols for the use of steroids and other immunosuppressants. Therefore, we conducted 2 prospective randomized clinical trials and 1 prospective nonrandomized clinical trial on keratoplasty postoperative treatment. One study evaluated the efficacy and safety of long-term topical corticosteroids after a penetrating keratoplasty was performed. Patients who underwent keratoplasty and maintained graft clarity for >1 year were randomly assigned to either a steroid or a no-steroid group. At the 12-month follow-up, the no-steroid group developed significantly more endothelial rejection than did the steroid group. A second study elucidated the effectiveness and safety of systemic cyclosporine in high-risk corneal transplantation. The patients were assigned to a systemic cyclosporine or control group. At a mean follow-up of 42.7 months, no difference was observed in the endothelial rejection rates and graft clarity loss between the 2 groups. A third study elucidated the effectiveness and the safety of systemic tacrolimus in high-risk corneal transplantation. Of 11 consecutive eyes decompensated despite systemic cyclosporine treatment, there was no irreversible rejection in eyes treated with tacrolimus, which was significantly better than in previous penetrating keratoplasty with systemic cyclosporine treatment. Prognosis after keratoplasty in patients with keratoconus is relatively good, but special attention is required for patients with atopic dermatitis. Postkeratoplasty atopic sclerokeratitis (PKAS) is a severe form of sclerokeratitis after keratoplasty in atopic patients. Our retrospective study showed that 35 eyes of 29 patients from a total of 247 keratoconus eyes undergoing keratoplasty were associated with atopic dermatitis, of which 6 eyes of 5 patients developed PKAS. Eyes with PKAS had a significantly higher incidence of atopic blepharitis and preoperative corneal neovascularization, and therefore, we suggest systemic corticosteroids or cyclosporine to prevent PKAS in such high-risk cases.

Topics: Adrenal Cortex Hormones; Adult; Aged; Aged, 80 and over; Clinical Trials as Topic; Cyclosporine; Dermatitis, Atopic; Female; Graft Rejection; Humans; Immunosuppressive Agents; Keratoplasty, Penetrating; Male; Middle Aged; Postoperative Care; Prospective Studies; Tacrolimus; Young Adult

Topics: Dermatitis, Atopic; Dermatologic Agents; Double-Blind Method; Humans; Immunity, Innate; Interleukin-13; RNA, Messenger; Tacrolimus

Topics: Administration, Cutaneous; Anti-Inflammatory Agents; Dermatitis, Atopic; Dermatologic Agents; Drug Administration Schedule; Humans; Kaplan-Meier Estimate; Ointments; Republic of Korea; Secondary Prevention; Tacrolimus; Treatment Outcome

Tacrolimus ointment is effective for treatment of moderate to severe atopic dermatitis (AD) in children aged ≥2 years (Br J Dermatol, 2004; 150: 554). Here, efficacy and tolerability of tacrolimus 0.03% ointment were evaluated in 50 infants aged <2 years at start of treatment.. Infants with AD previously enrolled in a tacrolimus ointment pharmacokinetics trial were eligible for a 24-month open-label phase II study. Tacrolimus 0.03% ointment was applied to affected areas until clearance. In cases of exacerbation or clinical worsening, patients restarted treatment.. Mean ± SD Eczema Area and Severity Index (EASI) score improved, from 11.2 ± 10.5 baseline to 2.6 ± 4.1 at endpoint (24 months); mean affected body surface area decreased from 25.2 ± 21.1% to 5.1 ± 9.0%, with improvement on all items of the Physicians' Assessment of Individual Signs. The Physicians' Global Evaluation of Clinical Response showed a result of "cleared"/"excellent" for 63.3% of patients; 85.7% of parents/guardians assessed symptoms as "much better." Treatment was well tolerated, with common, nonserious respiratory infections and gastroenteritis the most frequently reported adverse events. The most common application-site events were infections and pruritus. Over 98% of blood samples showed tacrolimus concentrations <1.0 ng/ml; >40% showed concentrations below the lower limit of quantification (0.0250 ng/ml).. Over a period of two years, tacrolimus 0.03% ointment was associated with substantial clinical improvement of AD in infants aged <2 years. Treatment tolerability was similar to that seen in older children.

Topics: Dermatitis, Atopic; Eczema; Female; Humans; Immunosuppressive Agents; Infant; Male; Ointments; Tacrolimus; Treatment Outcome

Efficacy and steroid sparing effects of pimecrolimus 1% cream in atopic dermatitis have been shown recently, but there is no data on efficacy in long term management of atopic hand dermatitis. This study aims to investigate the efficacy of pimecrolimus 1% cream as maintenance therapy in patients suffering from atopic hand dermatitis.. A double-blind vehicle controlled study in 40 adult patients with atopic hand dermatitis (IGA ≤ 3) comparing the efficacy of twice daily application of pimecrolimus 1% cream given as maintenance treatment versus vehicle over a 8 week period after clinical response (IGA ≤ 2) to a 1-3 week pre-treatment with mometasone fuorate 0.1% was performed. Primary endpoint was the time to relapse (IGA ≥ 3).. Thirty-six out of 40 patients were randomised to receive either pimecrolimus 1% (P) or vehicle cream (V). The number of patients with stable remission in patients randomised to pimecrolimus (53.8%) and vehicle (43.8%) did not achieve statistical significance between the groups (p = 0.41). Subgroup analysis of patients with initially moderate dermatitis (IGA = 3, n = 20) showed a trend towards a better outcome for the pimecrolimus group (stable remission P = 81.8% versus V = 55.6%) (p = 0.244).. Pimecrolimus 1% cream twice daily was not superior to vehicle in the sequential maintenance therapy of atopic hand dermatitis, but efficacy in moderate forms should be investigated in further studies.

Topics: Adolescent; Adult; Aged; Dermatitis, Atopic; Dermatologic Agents; Double-Blind Method; Female; Hand Dermatoses; Humans; Male; Middle Aged; Tacrolimus; Treatment Outcome; Young Adult

Topical corticosteroids and calcineurin inhibitors are well-known treatments of atopic dermatitis (AD) but differ in their efficacy and side effects. We recently showed that betamethasone valerate (BM) although clinically more efficient impaired skin barrier repair in contrast to pimecrolimus in AD.. This study elucidates the mode of action of topical BM and pimecrolimus cream in AD.. Lesional AD skin samples after topical treatment with either BM or pimecrolimus were subjected to gene expression profile analysis.. Betamethasone valerate resulted in a significant reduction in mRNA levels of genes encoding markers of immune cells and inflammation, dendritic cells, T cells, cytokines, chemokines, and serine proteases, whereas pimecrolimus exerted minor effects only. This corroborates the clinical finding that BM reduces inflammation more effectively than pimecrolimus. Genes encoding molecules important for skin barrier function were differently affected. Both BM and pimecrolimus normalized the expression of filaggrin and loricrin. BM, but not pimecrolimus, significantly reduced the expression of rate-limiting enzymes for lipid synthesis and the expression of involucrin and small proline-rich proteins, which covalently bind ceramides. This may explain the lack of restoration of functional stratum corneum layers observed after BM treatment.. The gene expression profiles are consistent with our previous findings that corticosteroids may exert a more potent anti-inflammatory effect but may impair the restoration of the skin barrier. Corticosteroids are still the main treatment for severe and acutely exacerbated AD; pimecrolimus may be preferable for long-term treatment and stabilization.

Topics: Adult; Betamethasone; Calcineurin; Calcineurin Inhibitors; Cell Membrane Permeability; Dermatitis, Atopic; Double-Blind Method; Female; Filaggrin Proteins; Gene Expression Profiling; Glucocorticoids; Humans; Male; Oligonucleotide Array Sequence Analysis; Proteins; Skin; Tacrolimus; Treatment Outcome; Young Adult

Systemic treatment options for generalized atopic dermatitis (AD) are limited. To our knowledge, there have been no prospective trials examining the use of oral tacrolimus, a calcineurin inhibitor, in AD.. We assessed the safety and efficacy of sequential therapy with oral tacrolimus and topical tacrolimus in the treatment of generalized AD using the Eczema Area and Severity Index and the Physician Global Assessment scores as the primary end points.. Twelve patients with AD covering at least 50% body surface area were enrolled. Patients in both phases of the study received sequential therapy with oral and topical tacrolimus over a 14-week treatment period. Eczema Area and Severity Index, Physician Global Assessment, and pruritus scores were calculated at each study visit.. Patients recorded a 67% improvement in the Eczema Area and Severity Index score, a 45% improvement in the Physician Global Assessment score, and a 69% reduction in the pruritus score.. This investigator-initiated, open-label, single-center, proof-of-concept study lacks a large sample size and placebo control group.. Sequential therapy with oral tacrolimus and topical tacrolimus may be an effective treatment for AD. A large, randomized control study is warranted.

Topics: Administration, Oral; Administration, Topical; Adult; Calcineurin Inhibitors; Dermatitis, Atopic; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Pilot Projects; Severity of Illness Index; Tacrolimus; Treatment Outcome; Young Adult

Alterations of Toll-like receptors (TLRs) seem to play a role in susceptibility to atopic dermatitis (AD).. To investigate the expression of TLRs in moderate to severe chronic AD in adults before and after a 3-week treatment with 0.1% tacrolimus ointment, compared with 0.1% topical hydrocortisone-17-butyrate.. In total, 21 adult patients with AD were enrolled: 11 were given tacrolimus ointment and 10 were given hydrocortisone butyrate; a further 6 healthy adults formed the control group. The clinical efficacy of the treatment was assessed using the SCORing Atopic Dermatis (SCORAD) index. Biopsies were taken from lesional skin before and after treatment, which were stained immunohistochemically with monoclonal antibodies to TLR-1, -2, -4 and -9.. Both 3-week topical treatments improved signs and symptoms in all 21 patients considered, with no significant difference between the two groups. In the skin of patients with AD, TLR-1 was overexpressed and TLR-2 underexpressed compared with healthy controls, whereas no differences were found for TLR-4 and TLR-9. Staining for TLR-1 was decreased in both groups after treatment. AD specimens had higher levels of TLR-2 expression after either treatment compared with baseline, and levels were higher after tacrolimus treatment than after hydrocortisone butyrate. Neither tacrolimus nor hydrocortisone butyrate affected expression of TLR-4 or TLR-9.. Short-term therapy with tacrolimus ointment reduced expression of TLR-1, which may inhibit the antimicrobial potential of TLR-2, and also reversed the impairment of TLR-2 in AD lesions. Expression of TLR-4 and TLR-9 was not affected by tacrolimus.

Topics: Adult; Aged; Dermatitis, Atopic; Dermatologic Agents; Female; Humans; Hydrocortisone; Immunosuppressive Agents; Male; Middle Aged; Ointments; Skin; Tacrolimus; Toll-Like Receptor 1; Toll-Like Receptor 2; Toll-Like Receptors; Young Adult

Topical pimecrolimus may maintain remissions of atopic dermatitis (AD) by inhibiting subclinical inflammation.. To evaluate clinical and cytological effects of pimecrolimus in topical corticosteroid-treated and resolved AD lesions.. Patients (n=67) with resolved AD lesions were randomized to 3-week double-blind treatment with either pimecrolimus cream 1% or vehicle cream. Outcome measures were reduction in Eczema Area and Severity Index (EASI) and number of leukocytes in skin biopsies in all randomized patients who were evaluable at the end of study.. The proportion of patients with a localized EASI<2 at the end of study was higher with pimecrolimus cream 1% than with vehicle cream (73.5 vs. 39.4%, respectively). There was a significant decrease in the number of infiltrating CD45+ cells in pimecrolimus cream 1% compared with placebo cream (-88.2 vs. 43.2 cells/mm(2), respectively, p=0.047) and a slight but nonsignificant reduction in the number of dermal dendritic cells, Langerhans cells, T cells and macrophages with pimecrolimus versus vehicle cream.. This was an exploratory study.. Topical pimecrolimus was effective at maintaining betamethasone-17α-valerate-induced AD remission by inhibiting recurrences of the inflammatory infiltrate in the skin.

Topics: Adult; Aged; Betamethasone Valerate; Dermatitis, Atopic; Dermatologic Agents; Double-Blind Method; Eczema; Glucocorticoids; Humans; Leukocyte Count; Male; Middle Aged; Remission Induction; Secondary Prevention; Severity of Illness Index; Statistics, Nonparametric; Tacrolimus; Young Adult

The purpose of this study was to investigate the clinical effect of a supplementary diet containing heat-killed lactic acid bacterium Lactobacillus paracasei K71 (LAB diet) on adult patients with atopic dermatitis (AD). A randomized, double-blind, placebo-controlled study was conducted in 34 adult type AD subjects who were treated with conventional topical corticosteroid and tacrolimus. LAB diet or placebo was added over 12 weeks. The primary end-point was the clinical severity of AD which was evaluated by a severity scoring system proposed by the guideline of the Japanese Dermatological Association. The effect was also secondarily evaluated by itch scores of visual analog scales (VAS), quality-of-life (QOL) impairment scores of Skindex 16 and consumption amounts of topical therapeutics. Data on these four assessment variables were collected at baseline and at week 4, 8 and 12. Within the study population, the skin severity scores were significantly decreased from baseline at week 8 (P<0.05) and at week 12 (P<0.01) in the LAB diet group but not in the placebo group. Influence of LAB diet on itch scores or QOL impairment scores was not evident. The consumption of topical therapeutics in the placebo group was 1.9-times greater in total amount compared with the corresponding value in the LAB diet group during the intervention period, although there was no significant difference. No LAB diet- or placebo-related adverse events were observed. We concluded that the LAB diet may have some benefits as a complementary therapy for adult AD patients who are managed with the conventional treatment.

Topics: Adrenal Cortex Hormones; Adult; Aged; Complementary Therapies; Dermatitis, Atopic; Double-Blind Method; Female; Hot Temperature; Humans; Lactobacillus; Male; Middle Aged; Practice Guidelines as Topic; Probiotics; Pruritus; Quality of Life; Severity of Illness Index; Tacrolimus; Treatment Outcome

Topical corticosteroids have been the mainstay of treatment for atopic dermatitis (AD) over the last decade, especially in the setting of acute flares. However, heavy and prolonged use of topical corticosteroid is undesirable as it is associated with side effects such as, skin atrophy, telangiectasia, striae, steroid-induced dermatoses, rosacea, acne exacerbation, and in some severe and rare cases, systemic effects such as hypothalamic-pituitary-adrenal axis suppression, growth retardation and ocular problems. Non-steroidal ant-inflammatory agents specific for the treatment of AD (topical calcineurin inhibitors, or TCIs) are now available and they are a viable alternative to topical corticosteroids in treating dermatitis of the face, neck, eyelids, and intertriginous areas where there is a greater risk of the steroid-induced side effects. More recently, medical device emollients have entered the marketplace. These medical devices provide, but are not limited to, anti-oxidant, anti-protease, anti-inflammatory activity, and aid in restoring the natural balance of lipids, which is one of the causes of the epidermal abnormalities seen with AD. The present study evaluated the short-term effectiveness and appeal of a non-steroidal medicated device foam as compared to pimecrolimus cream 1% in the treatment of AD within a wide age group of subjects with active disease at baseline. In this study, both pimecrolimus and the medical device foam exhibited efficacy in mild-to-moderate AD. Primary efficacy was measured by IGA. After four weeks of treatment with the medical device foam, 82% of target lesions were scored "clear" (0) or "almost clear" (1) compared to 71% of target lesions under the pimecrolimus arm. This study confirmed that pimecrolimus cream 1% and the medical device foam work well in the treatment of AD in both adults and children with no associated adverse effects.

Topics: Administration, Cutaneous; Adolescent; Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; Ceramides; Child; Child, Preschool; Dermatitis, Atopic; Dermatologic Agents; Drug Combinations; Female; Follow-Up Studies; Humans; Hyaluronic Acid; Male; Middle Aged; Single-Blind Method; Tacrolimus; Treatment Outcome; Young Adult

Corticosteroids are the mainstay of therapy for atopic dermatitis, but long-term use is associated with adverse effects. We sought to evaluate the clinical efficacy of two steroid-sparing creams for atopic dermatitis. Twenty patients were enrolled in an investigator-blinded, bilateral comparison study. Patients applied pimecrolimus cream twice daily to a target lesion on one side of the body and also applied a topical medical device cream three times daily on a symmetrical target lesion on the opposite side of the body for four weeks. Clinical assessments including Physician Global Assessment (PGA), Target Lesion Symptom Score (TLSS), subject self-assessment and digital photography were performed at the baseline, 2 week, and 4 week visits. Seventy-five percent of patients (pimecrolimus, 15 of 20; topical medical device, 15 of 20) were rated "clear" (0) or "almost clear" (1) by PGA for both medications after four weeks. Percent improvement of the PGA from randomization for pimecrolimus cream and the topical medical device cream were 72.50 and 71.67 respectively (P=0.9283). PGA scores decreased significantly from baseline for both treatments (P=0.004). Overall, there was no statistically significant difference between treatment groups for PGA scores throughout the study (P=0.8236). No cutaneous side effects were noted. Our study was limited by a small sample size and lack of double-blinding; however, both treatments were found to be safe and effective in treating atopic dermatitis over four weeks. Significant improvements were noted for all efficacy variables. In conclusion, a lipid-rich, non-steroidal, topical medical device cream was as effective in improving atopic dermatitis as pimecrolimus cream.

Topics: Administration, Cutaneous; Administration, Topical; Adolescent; Adult; Anti-Inflammatory Agents, Non-Steroidal; Cetomacrogol; Dermatitis, Atopic; Dermatologic Agents; Drug Combinations; Fatty Alcohols; Female; Humans; Male; Middle Aged; Mineral Oil; Petrolatum; Single-Blind Method; Tacrolimus; Treatment Outcome; Young Adult

Topical corticosteroids are widely used to treat atopic dermatitis (AD), but their anti-inflammatory mode of action can be accompanied by several unwanted side effects including skin atrophy and telangiectasia. In this 8-week, investigator-blinded, intraindividual right-left comparison study with patients with mild-to-moderate AD, hydrocortisone 1% cream (HCT) was applied twice daily for 4 weeks on one side of forehead skin without clinical signs of AD and pimecrolimus 1% cream (PIM) on the other. Epidermal and dermal thickness were assessed by optical coherence tomography (OCT) and high-frequency ultrasound, respectively. Skin atrophy and telangiectasia were assessed by contact dermatoscopic photography (Dermaphot(®)). Treatment with HCT leads to a significant decrease in epidermal thickness after only 2 weeks of treatment, while the decrease in PIM-treated sites was less pronounced and was not statistically significant. By 4 weeks after the end of treatment, epidermal thickness returned to baseline values. No dermal thinning or development of telangiectasia could be observed by means of ultrasound or Dermaphot(®), respectively. In summary, this study indicates that a 2-week single course of topical treatment with a mildly potent steroid can cause transient epidermal thinning, an effect not seen in the PIM group. The slight decrease with PIM - although not significant - could be due to normalization of the increased skin thickness caused by a subclinical inflammation in AD. This study suggests that PIM may be safer for treatment of AD in sensitive skin areas like the face, especially when repeated application is required.

Topics: Adult; Atrophy; Calcineurin Inhibitors; Dermatitis, Atopic; Dermatologic Agents; Female; Humans; Hydrocortisone; Male; Middle Aged; Single-Blind Method; Skin; Tacrolimus; Tomography, Optical Coherence; Ultrasonography; Young Adult

To assess the efficacy and safety of tacrolimus ointment in a large population of patients with atopic dermatitis (AD) by pooling data from individual Asian studies, and to compare the results of this study with those in the United States, Europe, and Japan.. We analyzed the pooled data from individual studies conducted in the eight Asian areas. The efficacy assessments included success rate based on Physician's Global Evaluation of Clinical Response, Eczema Area Severity Index (EASI), Percent Body Surface Area (%BSA) affected, Patient's Assessment of Itch (Itch), Dermatology Life Quality Index (DLQI) and children's DLQI (CDLQI). The results that were published in the United States, Europe, and Japan were cited.. A total of 860 patients were included in this study. The success rates were more than 80% in both adult and pediatric patients. Similar success rates were shown in the United States, European, and Japanese studies. There were no differences in the improvements in %BSA affected, EASI, and Itch between this study and the United States study. In both Asia and the United States, tacrolimus therapy improved total quality of life and all subscales in DLQI and CDLQI. Skin burning and pruritus were common adverse events among the Asian, United States and European studies.. Tacrolimus ointment is an effective and well-tolerated treatment option in patients with AD in Asia. In this study, the efficacy and safety of tacrolimus are similar to those in the United States, European, and Japan studies.

Topics: Administration, Topical; Adult; Asia, Eastern; Asia, Southeastern; Calcineurin Inhibitors; Child; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Ointments; Tacrolimus; Treatment Outcome

Tacrolimus 0.03% ointment is licensed for second-line treatment of children with atopic dermatitis (AD). Although data are available from clinical trials, no study has enrolled only second-line patients. This double-blind, non-inferiority study compared tacrolimus 0.03% and fluticasone 0.005% ointments in children with moderate-to-severe AD, who had responded insufficiently to conventional therapies. Children (aged 2-15 yr) were randomized to tacrolimus ointment (n = 240) or fluticasone ointment (n = 239), twice daily until clearance or for a maximum of 3 wk and, if lesions remained, once daily for up to 3 wk further. Primary end-point was week 3 response rate (improvement of >or=60% in modified Eczema Area and Severity Index and not withdrawn for lack of efficacy). Secondary end-points included pruritus and sleep quality, global assessment of clinical response, incidence of new flares and safety. Response rates were 86.3% with tacrolimus ointment and 91.5% with fluticasone. Lower limit of the 95% confidence interval was -11.8%, exceeding the non-inferiority limit of -15% and meeting the primary end-point. Moderate or better improvement on the physicians' global assessment occurred in 93.6% and 92.4% of patients in the tacrolimus ointment and fluticasone arms, respectively, while median pruritus scores improved by 84.0% and 91.5%. Sleep quality improved by approximately 92% in both treatment arms. After day 21, new flare-up occurred in 5.5% and 11.3% of patients receiving tacrolimus ointment and fluticasone, respectively; mean times to new flares were 6.5 +/- 5.0 and 8.6 +/- 5.2 days. Adverse events were similar between the two arms, with the exception of application-site skin burning sensation in the tacrolimus ointment group. In conclusion, efficacy of tacrolimus 0.03% ointment as second-line treatment was not inferior to that of fluticasone 0.005% ointment, with similar benefits on global disease improvement and quality of sleep.

Topics: Adolescent; Androstadienes; Calcineurin Inhibitors; Child; Child, Preschool; Dermatitis, Atopic; Dermatologic Agents; Female; Fluticasone; Humans; Male; Ointments; Pruritus; Recurrence; Sleep Wake Disorders; Tacrolimus; Treatment Outcome

Twice-weekly tacrolimus ointment for mild to severe atopic dermatitis (AD) significantly reduced the number of flares and prolonged flare-free intervals compared with standard treatment in the CONTROL studies.. Post hoc analysis of data from the CONTROL studies was carried out on patients with moderate to severe disease. Patients applied tacrolimus 0.1% (adults; n = 183) or 0.03% (children; n = 166) ointment twice-daily for

Topics: Adult; Child; Child, Preschool; Dermatitis, Atopic; Double-Blind Method; Drug Administration Schedule; Humans; Immunosuppressive Agents; Severity of Illness Index; Tacrolimus; Treatment Outcome; Young Adult

Adult and pediatric patients (n = 347) with atopic dermatitis enrolled in three multicenter, randomized, 6-week studies who had previously used steroids were analyzed to examine the null hypothesis that improvement in atopic dermatitis initiated after prior treatment with steroids eliminates any subsequent treatment differences between tacrolimus ointment and pimecrolimus cream. Of these patients, 171 were randomized to tacrolimus ointment and 176 to pimecrolimus cream. Based on improvement in the Eczema Area and Severity Index at the end of study, tacrolimus ointment was significantly more effective than pimecrolimus cream (p = 0.0002). Tacrolimus ointment was also significantly more effective than pimecrolimus cream at the end of study in all secondary end-points. Overall, the frequency of adverse events was comparable between treatment groups (24.0% for tacrolimus ointment vs. 25.6% for pimecrolimus cream). Tacrolimus ointment is more effective, with a similar safety profile, compared with pimecrolimus cream in patients with atopic dermatitis previously treated with topical corticosteroids.

Topics: Administration, Topical; Adolescent; Adrenal Cortex Hormones; Adult; Child; Child, Preschool; Dermatitis, Atopic; Dermatologic Agents; Humans; Immunosuppressive Agents; Linear Models; Ointments; Prospective Studies; Severity of Illness Index; Tacrolimus; Time Factors; Treatment Outcome; United States; Young Adult

Rational healthcare decision-making based on clinical and economic evidence is essential to provide the best possible care for patients with atopic dermatitis (AD).. To evaluate treatment outcomes, resource use and cost associated with twice-weekly tacrolimus 0.03% ointment treatment vs. standard flare-only therapy in children with moderate-to-severe AD.. In a pan-European, Phase III multicentre randomized clinical trial, children with mild-to-severe AD were randomized to 0.03% tacrolimus ointment or vehicle twice weekly for 12 months. Disease flares were treated using open-label tacrolimus 0.03% ointment twice daily. Clinical efficacy data were evaluated in a subgroup of 153 children with moderate-to-severe AD, with resource use data--collected prospectively using caregiver questionnaires--available from 146 children. Pooled costs of resource use were determined using German unit cost data. Direct and indirect costs were considered from third-party payer, patient and caregiver, and societal perspectives.. Twice-weekly tacrolimus ointment reduced the number of flares compared with standard therapy (P < 0.001) and prolonged time to first flare (146 vs. 17 days, P < 0.001). Mean +/- SD annual costs per patient for standard and twice-weekly therapy respectively were 2002 euro +/- 2315 vs. 1571 euro+/- 1122 for severe AD and 1136 euro +/- 1494 vs. 1233 euro +/- 1507 for moderate AD.. In children with AD, twice-weekly treatment with tacrolimus 0.03% ointment reduces the number of flares and prolongs time spent free from flares with no additional cost in children with moderate AD, and may be cost-saving in those with severe AD.

Topics: Administration, Topical; Adolescent; Child; Child, Preschool; Dermatitis, Atopic; Drug Administration Schedule; Drug Costs; Humans; Immunosuppressive Agents; Ointments; Tacrolimus; Treatment Outcome

A one-year, randomized, double-blind study was conducted in 80 patients with atopic dermatitis treated with tacrolimus ointment or a corticosteroid regimen (hydrocortisone acetate 1% ointment for head and neck, hydrocortisone butyrate 0.1% ointment for trunk and limbs) to compare efficacy and safety, and effects on Th2-reactivity. The study was completed by 36/40 patients in the tacrolimus group, and 31/40 patients in the corticosteroid group. In both groups affected body surface area, eczema area and severity index, and transepidermal water loss decreased at months 6 and 12. Tacrolimus was superior for all efficacy scores at month 6, and in the head and neck area at month 12. Recall antigen reactivity increased at month 12 in both groups. Adverse events were reported by 40/40 patients in the tacrolimus, and by 34/40 patients in the corticosteroid group. Long-term treatment with topical tacrolimus or a corticosteroid regimen improves atopic dermatitis and recall antigen reactivity, suggesting an improvement in the Th1/Th2-balance.

Topics: Administration, Topical; Adrenal Cortex Hormones; Adult; Anti-Inflammatory Agents; Butyrates; Dermatitis, Atopic; Double-Blind Method; Female; Finland; Humans; Hydrocortisone; Immunoglobulin E; Immunosuppressive Agents; Male; Ointments; Tacrolimus; Time Factors; Treatment Outcome; Water Loss, Insensible; Young Adult

Vitiligo is a common acquired idiopathic hypomelanotic disorder characterized by circumscribed depigmented maculae. The conventional treatments are limited by their inconsistent and incomplete responses, relapse rate, inconvenience to apply, side-effects and especially long-term effects. The aim of the present study was to determine the efficacy and safety of topical tacrolimus as monotherapy for the treatment of face/neck vitiligo in Taiwan. This was a multicenter, open-label, non-comparative study. Patients were at least 16 years old and had vitiligo lesions with Vitiligo Index of Disease Activity score +1 or more on face or neck. Patients received a monotherapy with 0.1% of tacrolimus ointment twice daily for 12 weeks. The efficacy was measured by the percentage of repigmentation of target lesion, which was graded as minimal (1-25%), mild (26-50%), moderate (51-75%) or excellent (76-100%). Patients who had at least mild repigmentation were defined as responders. A total of 61 patients were enrolled in this investigation. Most of the patients showed repigmentation at week 4. At the end of treatment, all patients showed repigmentation and 45.9% of patients were responders. During the study, 15 adverse events related to the ointment were reported. All the reported adverse events were mild and similar to the well-known adverse effect of tacrolimus in the treatment of atopic dermatitis. Tacrolimus ointment is effective and well tolerated for the treatment of patients with vitiligo in Taiwan. It will be another drug of choice for persons with vitiligo who are unable to receive regular phototherapy and fear the side-effects of topical steroid in long-term use.

Topics: Administration, Cutaneous; Adolescent; Adult; Aged; Child; Dermatitis, Atopic; Face; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Neck; Prospective Studies; Skin Pigmentation; Tacrolimus; Taiwan; Vitiligo; Young Adult

Pimecrolimus and topical corticosteroids (TCS) combination therapy may provide an alternative treatment for patients with severe atopic dermatitis (AD), with faster clearance of disease flares, consequently reducing the duration of TCS treatment.. To assess the safety profile of pimecrolimus cream 1% combined with fluticasone versus fluticasone alone in paediatric patients with severe AD.. Patients (n = 376) were randomized to a combination of pimecrolimus cream 1% with fluticasone or vehicle plus fluticasone for 4 weeks. The primary outcome measure was the frequency of clinically relevant pre-defined adverse events (AEs) associated with the topical use of corticosteroids in patients with severe AD.. Erythematous rash was the only AE, occurring more frequently in the combination group, while there were no noticeable differences in the frequency of other AEs of clinical interest between treatment groups. Efficacy variables were comparable between the two groups. A trend for greater time to relapse was observed for the combination of pimecrolimus cream 1% with fluticasone in patients who were clear at the end of treatment, with a marked improvement in facial AD.. In paediatric patients with severe AD the overall safety profile of pimecrolimus cream 1% combined with fluticasone was similar to that of fluticasone alone.

Topics: Administration, Topical; Adrenal Cortex Hormones; Androstadienes; Dermatitis, Atopic; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Fluticasone; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Ointments; Risk Assessment; Severity of Illness Index; Tacrolimus; Treatment Outcome

Increased transepidermal water loss (TEWL) and downregulated antimicrobial peptides (AMPs) are observed in patients with atopic dermatitis (AD). Tacrolimus and ceramide-dominant emollients are effective in the treatment of AD by preventing the production of inflammatory cytokines and by correcting skin barrier dysfunctions, respectively. Present study was designed to investigate the relationship between antimicrobial and barrier factors by measuring the changes of AMPs and TEWL after topical application of tacrolimus and ceramide-dominant emollient in the patients with AD. A total of three patients with AD were treated with tacrolimus in one lesion and ceramide-dominant emollient in another lesion for 4 weeks. RT-PCR and western blotting revealed that the mRNA and protein expression levels of hBD-2 and LL-37 were increased on the both study sites. Immunohistochemical analysis showed significant increase of AMPs and IL-1alpha, while, IL-4 was decreased on the both study sites. The mean changes of TEWL and AMPs showed no statistical difference between both sites. Tacrolimus and ceramide-dominant emollient influence on both TEWL and AMPs expression in patients with AD, namely they have similar effects on both of the two. This study shows that restoration of permeability barrier function is accompanied by the concomitant improvement of antimicrobial defense in patients with AD.

Topics: Administration, Topical; Adolescent; Antimicrobial Cationic Peptides; Ceramides; Dermatitis, Atopic; Emollients; Female; Humans; Immunosuppressive Agents; Male; Skin Absorption; Tacrolimus; Treatment Outcome; Water Loss, Insensible; Young Adult

The purpose of this study was to measure change in quality of life (QoL) and estimate health-related utility in adults with moderate and severe atopic dermatitis (AD) following the use of either tacrolimus ointment or topical corticosteroids.. Data were analysed from a double-blind, randomized controlled trial comparing the treatment of adults with moderate and severe AD with either tacrolimus ointment or a standard corticosteroid regimen. Following randomisation, patients applied their medication twice-daily for 6 months. Monthly assessments determined response and QoL. Health-related utility (EQ5Dindex) was estimated by Monte Carlo simulation from SF-12 responses via a published mapping algorithm.. At baseline, estimated utility data were available for 926 (95%) of the intention-to-treat patients, 57% of whom had AD of moderate severity (43% severe). The mean age at baseline was 32.5 years (SD +/- 11.8), 46.2% were male, with a mean EQ5Dindex for moderate cases of 0.770 (SD +/- 0.157), and 0.665 (SD +/- 0.225) for those with severe disease (P < 0.001). Patients treated with tacrolimus ointment showed significantly greater improvement in all but one domain of the SF-36. At baseline, there was no difference in estimated utility between the two groups; however, a difference in utility in favour of tacrolimus ointment emerged after 1 month's treatment (0.849 vs. 0.820; P = 0.004). Over the 6-month study period, the mean, marginal utility difference between the study arms was 0.032 U (utility) in favour of tacrolimus (P < 0.001).. Treatment with 0.1% tacrolimus ointment rather than a standard topical corticosteroid ointment regimen was associated with clinically significant, incremental improvement in QoL, sustained over a 6-month period. A within-trial cost-utility estimate based on study medication cost alone suggests that tacrolimus ointment is highly cost-effective given existing willingness-to-pay thresholds.

Topics: Administration, Topical; Adrenal Cortex Hormones; Adult; Cost-Benefit Analysis; Dermatitis, Atopic; Double-Blind Method; Drug Utilization Review; Female; Humans; Immunosuppressive Agents; Male; Ointments; Quality of Life; Quality-Adjusted Life Years; Severity of Illness Index; Tacrolimus; Treatment Outcome; United Kingdom

To evaluate the systemic exposure of pimecrolimus cream 1% applied under occlusion in atopic dermatitis (AD) patients.. A noncomparative, open-label study conducted in 3 groups of moderate to severe AD patients: A (adults, n = 9), B (adolescents, n = 4) and C (children, n = 6). Pimecrolimus cream 1% was applied twice daily for 8.5 days with overnight occlusion in patients with investigator's global assessment scores of ≥3 and AD involving at least 30% of their body surface area. Pimecrolimus blood concentrations were analyzed.. The highest pimecrolimus blood concentrations observed in adults, adolescents and children were 1.84, 0.55 and 1.29 ng/ml, respectively. Pimecrolimus blood concentrations and affected body surface area showed no apparent correlation.. No measurable differences were found in pimecrolimus blood concentrations, efficacy and safety profile when pimecrolimus cream 1% was applied under occlusion versus application without occlusion. These findings reflect the high lipophilic properties of pimecrolimus.

Topics: Adolescent; Adult; Child; Child, Preschool; Dermatitis, Atopic; Female; Humans; Immunosuppressive Agents; Male; Severity of Illness Index; Skin Absorption; Tacrolimus; Treatment Outcome; Young Adult

Topics: Administration, Topical; Adolescent; Child; Child, Preschool; Dermatitis, Atopic; Female; Follow-Up Studies; Humans; Male; Office Visits; Ointments; Patient Compliance; Pilot Projects; Tacrolimus; Treatment Outcome

In this double-blind, within-patient vehicle-controlled study, patients with mild-to-moderate atopic dermatitis (AD) were treated for 3 weeks twice daily with pimecrolimus cream 1% on one forearm and with vehicle cream on the other forearm. Efficacy of treatment was assessed clinically using the Atopic Dermatitis Severity Index (ADSI), the Investigators Global Assessment (IGA) and the pruritus visual analogue scale. In parallel, blood microcirculation in the skin was measured as an objective parameter for skin inflammation. Skin hydration and transepidermal water loss (TEWL) were monitored as parameter relevant for the barrier function. Treatment with pimecrolimus cream 1% resulted in a quick and marked improvement of signs and symptoms of AD and a significant reduction of microcirculation from 33.90 to 15.55 AU (P < 0.0001). Skin hydration increased continually from 42.86 to 52.69 AU (P = 0.002) and TEWL decreased from 35.30 to 21.50 g/m(2)/h (P = 0.001), indicating restoration of skin barrier. At vehicle-treated sites changes of skin physiological parameters were less pronounced and observed only initially with later plateau or even reversal. At the end of the study, there were significant differences for all measured skin physiological parameters between pimecrolimus cream 1% and vehicle: microcirculation 12.15 AU (P = 0.004), skin hydration 7.12 AU (P = 0.002), TEWL 11.38 g/m(2)/h (P = 0.004). Non-invasive evaluation of microcirculation and barrier functionality thus represent a valuable tool for the objective assessment of treatment response to pimecrolimus cream 1%.

Topics: Administration, Topical; Adolescent; Adult; Dermatitis, Atopic; Dermatologic Agents; Dermatology; Double-Blind Method; Female; Humans; Male; Middle Aged; Placebos; Skin; Tacrolimus; Treatment Outcome

The efficacy of combination therapy with topical corticosteroids and tacrolimus in the treatment of atopic dermatitis remains to be established.. Our aim was to determine whether a regimen of sequential application of topical corticosteroids and topical tacrolimus is effective in the treatment of pediatric atopic dermatitis. A second goal was to assess the impact of this treatment regimen on quality of life (QOL) and the response shift on QOL changes.. The study regimen consisted of 3 phases. In the induction phase, patients were treated for a 2-week period with application of 0.03% tacrolimus ointment in the morning and application of a strong- or weak-potency corticosteroid ointment in the evening. In the transitional phase, they were treated for an additional 2 weeks with 0.03% tacrolimus ointment twice daily on weekdays and concurrent application of tacrolimus and a topical corticosteroid ointment on weekend days. In the maintenance phase, the corticosteroid ointment was discontinued and 0.03% tacrolimus ointment was applied twice daily for an additional 2 weeks. Daily application of tacrolimus ointment was then discontinued and replaced by an emollient with application of 0.03% tacrolimus ointment only when necessary for an additional 6 weeks. The Eczema Area and Severity Index score, Investigators' Global Assessment, severity of pruritus and sleep disturbance scores, and QOL evaluation were measured. After 12 weeks, the patients completed a retrospective version of the pretreatment QOL evaluation for analysis of response shift bias.. Eczema Area and Severity Index scores decreased by the sixth week, and continued improvement was observed during an additional 6-week period. Both the pruritus and sleep disturbance scores decreased throughout the study. Of patients, 90% showed marked clinical improvement at week 6 and 96% at week 12. On the Children's Dermatology Life Quality Index and the Infant's Dermatology QOL Index survey, mean QOL scores improved after completion of therapy at week 12. The mean difference between the pretest and the retrospective pretest scores indicated the presence of a response shift bias.. This was an uncontrolled, open-label study. Conclusions are limited by the small sample size.. A fixed sequential regimen of application of tacrolimus ointment with tapering of topical corticosteroids may limit the long-term use and adverse effects of topical corticosteroids, while maintaining clinical control of pediatric atopic dermatitis and improving the QOL. The finding of a response shift bias suggests that parents/guardians underestimate the seriousness of skin disease and its impact on QOL.

Topics: Administration, Topical; Adolescent; Adrenal Cortex Hormones; Child; Child, Preschool; Dermatitis, Atopic; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Infant; Male; Pilot Projects; Quality of Life; Tacrolimus; Treatment Outcome

Atopic dermatitis (AD) is most prevalent in areas of reduced skin barrier reserve, like face and neck, especially in children. Treatment with topical corticosteroids (TCS) is limited due to heightened risk of treatment-associated side-effects, thus necessitating alternative AD therapies.. The primary study objective was to determine the efficacy of pimecrolimus cream 1% in children with mild-moderate facial AD dependent on/intolerant of TCS. Secondary objectives included effects on overall Eczema Area and Severity Index (EASI), head/neck EASI, pruritus severity and time to clearance of facial AD.. A multicentre, double-blind (DB) study of < or = 6 weeks, followed by a 6-week, open-label (OL) phase was conducted. Two hundred patients (aged 2-11 years) were randomized 1:1 to pimecrolimus cream 1% (n = 99) or vehicle (n = 101) twice daily until clearance of facial AD or for a maximum of 6 weeks (DB phase). Sixteen patients receiving vehicle were allowed to switch to the OL phase at day 22.. Significantly more pimecrolimus-treated vs. vehicle-treated patients were cleared/almost cleared of facial AD (Investigators' Global Assessment 0/1): 74.5% vs. 51.0%, P < 0.001 (day 43) [57.1% vs. 36.0%, P = 0.004 (day 22)]. Median time to clearance was 22.0 vs. 43.0 days (pimecrolimus vs. vehicle, respectively). Statistically significant differences for pimecrolimus vs. vehicle were also seen on head/neck EASI, overall EASI, and head/neck pruritus scores. Adverse events were mainly mild-moderate, occurring with similar frequency in both treatment groups.. In children with facial dermatitis intolerant of/dependent on TCS, pimecrolimus cream 1% effectively controls eczema and pruritus and is well tolerated.

Topics: Adrenal Cortex Hormones; Child; Child, Preschool; Dermatitis, Atopic; Dermatologic Agents; Double-Blind Method; Eczema; Facial Dermatoses; Female; Humans; Male; Pharmaceutical Vehicles; Pruritus; Severity of Illness Index; Tacrolimus; Treatment Outcome

Systemic exposure to tacrolimus following topical application of tacrolimus ointment is minimal. There are, however, no data on the distribution of tacrolimus in the skin.. To assess the distribution of tacrolimus in the skin and the systemic pharmacokinetics of tacrolimus in adults with moderate to severe atopic dermatitis after first and repeated application of tacrolimus ointment.. We investigated skin distribution of topically applied tacrolimus and systemic pharmacokinetics of percutaneously absorbed tacrolimus in adults with atopic dermatitis after topical application of tacrolimus 0.1% ointment twice daily for 2 weeks. Tacrolimus concentrations were assessed in full-thickness skin biopsies and blood samples.. Of 14 patients, 11 completed treatment and were analysed. Mean +/- SD tacrolimus concentrations in the skin at 24 h after first and last ointment applications were 94 +/- 20 and 595 +/- 98 ng cm(-3), respectively. At 168 h after stopping treatment, values were 97% lower than at 24 h after last application. Tacrolimus concentration decreased with increasing skin depth. Systemic tacrolimus exposure after ointment application was low and highly variable, with 31% of samples below the limit of quantification (0.025 ng mL(-1)) and 94% below 1 ng mL(-1). Blood concentrations at 24 h after the first and last ointment applications were 750 and 1800 times lower, respectively, than those in skin. Physicians' assessments showed that tacrolimus ointment was effective and well tolerated.. Tacrolimus was primarily partitioned in the skin, with minimal systemic absorption after topical application, in patients with atopic dermatitis.

Topics: Adult; Aged; Biopsy; Dermatitis, Atopic; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Ointments; Skin; Skin Absorption; Tacrolimus; Treatment Outcome; Young Adult

In adults and children aged > 2 years, systemic absorption of tacrolimus from tacrolimus ointment is very low. In this study, the pharmacokinetics of tacrolimus 0.03% ointment were investigated in infants aged 3-24 months.. The pharmacokinetics of tacrolimus after first and repeated topical application of tacrolimus 0.03% ointment were evaluated in 53 infants (age, 3-24 month) with atopic dermatitis requiring treatment with mid-potency topical corticosteroids. Patients were grouped according to percentage of body surface area affected (Group 1: 5-20%; Group 2: > 20-40%; Group 3: > 40%). After stratification, patients were randomized (double-blind) to receive once-daily or twice-daily tacrolimus 0.03% ointment.. Blood samples taken on days 1 and 14 (first and last application) showed minimal systemic tacrolimus exposure. Overall, 97% of blood samples assayed contained tacrolimus concentrations < 1 ng/ml, and 20% were below the lower limit of quantification (0.025 ng/ml). Systemic tacrolimus exposure was variable, but tended to increase as the treated body surface area increased. Mean apparent half-life of tacrolimus was 80 +/- 35 h (range: 25-175 h). Most patients experienced substantial clinical improvement in their atopic dermatitis. There were no clinically significant changes in laboratory values, and the most frequently reported adverse events were minor infections and local skin irritations.. Tacrolimus 0.03% ointment in infants is associated with very low systemic exposure to tacrolimus. Treatment was well tolerated and led to considerable clinical improvement.

Topics: Administration, Topical; Dermatitis, Atopic; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Infant; Male; Ointments; Tacrolimus; Treatment Outcome

There is increasing evidence that neuropeptides may be involved in the pathogenesis of atopic dermatitis (AD). Objectives To investigate the effects of tacrolimus on the neuropeptides substance P (SP), nerve growth factor (NGF), and neurotrophin-3 (NT-3) in the skin, and SP and NGF in the serum, of patients with AD.. Lesional skin specimens were obtained from eight AD patients and eight normal controls. For 8 weeks, AD patients applied 0.03% tacrolimus ointment to all affected areas twice daily. Blood samples and skin biopsies were then repeated. The participants' serum SP and NGF levels, as well as the SP, NGF, and NT-3 immunoreactive cell counts, were evaluated in the epidermal, dermal, and perivascular areas of lesional skin before and after treatment.. The immunoreactive cell counts of SP, NGF, and NT-3 in skin were higher in AD patients than in normal controls. Most cell counts decreased significantly after treatment; however, the change in serum SP and NGF was not statistically significant.. We demonstrated semiquantitative differences in neuropeptides in the skin of AD patients. In addition, topical tacrolimus reduced the levels of neuropeptides in the tissues of AD patients.

Topics: Administration, Topical; Adolescent; Adult; Biopsy; Child; Dermatitis, Atopic; Female; Humans; Immunosuppressive Agents; Male; Nerve Fibers; Nerve Growth Factor; Neurotrophin 3; Skin; Substance P; Tacrolimus; Young Adult

Genetic defects leading to skin barrier dysfunction were recognized as risk factors for atopic dermatitis (AD). It is essential that drugs applied to patients with AD restore the impaired epidermal barrier to prevent sensitization by environmental allergens.. We investigated the effect of 2 common treatments, a calcineurin inhibitor and a corticosteroid, on the skin barrier.. In a randomized study 15 patients with AD were treated on one upper limb with pimecrolimus and on the other with betamethasone twice daily for 3 weeks.. Stratum corneum hydration and transepidermal water loss, a marker of the inside-outside barrier, improved in both groups. Dye penetration, a marker of the outside-inside barrier, was also reduced in both drugs. Electron microscopic evaluation of barrier structure displayed prevalently ordered stratum corneum lipid layers and regular lamellar body extrusion in pimecrolimus-treated skin but inconsistent extracellular lipid bilayers and only partially filled lamellar bodies after betamethasone treatment. Both drugs normalized epidermal differentiation and reduced epidermal hyperproliferation. Betamethasone was superior in reducing clinical symptoms and epidermal proliferation; however, it led to epidermal thinning.. The present study demonstrates that both betamethasone and pimecrolimus improve clinical and biophysical parameters and epidermal differentiation. Because pimecrolimus improved the epidermal barrier and did not cause atrophy, it might be more suitable for long-term treatment of AD.

Topics: Administration, Cutaneous; Anti-Inflammatory Agents; Betamethasone; Dermatitis, Atopic; Dermatologic Agents; Epidermis; Humans; Microscopy, Electron, Transmission; Skin Absorption; Tacrolimus; Water Loss, Insensible

No specific data are available on tacrolimus ointment as a second-line treatment in adults with facial eczema.. To compare tacrolimus 0.1% and fluticasone 0.005% ointments in adults with moderate to severe atopic dermatitis (AD) of the face in whom conventional treatment was ineffective or poorly tolerated.. Patients were randomized to double-blind treatment of facial AD with twice-daily tacrolimus ointment (n = 288) or fluticasone ointment (n = 280) for 3 weeks or until clearance. After day 21, patients could continue without the study treatment, apply the same ointment once daily, or switch to the other medication twice daily, depending on lesion clearance and patient/physician satisfaction. The primary endpoint was the day-21 response [> or = 60% reduction in the modified Local Eczema and Severity Index (mLEASI) score]. Secondary endpoints included facial erythema and pruritus, global clinical response, treatment switching at day 21 and safety. RESULTS Response with tacrolimus ointment (93%) was superior to that with fluticasone (88%; P = 0.026). Improvements in mLEASI components were also greater with tacrolimus ointment. Facial erythema and pruritus improved in both groups. Global clinical response was rated 'marked improvement' or better in 88% and 79% of patients in the tacrolimus ointment and fluticasone groups, respectively. At day 21, 9% of patients switched from fluticasone to tacrolimus ointment, while 4.5% switched from tacrolimus ointment to fluticasone. Adverse events were more frequent with tacrolimus ointment as a result of the higher incidence of application-site skin burning sensation. Safety of both drugs was in line with their respective summary of product characteristics.. Tacrolimus 0.1% ointment has superior efficacy to fluticasone 0.005% ointment for twice-daily treatment of adults with moderate to severe facial AD in whom conventional therapy was inadequately effective or not tolerated. Tacrolimus 0.1% ointment is a safe and effective second-line treatment for the control of moderate to severe AD of the face.

Topics: Administration, Cutaneous; Adolescent; Adult; Aged; Androstadienes; Dermatitis, Atopic; Dermatologic Agents; Double-Blind Method; Drug Administration Schedule; Facial Dermatoses; Female; Fluticasone; Humans; Immunosuppressive Agents; Male; Middle Aged; Ointments; Tacrolimus; Treatment Outcome; Young Adult

Colonization with Staphylococcus aureus in atopic dermatitis (AD) is often associated with worsening of clinical symptoms. Staphylococcus aureus produces superantigens that contribute to cutaneous inflammation and corticosteroid (CS) resistance.. To investigate the relationship between CS insensitivity, S. aureus colonization and superantigen production in AD, and to explore the efficacy of pimecrolimus cream in CS-insensitive AD.. This was a randomized, double-blind, vehicle-controlled, multicentre, parallel-group study. Seventy-three patients with AD, aged 2-49 years, who had a documented clinical insensitivity to topical CS, were recruited. The primary efficacy parameters combined laboratory (including S. aureus colonization, superantigens) and clinical assessments [including Eczema Area and Severity Index (EASI), whole body Investigator's Global Assessment (IGA), pruritus assessment score, patient's assessment score of disease control].. An increase in S. aureus counts correlated with worsening of clinical score (week 6 vs. baseline) when assessed by IGA, pruritus severity and patient assessment. The presence of superantigens correlated with this worsening. During the 6-week double-blind phase, disease improvement in the pimecrolimus cream group was demonstrated by decreasing EASI scores compared with vehicle. Mean EASI scores for the head and neck showed greater improvement in the pimecrolimus cream group than in the vehicle group at all observed time points.. In a cohort of patients with clinical insensitivity to CS there was a significant positive correlation between S. aureus and disease severity. Results suggest that for some of these patients, treatment with pimecrolimus cream 1% is useful, especially in the head/neck area.

Topics: Administration, Cutaneous; Adolescent; Adult; Child; Child, Preschool; Dermatitis, Atopic; Dermatologic Agents; Double-Blind Method; Drug Resistance; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Pharmaceutical Vehicles; Staphylococcal Skin Infections; Staphylococcus aureus; Superantigens; Tacrolimus; Young Adult

Topics: Administration, Topical; Antibodies; Antigens, CD; Child; Dermatitis, Atopic; Humans; Lymphocyte Count; T-Lymphocyte Subsets; Tacrolimus; Treatment Outcome

Long-term maintenance treatment with 0.1% tacrolimus ointment for the prevention of flares has been demonstrated to be well tolerated and effective in adults for the treatment of atopic dermatitis (AD) but its impact on health-related utility has not been reported.. The purpose of this study was to estimate utility changes associated with the use of tacrolimus ointment in the maintenance treatment of adults with AD.. Data were collected from a clinical trial investigating long-term maintenance treatment with 0.1% tacrolimus ointment in adults with AD. All patients were treated with twice-daily tacrolimus ointment during an open-label period (OLP) of up to 6 weeks, with subsequent randomization to a double-blind disease-control period (DCP) of 12 months comparing tacrolimus ointment, used twice weekly as maintenance treatment, vs. the emollient vehicle as standard treatment. Health-related utility (EQ-5D(index)) was estimated by Monte Carlo simulation from SF-12 responses by application of a published response mapping algorithm and the U.K. tariff for EQ-5D responses and SF-6D responses, respectively.. Evaluable data were available for 257 patients stratified into mild, moderate or severe AD with a median age at screening of 28 years [interquartile range (IQR) 22-38] and 40% male. At screening the median EQ-5D(index) across the strata was 0.848 units (IQR 0.704-0.882) for mild cases, 0.796 (0.737-0.876) for moderate cases, and 0.760 (0.661-0.823, P < 0.001) for those with severe disease. At the end of the OLP, mean utility improvement across all strata was 0.027 [95% confidence interval (CI) -0.011 to 0.065, P = 0.165] for mild cases, 0.046 (95% CI 0.015-0.064, P = 0.002) for moderate cases and 0.076 (95% CI 0.035-0.118, P < 0.001) for those with severe disease. At the end of the blinded DCP, repeated measures analysis showed an age- and sex-adjusted mean change of 0.045 units (P < 0.001) for subjects treated with tacrolimus ointment over those treated with emollient vehicle.. Patients with AD of all severities showed considerable decrements in health-related utility. However, treatment with 0.1% tacrolimus ointment was associated with clinically significant improvement in health-related utility for patients with moderate and severe AD, which was sustained over a 12-month maintenance period compared with those using standard treatment with an emollient vehicle.

Topics: Adult; Dermatitis, Atopic; Double-Blind Method; Drug Administration Schedule; Female; Humans; Immunosuppressive Agents; Male; Ointments; Quality of Life; Tacrolimus; Time Factors; Treatment Outcome; Young Adult

For reimbursement purposes of pimecrolimus cream 1%, the Belgian authorities asked to document its consumption, its topical corticosteroid-sparing effect and quality of life within the routine clinical practice.. We aimed to address the 3 queries of the Belgian authorities.. An open-label, observational, multicentre, 1-year study under drug prescription was performed.. A total of 416 consecutive patients were enrolled in 49 centres. The mean annual amount of prescribed pimecrolimus cream 1% per patient was 120.8 g (SD = 117.0), with an estimated consumption of 104.4 g (SD = 117.6). The median annual amount prescribed was 90.0 g [interquartile range (IQR) = 45-150] and the estimated consumption 63.6 g (IQR = 32.4-132). Topical corticosteroids had been used before the study in 81.7% of the population. With pimecrolimus cream 1% during the study, 83.3% of the previous corticosteroid users stated less topical corticosteroid use than before and 36% of them did not apply topical corticosteroids at all during the study. The mean improvements compared to baseline in Parents' Index Quality of Life-Atopic Dermatitis and Quality of Life Index-Atopic Dermatitis scores were 34.5% (SD = 84.3) and 31.2% (SD = 70.8), respectively. The median improvements were 50.0% (IQR = 12.5-85.7%) and 46.4% (IQR = 0.0-85.0%), respectively.. In routine practice the consumption of pimecrolimus cream 1% is relatively low, with corticosteroid-sparing effect, improvement in quality of life and good tolerability.

Topics: Administration, Cutaneous; Adolescent; Adult; Belgium; Child; Child, Preschool; Confidence Intervals; Dermatitis, Atopic; Dermatology; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Utilization; Emollients; Female; Follow-Up Studies; Humans; Infant; Male; Multivariate Analysis; Probability; Quality of Life; Regression Analysis; Severity of Illness Index; Tacrolimus; Treatment Outcome

Long-term treatment for atopic dermatitis (AD) using low dose, intermittent, topical anti-inflammatory agents may control acute disease and prevent relapses. This 12-month, European, multicentre, randomized study investigated whether the proactive use of 0.1% tacrolimus ointment applied twice weekly can keep AD in remission and reduce the incidence of disease exacerbations (DE).. During the initial open-label period, 257 adults with AD applied 0.1% tacrolimus ointment twice daily (b.i.d.) for up to 6 weeks to affected areas. When an Investigator Global Assessment (IGA) score of

Topics: Administration, Cutaneous; Adult; Dermatitis, Atopic; Double-Blind Method; Drug Administration Schedule; Female; Humans; Immunosuppressive Agents; Male; Ointments; Severity of Illness Index; Tacrolimus; Treatment Outcome

This study was performed to investigate the efficacy and safety of a prevention-of-flare-progression strategy with pimecrolimus cream 1% in children and adolescents with atopic dermatitis (AD).. A 26-week multi-centre, randomized, double-blind, vehicle-controlled study was conducted in 521 patients aged 2-17 years, with a history of mild or moderate AD, who were clear/almost clear of disease before randomization to pimecrolimus cream 1% (n = 256) or vehicle cream (n = 265). Twice-daily treatment with study medication was started at the first signs and/or symptoms of recurring AD. If, despite the application of study medication for at least 3 days, AD worsened (as confirmed by the investigator), treatment with a moderately potent topical corticosteroid (TCS) was allowed in both groups. The primary efficacy end point was the number of days on study without TCS use for a flare.. The mean number of TCS-free days was significantly higher (P < 0.0001) in the pimecrolimus cream 1% group (160.2 days) than in the control group (137.7 days). On average, patients on pimecrolimus cream 1% experienced 50% fewer flares requiring TCSs (0.84) than patients on vehicle cream (1.68) (P < 0.0001). Patients on pimecrolimus cream 1% also had fewer unscheduled visits (87) than patients on vehicle cream (246).. In children and adolescents with a history of mild or moderate AD but free/almost free of signs or symptoms of the disease, early treatment of subsequent AD exacerbations with pimecrolimus cream 1% prevented progression to flares requiring TCS, leading to fewer unscheduled visits and reducing corticosteroid exposure.

Topics: Administration, Topical; Adolescent; Child; Child, Preschool; Dermatitis, Atopic; Dermatologic Agents; Disease Progression; Double-Blind Method; Humans; Tacrolimus; Treatment Outcome

Hand dermatitis is a chronic inflammatory skin disorder for which systemic immunosuppressive therapy is often needed. Topical treatments could complement the use of systemic corticosteroids.. To evaluate symptoms of hand dermatitis in subjects treated with a prednisone taper combined with topical tacrolimus 0.1% ointment versus vehicle.. Thirty-two subjects with moderate to severe hand dermatitis were enrolled in a randomized double-blind controlled trial. Subjects received a 3-week taper of prednisone and was randomized 2:1 to apply topical tacrolimus or its vehicle twice daily for 12 weeks. Disease severity was evaluated at baseline and at 5 follow-up visits (weeks 1-14). Any occurrence of relapse was recorded by patients.. Twenty-two of the 32 subjects (69%) had relapse of their disease. The mean time to recurrence for tacrolimus versus vehicle was 48 versus 39 days, respectively (P = .78). A greater improvement of induration (P = .003) and scaling (P = .003) for patients with tacrolimus compared to vehicle was detected, as well as subjective improvement (%) from week 1 to week 12 (P = .04) compared to vehicle. Improvement in erythema (P < .0001), fissuring (P = .0003), pruritus (P = .06), and investigator's global assessment (P < .0001) with tacrolimus was not found to exceed improvement with vehicle.. Small sample size provides limited power to detect differences in response.. Topical tacrolimus improves induration and scaling, and there is a trend suggesting it prolongs the time to recurrence.

Topics: Administration, Oral; Administration, Topical; Adult; Aged; Dermatitis, Atopic; Dermatitis, Contact; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Glucocorticoids; Hand Dermatoses; Humans; Immunosuppressive Agents; Male; Middle Aged; Prednisone; Tacrolimus

Rational health care decision-making based on outcomes and economic evidence is essential to provide the best possible care for individual patients with atopic dermatitis (AD).. To describe treatment outcomes and to evaluate resource utilization and associated cost of maintenance use of tacrolimus ointment (MU) vs. standard use of tacrolimus ointment (SU) in adults with AD.. A pan-European, phase III multicentre randomized clinical trial was conducted. Patients with mild to severe AD were randomized to tacrolimus 0.1% ointment (MU) or vehicle (SU) twice per week for 12 months. Disease exacerbations were treated by using open-label tacrolimus 0.1% ointment twice daily. Resource utilization data were collected prospectively alongside the clinical trial. Costs of pooled resource data were determined using German unit cost data. Direct and indirect costs were considered from third party payer, patient and societal perspectives.. All patients with moderate and severe AD were included in a subanalysis, 75 patients in the MU arm (57% moderately affected) and 59 patients in the SU arm (59% moderately affected). In patients with moderate AD, the number of disease exacerbations in the MU arm was 2.4 vs. 5.5 in the SU arm (P<0.001); in patients with severe AD corresponding figures were 2.3 vs. 7.4 (P<0.001), respectively. Mean+/-SD total annual cost per patient was euro1525+/-1081 (MU) vs. euro1729+/-1209 (SU) in patients with moderate AD and euro2045+/-2013 (MU) vs. euro2904+/-1510 (SU) in patients with severe AD.. Maintenance treatment with 0.1% tacrolimus ointment is more effective and leads to cost savings and improved health-related quality of life in comparison with standard use of 0.1% tacrolimus ointment, especially in patients with severe AD.

Topics: Adult; Cost-Benefit Analysis; Dermatitis, Atopic; Drug Administration Schedule; Female; Health Care Costs; Health Status; Humans; Immunosuppressive Agents; Male; Quality of Life; Tacrolimus; Young Adult

Long-term treatment for atopic dermatitis (AD) using low-dose, intermittent, topical anti-inflammatory agents may control acute disease and prevent exacerbations.. This 12-month, European, multicentre, randomized study investigated if proactive, twice-weekly application of 0.03% tacrolimus ointment can keep AD in remission and reduce the incidence of disease exacerbation (DE) in children.. During the initial open-label period, 267 children with AD applied 0.03% tacrolimus ointment twice daily for up to 6 weeks to all affected areas. When an Investigator Global Assessment (IGA) score of

Topics: Adolescent; Child; Child, Preschool; Dermatitis, Atopic; Emollients; Female; Humans; Immunosuppressive Agents; Male; Tacrolimus; Treatment Outcome

Long-term, safe and effective therapeutic options for managing the chronic relapsing nature of atopic dermatitis are essential for improving patient quality of life. To minimize the risks of continued topical corticosteroid usage and potentially reduce the incidence of flares, we tested the efficacy and safety of a rotational paradigm of initial brief application of topical corticosteroid followed by long-term intermittent application of non-steroidal tacrolimus ointment to previously inflamed sites of dermatitis.. In this 2-phase study, patients who were 2 to 15 years of age and had moderate to severe atopic dermatitis were randomly assigned to 4 days of twice-daily double-blind therapy with either alclometasone ointment 0.05% or tacrolimus ointment 0.03% (Phase I acute), followed by up to 16 weeks of twice-daily open-label tacrolimus ointment 0.03% (Phase I short-term). Patients whose disease stabilized underwent new randomization to double-blind tacrolimus ointment 0.03% or vehicle applied once daily, 3 times per week to clinically normal-appearing skin for up to 40 weeks (Phase II). Corticosteroid use was prohibited.. Of 206 randomly assigned patients, 152 completed Phase I; 105 of 152 were randomly assigned into Phase II (68 tacrolimus ointment and 37 vehicle). There were no differences in adverse events between alclometasone and tacrolimus (Phase I) or between tacrolimus and vehicle (Phase II). In the acute period, alclometasone-treated patients showed greater improvement in atopic dermatitis signs and symptoms; thereafter, when all patients applied tacrolimus ointment (short-term), there were no differences. In Phase II, tacrolimus-treated patients had significantly more disease-free days compared with vehicle, significantly longer time to first relapse, and significantly fewer disease relapse days.. For patients with stabilized moderate to severe atopic dermatitis, long-term intermittent application of tacrolimus ointment to normal-appearing but previously affected skin was significantly more effective than vehicle at maintaining disease stabilization, with a safety profile similar to vehicle.

Topics: Administration, Topical; Adolescent; Age Factors; Child; Child, Preschool; Dermatitis, Atopic; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Multivariate Analysis; Ointments; Probability; Risk Assessment; Secondary Prevention; Severity of Illness Index; Sex Factors; Statistics, Nonparametric; Tacrolimus; Treatment Outcome

The objective of this study was to compare the efficacy and safety of tacrolimus ointment and pimecrolimus cream in adults with moderate atopic dermatitis (AD). A randomized, investigator-blinded, 6-week, multicenter study enrolled patients (> or =16 years) with mild to very severe AD. Patients with moderate AD at baseline were analyzed. At study completion, tacrolimus ointment-treated patients had significantly greater improvement in Eczema Area Severity Index score compared with pimecrolimus cream-treated patients (59% versus. 43% reduction, respectively; P=.01). Significantly more tacrolimus ointment-treated patients than pimecrolimus cream-treated patients improved by 1 or more grades on the Investigators' Global Atopic Dermatitis Assessment (P<.02). A total of 5 pimecrolimus cream-treated patients discontinued the study early due to lack of efficacy compared with no tacrolimus ointment-treated patients (P=.02). Overall, reported adverse events occurred at a similar frequency for both treatment groups. Tacrolimus ointment is more effective than pimecrolimus cream in the management of adults with moderate AD.

Topics: Administration, Cutaneous; Adult; Dermatitis, Atopic; Female; Follow-Up Studies; Humans; Male; Middle Aged; Ointments; Prospective Studies; Severity of Illness Index; Single-Blind Method; Tacrolimus

Pimecrolimus cream 1% has been shown to effectively control atopic eczema (AE) when applied twice daily from the first signs or symptoms of AE until clearance. Moreover, pimecrolimus cream 1% has a favourable safety profile, lacking topical corticosteroid-related side-effects such as skin atrophy, making it particularly useful to treat delicate body regions (e.g. the face).. The objective of this naturalistic study was to monitor the safety, tolerability and efficacy of pimecrolimus when used in the long-term management of AE in a real-life setting.. A multicentre, open-label study was conducted in 2034 patients aged >or= 3 months with mild to moderate AE for up to 12 months' duration. Patients applied pimecrolimus cream twice daily, initiating treatment at first signs or symptoms of AE, continuing until clearance.. Patients (n= 1847; 91%) completed 3 months of the study. Treatment success (clear or almost clear AE) after 3 months of treatment was observed on the whole body in 59% of patients and on the face in 81% of patients. Disease improvement of whole body and face was seen in 77% and 63% of patients, respectively. Pruritus was absent or mild in 79% of patients. Pimecrolimus cream was well tolerated throughout the study.. In a daily practice setting, pimecrolimus cream 1% effectively and safely controls AE.

Topics: Adolescent; Child; Child, Preschool; Dermatitis, Atopic; Dermatologic Agents; Dose-Response Relationship, Drug; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Infant; Male; Ointments; Pruritus; Tacrolimus; Treatment Outcome

Atopic dermatitis is a chronic or recurrent inflammatory skin disease that often requires treatment over years. According to its severity, atopic dermatitis is often managed with use of emollients, topical corticosteroids, topical calcineurin inhibitors or systemic agents. This long-term study compares the efficacy of tacrolimus 0.1% ointment with topical corticosteroids as standard therapy in patients with moderate atopic dermatitis.. 50 patients were enrolled. They were allocated to treatment groups by the investigator (tacrolimus group or standard group), and followed over a period of six to twenty months. Efficacy was evaluated by the Eczema Area Severity Index (EASI), the percentage of affected body surface area, and the score of Rajka and Langeland. In addition, ointment usage was documented and analyzed.. The improvement of the skin condition was statistically significant in both groups. The comparison of the two groups, however, did not show a statistically significant advantage of one or the other treatment. Ointment usage was slightly higher in the standard group.. The efficacy of tacrolimus 0.1% ointment was confirmed. In terms of emollient usage, no regular pattern could be demonstrated.

Topics: Administration, Topical; Adolescent; Adrenal Cortex Hormones; Adult; Dermatitis, Atopic; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Long-Term Care; Male; Middle Aged; Tacrolimus; Young Adult

The aim of this post hoc analysis was to evaluate whether treatment of patients with atopic dermatitis (AD) with pimecrolimus cream 1% can decrease the development of flares necessitating the use of a topical corticosteroid on the face and thus reduce the need for use of topical corticosteroids in this sensitive skin area.. In a controlled, double-blind, multicentre study, 140 patients, aged 2 to 17 years, with facial involvement and mild to moderate disease after treatment of the initial flare with prednicarbate 0.25% cream were randomized to an intermittent treatment with pimecrolimus cream 1% twice daily or vehicle for 24 weeks. If a flare occurred, defined as an exacerbation (unacceptable severity of itching/scratching or onset of oozing) not controlled by study medication, patients were treated with prednicarbate 0.25% cream instead.. Patients in the vehicle group needed prednicarbate treatment on the face on 20.7% of the days vs. 11.7% of the study days in the pimecrolimus group (P = 0.0024). Fifty per cent of patients in the pimecrolimus group had no flare on the face during the treatment period compared with 37.5% of patients in the vehicle group (P = 0.012). The median time to first flare in pimecrolimus-treated patients was twice as long as in patients receiving vehicle (138 vs. 68 days, P = 0.01). Three adverse events (one case of skin burning) suspected to be related to use of the study medication were reported for three patients (3.9%) in the pimecrolimus group.. Long-term intermittent treatment of facial AD in children and adolescents with pimecrolimus cream 1% does significantly reduce the need for topical corticosteroids.

Topics: Administration, Topical; Adolescent; Child; Child, Preschool; Dermatitis, Atopic; Dermatologic Agents; Double-Blind Method; Face; Humans; Tacrolimus; Treatment Outcome

Previous studies suggested that early intervention with pimecrolimus cream 1% at the first signs and/or symptoms of a relapse of atopic dermatitis (AD) following remission may prevent the occurrence of more severe flares and therefore reduce corticosteroid exposure in the long term. However, this possibility was not rigorously evaluated.. To evaluate the effectiveness of pimecrolimus cream 1% for the prevention of flare progression in adults with AD.. A 26-week randomized controlled study was conducted in 543 patients aged>or=18 years, with a history of mild or moderate AD, who were clear/almost clear of disease before randomization to pimecrolimus cream 1% (n=277) or matching vehicle cream (n=266). Twice-daily treatment with study medication was started at the onset of the first signs and/or symptoms of a relapse. If disease worsened, despite the application of study medication for at least 3 days, treatment with a moderately potent topical corticosteroid (TCS) was allowed in both groups. The primary efficacy endpoint was the number of days without TCS use for disease worsening.. The mean number of TCS-free days was significantly higher (P<0.001) in the pimecrolimus cream 1% group (152 days) than in the vehicle cream group (138.7 days). In comparison with vehicle cream, pimecrolimus cream 1% reduced the mean number of flares requiring TCS use from 1.39 to 0.97 (P=0.0014). Patients on pimecrolimus cream 1% made 30% fewer unscheduled visits (156) than patients on vehicle cream (223).. In adults with a history of mild or moderate AD but free of active skin lesions, intervention with pimecrolimus cream 1% at the first signs and/or symptoms of a subsequent recurrence reduces the number of flares requiring TCS use and decreases the number of disease-related office visits.

Topics: Administration, Cutaneous; Adolescent; Adult; Aged; Aged, 80 and over; Anti-Inflammatory Agents, Non-Steroidal; Dermatitis, Atopic; Dermatologic Agents; Double-Blind Method; Female; Humans; Male; Middle Aged; Secondary Prevention; Tacrolimus

Intermittent dosing of a topical calcineurin inhibitor for preventing atopic dermatitis (AD) disease relapse in patients with stabilized AD has not been evaluated.. We sought to evaluate the long-term efficacy and safety of 3-times-weekly use of tacrolimus ointment in preventing AD disease relapse.. Adult and pediatric patients with moderate to severe AD who were clear of disease after up to 16 weeks of treatment with tacrolimus ointment were randomized in a double-blind fashion to 3-times-weekly treatment with either tacrolimus ointment (0.03% or 0.1%) or vehicle for 40 weeks. The primary end point was the number of flare-free treatment days.. A total of 125 patients were randomized to tacrolimus and 72 patients to vehicle. The mean number of flare-free treatment days was 177 for tacrolimus and 134 for vehicle (P = .003). Median time to first relapse was 169 days for tacrolimus and 43 for vehicle (P = .037).. Generalizability to all patients seen in clinic may be limited because only patients who responded to tacrolimus ointment in the stabilization phase were randomized into the maintenance phase of the trial.. Maintenance therapy with tacrolimus ointment was associated with significantly more flare-free days compared with vehicle, and a significantly longer time until first disease relapse.

Topics: Adolescent; Child; Child, Preschool; Dermatitis, Atopic; Double-Blind Method; Drug Administration Schedule; Female; Humans; Immunosuppressive Agents; Male; Ointments; Tacrolimus; Time Factors

Long-term treatment for atopic dermatitis (AD) using low dose, intermittent, topical anti-inflammatory agents may control acute disease and prevent relapses. This 12-month, European, multicentre, randomized study investigated whether the proactive use of 0.1% tacrolimus ointment applied twice weekly can keep AD in remission and reduce the incidence of disease exacerbations (DE).. During the initial open-label period, 257 adults with AD applied 0.1% tacrolimus ointment twice daily (b.i.d.) for up to 6 weeks to affected areas. When an Investigator Global Assessment (IGA) score of < or =2 was achieved, the patient entered the disease control period (DCP) and was randomized to either proactive tacrolimus (n = 116) or vehicle ointment (n = 108) twice weekly for 12 months. Exacerbations were treated with 0.1% tacrolimus ointment b.i.d. until an IGA < or =2 was regained, then randomized treatment was restarted. The primary endpoint was the number of DEs during the DCP that required a substantial therapeutic intervention.. Proactive tacrolimus 0.1% ointment application significantly reduced the number of DEs requiring substantial therapeutic intervention (median difference 2; P < 0.001; Wilcoxon rank sum test), the percentage of DE treatment days (median difference: 15.2%; P < 0.001; Wilcoxon rank sum test) and increased the time to first DE (median 142 vs 15 days; P < 0.001; stratified log-rank test). The adverse event profile was similar for the two treatment approaches.. A 12-month, twice weekly proactive tacrolimus ointment application was an effective treatment in most study patients which prevented, delayed and reduced the occurrence of AD exacerbations.

Topics: Adult; Dermatitis, Atopic; Female; Humans; Immunosuppressive Agents; Male; Ointments; Tacrolimus; Treatment Outcome

The main objective of this explorative study was to evaluate if tacrolimus ointment could be safer than corticosteroid ointment, with special reference to the intraocular pressure in the treatment of eyelid eczema in patients with atopic keratoconjunctivitis (AKC). Secondary aims were to compare the effects of the treatments on eyelid eczema and their potential impact on ocular surface inflammation.. Tacrolimus 0.1% ointment and clobetasone butyrate 0.05% ointment were compared in a double-masked explorative crossover study. In total, 25 AKC patients were included. Each ointment was applied twice daily for 3 weeks, with 2 weeks of washout before, between, and after treatments. Efficacy was determined by eye examination and the patients' own symptom scoring. Cytology and cytokine measurements were performed on tear samples. Safety parameters were intraocular pressure, presence of bacteria and fungi, and the patients' reports of adverse events. The validity of the crossover design was explored with analysis of variance, and the effect of each medication was calculated with paired t-test and Wilcoxon paired test.. A total of 20 patients completed the study. Both treatments were effective in reducing signs and symptoms of eyelid eczema, with a near superior benefit for tacrolimus in terms of eczema (total skin score) signs (P=0.05). No serious adverse events occurred and interestingly, intraocular pressure was not evidently affected by either treatment.. Tacrolimus 0.1% ointment is a promising alternative therapy for eyelid eczema in AKC patients. Long-term studies are needed to further determine the value of tacrolimus in this patient group.

Topics: Adolescent; Adult; Aged; Antibodies, Bacterial; Biomarkers; Blepharitis; Clobetasol; Cross-Over Studies; Cytokines; Dermatitis, Atopic; Eyelids; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Inflammation Mediators; Intraocular Pressure; Keratoconjunctivitis; Male; Middle Aged; Ointments; Tacrolimus; Tears; Treatment Outcome

While many studies have demonstrated the efficacy and safety of tacrolimus ointment in the treatment of atopic dermatitis (AD), only a few have investigated the effects of tacrolimus on inflammatory cells and their cytokine gene expression in patients with AD.. To characterize further the immunophenotype of infiltrating cells and the production of certain cytokines before and after treatment with topical tacrolimus and hydrocortisone butyrate.. Nine adult patients with moderate to severe AD were treated with tacrolimus ointment, while seven control patients were treated with hydrocortisone butyrate ointment. We performed lesional skin biopsies before and after treatment. These were stained immunohistochemically with a panel of monoclonal antibodies including those to CD1a, CD3, CD4, CD8, myeloperoxidase, EG1, EG2, tryptase, interferon-gamma, interleukin (IL)-4, IL-5, IL-12, IL-13, receptors for CXC chemokines (CXCR) 3 and 4, and receptor 3 for CC chemokines.. CD3+, CD4+ and CD8+ lymphocytes, and eosinophil and neutrophil granulocytes were significantly reduced in post-treatment tacrolimus specimens, while CD1a+ cells and mast cells were not. The expression of cytokines and chemokine receptors tested, except for CXCR3, was diminished by tacrolimus treatment. Moreover, tacrolimus produced a greater reduction of lymphocytes, eosinophils and most cytokines than that induced by hydrocortisone butyrate.. Tacrolimus not only inhibits T-lymphocyte proliferation and cytokine production, but also plays an important role in the IL-12-induced shift from a T-helper (Th) 2 to a Th1 cytokine profile that characterizes the development of chronic AD. Tacrolimus also demonstrates wider pharmacodynamic effects than hydrocortisone.

Topics: Administration, Topical; Adult; Aged; Antibodies, Monoclonal; Cytokines; Dermatitis, Atopic; Female; Humans; Hydrocortisone; Immunohistochemistry; Immunosuppressive Agents; Male; Middle Aged; Ointments; Receptors, Cytokine; Tacrolimus; Treatment Outcome

The skin of patients with atopic dermatitis (AD) exhibits a striking susceptibility to colonization and infection by Staphylococcus aureus. Treatment with topical anti-inflammatory drugs alone can reduce S. aureus colonization.. To compare the clinical severity of AD and the S. aureus colonization rate between AD patients treated with topical glucocorticoids and those treated with tacrolimus and to evaluate the effects of complementary topical antistaphylococcal antibiotic therapy and the development of fusidic acid-resistant S. aureus.. Sixty AD patients were enrolled in a prospective, parallel, randomized study of an 8-week treatment with topical 0.05% fluticasone propionate or 0.03% tacrolimus, with or without complementary fusidic acid. Disease severity scoring of AD based on SCORing of Atopic Dermatitis (SCORAD), colonization rate and density of S. aureus on the skin, and antibiotic susceptibility of S. aureus isolates were evaluated.. The reduction in SCORAD scores correlated with the reduction of S. aureus numbers. Treatment with topical tacrolimus resulted in a comparable reduction in SCORAD scores to fluticasone but a slower eradication of S. aureus. Complementary fusidic acid had no additional benefit compared with fluticasone or tacrolimus alone. Two patients developed fusidic acid-resistant S. aureus after 8 weeks of fusidic acid treatment.. Tacrolimus is an appropriate alternative treatment for chronic AD. Topical anti-inflammatory therapy alone to improve the allergic skin inflammation of AD can reduce S. aureus colonization of the skin. Topical antibiotics should be reserved for short-term use in obvious secondary bacterial infection.

Topics: Adolescent; Adult; Androstadienes; Anti-Bacterial Agents; Anti-Inflammatory Agents; Child; Child, Preschool; Dermatitis, Atopic; Drug Therapy, Combination; Female; Fluticasone; Fusidic Acid; Humans; Immunosuppressive Agents; Infant; Male; Staphylococcal Skin Infections; Staphylococcus; Tacrolimus

Topical glucocorticosteroids are the gold standard in treatment of atopic dermatitis (AD). Recently, topical calcineurin inhibitors have been developed for treatment of this condition. This study compared efficacy and safety of 0.1% methylprednisolone aceponate (MPA) ointment with 0.03% tacrolimus ointment for 3 weeks, in children and adolescents with severe to very severe flare of AD.. The primary end point was treatment success, defined as a score of 'clear' or 'almost clear' in the static Investigator's Global Assessment (IGA) score. Secondary end points were the percentage change in the Eczema Area and Severity Index (EASI) and patients' assessment of itch and sleep, Children's Dermatology Life Quality Index, patient's assessment of global response, affected Body Surface Area and medication costs.. 265 patients were randomized to either MPA (n = 129) or tacrolimus (n = 136) treatment, 257 patients completed the study. Methylprednisolone aceponate 0.1% ointment once daily provided rapid and relevant clinical benefit. Tacrolimus 0.03% ointment twice daily was equally effective with regard to success rate. Methylprednisolone aceponate was superior to tacrolimus for EASI, itch and sleep. Both treatments were well tolerated. Drug-related adverse events were only observed in the tacrolimus group. Medication costs were significantly lower for MPA.. While both treatment groups showed similar efficacy results regarding treatment success (IGA), significant advantages were observed for EASI, itch and sleep with MPA 0.1%. These advantages and the significantly lower treatment costs highlight the benefits of MPA treatment, underlining its first-line role in treatment of children and adolescents with severe AD.

Topics: Adolescent; Anti-Inflammatory Agents; Child; Child, Preschool; Dermatitis, Atopic; Double-Blind Method; Drug Costs; Female; Humans; Immunosuppressive Agents; Male; Methylprednisolone; Tacrolimus

The objective of this study was to assess time to onset of pruritus improvement in a pediatric population treated with pimecrolimus cream 1%. This 8-day, double-blinded, vehicle-controlled study randomized 174 children and adolescents (aged 2-17 years) with mild to moderate atopic dermatitis (AD) and moderate to severe pruritus to twice-daily applications of pimecrolimus cream 1% or vehicle. There were no significant between-group differences in demographics or baseline disease characteristics. Pruritus was assessed by subjects using a 4-point pruritus severity scale (0-3). The primary efficacy variable was time to a 1 point or more improvement in pruritus score from baseline. The 2 treatment groups were compared using log-rank testing of the time-to-event data. In the per-protocol (PP) population, median times to a 1 point or more improvement in pruritus score were 48 and 72 hours for pimecrolimus and vehicle groups, respectively (P = .038). From day 3 onward, significantly more subjects (P = .023) in the pimecrolimus group versus the vehicle group reported complete pruritus resolution. Pimecrolimus cream 1% improved pruritus within 48 hours in children and adolescents with mild to moderate AD and achieved complete resolution of pruritus in a significantly greater number of subjects in the pimecrolimus group versus the vehicle group by the end of the 7-day treatment period (P = .008).

Topics: Adolescent; Calcineurin Inhibitors; Case-Control Studies; Child; Child, Preschool; Dermatitis, Atopic; Dermatologic Agents; Double-Blind Method; Drug Administration Schedule; Emollients; Follow-Up Studies; Humans; Immunosuppressive Agents; Peptidylprolyl Isomerase; Pharmaceutical Vehicles; Placebos; Pruritus; Severity of Illness Index; Tacrolimus; Time Factors; Treatment Outcome

There is little information on the relative efficacy of topical tacrolimus and corticosteroids in the treatment of atopic dermatitis (AD) in children. In a single-centre, prospective, observer-blinded, side-to-side comparative study (ISRCTN65507338), 96 children with moderately severe AD were enrolled. The study aimed to compare the relative effectiveness of the child's usual topical corticosteroid with 0.03% tacrolimus ointment applied for 1 week, and if there was no difference, 0.1% tacrolimus ointment applied for a further week. Topical tacrolimus was found to be more effective than topical corticosteroid in 72 of the 93 children (77%) who completed the study. Using multiple-regression analysis with age, gender, pretreatment surface area affected and pretreatment corticosteroid potency as covariants, the only factor that reduced the chance of observing a beneficial effect with tacrolimus was moderate or potent topical corticosteroid use (OR = 0.13; 95% CI 0.02-0.74).

Topics: Administration, Topical; Adolescent; Adrenal Cortex Hormones; Child; Child, Preschool; Dermatitis, Atopic; Female; Humans; Immunosuppressive Agents; Infant; Male; Prospective Studies; Tacrolimus

Pimecrolimus cream 1% is a topical calcineurin inhibitor for the treatment of atopic dermatitis. Minimal systemic exposure to pimecrolimus has been previously observed in Caucasian pediatric patients treated with the cream twice daily for up to 1 year. The objective of this open-label, non-comparative, multicenter study was to assess the systemic exposure, tolerability and efficacy of pimecrolimus cream 1% when used twice daily for 3 weeks in pediatric patients of Japanese background. The patient cohort consisted of 17 Japanese infants and children (age range, 3.6 months to 11.6 years) with atopic dermatitis of at least mild severity affecting >or=10% of the total body surface area (range, 10-48%). Pimecrolimus cream 1% was applied twice daily for 3 weeks. Blood levels of pimecrolimus were determined on days 1, 10 and 22. Safety and tolerability were evaluated by monitoring adverse events, laboratory parameters, physical condition and vital signs. Efficacy parameters included the Eczema Area and Severity Index, the Investigators' Global Assessment and the pruritus score. The median exposure to pimecrolimus cream 1% was 22 treatment days (range, 9-29 treatment days). Pimecrolimus blood concentrations were <0.5 ng/mL in 94% of samples on day 1, in 93% of samples on day 10 and in 100% of samples on day 22, with no indication of an increase with increasing body surface area treated (up to 48% of the total body surface area). No drug-related systemic adverse events or serious adverse events were reported. Treatment was effective according to all efficacy parameters. The findings of this study indicate that the use of pimecrolimus cream 1% results in minimal systemic absorption of the active ingredient in pediatric patients of Japanese background with extensive disease.

Topics: Asian People; Child; Child, Preschool; Dermatitis, Atopic; Dermatologic Agents; Female; Humans; Infant; Male; Tacrolimus; Treatment Outcome

To determine blood concentrations of pimecrolimus after long-term intermittent administration of pimecrolimus cream 1% in adult patients with extensive atopic dermatitis (AD).. This was an open-label, multiple topical dose study in adults with moderate to severe AD and a total body surface area (TBSA) involvement of at least 20%. Pimecrolimus cream 1% was administered twice daily according to treatment need for up to 12 months to all lesions, including the neck and face. Blood samples were collected at regular time points and pimecrolimus concentrations were measured using a radioimmunoassay with a limit of quantitation (LoQ) of 0.5 ng/ml.. Forty patients (19 females), aged from 19 to 59 years, with moderate to severe AD entered the study. Twenty patients completed 6 months and 13 completed 1 year in the study. The individual blood concentrations of pimecrolimus were consistently low and there was no sign of drug accumulation. In 900 of the 918 samples examined (98%), pimecrolimus concentrations remained below the LoQ. The maximum concentration observed throughout the entire study was 0.8 ng/ml.. Long-term intermittent treatment of adult patients with extensive AD with pimecrolimus cream 1% is associated with minimal systemic exposure and no evidence of drug accumulation.

Topics: Administration, Cutaneous; Adult; Dermatitis, Atopic; Dermatologic Agents; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Ointments; Tacrolimus; Treatment Outcome

To characterize the pharmacokinetics of tacrolimus after topical application in adult and pediatric patients with moderate to severe atopic dermatitis from all clinical trials in which tacrolimus blood levels were obtained.. Tacrolimus ointment 0.03% or 0.1% was applied twice daily. In the adult and pediatric pharmacokinetic studies, serial blood samples were obtained after single and repeated topical application. During the 12 clinical efficacy trials of tacrolimus ointment, single blood samples were obtained at various times relative to tacrolimus ointment application.. In the pharmacokinetic studies, 89% to 95% of tacrolimus whole blood concentration samples were less than 1 ng/mL; mean maximum concentrations ranged from 0.2 to 1.6 ng/mL and mean area under the blood concentration-time curves (0-12 hours) ranged from 1.4 to 13.1 ng x hr/mL. Likewise, in the clinical efficacy trials, the majority (85%-99%) of tacrolimus concentration samples were less than 1 ng/mL.. Tacrolimus ointment is associated with minimal systemic absorption and no evidence of systemic accumulation in patients with moderate to severe atopic dermatitis and extensive disease.

Topics: Adolescent; Adult; Age Factors; Aged; Child; Child, Preschool; Clinical Trials as Topic; Dermatitis, Atopic; Drug Monitoring; Female; Humans; Male; Middle Aged; Ointment Bases; Ointments; Pharmacokinetics; Tacrolimus

There is ample evidence that the skin barrier function is altered in atopic dermatitis. Little information is available about the effect of topical corticosteroids and calcineurin inhibitors on this function.. To assess the water content and its rate of accumulation in the stratum corneum of atopic patients using an indirect electrometric method while on tacrolimus or betamethasone valerate treatment.. Twenty-one patients with moderate atopic dermatitis affecting both forearms completed this double-blind randomized study. One forearm was treated twice daily for 3 weeks with 0.1% tacrolimus ointment. The other forearm was similarly treated with 0.12% betamethasone valerate ointment. Electrometric measurements were made under continuous occlusion secured by a Nova Dermal Phase Meter sensor probe. Assessments were performed at inclusion, after the 3-week treatment and after a further 3-week follow-up out of treatment.. During treatment, both compounds yielded a similar improvement in skin barrier function. Indeed, under probe occlusion, the rate of water accumulation was significantly decreased. This improvement was sustained after stopping the tacrolimus treatment. By contrast, the benefit was in part lost at the site that had been treated by betamethasone valerate.. The difference in the effect of the 2 compounds may be due to the negative influence of betamethasone valerate on the epidermal metabolism leading to progressive atrophy of the tissue. The better preservation of the skin barrier function after stopping tacrolimus treatment may help retarding relapses of atopic dermatitis.

Topics: Administration, Topical; Adult; Betamethasone Valerate; Dermatitis, Atopic; Dermatologic Agents; Double-Blind Method; Epidermis; Humans; Male; Ointments; Tacrolimus; Water; Water Loss, Insensible

To compare the efficacy and safety of tacrolimus ointment 0.1% and pimecrolimus cream 1% in adult patients with moderate to very severe atopic dermatitis (AD).. A total of 281 patients (141 treated with tacrolimus and 140 treated with pimecrolimus) were randomized to a multicenter, investigator-blinded, 6-week study.. Tacrolimus-treated patients had significantly greater improvements in the Eczema Area Severity Index score compared with pimecrolimus-treated patients (mean percent reduction from baseline to study end: 57% vs 39%, respectively; p=0.0002). Treatment success was also significantly greater among the tacrolimus-treated patients compared with pimecrolimus-treated patients (40% vs 22% at study end; p=0.001), as was the improvement in percentage of total body surface area affected (a reduction of 49% vs 34% at study end; p=0.01). Both treatment groups had similar improvements in patient assessment of itch. There were no significant differences in the incidences of adverse events, including application-site burning and application-site pruritus, the two most commonly reported adverse events. Significantly more pimecrolimus-treated patients than tacrolimus-treated patients withdrew from the study due to lack of efficacy (10 vs 1, p=0.005).. Tacrolimus ointment is more effective than pimecrolimus cream in adults with moderate to very severe AD. Both agents have a similar safety profile.

Topics: Administration, Cutaneous; Adult; Dermatitis, Atopic; Double-Blind Method; Female; Humans; Immunologic Factors; Male; Ointments; Prospective Studies; Severity of Illness Index; Tacrolimus; Treatment Outcome; United States

Combination therapy with pimecrolimus cream 1%, a topical calcineurin inhibitor (TCI), and fluticasone propionate cream 0.05% (FP), a mid-potency topical corticosteroid, may have a synergistic effect for treatment of atopic dermatitis (AD) because their mechanism of action differs.. To assess the efficacy of concomitant pimecrolimus twice daily/FP once daily vs. vehicle twice daily/FP once daily in patients with severe AD.. An exploratory, 2-week, double-blind, randomized, within-patient study was conducted (n = 45). Two target areas of similar severity, size and location were assessed. Assessments included the modified Eczema Area and Severity Index (0-12 scale) (primary variable), localized investigator global assessment (0-4 scale) and Patients' Self-Assessment of Disease Severity (0-4 scale).. Data for all variables were similar for the TCI/FP and vehicle/FP treatments.. The efficacy observed for treatment of severe AD flares with this TCI/FP combination regimen was equivalent to that of vehicle/FP.

Topics: Administration, Cutaneous; Adolescent; Adult; Aged; Androstadienes; Anti-Inflammatory Agents; Child; Child, Preschool; Dermatitis, Atopic; Dermatologic Agents; Double-Blind Method; Drug Therapy, Combination; Female; Fluticasone; Humans; Male; Middle Aged; Severity of Illness Index; Tacrolimus; Treatment Outcome

Atopic dermatitis (AD) increases health care utilization, affects patient quality of life, places a burden on caregivers, decreases patient/parent productivity, and adds to health care costs. Few studies have examined the effect of specific treatment modalities across a variety of AD-related outcomes. This prospective, multicenter, open-label longitudinal study of adult and pediatric patients with moderate to severe AD was conducted to evaluate the effect of a specific therapeutic intervention on AD-related outcomes over a period of 6 months. Surveys collected physician clinical assessments and patient- and caregiver-reported data across the following domains: clinical outcome, health care utilization/costs, quality of life, physical appearance, productivity/absenteeism, and medication compliance. This study is intended to help guide future research efforts on the net costs and benefits of different interventions across a diverse set of domains and in larger populations.

Topics: Administration, Topical; Adolescent; Child; Child, Preschool; Cost of Illness; Dermatitis, Atopic; Female; Humans; Immunosuppressive Agents; Male; Nonprescription Drugs; Ointments; Patient Compliance; Patient Dropouts; Prospective Studies; Quality of Life; Severity of Illness Index; Surveys and Questionnaires; Tacrolimus; Time Factors; Treatment Outcome

Atopic dermatitis often requires long-term treatment. This European, multicentre, non-comparative, 24-month, follow-up study investigated the efficacy and safety of 0.1% tacrolimus ointment applied to adults with atopic dermatitis. Patients (n=672) applied a thin layer of 0.1% tacrolimus ointment twice daily for 3 weeks to all affected body areas. After 3 weeks, ointment was applied once daily. Clinical improvement became apparent after 2 weeks of treatment and 65.5% of patients had a rating of clearance, excellent or marked improvement by month 3. Skin burning (31.7%) was the most common causally-related adverse event, followed by pruritus (11.3%) folliculitis (6.4%), alcohol intolerance (5.7%), herpes simplex (5.7%), skin infection (4.6%), skin erythema (3.3%) and hyperaesthesia (2.4%). The most commonly reported infections were flu syndrome (12.9%), skin infection (9.8%), folliculitis (7.4%) and herpes simplex (7.0%). Long-term treatment up to 24 months with 0.1% tacrolimus ointment is safe and efficacious in adults with atopic dermatitis.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Dermatitis, Atopic; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Infections; Male; Middle Aged; Ointments; Patient Satisfaction; Quality of Life; Tacrolimus; Treatment Outcome

To investigate if pimecrolimus cream 1% reduces the need for steroids in the long-term management of severe pediatric atopic dermatitis (AD).. A total of 184 pediatric patients (aged 2-17 years) with a history of severe AD according to Rajka and Langeland were enrolled. Patients were randomized to treatment with pimecrolimus cream or vehicle cream for a 24-week period. Prednicarbate 0.25% was applied as rescue medication.. Patients on pimecrolimus required steroids on a mean of 29% of study days, compared with 35% of patients on vehicle (p = 0.1841). On the head and neck only, the respective figures were 10 versus 19% (p = 0.0009). In patients enrolled with acute severe disease (Investigator's Global Assessment > or = 4), steroids were used on 28% of the days in the pimecrolimus group compared to 45% in the control group (p = 0.0024). On the head and neck, steroids were used on 10% of study days with pimecrolimus versus 30% with vehicle (p < 0.0001).. The results indicate that the need for topical steroids on the head and neck is reduced with pimecrolimus cream 1% in the management of severe pediatric AD according to the definition of Rajka and Langeland.

Topics: Administration, Topical; Adolescent; Calcineurin Inhibitors; Child; Child, Preschool; Dermatitis, Atopic; Dermatologic Agents; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Female; Follow-Up Studies; Glucocorticoids; Humans; Male; Ointments; Prednisolone; Tacrolimus; Treatment Outcome

There is a need for alternative treatments for atopic dermatitis (AD) of the face and neck as long-term use of topical corticosteroids (TCS) is associated with skin atrophy and telangiectasia and some patients develop allergy, intolerance or other side-effects.. This study was designed to assess the efficacy and safety of pimecrolimus cream 1% in patients with AD of the face and neck who are either dependent on, or intolerant of, TCS.. A 12-week study comprising a 6-week, double-blind, randomized, vehicle-controlled phase was conducted, followed by a 6-week, open-label phase. Two hundred patients aged 12 years or over with mild to moderate head and neck AD, intolerant of, or dependent on, TCS were randomized to either pimecrolimus cream or vehicle cream. The primary efficacy criterion was the facial investigator's global assessment score at 6 weeks. Secondary efficacy criteria were head and neck Eczema Area and Severity Index (EASI), pruritus score and eyelid dermatitis. Facial skin atrophy and telangiectasia were assessed with dermatoscopy.. A significantly higher percentage of patients treated with pimecrolimus was cleared or almost cleared of facial AD compared with vehicle (47% vs. 16%, respectively). A statistically significant difference was also seen on head and neck EASI and pruritus score. Significantly more pimecrolimus-treated patients than vehicle-treated patients achieved clearance of eyelid dermatitis (45% vs. 19%, respectively). Among the 77 patients with skin atrophy at baseline, treatment with pimecrolimus was associated with a reversal in skin thinning. Of the 112 patients with telangiectasia at baseline, no statistically significant difference was seen between treatment groups. Adverse events occurred with similar frequency in both groups.. Pimecrolimus cream 1% is effective in patients with head and neck dermatitis intolerant of, or dependent on, TCS. Reversion of skin atrophy may occur during TCS-free intervals.

Topics: Administration, Topical; Adolescent; Adrenal Cortex Hormones; Adult; Anti-Inflammatory Agents, Non-Steroidal; Dermatitis, Atopic; Double-Blind Method; Female; Head; Humans; Male; Neck; Ointments; Tacrolimus; Treatment Outcome

Systemic drug exposure following the application of topical agents is a very important safety consideration, particularly in infants, who have a significantly higher ratio of body surface area to body mass than older children and adults. Here, we report on drug exposure in five infants aged 5.7-11.9 months at baseline, with extensive, moderate-to-severe atopic dermatitis (AD). Patients were treated bid for 1 year, as needed, with pimecrolimus cream 1% in an open-label, non-controlled study. No indication of drug accumulation was found; pimecrolimus blood concentrations were consistently low, ranging from below the limit of quantitation (0.1 ng/ml) to 1.94 ng/ml. Treatment over this prolonged period was well tolerated, with no evidence of any treatment-related adverse events. The results of this 1-year study indicate that long-term management of AD with pimecrolimus cream 1% is associated with consistently very low systemic absorption, even in the youngest patients with extensive disease.

Topics: Administration, Cutaneous; Anti-Inflammatory Agents, Non-Steroidal; Dermatitis, Atopic; Female; Humans; Infant; Male; Tacrolimus

Pimecrolimus cream 1% (Elidel, Novartis Pharmaceuticals AG) effectively improves/relieves pruritus associated with atopic dermatitis (AD), but few data are available regarding the timing of relief. The purpose of this study was to investigate the timing of pruritus relief produced with pimecrolimus in adults with mild/moderate AD and moderate/severe pruritus.. Patients were randomized to 7 days of treatment with pimecrolimus (n = 100) or vehicle (n = 98). Pruritus severity was assessed daily on a 4-point scale (0 = absent, 3 = severe), reflecting the previous 24 h experience. Patients who completed this core study were eligible to enter a voluntary 5-week, open-label extension study.. A significant effect was noted within 48 h of treatment, with pruritus improving in 56% of pimecrolimus-treated patients and 34% of vehicle-treated patients (P = 0.003). Pruritus relief was maintained during the remainder of the core and extension phases, and was accompanied by an improvement in the Investigator's Global Assessment score.. Pimecrolimus cream 1% significantly reduced pruritus within 48 h.

Topics: Administration, Topical; Adolescent; Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; Dermatitis, Atopic; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Male; Middle Aged; Ointments; Probability; Pruritus; Reference Values; Severity of Illness Index; Tacrolimus; Treatment Outcome

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.

Topics: Administration, Topical; Adolescent; Child; Child, Preschool; Dermatitis, Atopic; Dermatologic Agents; Female; Humans; Male; Ointments; Prospective Studies; Pruritus; Severity of Illness Index; Tacrolimus; Treatment Outcome; Ultraviolet Therapy

Although several controlled clinical trials have demonstrated the efficacy and good tolerability of 1% pimecrolimus cream for the treatment of atopic dermatitis, the results of these trials may not apply to real-life usage. The objective of this study was to evaluate the safety and efficacy of a pimecrolimus-based regimen in daily practice.. This was a 6-month, open-label, multicenter study in 947 patients aged >or=3 months with atopic dermatitis of all severities. The investigators incorporated 1% pimecrolimus cream into patients' standard treatment protocols on the basis of their clinical diagnosis. Use of topical corticosteroids was allowed at the discretion of the physician. Safety and tolerability were evaluated by monitoring adverse events. Efficacy was evaluated by recording changes in the Investigators' Global Assessment scores and pruritus scores at each visit.. No clinically unexpected adverse events were reported. The discontinuation rate for adverse events was 2.3%. The disease improvement rate was 53.7% at week 1 and 66.9% at week 24. The pimecrolimus-based regimen was particularly effective for the treatment of lesions involving the face (improvement rate: 61.9% at week 1 and 76.7% at week 24). The greatest therapeutic response was experienced by pediatric patients with mild or moderate disease. Nonetheless, 64% and 65% of infants and children, respectively, with severe/very severe facial disease at baseline were clear/almost clear of signs of atopic dermatitis on their face at week 24. In patients aged <18 years, most of the improvement occurred within the first week of treatment, while in adults a progressive improvement was observed over the entire study period. Worsening of disease by the end of the study occurred in 9.5% of patients and was most frequent in adults (12.6%). The discontinuation rate for unsatisfactory therapeutic effect was 4.8%. The mean number of treatment days was 135.6 (SD 53.2). The mean drug consumption (non-US centers only) was 4.2 g per treatment day. Drug consumption decreased over time as disease improved. In total, 47% of patients who completed the study never used topical corticosteroids over 6 months.. In daily practice, incorporation of 1% pimecrolimus cream into patients' standard treatment regimen is well tolerated and improves atopic dermatitis in approximately two-thirds of patients. Disease improvement is particularly evident on the face. The greatest therapeutic response is experienced by pediatric patients with mild or moderate disease. In these patients, most of the improvement is observed within 1 week from the start of treatment.

Topics: Administration, Topical; Adolescent; Adult; Aged; Aged, 80 and over; Child; Child, Preschool; Dermatitis, Atopic; Dermatologic Agents; Dose-Response Relationship, Drug; Female; Humans; Infant; Male; Middle Aged; Tacrolimus

The atopy patch test (APT) is an in vivo model to study the induction of eczema by inhalant allergens in atopic dermatitis patients. We studied the effect of pretreatment with topical tacrolimus 0.1% on APT in nonlesional skin of patients with atopic dermatitis.. Nonlesional skin of the back of patients with atopic dermatitis (n = 8) was treated once daily for 3 weeks with tacrolimus 0.1% ointment. Cetomacrogol ointment (placebo) was used as a negative control and triamcinolone acetonide 0.1% ointment as positive control. Twenty-four hours after the last APT application, samples were taken from the three treated areas (t = 0 and 24 h) for immunohistochemical analysis.. Pretreatment with tacrolimus ointment did not suppress nonlesional skin infiltrate, in contrast to triamcinolone acetonide. Furthermore, tacrolimus did not inhibit the induction of the APT macroscopically (t = 24 h). An equal influx of T cells, eosinophils, dendritic cells, CD64+ and Fc epsilon RI-positive cells was present compared with placebo. Only CD36+ and CD68-positive cells were inhibited compared with placebo. All cell types were significantly inhibited in triamcinolone acetonide-treated sites compared with placebo.. Pretreatment with tacrolimus 0.1% ointment does not inhibit the APT reaction in patients with atopic dermatitis.

Topics: Adult; Allergens; Biopsy; Cetomacrogol; Dendritic Cells; Dermatitis, Atopic; Eczema; Eosinophils; Female; Humans; Immunosuppressive Agents; Male; Patch Tests; Predictive Value of Tests; Receptors, IgG; Surface-Active Agents; T-Lymphocytes; Tacrolimus; Time Factors; Triamcinolone Acetonide

Ultraviolet (UV)-induced pyrimidine dimers are an early step in skin carcinogenesis, which is accelerated in the setting of long-term immunosuppression with systemic calcineurin inhibitors. It is not known whether topical application of calcineurin inhibitors exposes to a similar risk.. To assess the formation and clearance of UV-induced dipyrimidine dimers in human epidermis treated with topical pimecrolimus as compared to topical steroid, vehicle and untreated control.. Pretreated buttock skin of 20 human volunteers with (10) or without (10) atopic dermatitis was exposed to two minimal erythema doses (MED) of simulated solar radiation. DNA was extracted from epidermis 1 and 24 h postirradiation. Pyrimidine dimers were visualized by immuno slot blots and quantified by chemoluminescence image analysis.. One-hour postirradiation, pimecrolimus-treated epidermis contains less DNA damage as compared to untreated control, but there were no statistically significant differences between pimecrolimus, triamcinolone acetonide and vehicle. Dimer levels at 24 h postirradiation showed no significant differences between different treatments.. Treatment with pimecrolimus cream, triamcinolone acetonide cream and vehicle is not associated with increased epidermal DNA damage at 1 and 24 h post-UV exposure.

Topics: Administration, Cutaneous; Adult; Calcineurin Inhibitors; Case-Control Studies; Colorimetry; Dermatitis, Atopic; Epidermis; Glucocorticoids; Humans; Immunosuppressive Agents; Pyrimidine Dimers; Tacrolimus; Triamcinolone Acetonide; Ultraviolet Rays

Topical application of the calcineurin inhibitors pimecrolimus and tacrolimus is a current major advance in the therapy of atopic dermatitis. The aims of this post-marketing surveillance were: a) to acquire data on the efficacy and tolerability of pimecrolimus ointment (Elidel) on a very large cohort of patients from outpatient clinics, and b) to assess changes in their quality of life, a parameter not often considered in previous studies.. Included were 5,665 patients with atopic dermatitis. During the observation period, data on efficacy and tolerability were obtained at the beginning of the study, 3 to 10 days after initiation of therapy and after 4 to 6 weeks. Evaluation of symptoms as well as assessment of efficacy and tolerability were based on linear scales and on the percentage of the body surface area (% BSA) involved. Quality of life was assessed by the German version of the "Dermatology Life Quality Index (DLQI)" or the "Children's Dermatology Life Quality Index (CDLQI)".. In this largest post-marketing surveillance hitherto performed in Germany, the efficacy of pimecrolimus was judged as "good" by 79.3 % of physicians and by 76.5 % of patients. Tolerability was assessed as "good" by 87.2 % of physicians and by 83.1 % of patients. Major symptoms of atopic dermatitis such as pruritus, erythema or lichenification showed marked reduction after just 3 to 10 days, signalling general improvement of the skin disease. In addition, application of pimecrolimus resulted in a significant improvement of the quality of life scores in both children and adults.. The present study demonstrates that the good efficacy and tolerability of pimecrolimus ointment which had been shown in controlled trials: i) could also be demonstrated on a very large cohort of patients with atopic dermatitis when used in the outpatient setting, and ii) were paralleled by a significant improvement in the quality of life.

Topics: Adolescent; Calcineurin Inhibitors; Child; Child, Preschool; Dermatitis, Atopic; Dermatologic Agents; Female; Germany; Humans; Infant; Infant, Newborn; Male; Prevalence; Product Surveillance, Postmarketing; Prognosis; Quality of Life; Tacrolimus; Treatment Outcome

Atopic dermatitis (AD) is characterized both by inflammation and by abnormally low ceramide levels in the stratum corneum. Tacrolimus, effective in the treatment of AD, inhibits transcription and release of inflammatory cytokines operative in AD, but it is unknown if tacrolimus normalizes ceramide levels.. Stratum corneum ceramides of seven subjects with lesional AD were measured before and after treatment with tacrolimus ointment.. Treatment with tacrolimus ointment did not increase the ceramide fractions toward or to normal.. These findings suggest that tacrolimus ointment is effective in the treatment of atopic dermatitis due to its anti-inflammatory actions rather than to any restorative effect on stratum corneum ceramides.

Topics: Adolescent; Adult; Ceramides; Dermatitis, Atopic; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Ointments; Pilot Projects; Reference Values; Skin; Tacrolimus

In a subgroup of patients with atopic eczema (AE), aeroallergens are relevant eliciting factors. The atopy patch test (APT) was proposed as inflammation model for AE.. It was the aim of this study to investigate the effect of pretreatment with 1% pimecrolimus cream (Elidel) on the APT and skin prick test (SPT).. In a randomized, controlled, double-blind study, 20 patients with AE and positive SPT and APT screening reaction to house dust mite Dermatophagoides pteronyssinus, cat dander, grass or birch pollen were enrolled (age 20 +/- 11 years, 55% males). For 2 weeks, patients twice daily applied pimecrolimus and vehicle control to marked fields on their backs and forearms. Then, APT was performed (200 index of reactivity/g extracts in petrolatum; Stallergènes, France) on both fields on the back and SPT was performed on the pretreated forearms.. Including only patients with different readings (n = 13), stronger APT suppression of at least 1 ETFAD (European Task Force on Atopic Dermatitis) grade in the pimecrolimus area versus intraindividual control was observed in 10 of these patients after 48 and 72 h (p < 0.05; 90% CI 50.5-93.4). Including all 20 subjects, the analysis still showed a borderline significance compared with the vehicle (p = 0.0564). SPT with histamine and aeroallergens showed a median 7.5-10% reduction in actively pretreated areas (p = 0.086). Immunohistochemical analysis in 2 patients revealed an induction of interferon-gamma in primecrolimus-pretreated skin.. APT can be used as a model for AE skin inflammation. It was shown for the first time that pimecrolimus pretreatment has a potential to suppress the development of lesions induced by aeroallergen exposure in patients with AE.

Topics: Adult; Allergens; Animals; Biopsy, Needle; Cats; Cytokines; Dermatitis, Atopic; Dermatologic Agents; Double-Blind Method; Female; Humans; Immunoglobulin E; Immunohistochemistry; Male; Middle Aged; Patch Tests; Pyroglyphidae; Skin Tests; Statistics, Nonparametric; Tacrolimus

Only very recently studies were conducted in order to evaluate the impact of regulatory T (Treg) cells in the pathophysiology of atopic dermatitis (AD). Nine adult patients with moderate-to-severe AD in riacutization period of a chronic disease were given tacrolimus ointment, while seven hydrocortisone butyrate ointment, that served as controls. We performed lesional-skin biopsies before and after treatment, that were stained immunohistochemically with monoclonal antibodies to CD4, CD25, forkhead/winged helix transcription factor (FoxP3), interleukin (IL)-10 and transforming growth factor (TGF)-beta. CD4+ cells were significantly reduced in post-treatment series. Tacrolimus treatment achieved a significant reduction of CD25+ cells. FoxP3+ cells were present in untreated AD lesions. Both treatments did not significantly modify the number of FoxP3+ cells. The number of IL-10+ cells increased in post-treatment series. Tacrolimus enhanced the production of TGF-beta, while hydrocortisone did not. Restoration of TGF-beta-producing Treg cells may represent another important pharmacodynamic effect of tacrolimus on AD.

Topics: Adult; Biopsy; Chronic Disease; Dermatitis, Atopic; Female; Forkhead Transcription Factors; Humans; Hydrocortisone; Immunohistochemistry; Interleukin-10; Male; Middle Aged; Ointments; T-Lymphocytes, Regulatory; Tacrolimus; Transforming Growth Factor beta

Concern exists that the prolonged application of immunomodulators to treat atopic dermatitis may cause systemic immunosuppression.. In a 7-month, multicentre, randomised, controlled trial, we investigated the equivalence of response to vaccination against meningococcal serogroup C disease with a protein-conjugate vaccine in children (2-11 years) with moderate to severe atopic dermatitis, by applying either 0.03% tacrolimus ointment (TAC-O; n = 121[corrected]) or a hydrocortisone ointment regimen (HC-O; n = 111).. TAC-O was applied twice daily (bid) for 3 weeks, and thereafter daily until clearance. 1% hydrocortisone acetate (HA) for head/neck and 0.1% hydrocortisone butyrate ointment for trunk/limbs was applied bid for 2 weeks; thereafter HA was applied bid to all affected areas. At week 1, patients were vaccinated with protein-conjugate vaccine against meningococcal serogroup C, and challenged at month 6 with low dose meningococcal polysaccharide vaccine. The control group (44 non-atopic dermatitis children) received the primary vaccination and challenge dose. Assessments were made at baseline, weeks 1 and 5, and months 6 and 7. The primary end point was the percentage of patients with a serum bactericidal antibody (SBA) titre > or = 8 at the week 5 visit.. The response rate (patients with SBA titre > or = 8) was 97.5% (confidence interval (CI) approximately 97.3 to 100), 99.1% (94.8 to 100) and 97.7% (93.3 to 100) in the TAC-O, HC-O and control groups, respectively.. The immune response to vaccination against meningococcal serogroup C in children with atopic dermatitis applying either 0.03% TAC-O or HC is equivalent. Ointment application does not affect the immediate response to vaccination, generation of immune memory or humoral and cell-mediated immunity.

Topics: Administration, Topical; Antigens, CD; Child; Child, Preschool; Dermatitis, Atopic; Double-Blind Method; Female; Humans; Immunity, Cellular; Immunoglobulin Isotypes; Immunologic Memory; Immunosuppressive Agents; Male; Meningococcal Infections; Meningococcal Vaccines; Neisseria meningitidis, Serogroup C; Tacrolimus

To assess early intervention with pimecrolimus combined with corticosteroid (CS) for major flares in patients with severe atopic dermatitis (AD).. In this 6-month, double-blind, multicenter, randomized, vehicle-controlled, parallel-group in 35 US centers, 275 children aged 3 months to 11 years with mild to severe AD applied the study medication twice daily at first signs/symptoms of AD. For major flares not controlled with study medication, a mid-potency CS cream replaced the evening study drug for up to 3 weeks. The percentage of subjects with no major flares was the main outcome measure.. Pimecrolimus reduced the major flare incidence and prolonged flare-free intervals. Significantly more pimecrolimus subjects (52%) had no major flares compared with vehicle subjects (34%; p = 0.007). Pimecrolimus significantly delayed the first flare (median, 53 days vs 13 days; p<0.001), and increased the time between flares (median, 31 days vs 15 days). Additionally, there was earlier pruritus improvement (median, day 3 vs day 6; p = 0.034) in the pimecrolimus group, as well as a reduced need for CS by 37% (p = 0.020) [corrected] Adverse events (AEs) incidence and type were comparable between groups. Combination therapy with pimecrolimus used at half the recommended dose did not shorten the mean flare duration or alter the AE profile.. Early treatment of signs/symptoms of AD with pimecrolimus cream 1% provided an effective steroid-sparing option that reduced the incidence of major flares.

Topics: Administration, Cutaneous; Adrenal Cortex Hormones; Calcineurin Inhibitors; Child; Child, Preschool; Dermatitis, Atopic; Dermatologic Agents; Double-Blind Method; Drug Therapy, Combination; Female; Florida; Humans; Infant; Male; Missouri; New Jersey; Ohio; Severity of Illness Index; Tacrolimus; Treatment Outcome

Topical tacrolimus represents an effective and well-tolerated treatment for atopic dermatitis (AD). Its known effects include reduced production of proinflammatory cytokines and reduced chemokine gradient. We performed lesional skin biopsies on adult patients affected by moderate-to-severe AD. Then, patients were randomized to receive local treatment with tacrolimus ointment 0.1% and hydrocortisone butyrate ointment 1%. On the 21st day of treatment, another skin specimen was taken. Nine patients treated with tacrolimus and seven treated with hydrocortisone successfully concluded the trial. By immunohistochemistry (alkaline phosphatase/antialkaline phosphatase method), we demonstrated that endothelial leucocyte adhesion molecule (ELAM)-1, vascular cell adhesion molecule (VCAM)-1 and intercellular adhesion molecule (ICAM)-1 showed different intensities and patterns of expression in untreated AD lesions. Tacrolimus-treated specimens featured a significant reduction of the expression of ELAM-1, VCAM-1 and ICAM-1, while hydrocortisone-treated lesions did not. Inhibition of adhesion molecule expression may represent another selective mechanism of action of topical tacrolimus in AD.

Topics: Adult; Aged; Biopsy; Cell Adhesion Molecules; Dermatitis, Atopic; Dermatologic Agents; E-Selectin; Humans; Hydrocortisone; Immunoenzyme Techniques; Immunosuppressive Agents; Intercellular Adhesion Molecule-1; Middle Aged; Ointments; Skin; Tacrolimus; Vascular Cell Adhesion Molecule-1

Controlled studies established the efficacy and good tolerability of pimecrolimus cream 1% for the treatment of atopic dermatitis but they may not reflect real-life use.. To evaluate the efficacy, tolerability and cosmetic acceptance of a pimecrolimus-based regimen in daily practice in Switzerland.. This was a 6-month, open-label, multicentre study in 109 patients (55% > or = 18 years) with atopic dermatitis. Pimecrolimus cream 1% was incorporated into patients' standard treatment protocols.. The pimecrolimus-based treatment was well tolerated and produced disease improvement in 65.7% of patients. It was particularly effective on the face (improvement rate: 75.0%). Mean pimecrolimus consumption decreased from 6.4 g/day (months 1-3) to 4.0 g/day (months 3-6) as disease improved. Most patients (74.1%) rated their disease control as 'complete' or 'good' and 90% were highly satisfied with the cream formulation.. The use of a pimecrolimus-based regimen in everyday practice was effective, well tolerated and well accepted by patients.

Topics: Administration, Cutaneous; Adolescent; Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; Calcineurin Inhibitors; Child; Child, Preschool; Cohort Studies; Dermatitis, Atopic; Facial Dermatoses; Female; Follow-Up Studies; Humans; Infant; Male; Middle Aged; Ointments; Patient Satisfaction; Peptidylprolyl Isomerase; Safety; Tacrolimus; Treatment Outcome

Long-term in vitro compatibility of desoximetasone and tacrolimus ointments prompted the current trial in humans. We aimed to evaluate the efficacy of twice-daily simultaneous application of desoximetasone and tacrolimus in the treatment of atopic dermatitis versus tacrolimus monotherapy. Eighty-two subjects were treated in this multicenter, single-group, double-blinded, paired, 3-week follow-up clinical study of desoximetasone 0.25% and tacrolimus 0. 1% ointments versus tacrolimus 0.1% ointment and vehicle. Subjects were treated twice daily for 21 days or until clearing. Safety and efficacy were assessed at days 3, 7, 14, and 21. The combination of desoximetasone and tacrolimus ointment was superior to tacrolimus alone (P=.0002) in treating atopic dermatitis as measured by the summary of the scores for erythema, lichenification, pruritus, scaling/dryness, and oozing/crusting. Of note, pruritus at the application site was diminished in subjects treated with desoximetasone and tacrolimus together compared with tacrolimus alone (P=.04). Combination treatment with desoximetasone and tacrolimus offered increased efficacy and tolerability over tacrolimus alone in patients with atopic dermatitis.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Inflammatory Agents; Dermatitis, Atopic; Desoximetasone; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Middle Aged; Ointments; Tacrolimus

Atopic dermatitis (AD) is an immunological skin disease. It is common in pediatric populations and often requires topical steroid treatment. Moderate to severe AD may not respond to topical steroids. They often require systemic steroids, which may result in growth retardation. Protopic, a non-steroid, tacrolimus based ointment which is a calcinurin inhibitor has been proved to be effective in caucacian with AD.. To evaluate safety and efficacy of 0.03% tacrolimus ointment (Protopic&) in moderate to severe AD in pediatric patients age 2-12 years.. This was a one month multicenter open-label clinical trial using tacrolimus ointment twice daily in 61 subjects with moderate to severe AD from September to December 2004. Efficacy assessments were measured by Physician's Global Evaluation of Clinical Response (PhGECR), Eczema area and Severity Index (EASI), Patient's Global Evaluation of Clinical Response (PaGECR), and Quality of Life (QOL). Safety assessment was measured by incidence rate of adverse events.. Fifty-eight patients completed the studies. Twenty-two patients were male; thirty-nine patients were female. Twenty-nine patients had moderate AD. Thirty-two patients had severe AD. Three cases had discontinued treatment at the third week due to increase in severity. Over all PhGECR were significantly increased, 94% showed moderate improvement in PhGECR at week 4 or end of treatment (EOT)and 83% had better improvement in PaGECR at EOT Within 7 days, tacrolimus demonstrated rapid onset in reduction of EASI score and itch in patients. Mean QOL were significantly decreased at the end of the present study. Incidence of adverse events included application site burning (21%), itching (17%), pruritus (9%), infections(3%), and erythema and folliculitis (2%). Burning sensation, erythema, pruritus and itching were resolved after the first week.. Topical tacrolimus ointment is effective and safe in moderate to severe AD. It significantly improved PhGECR, EASI, PaGECR, and QOL in pediatric patients after the first week of treatment and continued through the end of the study. The major adverse events were burning, itching, and pruritus, which were resolved within the first week of therapy.

Topics: Administration, Topical; Child; Dermatitis, Atopic; Female; Humans; Immunosuppressive Agents; Male; Ointments; Quality of Life; Severity of Illness Index; Tacrolimus; Treatment Outcome

Pimecrolimus cream 1%, a cell-selective inhibitor of inflammatory cytokines, has been shown to be effective in treating atopic dermatitis (AD). This report examines the effect of ethnic origin and baseline disease severity on treatment outcomes in pediatric patients with AD treated with pimecrolimus cream 1%.. The analysis included 589 patients aged 3 months to 17 years from three 6-week, randomized, multicenter studies of similar design. Patients were treated with pimecrolimus cream 1% or vehicle twice daily. Efficacy, safety and tolerability in Caucasian and non-Caucasian groups were compared. In addition, the effect of baseline disease severity on treatment outcome was investigated.. A total of 321 Caucasian and 268 non-Caucasian patients [Blacks, Asians and others (including Hispanics)] with mild, moderate or severe disease at baseline were included. Baseline characteristics were comparable between the pimecrolimus and vehicle control groups and between Caucasian and non-Caucasian groups. Significantly higher efficacy [measured by Investigators' Global Assessment and Eczema Area and Severity Index (EASI) scores] was achieved in the pimecrolimus-treated group, compared with the vehicle group, irrespective of ethnic origin. Baseline disease severity had no effect on treatment outcome: patients with both mild and moderate AD responded well to pimecrolimus (absolute change from baseline in EASI score -2.60 and -5.48, respectively; both P < 0.001). Pimecrolimus cream 1% was safe and well tolerated in all ethnic groups and at all levels of disease severity.. Ethnic origin and baseline disease severity had no effect on treatment outcome with pimecrolimus cream 1% in patients with AD.

Topics: Adolescent; Asian; Black People; Calcineurin Inhibitors; Child; Child, Preschool; Dermatitis, Atopic; Dermatologic Agents; Double-Blind Method; Ethnicity; Hispanic or Latino; Humans; Infant; Peptidylprolyl Isomerase; Pharmaceutical Vehicles; Safety; Severity of Illness Index; Tacrolimus; Treatment Outcome; White People

The safety and efficacy of treatment with pimecrolimus cream 1% was evaluated for up to 2 years in infants and young children with atopic dermatitis. Ninety-one patients participated in a 1-year, open-label extension to a 1-year double-blind study. Of these, 76 received pimecrolimus for 2 years. Pimecrolimus was applied twice daily at the first signs or symptoms of the disease until clearance. Outcome measures included the incidence of adverse events and the Eczema Area and Severity Index (EASI).. No patient discontinued because of adverse events. The incidence of systemic and skin infections did not increase over time. Over the 2-year period, 2 patients experienced an episode of clinically diagnosed eczema herpeticum. In patients receiving pimecrolimus for 2 years, the mean decrease in EASI score from baseline was 68.7% at 3 months and 70.8% at 24 months.. Treatment with pimecrolimus cream 1% for up to 2 years was well tolerated and resulted in a marked and sustained improvement of atopic dermatitis.

Topics: Administration, Cutaneous; Dermatitis, Atopic; Double-Blind Method; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Infant; Male; Ointments; Remission Induction; Tacrolimus; Treatment Outcome

We investigated whether treatment of atopic dermatitis with pimecrolimus cream 1% in infants affects the development of a normal antibody response to vaccinations.. In all, 91 patients participated in a 1-year, open-label extension to a 1-year double-blind study: 76 used pimecrolimus twice daily at the first signs or symptoms of the disease until clearance for 2 years and 15 only in the second year. Serum concentrations of antibodies against tetanus, diphtheria, measles, and rubella were measured at months 18 and 24.. The seropositivity rates of 93.6% for tetanus, 88.6% for diphtheria, 88.5% for measles, and 84.4% for rubella were comparable with those reported in literature. Seropositivity was not significantly affected by the use of pimecrolimus at the time of vaccinations (+/- 28 days).. Treatment of atopic dermatitis with pimecrolimus cream 1% in early childhood does not appear to interfere with the development of a normal immune response to vaccinations.

Topics: Administration, Cutaneous; Antibodies, Bacterial; Antibodies, Viral; Antibody Formation; Clostridium tetani; Corynebacterium diphtheriae; Dermatitis, Atopic; Diphtheria Toxoid; Double-Blind Method; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Infant; Male; Measles Vaccine; Measles virus; Ointments; Prospective Studies; Rubella Vaccine; Rubella virus; Tacrolimus; Tetanus Toxoid; Vaccination

This investigator-blinded randomized controlled trial was designed to determine whether tacrolimus ointment (Protopic, Fujisawa Healthcare) decreased the severity of localized lesions of canine atopic dermatitis (AD). Twenty dogs with AD were enrolled if they exhibited lesions on both front metacarpi. Each foot was randomized to be treated with 0.1% tacrolimus or placebo (vaseline) ointment twice daily for 6 weeks. Before, and every 2 weeks during the study, erythema, lichenification, oozing and excoriations each were graded on a 10-point scale (maximal total score: 40). The primary outcome measures were the percentage reduction from baseline of lesional scores and the number of subjects whose scores had decreased by 50% or greater at study end. Intention-to-treat analyses were used. At study onset, lesional scores were not significantly different between sites treated with tacrolimus or placebo. After 6 weeks, the percentage reduction from baseline scores was higher for tacrolimus-treated sites (median: 63%; 95% confidence interval: 39-67) than for placebo-treated feet (median: 3%; confidence interval: -2-13) (Wilcoxon test; P = 0.0003). When tacrolimus was applied, lesions decreased by 50% or greater in 15/20 dogs (75%); these dogs were those that completed the study. In contrast, this benchmark was not reached for any placebo-treated feet (Fisher's test; P < 0.0001). Adverse drug events consisted of minor irritation in some lesional areas treated with tacrolimus. Results of this trial suggest that the application of 0.1% tacrolimus ointment is useful for reducing the severity of localized skin lesions of canine AD.

Topics: Administration, Topical; Animals; Dermatitis, Atopic; Dog Diseases; Dogs; Double-Blind Method; Female; Immunosuppressive Agents; Male; Ointments; Severity of Illness Index; Tacrolimus; Treatment Outcome

The pharmacokinetics of tacrolimus after first and repeated application of 0.1% tacrolimus ointment were evaluated in 39 children, aged 6-12 y, with moderate to severe atopic dermatitis. The patients were grouped according to the size of the affected body surface area to be treated: Group 1< or =1500 cm(2); Group 2 >1500 cm(2) < or =3000 cm(2); Group 3 >3000 cm(2) < or =5000 cm(2). Serial blood samples to calculate pharmacokinetic parameters taken on Day 1 (first ointment application) and Day 14 (last application) showed minimal systemic exposure to tacrolimus. Overall, 92% of the blood samples assayed contained tacrolimus concentrations below 1 ng per mL and 17% of samples were below 0.025 ng per mL, the lower limit of quantification. Systemic exposure to tacrolimus varied between patients and tended to increase proportionally as the size of the treated body surface area increased. Absorption decreased with time as the skin lesions healed and there was no evidence of systemic accumulation. The mean apparent half-life of tacrolimus (t(1/2, z)) was 66+/-27 h (range 19-125 h). Most patients experienced substantial clinical improvement in their atopic dermatitis. There were no clinically relevant changes in laboratory values, and the most frequently reported adverse event was skin burning, which resolved quickly as the skin condition improved.

Topics: Administration, Topical; Child; Dermatitis, Atopic; Female; Humans; Immunosuppressive Agents; Male; Ointments; Patient Dropouts; Severity of Illness Index; Tacrolimus

To compare the efficacy and safety of tacrolimus ointment and pimecrolimus cream in adult and pediatric patients with mild to very severe atopic dermatitis (AD).. One thousand and sixty-five patients were randomized to treatment in 3 multicenter, randomized, investigator-blinded, 6-week studies.. Based on the Eczema Area Severity Index (EASI), tacrolimus ointment was more effective than pimecrolimus cream at the end of the study in adults (54.1% vs. 34.9%, respectively; P < .0001), in children with moderate/severe disease (67.2% vs. 56.4%, respectively; P = .04), in the combined analysis (52.8% vs. 39.1%, respectively; P < .0001), and at week 1 in children with mild disease (39.2% vs. 31.2%, respectively; P = .04). Tacrolimus was also more effective than pimecrolimus based on the Investigator Global AD Assessment (IGADA), improvement in percentage of total body surface area affected, and improvement in itch scores (P < or = .05), with a faster onset of action. There was no significant difference in the incidence of adverse events (AEs), including application site reactions in the 2 studies involving 650 children. Adults treated with tacrolimus experienced a greater number of local application site reactions on day 1; both groups reported a similar incidence of application site reactions thereafter. More pimecrolimus-treated patients than tacrolimus-treated patients withdrew from the studies because of a lack of efficacy (P < or = .03) or adverse events (P = .002; pediatric mild).. Tacrolimus ointment is more effective and has a faster onset of action than pimecrolimus cream in adults and children with AD; their safety profiles are similar.

Topics: Adolescent; Adult; Child; Child, Preschool; Dermatitis, Atopic; Female; Humans; Male; Ointments; Patient Satisfaction; Tacrolimus

It is well known that topical tacrolimus is safe and effective in the treatment of atopic dermatitis (AD) patients. Tacrolimus is primarily an immunosuppressive agent without any antistaphylococcal effects. Thus colonization of Staphylococcus aureus on the skin of patients treated with this agent might be increased. The purpose of this study was to determine the effect of tacrolimus on S. aureus colonization in patients with AD and to compare the results with clinical severity and skin barrier function. We enrolled 65 patients with moderate to severe AD. They were treated with 0.03% tacrolimus ointment twice daily for 4 weeks. Clinical severity was assessed by the eczema area and severity index (EASI). S. aureus colonization was measured by the tape method. Skin barrier function was checked by measuring transepidermal water loss (TEWL). Evaluations were performed at weeks 0 (baseline), 1, 2 and 4. The results were compared and statistical analysis was performed. S. aureus colonization was significantly decreased with tacrolimus treatment at week 1 compared with baseline. However, there were no differences among weeks 1, 2 and 4. EASI and TEWL showed a decreasing tendency in a time-dependent fashion. The correlations between data were variable.

Topics: Administration, Topical; Adolescent; Adult; Blood-Air Barrier; Child; Child, Preschool; Colony Count, Microbial; Dermatitis, Atopic; Eczema; Female; Humans; Immunosuppressive Agents; Male; Seasons; Skin; Staphylococcus; Tacrolimus; Water Loss, Insensible

Apart from the long-used corticosteroids, topical calcineurin inhibitors (tacrolimus, pimecrolimus) represent novel therapeutic options for the treatment of atopic dermatitis.. This study was designed to investigate the pathophysiological target cells and mode of action of pimecrolimus in atopic skin.. Twenty-two patients were randomly assigned to treatment with pimecrolimus cream 1%, matching vehicle cream, or beta-methasone-17-valerate (BMV) cream 0.1% in a randomized, double-blind, vehicle-controlled, parallel group clinical trial. Treatment was given twice daily for 3 weeks. Cryostat sections of skin biopsies were taken before as well as at selected time points after initiation of therapy. For certain experiments, healthy volunteers were topically treated with the creams described twice a day on 5 consecutive days. Epidermal sheets were prepared from suction blisters. For in vitro experiments, untreated, healthy human skin was obtained from patients undergoing plastic surgery. The effect of pimecrolimus and BMV on Langerhans cells (LCs), inflammatory dendritic epidermal cells, and T cells was investigated by using immunofluorescence and flow-cytometry techniques.. While topical BMV treatment depleted LCs in healthy and atopic skin, pimecrolimus did not affect their number. Correlating with the disappearance of inflammatory cells, we observed a depletion of inflammatory dendritic epidermal cells and T cells on pimecrolimus and BMV treatment. Furthermore, we show that pimecrolimus depletes T cells by the induction of apoptosis.. In summary, our data show that pimecrolimus reduces pathological T cells in atopic dermatitis skin via apoptosis, whereas LCs remain unaffected.

Topics: Administration, Topical; Adolescent; Adult; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Cell Division; Dermatitis, Atopic; Double-Blind Method; Female; Humans; Langerhans Cells; Male; Middle Aged; Skin; T-Lymphocytes; Tacrolimus

Atopic dermatis (AD) is a chronic disease that often requires long-term treatment. Topical corticosteroids are the usual therapy for patients with AD, but prolonged usage can result in skin atrophy and other side-effects.. In a randomized, double-blind, comparative study, to compare the efficacy and safety of a 6-month treatment period with 0.1% tacrolimus ointment vs. a corticosteroid ointment regimen in adults with moderate to severe AD.. Treatment was applied twice daily for a maximum of 6 months. Patients in the tacrolimus treatment group (n = 487) applied 0.1% tacrolimus ointment to all affected areas over the whole body. The patients treated with the corticosteroid regimen (n = 485) applied 0.1% hydrocortisone butyrate ointment to affected areas on the trunk and extremities and 1% hydrocortisone acetate ointment to affected areas on the face and neck. The study primary endpoint was the response rate, i.e. the proportion of patients with at least 60% improvement in the modified Eczema Area and Severity Index (mEASI) between baseline and month 3.. By month 3, more patients in the 0.1% tacrolimus group responded to treatment (72.6% vs. 52.3% in the corticosteroid group, P < 0.001). The patients treated with 0.1% tacrolimus also showed greater improvement in mEASI, EASI, affected body surface area and physician and patient assessments of global response. Patients applying 0.1% tacrolimus ointment experienced more skin burning (52.4% vs. 13.8% in the corticosteroid group; P < 0.001). In most patients, skin burning was mild to moderate in severity and decreased rapidly after the first week of treatment. There was no increase in the incidence of infections or malignancies over time in either treatment group.. Long-term treatment with 0.1% tacrolimus ointment is significantly more efficacious than a corticosteroid ointment regimen in adults with moderate to severe AD.

Topics: Adult; Chi-Square Distribution; Dermatitis, Atopic; Dermatitis, Irritant; Double-Blind Method; Drug Administration Schedule; Female; Glucocorticoids; Herpes Simplex; Humans; Hydrocortisone; Immunosuppressive Agents; Male; Ointments; Sample Size; Statistics, Nonparametric; Tacrolimus; Time Factors; Treatment Outcome

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.. To investigate the efficacy and safety of oral pimecrolimus, and to determine the response to three different doses in the treatment of AD.. 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.. 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.. 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.

Topics: Administration, Oral; Adolescent; Adult; Aged; Analysis of Variance; Dermatitis, Atopic; Double-Blind Method; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Middle Aged; Safety; Tacrolimus

The systemic exposure to tacrolimus after first and repeated application of 0.1% tacrolimus ointment was investigated in 32 adults with moderate to severe atopic dermatitis. Patients were allocated to treatment groups according to the size of the affected area to be treated: Group 13000 cm(2)6000 cm(2)

Topics: Administration, Cutaneous; Adult; Dermatitis, Atopic; Female; Humans; Immunosuppressive Agents; Male; Ointments; Tacrolimus; Time Factors

This study was designed to evaluate the long-term safety and efficacy of 0.1% tacrolimus ointment in adult and pediatric patients with atopic dermatitis (AD).. A total of 408 adult and 391 pediatric patients with AD who had participated in a previous clinical trial of tacrolimus ointment were enrolled in this long-term, open-label, noncomparative trial. Tacrolimus ointment 0.1% was applied twice daily either intermittently or continuously to the affected areas. Efficacy and safety assessments included percent body surface area affected, Eczema Area and Severity Index score, individual signs of AD, and the incidence of adverse events.. A total of 799 patients were evaluated, of whom 300 (37.5%) were followed for more than 3 years (maximum 49 months). Improvements in efficacy parameters were observed within 1 week of treatment and continued for the duration of the study. Common adverse events included skin burning, pruritus, skin infection, skin erythema, flu-like symptoms, and headache. The incidence of adverse events, including cutaneous infections, did not increase with time on study.. Tacrolimus ointment therapy is a rapidly effective and safe treatment for the management of AD in pediatric and adult patients for up to 4 years.

Topics: Adolescent; Adult; Child; Child, Preschool; Dermatitis, Atopic; Female; Humans; Immunosuppressive Agents; Male; Ointments; Tacrolimus; Time Factors

Pimecrolimus cream 1% (Elidel), a non-steroid inhibitor of inflammatory cytokines, is effective in the treatment of atopic dermatitis, without corticosteroid-related side effects such as skin atrophy. It is indicated for twice-daily application. More frequent applications might be expected either to enhance efficacy or increase toxicity. This study compared the safety, efficacy and systemic absorption of pimecrolimus administered twice daily (recommended dose) and four times daily early in the treatment of patients with moderate to severe atopic dermatitis.. Adolescent and adult patients with moderate to severe atopic dermatitis were randomly assigned to a twice daily (BID) treatment group (n = 24) or a four times daily (QID) group (n = 25). During days 1-7, patients in the QID group applied pimecrolimus four times daily, and patients in the BID group applied pimecrolimus twice daily plus vehicle equivalent twice daily. During days 8-21, all patients were required to use pimecrolimus twice daily and had the option to use up to two further daily treatments (pimecrolimus in the QID group and vehicle equivalent in the BID group). Blood sampling occurred 2, 4, and 6 hours after the first morning application on days 1 and 5 and then prior to the first morning application on days 8 and 15, and any time on day 22.. Only 3 (12%) QID patients and 4 (17%) BID patients reported adverse events (primarily mild, transient application-site burning) with no significant difference between treatment groups in the frequency, type, or severity of adverse events. The median daily number of applications in the QID group during days 8-21 when two additional doses were optional remained at four. Pimecrolimus blood levels from a subgroup of 22 patients showed no difference in systemic exposure between the two dosing regimens. All but three (one in the QID group, two in the BID group) patients had blood levels below the limit of quantification; the highest single blood level of pimecrolimus measured in any patient was 1.37 ng/ml (QID group). Both the QID and BID regimens improved the signs and symptoms of atopic dermatitis similarly as measured by improvements in pruritus severity score, Investigator's Global Assessment, Eczema Area and Severity Index, percentage of body surface area affected, and patient's self-assessment of disease control.. The data suggest that increasing pimecrolimus application from twice daily to four times daily to treat moderate to severe atopic dermatitis for up to 3 weeks does not alter the safety profile nor does it increase the efficacy of treatment. Systemic absorption of pimecrolimus applied BID and QID is minimal and is not different between dosing regimens. Patients and physicians familiar with the potential hazards of overuse of topical corticosteroids should be reassured that if pimecrolimus is applied at twice the recommended BID dose for short periods of time, there is no effect on safety, tolerability, or systemic absorption.

Topics: Administration, Topical; Adolescent; Adult; Analysis of Variance; Area Under Curve; Dermatitis, Atopic; Dermatologic Agents; Double-Blind Method; Female; Humans; Male; Ointments; Prospective Studies; Safety; Statistics, Nonparametric; Tacrolimus; Treatment Outcome; United States

To determine whether atopic dermatitis (AD) patients treated with tacrolimus ointment experienced an increased risk of non-melanoma skin cancer (NMSC).. Data were collected from 9813 adult and paediatric patients with AD who applied 0.03% or 0.1% tacrolimus ointment twice daily and were examined every 3 months during the tacrolimus ointment development programme.. Thirteen adult patients were diagnosed with NMSC during the follow-up period. All patients with NMSC were white adults and 12 were over 40 years of age. Based on 1718 patient-years of tacrolimus ointment exposure in patients 40 years of age, the calculated incidence of NMSC did not suggest an increased risk of first NMSC over that of a similarly aged US cohort.. This study does not indicate an increased risk for the development of NMSC in patients with AD treated with tacrolimus ointment for a mean duration of 208 days with a maximum observation period of 1479 days.

Topics: Administration, Topical; Adult; Aged; Dermatitis, Atopic; Double-Blind Method; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Ointments; Skin Neoplasms; Tacrolimus; Treatment Outcome

This study was designed to compare the safety and efficacy of tacrolimus ointment 0.03% with vehicle ointment for the treatment of mild to moderate atopic dermatitis (AD) in pediatric patients.. A total of 317 patients (2-15 years of age) with mild to moderate AD were randomized to receive tacrolimus ointment or vehicle ointment twice daily in a 6-week, multicenter, double-blind study. Efficacy evaluations, including the Investigators' Global Atopic Dermatitis Assessment, eczema area and severity index, percentage of total body surface area affected, and patient assessment of itch occurred at baseline, day 4, and weeks 2, 4, and 6. Cutaneous adverse events were recorded to evaluate safety.. At the end of study, 50.6% (80 of 158) of the patients were treated successfully with tacrolimus ointment based on Investigators' Global Atopic Dermatitis Assessment scores, a significant improvement compared with patients treated with vehicle ointment (25.8% [41 of 159]). The percent improvement from baseline in eczema area and severity index scores was also significantly greater in tacrolimus-treated patients (54.8%) compared with vehicle-treated patients (20.8%). There was also a significant improvement in the percentage of total body surface area affected of tacrolimus-treated patients (50.5% reduction from baseline) compared with vehicle-treated patients (16.4%). Patient itch scores were significantly lower in tacrolimus-treated patients (2.1) versus vehicle-treated patients (3.7). Overall, the incidence of cutaneous adverse events reported was similar for both treatment groups. There was no significant difference in the incidence of burning or stinging between treatment groups. Significantly fewer tacrolimus-treated patients prematurely discontinued from the study because of a cutaneous adverse event in the treatment area or experienced increased itching and erythema at the application site.. Monotherapy with tacrolimus ointment 0.03% is a safe and effective treatment alternative for pediatric patients with mild to moderate AD.

Topics: Administration, Topical; Adolescent; Child; Child, Preschool; Dermatitis, Atopic; Double-Blind Method; Humans; Immunosuppressive Agents; Ointments; Pharmaceutical Vehicles; Tacrolimus

Atopic eczema begins primarily in infancy or early childhood, and sleep loss due to night-time pruritus can have a considerable impact on patients' and parents' quality of life (QoL). In this study, infants (n = 196) with mild to severe atopic eczema were randomized 2:1, double-blind, to receive either pimecrolimus cream 1% (Elidel, Novartis Pharma, Nürnberg, Germany) or the corresponding vehicle bid for 4 wk, followed by a 12 wk, open-label phase and a 4 wk, treatment-free, follow-up period. The parents' QoL was measured at baseline and at the end of the double-blind phase, using the questionnaire 'QoL in Parents of Children with Atopic Dermatitis' (PQoL-AD), thus data presented here refer to the initial 4-wk treatment phase only. After 4 wk of double-blind treatment, an increase in the mean percentage change from baseline in eczema area and severity index of 71.5% was observed with pimecrolimus, compared with 19.4% with vehicle. The increase in efficacy was paralleled by the following mean percentage changes from baseline in the five domains of the questionnaire in pimecrolimus and vehicle, respectively: psychosomatic well-being: 14.6% vs. 6.2%; effects on social life: 6.7% vs. 2.3%; confidence in medical treatment: 10.0% vs. 3.7%; emotional coping: 16.1% vs. 6.5%; acceptance of disease: 19.6% vs. 7.0%. Analysis (ancova) of the dependent variable difference from baseline and the covariate baseline value revealed values of p < 0.05 for all five domains, despite the very short duration of the study. It is concluded that improvements in atopic eczema in infants achieved by treatment with pimecrolimus have a significant beneficial effect on the QoL of parents.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Child, Preschool; Dermatitis, Atopic; Dermatologic Agents; Double-Blind Method; Female; Follow-Up Studies; Humans; Infant; Infant Welfare; Male; Parents; Quality of Life; Severity of Illness Index; Tacrolimus; Treatment Outcome

We sought to compare pharmacokinetics of pimecrolimus cream 1% and tacrolimus ointment 0.1% in adults with extensive, moderate to severe atopic dermatitis. Secondary end points included efficacy and safety.. Patients received twice-daily treatment for 13 days. Blood concentrations of pimecrolimus and tacrolimus were measured at days 1, 5, and 13. Treatment success was defined as an Investigators' Global Assessment score of 0 (clear) or 1 (almost clear).. Tacrolimus was detectable in 36% of blood samples and pimecrolimus was detectable in 12%. In patients with measurable blood drug concentrations, systemic exposure to tacrolimus (mean area under the curve(0-10h) < 9.7 ng.h/mL; n = 7) was higher than to pimecrolimus (mean area under the curve(0-10h) < 2.5 ng.h/mL; n = 2). Whole-body treatment success (day 13) was achieved in 1 of 18 (5.6%) and 2 of 19 (10.5%) patients treated with pimecrolimus and tacrolimus, respectively, and face/neck treatment success in 5 of 18 (27.8%) and 5 of 19 (26.3%) patients, respectively. Patients included in the study were adult patients with severe atopic dermatitis. The results and conclusions drawn from this study population may not be applicable for the majority of patients with atopic dermatitis who have mild to moderate disease.. Pimecrolimus appears to be associated with lower systemic drug exposure than tacrolimus.

Topics: Adult; Area Under Curve; Calcineurin Inhibitors; Dermatitis, Atopic; Dermatologic Agents; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Single-Blind Method; Tacrolimus

To validate the Eczema Area and Severity Index (EASI) by assessing its internal consistency, reliability and sensitivity to change and by correlating it to other efficacy parameters.. Three short-term and two long-term double-blind, randomized, controlled trials, performed in 138 study centres in Europe, South Africa, Australia, New Zealand, and North and South America.. In total, 1550 paediatric patients with atopic dermatitis were studied. Pimecrolimus cream 1% was used twice daily to treat atopic dermatitis. The three short-term studies were placebo controlled. The two long-term studies evaluated the efficacy and safety of early intervention with pimecrolimus to prevent progression to disease flare requiring topical corticosteroid treatment, compared with reactive treatment with topical corticosteroids to treat flares of atopic dermatitis.. Five parameters were measured: (i) the EASI (range of score 0-72); (ii) Investigators' Global Assessment (IGA), using a six-point (0-5) scale; (iii) patients' assessment, using a four-point (0-3) scale; (iv) severity of pruritus assessment, using a four-point (0-3) scale; and (v) a quality-of-life evaluation.. The EASI score varied in parallel and in correlation with the IGA, pruritus and patients' assessment. All correlation coefficients were statistically different from 0 (P < 0.05). The EASI correlated well with each of its components, and all paired comparisons were within agreed limits. The EASI showed good sensitivity to changes in severity.. In a large, multinational patient population with atopic dermatitis, the EASI showed good validity, reliability and sensitivity to change and correlated well with other measures of severity. It therefore qualifies as a valid method of assessment in clinical studies of atopic dermatitis.

Topics: Adolescent; Child; Child, Preschool; Cohort Studies; Dermatitis, Atopic; Double-Blind Method; Humans; Immunosuppressive Agents; Reproducibility of Results; Sensitivity and Specificity; Severity of Illness Index; Tacrolimus; Treatment Outcome

Atopic dermatitis is a chronically relapsing, common inflammatory skin disease, which significantly affects quality of life negatively in many respects. Topical steroids are the mainstay of atopic dermatitis treatment but they carry the risk of local side effects. A topical formulation of tacrolimus, a macrolide calcineurin inhibitor, has recently been developed.. To evaluate the efficacy and safety of 0.03% tacrolimus ointment for the treatment of moderate to severe atopic dermatitis in Korea.. An open, non-comparative, multi-center study with 4 weeks' follow-up was performed. A total of 180 patients (aged 2-57 years old) were enrolled. Tacrolimus ointment (0.03%) was applied to all involved areas twice daily. Efficacy was evaluated by an investigator's global assessment, the eczema area and severity index score, and by the patient's assessment of pruritus and clinical response at baseline, and after weeks 1, 2 and 4. Dermatology life quality index (DLQI), children's DLQI (CDLQI) and toddler's DLQI were assessed at baseline and at week 4. The safety assessment included monitoring all adverse events and clinical laboratory values.. All efficacy parameters were improved. The mean EASI (eczema area and severity index) score was 19.7 at baseline and reduced to 8.0 at the end of the study. Moderate improvement was observed by the investigator's global assessment after 4 weeks' treatment. A marked decrease of pruritus was observed, and mild or moderate improvement was observed by patients' global assessments after the treatment period. Significant benefits in terms of quality of life in adults and children with atopic dermatitis were obtained. The most common adverse events associated with tacrolimus treatment were transient skin burning sensation (45.3%) and pruritus (41.6%) at the site of application.. 0.03% tacrolimus ointment should be considered effective and safe in both Korean children and adults with moderate to severe atopic dermatitis.

Topics: Administration, Cutaneous; Adolescent; Adult; Child; Child, Preschool; Dermatitis, Atopic; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Ointments; Tacrolimus

A multicenter, randomized, vehicle-controlled, 3-week study was conducted in patients with chronic hand dermatitis (HD) of various etiologies and locations to identify subgroups particularly responsive to twice-daily application of pimecrolimus cream 1% with overnight occlusion. A total of 294 patients were randomized to the study. By the final visit on day 22, there was a trend toward greater clearance in patients who received pimecrolimus than in those treated with vehicle cream. An analysis of treatment success by various stratification factors was performed, and it was found that palmar involvement had notable impact on response (P = .033). Patients in the pimecrolimus group continued to improve throughout the study; however, in the vehicle group, improvement plateaued after 15 days. Pimecrolimus was well tolerated, with a low rate of application-site reactions such as burning. Pimecrolimus cream 1%, when used twice daily with overnight occlusion, may be of benefit in the management of chronic HD.

Topics: Administration, Topical; Adolescent; Adult; Aged; Aged, 80 and over; Chronic Disease; Dermatitis, Atopic; Double-Blind Method; Emollients; Female; Follow-Up Studies; Hand Dermatoses; Humans; Male; Middle Aged; Probability; Reference Values; Risk Assessment; Tacrolimus; Treatment Outcome

There is clinical uncertainty concerning the effectiveness of the new topical immunomodulators vs. the conventional use of topical steroids for the treatment of atopic dermatitis.. To assess patient satisfaction with these two prescription topical remedies for atopic eczema.. In an open-label, 2-week, comparative study, 10 patients demonstrating atopiform dermatitis were given tacrolimus and 0.1% hydrocortisone butyrate in a 70% oil-in-water base to apply to the eczema on opposite sides of the body. After 2 weeks of applying the agents twice daily to their respective sides of the body surface, the study subjects completed a 12-question survey to assess their opinions of the two products.. There was a preference for the nonfluorinated topical steroid over tacrolimus in this cursory head-to-head study. There were no withdrawals from the study or side-effects reported with either product.. Trials of short duration with small numbers of patients do not adequately inform practitioners regarding the use of these topical remedies. However, the higher satisfaction of patients with 0.1% hydrocortisone butyrate in a 70% oil-in-water base over tacrolimus certainly warrants further investigation.

Topics: Administration, Cutaneous; Adolescent; Adult; Anti-Inflammatory Agents; Child; Dermatitis, Atopic; Female; Humans; Hydrocortisone; Immunosuppressive Agents; Male; Middle Aged; Patient Satisfaction; Pilot Projects; Surveys and Questionnaires; Tacrolimus; Treatment Outcome

Topical corticosteroids are the usual treatment for atopic dermatitis (AD) in children but can have side-effects.. This study compared the efficacy and safety of 0.03% tacrolimus ointment applied once or twice daily over a 3-week period with the twice daily application of 1% hydrocortisone acetate (HA) ointment in children with moderate to severe AD.. Patients applied ointment daily to all affected body surface areas. The primary study endpoint was the percentage change in the modified Eczema Area and Severity Index (mEASI) between baseline and treatment end.. Six hundred and twenty-four patients, aged 2-15 years, applied 0.03% tacrolimus ointment once daily (n = 207), twice daily (n = 210) or 1% HA twice daily (n = 207). By the end of treatment, application of 0.03% tacrolimus ointment both once or twice daily resulted in significantly greater median percentage decreases in mEASI (66.7% and 76.7%, respectively) compared with 1% HA (47.6%; P < 0.001). Furthermore, the median percentage decrease in mEASI was significantly greater for patients applying 0.03% tacrolimus twice daily compared with once daily (P = 0.007). Patients with severe AD benefited especially from twice daily application of 0.03% tacrolimus ointment compared with once daily application (P = 0.001). Transient mild to moderate skin burning occurred significantly more often in the 0.03% tacrolimus groups (P = 0.028) but resolved in most cases within 3-4 days. Laboratory parameters showed no clinically relevant changes.. 0.03% tacrolimus ointment applied once or twice daily is significantly more efficacious than 1% HA in treating moderate-severe AD in children. Twice daily application of 0.03% tacrolimus ointment results in the greatest improvement in mEASI, and is especially effective in patients with severe baseline disease.

Topics: Administration, Topical; Adolescent; Anti-Inflammatory Agents; Burns, Chemical; Child; Child, Preschool; Dermatitis, Atopic; Double-Blind Method; Drug Administration Schedule; Drug Eruptions; Female; Humans; Hydrocortisone; Immunosuppressive Agents; Male; Ointments; Patient Satisfaction; Severity of Illness Index; Tacrolimus; Treatment Outcome

Atopic dermatitis (AD) is a chronic allergic inflammatory disease, which manifests itself with eczematous skin lesions.. We compared the clinical efficacy of tacrolimus ointment (0.1%) given twice a day and oral cyclosporine (3 mg/kg) given once daily. Rescue medication for itching included cetirizine 10-20 mg (equal to one or two tables).. Thirty patients, aged 13-45 years (mean+/-SD 27.1+/-10.9), with a history of moderate-to-severe AD were randomized to treatments, 15 patients for each treatments. Assessment of efficacy was based on SCORAD, on scores of daily itching, erythema, interference with sleep, due to the skin condition and days without use of cetirizine tablets. SCORAD, measured on a scale (0-103), was evaluated before treatment (0) and at 7, 14, 21, 28, 35 and 42 days after treatment. Similarly, the means of daily symptoms, on a scale (0-3), were evaluated before the treatment (0) and at 7, 14, 21, 28, 35 and 42 days after treatment; finally, on day without use of cetirizine tablets. The safety of the study treatments was assessed through haematologic, biochemical and urinary testing and on systolic and diastolic blood pressures and heart rate measurements.. SCORAD decreased in the two treatment groups 14 days after the beginning of the period study. However, the patients in tacrolimus ointment group reported significantly lower SCORAD than those treated with oral cyclosporine. Overall SCORAD, as assessed by the area under the curve (AUC) day(0-42) (score/day), was significantly lower in the tacrolimus ointment group when compared with oral cyclosporine (P<0.001). Similarly, AUC day(0-42) (score/day) for itching, erythema and number of nights without interference with the sleep due to skin condition were significantly lower in the group of patients treated with tacrolimus compared with those treated with cyclosporine (P=0.003, 0.005 and 0.01, respectively). As regards the use of rescue medication, expressed by median of number of days without use of anti-H(1), it was significantly lower in the group treated with tacrolimus (82.5) than in the cyclosporine group (76.5) (P=0.03). There were no appreciable changes in haematological and biochemical indices, in both treatments groups.. The results of this comparative study demonstrate that tacrolimus ointment twice daily and cyclosporine administered orally once daily are effective on SCORAD, daily symptoms and anti-H(1) rescue. When we compared tacrolimus and cyclosporine there was a faster onset of action in the group treated with tacrolimus. The two drugs presented the same safety. However, these data support the preferential use of topical tacrolimus 0.1% in AD, because cyclosporine has potential side-effects.

Topics: Administration, Oral; Adolescent; Adult; Cyclosporine; Dermatitis, Atopic; Double-Blind Method; Drug Administration Schedule; Eosinophils; Female; Humans; Immunoglobulin E; Immunosuppressive Agents; Leukocyte Count; Male; Middle Aged; Ointments; Severity of Illness Index; Tacrolimus

The safety and efficacy of tacrolimus ointment 0.1% (Protopic) in the treatment of atopic dermatitis of the eyelids were assessed in an open-label clinical trial of 21 patients with moderate to severe eyelid dermatitis. Of those 21 patients, 20 received study drug and were followed. Patients applied tacrolimus ointment 0.1% twice daily for 8 weeks and were followed for 2 additional weeks after the last day of treatment. Complete eye examinations were conducted throughout the study. Efficacy was assessed through the investigator's evaluation of the patients' individual signs and symptoms of eyelid dermatitis and the physician global assessment (PGA) of eyelid clinical response. Improvement in the investigator's evaluation of the signs and symptoms of eyelid dermatitis was observed during the study. A total of 80% of patients (16/20) experienced marked improvement or better in PGA at 8 weeks. Adverse events were limited to local burning and itching after the first few applications of study medication. Of the 20 patients, 12 reported burning (60%), and 5 reported itching (25%). There was no statistically significant increase in intraocular pressure (IOP) during the study compared with baseline. In addition, none of the patients developed cataracts or glaucoma during the study. In summary, tacrolimus ointment 0.1% may be a safe and effective treatment option for patients with moderate to severe eyelid dermatitis.

Topics: Administration, Topical; Adult; Aged; Dermatitis, Atopic; Eyelids; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Middle Aged; Ointments; Severity of Illness Index; Tacrolimus; Treatment Outcome

Pimecrolimus cream 1% is a non-steroid, selective inflammatory cytokine inhibitor indicated for atopic dermatitis (AD).. To compare the safety and efficacy of pimecrolimus cream 1%-based treatment versus conventional therapy in adults with moderate AD.. Patients were randomized to receive pimecrolimus cream 1% (n = 62) or vehicle (n = 68) at the first signs/symptoms of AD, for 24 weeks as required. A moderately potent topical corticosteroid (prednicarbate 0.25% cream) was allowed in both groups to treat flares.. Corticosteroids were required on fewer days in the pimecrolimus group, compared with the vehicle group (9.7 vs. 37.8%, p < 0.001). Furthermore, 59.7% of pimecrolimus-treated patients experienced no flares during the study period, compared with 22.1% of vehicle-treated patients (p < 0.001). Pimecrolimus cream 1% was well tolerated throughout the study.. For adults with moderate AD, pimecrolimus cream 1% is well tolerated, reduces the incidence of flares, reduces/eliminates corticosteroid use, improves long-term disease control and enhances the patients' quality of life.

Topics: Administration, Cutaneous; Adolescent; Adult; Dermatitis, Atopic; Dermatologic Agents; Double-Blind Method; Drug Administration Schedule; Female; Germany; Humans; Male; Middle Aged; Severity of Illness Index; Tacrolimus; Treatment Outcome

This randomized, double-blind, multi-centre study compared the long-term safety and tolerability of pimecrolimus cream 1% and topical corticosteroids (TCS) in 658 adults with moderate-severe atopic dermatitis (AD).. Patients applied either pimecrolimus or TCS (i.e. 0.1% triamcinolone acetonide cream and/or 1% hydrocortisone acetate cream) twice daily to all affected areas until complete clearance or for up to 1 year. The study was approved by the institutional review board or ethics committee at each centre.. A majority of patients treated with either pimecrolimus or TCS used the drug on a continuous basis over 1 year. In patients who had >30% of the body surface involved by AD, the incidence rate of all skin infections was significantly lower in the pimecrolimus group than in the TCS group (95% CI of the treatment difference: -25.3% to -3.4%). The most frequent application site reaction was burning (25.9% of patients on pimecrolimus and 10.9% on TCS), which was transient and mild-moderate in most cases. Three TCS-treated patients reported skin striae. There were no treatment-related serious or clinically significant systemic adverse events. Efficacy was better in patients on continuous TCS therapy, although patients completing the study were similarly well-controlled in both groups. About 42% of the pimecrolimus-treated patients were maintained for 1 year without TCS.. Pimecrolimus demonstrated a favourable safety profile when used to treat adult patients with moderate-severe AD for up to 1 year. A significant proportion of patients could be maintained without TCS for a year.

Topics: Administration, Cutaneous; Adolescent; Adrenal Cortex Hormones; Adult; Aged; Canada; Dermatitis, Atopic; Double-Blind Method; Drug Administration Schedule; Europe; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Severity of Illness Index; Tacrolimus; Treatment Outcome; United States

Topical corticosteroids decrease collagen synthesis during short-term treatment and can induce skin atrophy when applied over the long term. In contrast, short-term tacrolimus ointment therapy does not affect collagen synthesis.. Our aim was to evaluate the long-term effects of 0.1% tacrolimus ointment on collagen synthesis and on skin thickness in adults with moderate to severe atopic dermatitis (AD) and to compare the findings with the effects of conventional steroid-based therapy.. Fifty-six patients with AD were treated with 0.1% tacrolimus ointment in a 1-year, open-label, prospective clinical trial. Thirty-six patients with AD applied conventional steroid-based therapy and 27 healthy subjects were recruited as controls. The primary endpoint was the change in levels of procollagen propeptides I and III measured by radioimmunoassay between baseline and month 12. Additional endpoints included the change in skin thickness measured by ultrasound between baseline and month 12.. Procollagen propeptide baseline values were significantly lower in the group to be treated with tacrolimus ointment than in healthy controls. One-year treatment with tacrolimus ointment was associated with an increase in collagen synthesis; the median increase in combined procollagen propeptide levels was 272 micro g L-1 (+ 140.9%, P < 0.001) and was accompanied by a significant increase in skin thickness. In three patients with visible skin atrophy, this condition ameliorated. Corticosteroid-based therapy had no significant effect on collagen synthesis; the median increase in combined procollagen propeptide levels was 11 micro g L-1 (+ 3.9%). A significant reduction in skin thickness was demonstrated.. Long-term tacrolimus ointment therapy in patients with AD is nonatrophogenic and reverses corticosteroid-induced skin atrophy.

Topics: Administration, Topical; Adult; Case-Control Studies; Collagen; Collagen Type I; Collagen Type III; Dermatitis, Atopic; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Male; Middle Aged; Prospective Studies; Skin; Statistics, Nonparametric; Tacrolimus; Ultrasonography

Tacrolimus ointment (TAC) is an effective treatment for atopic dermatitis in humans and dogs. The purposes of the present study were to evaluate the effect of 4 weeks of TAC on intradermal skin testing (IST), and in case of suppression, to investigate if reactivity returned to baseline by 2 or 4 weeks post treatment. Intradermal skin test was performed using saline, histamine, lipopolysaccharide (LPS, 0.4 mg mL(-1)), house dust (25 PNU mL(-1)) and house dust mite (1 : 40 000 w/v) at weeks 0, 4, 6 and 8 on nine dogs enrolled in a blinded, crossover, clinical trial, using 0.1% TAC or placebo once daily for 4 weeks. Reactions were evaluated at 15 min, and at 4 and 6 h. Ointment was applied after the 15-min evaluation on weeks 0 and 4. Data were analysed using the statistical software SAS System for Windows. At week 4, TAC did not affect 15-min IST, but some reactions in the TAC group were suppressed at 6 h compared to baseline. In the TAC group, 4-h IST reactivity was reduced 2 weeks after discontinuation but returned to baseline by 4 weeks. In conclusion, TAC has no effect on immediate reactions but decreased some late-phase reactions. Therefore, no withdrawal is recommended to evaluate only immediate reactions, but a 4-week withdrawal may be necessary for evaluation of late-phase reactions.

Topics: Administration, Cutaneous; Allergens; Animals; Antigens, Dermatophagoides; Cross-Over Studies; Dermatitis, Atopic; Dog Diseases; Dogs; Double-Blind Method; False Negative Reactions; Female; Immunosuppressive Agents; Intradermal Tests; Male; Ointments; Skin; Tacrolimus

To evaluate pimecrolimus cream 1% and tacrolimus ointment 0.03% in pediatric patients with moderate atopic dermatitis (AD).. 141 patients (aged 2-17 years) were randomized to treatment with pimecrolimus cream 1% (n=71) or tacrolimus ointment 0.03% (n=70) twice daily for 6 weeks.. At day 4, local, application-site reactions were less common and of shorter duration with pimecrolimus than with tacrolimus. Incidence of erythema/irritation was 8% (6/71) with pimecrolimus compared with 19% (13/70) with tacrolimus (P=.039). Fewer patients receiving pimecrolimus (0%, 0/6) experienced erythema/irritation lasting >30 minutes, compared with those receiving tacrolimus (85%, 11/13; P <.001). Fewer patients reported itching with pimecrolimus (8%; 6/71) than with tacrolimus (20%; 14/70; P=.073). Incidence of warmth, stinging, and burning was similar in both groups; however, reactions lasting >30 minutes were fewer with pimecrolimus (0%, 0/14) than with tacrolimus (67%, 8/12; P <.001). More patients receiving pimecrolimus rated ease of application as 'excellent' or 'very good', compared with tacrolimus (76% vs 59%, respectively; P <.020). Efficacy was similar in both groups at day 43. Both treatments were generally well tolerated with no unexpected adverse events.. Pimecrolimus cream 1% had better formulation attributes and local tolerability than tacrolimus ointment 0.03% while providing similar efficacy and overall safety in pediatric patients with moderate AD.

Topics: Adolescent; Child; Child, Preschool; Dermatitis, Atopic; Dermatitis, Irritant; Dermatologic Agents; Drug Administration Schedule; Drug Combinations; Erythema; Female; Humans; Male; Ointments; Patient Satisfaction; Pruritus; Tacrolimus

Topics: Administration, Topical; Adolescent; Child; Dermatitis, Atopic; Female; Humans; Immunosuppressive Agents; Male; Pruritus; Skin; Sleep Wake Disorders; Tacrolimus; Treatment Outcome

Topics: Administration, Cutaneous; Administration, Topical; Adult; Allergens; Animals; Cats; Dermatitis, Atopic; Dogs; Double-Blind Method; False Negative Reactions; Humans; Hypersensitivity; Immunosuppressive Agents; Skin Tests; Tacrolimus

To investigate the role of nuclear factor kappaB (Rel/NF-kappaB) in pathogenesis of atopic dermatitis(AD) and the effect of topical 0.1%(mass fraction) or 0.03%(mass fraction) tacrolimus ointment on expression of NF-kappaB in lesional AD skin.. Immunohistochemistry has been employed to study the expression of NF-kappaB in normal skin and lesional AD skin before and after using topical tacrolimus ointment.. The expressions of NF-kappaBp50 and NF-kappaBp65 were scattering or negative in normal keratinocytes. NF-kappaBp50 was overexpressed on nuclear of basal and suprabasal keratinocytes in 9 cases of AD, NF-kappaBp65 was overexpressed in cytoplasm and perinuclear of basal and suprabasal keratinocytes. After using topical tacrolimus ointment for three weeks , nuclear NF-kappaBp50 expressed on basal and suprabasal keratinocytes were lost and NF-kappaBp50 was expressed sparsely on basal keratinocytes cytoplasm or nuclear. NF-kappaBp65 was expressed sparsely on basal and suprabasal keratinocytes cytoplasm.. These data suggest that increased NF-kappaB activity may represent the basis of initiation or maintenance of the skin inflammatory response in atopic dermatitis. Topical tacrolimus may directly or indirectly inhibit NF-kappaB nuclear expression in keratinocytes and inhibit skin innate immuno-inflammatory response in atopic dermatitis that related to NF-kappaB.

Topics: Administration, Cutaneous; Adolescent; Adult; Child; Child, Preschool; Dermatitis, Atopic; Drug Administration Schedule; Female; Humans; Immunohistochemistry; Immunosuppressive Agents; Keratinocytes; Male; Middle Aged; NF-kappa B; NF-kappa B p50 Subunit; Skin; Tacrolimus; Transcription Factor RelA; Treatment Outcome

Atopic dermatitis (AD) is a common, chronic, relapsing, severely pruritic, eczematous skin disease. Topical steroids are the mainstay of treatment. However, the adverse effects of steroids on hormonal function are the major obstacle for their use as long-term topical therapy. Intermittent dosing with potent topical steroids and/or combination therapy with steroid and tacrolimus have been frequently used in the daily management of AD to overcome the problems accompanying the long term use of steroids. We compared the clinical effects of topical steroid/tacrolimus and steroid/emollient combination treatments in 17 patients with AD. An intermittent topical betamethasone butyrate propionate/tacrolimus sequential therapy improved lichenification and chronic papules of patients with AD more efficiently than an intermittent topical betamethasone butyrate propionate/emollient sequential therapy after four weeks of treatment. Only one out of 17 patients complained of a mild, but temporary, burning sensation after tacrolimus application. The intermittent topical steroid/tacrolimus sequential therapy may be a useful adjunctive treatment for AD.

Topics: Acute Disease; Administration, Topical; Adolescent; Adult; Betamethasone; Chi-Square Distribution; Chronic Disease; Dermatitis, Atopic; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Emollients; Female; Follow-Up Studies; Humans; Male; Middle Aged; Probability; Risk Assessment; Tacrolimus; Treatment Outcome

Topical tacrolimus is successfully used in people with atopic dermatitis. Preliminary studies in dogs with atopic dermatitis using tacrolimus in a compounded lotion formulation indicated that tacrolimus significantly decreased erythema and pruritus according to investigator, but no significant improvement was reported by the dog owners. The objectives of this study were to evaluate the clinical efficacy and safety of the commercially available 0.1% tacrolimus ointment (Protopic) in dogs with atopic dermatitis. The study was designed as a double-blinded, placebo-controlled, cross-over study. Selected dogs were allocated to either tacrolimus or placebo for 4 weeks. After 4 weeks there was a wash-out period of 2 weeks and treatments were switched. Twelve dogs completed the study. Clinical signs were scored. Blood samples were collected for complete blood count, chemistry panels and tacrolimus levels at week 0 and 4 of each treatment. Tacrolimus ointment significantly decreased severity of symptoms for both owners and investigators at the end of the trial. When the same dogs received the placebo, there were no differences between week 0 and week 4 scores. Dogs with localized disease responded better than dogs with generalized disease. Tacrolimus was detected in the blood of animals receiving the active ingredient. Levels were below the level of toxicity and no adverse effects were reported in any of the dogs. No changes in complete blood count and chemistry parameters were detected between groups or within groups. In conclusion, tacrolimus appears to be a safe alternative treatment in dogs with atopic dermatitis, especially in those with localized disease.

Topics: Administration, Cutaneous; Animals; Cross-Over Studies; Dermatitis, Atopic; Dog Diseases; Dogs; Double-Blind Method; Female; Immunosuppressive Agents; Male; Ointments; Pedigree; Severity of Illness Index; Tacrolimus; Treatment Outcome

Data on the efficacy of pimecrolimus cream 1% within the first days of treatment are scarce, as in previous studies, the first postbaseline assessment was performed only after 1 week.. We sought to investigate the onset of action of pimecrolimus cream 1% in infants with mild to very severe atopic eczema.. We used pimecrolimus cream 1% (n = 129) or vehicle cream (n = 66) administered in a double-blind manner for 4 weeks and then open-label pimecrolimus cream 1% for 12 weeks, with a 4-week follow-up period.. Pimecrolimus cream 1% reduced the mean Eczema Area and Severity Index at 4 weeks by 71.5% compared with an increase of 19.4% with vehicle ( P < .001). The reduction in the Eczema Area and Severity Index with pimecrolimus cream 1% was significant at day 4 (38.5% vs 17.6% increase with vehicle). Significant improvements in caregivers' assessments of pruritus and sleep loss were observed with pimecrolimus cream 1% by day 2 ( P < .03) and day 3 ( P = .002), respectively, compared with vehicle. Responses to pimecrolimus cream 1% were sustained during the open-label phase, and pimecrolimus cream 1% was well tolerated. Symptoms of atopic eczema returned gradually after discontinuation.. Pimecrolimus cream 1% was well tolerated and effective in patients with mild to very severe atopic eczema, with rapid onset of action and no disease rebound after discontinuation.

Topics: Dermatitis, Atopic; Double-Blind Method; Female; Follow-Up Studies; Humans; Infant; Male; Ointments; Tacrolimus

In the published studies on the efficacy of the topical immunomodulator pimecrolimus, different eczema scores were used, and the impact on morphological key signs of eczema was not analysed.. To compare the influence of pimecrolimus cream 1% on different standard eczema scores in infants with atopic dermatitis and to analyse the impact of treatment on the individual morphological key signs of eczema.. Pimecrolimus cream 1% (n = 129) or double-blind vehicle control (n = 66) was administered for 4 weeks. The Eczema Area and Severity Index (EASI), Investigators' Global Assessment (IGA) and Scoring Atopic Dermatitis Index (SCORAD) were determined and were correlated with each other.. Following treatment with pimecrolimus, the EASI, IGA and SCORAD were significantly reduced on day 29 as compared with the vehicle group (p < 0.001, p < 0.001, p = 0.002, respectively). There was a close correlation between EASI, IGA and SCORAD. The single parameters of the EASI were already significantly decreased by day 4 in the pimecrolimus group as compared to vehicle (each p < 0.001).. Treatment with pimecrolimus 1% cream leads to a rapid improvement of all morphological signs of eczema. The close correlation of different scores was shown for the first time.

Topics: Administration, Topical; Biopsy, Needle; Dermatitis, Atopic; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Eczema; Female; Follow-Up Studies; Humans; Immunohistochemistry; Infant; Male; Ointments; Probability; Reference Values; Risk Assessment; Severity of Illness Index; Tacrolimus; Treatment Outcome

This report investigates the effect of pimecrolimus cream 1% (Elidel, Novartis pharma AG, Basel, Switzerland), a nonsteroid, cell-selective, cytokine inhibitor on the course of atopic dermatitis (AD), as assessed by changes in body surface involvement and pattern of drug use over time.. Data from 961 patients in two 1-year double-blind, multicenter, pediatric studies of similar design were analyzed: 250 infants (aged 3-23 months) were randomized 4 : 1 and 711 children (aged 2-17 years) were randomized 2 : 1 to receive pimecrolimus cream 1% or vehicle, respectively. Emollients were used by all patients to alleviate dry skin and, at the first signs or symptoms of AD, pimecrolimus or vehicle was applied twice daily to prevent progression to flares. If flares occurred in either group, moderately potent topical corticosteroids were mandated.. Pimecrolimus was applied for 68.4% (infants) and 53.8% (children) of study days, and frequency of use of pimecrolimus decreased over time, reflecting improvement in disease control. The mean total body surface area affected decreased continuously over time. Significantly more patients in the pimecrolimus than control groups were maintained without corticosteroid therapy (infants: 63.7% vs. 34.8%, P < 0.001; children: 57.4% vs. 31.6%, P < 0.001, respectively).. The need for pimecrolimus therapy decreases over time as the patients' disease improves. Hence, once long-term management of AD with pimecrolimus is established, the burden of disease for both the patient and the caregiver decreases significantly and disease-free periods become more frequent.

Topics: Administration, Cutaneous; Adolescent; Adrenal Cortex Hormones; Body Surface Area; Calcineurin Inhibitors; Child; Child, Preschool; Dermatitis, Atopic; Double-Blind Method; Follow-Up Studies; Humans; Infant; Longitudinal Studies; Ointments; Peptidylprolyl Isomerase; Pharmaceutical Vehicles; Tacrolimus; Time Factors; Treatment Outcome

(1) Symptomatic treatment of atopic dermatitis is initially based on simple measures and moisturising creams. Topical corticosteroids are reserved for treatment of inflammatory exacerbations. (2) After topical tacrolimus, marketing authorisation has been granted in France for a second topical immunosuppressant, pimecrolimus, as a short-term symptomatic treatment for atopic dermatitis in children from the age of two years, and intermittently for long-term prevention of new exacerbations. (3) Short-term treatment with pimecrolimus has been tested in three trials in children with mild to moderate dermatitis (against the excipient), in one adult trial against the excipient, and in one dose-finding study in adults that included a group treated with topical corticosteroids. (4) Longer term treatment periods of 6 to 12 months have been tested in two trials versus excipient in children, and two adult trials, one versus moderately active topical corticosteroids. (5) These trials show that pimecrolimus works better than the excipient, but not nearly as well as moderately active topical corticosteroids. Pimecrolimus has not been compared with topical corticosteroids in children, the age group most vulnerable to atopic dermatitis. (6) The commonest adverse effects observed in clinical trials were local and included a burning sensation at the site of application and skin infections. Systemic adverse effects (mainly infections) were most marked in infants. Long-term risks, especially the risk of skin cancer, have not been assessed. (7) In practice, the reference treatment for exacerbations of atopic dermatitis is a topical corticosteroid; in children, it seems best to begin with a weak preparation. There is no reason to use pimecrolimus, which is less active than topical corticosteroids and whose potential long-term adverse effects, especially in children, are unknown.

Topics: Administration, Cutaneous; Administration, Topical; Adrenal Cortex Hormones; Adult; Child; Child, Preschool; Dermatitis, Atopic; Double-Blind Method; Drug Approval; France; Humans; Immunosuppressive Agents; Infant; Multicenter Studies as Topic; Secondary Prevention; Tacrolimus; Treatment Outcome

The safety and efficacy of a 1% cream formulation of pimecrolimus, a selective, nonsteroid immunomodulator, was studied in infants with atopic dermatitis (AD).. During a 6-week double-blind phase, 186 infants with mild/moderate AD were randomly assigned to twice-daily pimecrolimus cream 1% or vehicle. All patients were subsequently treated with open-label pimecrolimus for 20 weeks.. At the end of the double-blind phase, 54.5% and 23.8% of patients in the pimecrolimus and vehicle groups, respectively, were clear or almost clear of AD (P <.001). Similar improvements were observed in the Eczema Area and Severity Index, pruritus assessment, and the care giver's assessment. By the first return visit, 69.9% and 36.5% of pimecrolimus and vehicle-treated patients, respectively, achieved absent or mild pruritus. Efficacy during the double-blind phase was maintained throughout the open-label phase. Vehicle-treated patients transferring to open-label pimecrolimus rapidly achieved disease control comparable to those receiving continuous pimecrolimus. There were no significant differences between groups in application site reactions or skin infections. Most adverse events were mild or moderate and unrelated to treatment.. Pimecrolimus was safe in infants with AD, with rapid and sustained efficacy. Pimecrolimus holds promise as a valuable new treatment option for the youngest patients with AD.

Topics: Administration, Cutaneous; Analysis of Variance; Anti-Inflammatory Agents, Non-Steroidal; Dermatitis, Atopic; Dermatologic Agents; Diarrhea; Double-Blind Method; Female; Fever; Humans; Infant; Male; Ointments; Pharyngitis; Respiratory Tract Infections; Safety; Severity of Illness Index; Tacrolimus; Time Factors; Treatment Outcome

Atopic dermatitis(AD) with head and neck involvement is common and therapeutically challenging.. Efficacy and safety data specific to treatment of head/neck regions with tacrolimus ointment (Protopic) from three double-blind, randomized, vehicle-controlled studies are reported. A total of 631 adult and 352 pediatric patients with moderate to severe atopic dermatitis applied the vehicle, 0.03% or 0.1% tacrolimus ointment twice daily to affected areas for up to 12 weeks.. Significant improvements from baseline to end of treatment for signs of atopic dermatitis (erythema, edema, excoriation, oozing, scaling, and lichenification) were noted for head/neck and non-head/neck areas treated with either 0.03% or 0.1% tacrolimus ointment (p<0.001). Within each treatment group, the overall 12-week adjusted incidence rate of application site adverse events was similar for both head/neck and non-head/neck areas. The incidence of common adverse events such as pruritus, "skin burning", erythema, infection, and skin tingling in head/neck areas was comparable to that observed in non-head/neck areas within each treatment group. The overall prevalence of application site adverse events decreased rapidly during the first few days of treatment.. Tacrolimus ointment is a safe and effective treatment for atopic dermatitis on the head and neck.

Topics: Adolescent; Adult; Aged; Child; Child, Preschool; Dermatitis, Atopic; Double-Blind Method; Female; Head; Humans; Immunosuppressive Agents; Male; Middle Aged; Neck; Ointments; Severity of Illness Index; Tacrolimus; Treatment Outcome

Pimecrolimus cream 1% (Elidel, SDZ ASM 981) is a novel, non-steroid inflammatory cytokine inhibitor, effective in the treatment of atopic dermatitis. Here, we evaluate the treatment of chronic hand dermatitis with pimecrolimus cream 1%.. To determine pimecrolimus blood concentrations, and evaluate the safety, tolerability and efficacy following application of pimecrolimus cream 1% to subjects with chronic hand dermatitis.. In this open-label, multiple-topical-dose, non-controlled, pharmacokinetic study, pimecrolimus cream 1% was applied twice daily to dorsal and palmar areas (affected and unaffected) of both hands. Evening applications (except day 8) were immediately followed by overnight occlusion (> or =6 h). Full pharmacokinetic profile (days 1, 8 and 22), trough concentrations (days 3 and 15), physical examinations, laboratory measurements and adverse events were recorded. Efficacy was assessed via Investigators' Global Assessment (IGA), total key signs and symptoms and the subject's overall self-assessment.. Twelve patients completed the study. The majority of pimecrolimus blood concentrations (73.6%) remained below the limit of quantitation (0.1 ng/ml). The maximum concentration observed was 0.91 ng/ml and the maximum area under the concentration-time curve from 0-12 h post dose was 7.6 ng.h/ml. Treatment was well tolerated locally and systemically. No serious adverse events occurred; 4/13 subjects showed a total of 6 adverse events at the application site: burning (n=4), and pruritus (n=2). No clinically relevant or drug-related changes were observed. Clear efficacy of the treatment was shown by all 3 assessment methods. Disease state at day 22 had improved in 11 (85%) subjects compared with baseline (IGA).. Twice daily topical treatment of moderate to severe chronic hand dermatitis with pimecrolimus cream 1% results in low pimecrolimus blood levels, is well tolerated, safe, and effective.

Topics: Administration, Topical; Adult; Biological Availability; Chronic Disease; Dermatitis, Atopic; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Hand Dermatoses; Humans; Immunosuppressive Agents; Male; Maximum Tolerated Dose; Middle Aged; Ointments; Tacrolimus; Treatment Outcome

This study was designed to evaluate the safety and efficacy of concomitant therapy with the corticosteroid clocortolone pivalate cream 0.1% (Cloderm Cream 0.1%) and the topical immunosuppressive agent tacrolimus ointment 0.1% (Protopic Ointment 0.1%) and to compare each drug alone for the treatment of atopic dermatitis in adolescents and adults. Concomitant therapy may minimize the potential adverse effects of both treatments taken alone and may potentially improve overall response. In this 21-day study with 57 patients with atopic dermatitis, groups of 19 patients were randomized to 1 of 3 treatments: concomitant treatment with clocortolone pivalate cream 0.1% and tacrolimus ointment 0.1% (CPC+ TO), monotherapy with clocortolone pivalate cream 0.1% (CPC), or monotherapy with tacrolimus ointment 0.1% (TO). CPC+ TO was statistically superior to TO alone in the percentage change for dermatologic sum score at days 14 (P = .024) and 21 (P = .033), excoriation at day 21 (P = .028), induration at day 21 (P = .033), and erythema at day 14 (P = .048). The dual therapy was also superior to CPC alone in excoriation at days 7 (P = .045) and 14 (P = .037), oozing or crusting at days 3 (P = .034) and 7 (P = .012), and lichenification at day 3 (P = .031). In addition, unlike the 2 single-therapy treatment groups, percentage reductions from baseline in scores for the sensation of transient pruritus and burning or stinging were statistically significant for the concomitant treatment at days 14 (P = .016) and 21 (P = .016).

Topics: Administration, Topical; Adolescent; Adult; Aged; Dermatitis, Atopic; Female; Fluocortolone; Humans; Immunosuppressive Agents; Male; Middle Aged; Statistics, Nonparametric; Tacrolimus; Treatment Outcome

To measure pimecrolimus blood concentrations and to evaluate tolerability and efficacy in children and infants treated topically for atopic dermatitis with pimecrolimus cream 1% for three weeks.. Three open label, non-controlled, multiple topical dose studies were conducted in children aged 8-14 years (study A, ten patients), and in infants aged 8-30 months (study B, eight patients) and 4-11 months (study C, eight patients). Pimecrolimus blood concentrations were determined on days 4 and 22 of treatment, and at end of study. Efficacy was assessed using the Eczema Area and Severity Index (EASI).. Pimecrolimus blood concentrations were consistently low, typically (81%) below 1 ng/ml, with more than half of the measurements below the assay limit of quantitation (0.5 ng/ml) in studies A and B. The highest blood concentration measured throughout the three studies was 2.6 ng/ml. The cream was well tolerated, locally and systemically. The most common adverse event suspected to be related to study medication was a transient mild to moderate stinging sensation at the application site in 5/26 patients. There was no indication of any systemic adverse effect. The patients responded well to therapy with a rapid onset of action, usually within four days. Median reductions of EASI from baseline at day 22 were 55% (study A), 63% (study B), and 83% (study C).. Three weeks treatment of children and infants with extensive atopic dermatitis, using pimecrolimus cream 1% twice daily, is well tolerated and results in minimal systemic exposure, at which no systemic effect is expected.

Topics: Adolescent; Child; Child, Preschool; Dermatitis, Atopic; Dermatologic Agents; Drug Administration Schedule; Female; Humans; Immunosuppressive Agents; Infant; Male; Severity of Illness Index; Tacrolimus; Treatment Outcome

Pimecrolimus cream 1% (Elidel, SDZ ASM 981), a nonsteroid selective inhibitor of inflammatory cytokines, is effective in the treatment of atopic dermatitis (AD). In this study we compared early intervention with pimecrolimus cream with treatment with a vehicle control.. The purpose of this investigation was to assess whether early treatment in infants of AD signs/symptoms with pimecrolimus could influence long-term outcome by preventing disease flares.. In this 1-year, double-blind controlled study, 251 infants aged 3 to 23 months with AD were randomized 4:1 to a pimecrolimus-based regimen (n = 204) or a conventional treatment regimen (n = 47). Both groups used emollients for dry skin. Early AD signs and symptoms were treated either with pimecrolimus cream to prevent flares or, in the control group, with vehicle. Vehicle was used to maintain blinding conditions. In the event of flares, moderately potent corticosteroid was permitted in both groups. The primary efficacy end point was the incidence of flares at 6 months.. Pimecrolimus significantly reduced the incidence of flares compared with control treatment (P <.001), with 67.6% versus 30.4% of patients completing 6 months with no flare and 56.9% versus 28.3% completing 12 months with no flare. Overall corticosteroid use was substantially lower in the pimecrolimus group: 63.7% versus 34.8% of patients did not use corticosteroids at all during the study. Pimecrolimus was also more effective than control treatment in the long-term control of pruritus and the signs of AD. There were no clinically significant differences in incidence of adverse events between the 2 treatment groups.. Treatment with pimecrolimus of early signs and symptoms significantly modified the disease course in infants by reducing the incidence of flares and improving overall control of AD. Pimecrolimus was safe and well tolerated.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Consumer Product Safety; Dermatitis, Atopic; Dermatologic Agents; Disease Management; Double-Blind Method; Humans; Immunosuppressive Agents; Infant; Tacrolimus; Time Factors; Treatment Outcome

The efficacy of 0.3% tacrolimus lotion (maximum dosage: 0.3 mg kg-1 per day) for treatment of atopic dermatitis (AD) was evaluated. Systemic absorption and effects on complete blood cell counts (CBC) and chemistry panels were also investigated. Eight dogs were assigned randomly to either a tacrolimus or a vehicle lotion treatment group. Both owners and investigator were blinded to the treatment. After 4 weeks, there was a 2-week wash-out period and treatments were reversed. Owners scored pruritus weekly while the investigator scored pruritus and erythema at the beginning and end of each treatment period. Investigator scores for pruritus in the tacrolimus group significantly decreased by the end of the study (P = 0.03). Investigator scores for erythema in the tacrolimus group were significantly lower than those in the placebo group at the end of the study (P = 0.005). There was no difference between groups with respect to owner scores for pruritus. No changes in the CBC and chemistry panels were noted. Mean blood concentrations of tacrolimus were below toxic levels.

Topics: Administration, Cutaneous; Animals; Dermatitis, Atopic; Dog Diseases; Dogs; Double-Blind Method; Immunosuppressive Agents; Pilot Projects; Tacrolimus; Treatment Outcome

Pimecrolimus cream (Elidel, SDZ ASM 981), a non-steroid inhibitor of inflammatory cytokines, is effective in the treatment of atopic dermatitis (AD). We assessed whether early treatment of AD signs/symptoms reduces the need for topical corticosteroids.. To investigate the efficacy and safety of pimecrolimus cream 1% in the long-term management of adult AD.. 192 adults with moderate to severe AD were randomised (1:1) for twice daily (b.i.d.) treatment of early signs or symptoms of AD with either pimecrolimus cream 1% or vehicle cream (control group) to prevent progression to flares. Treatment was given as needed for 24 weeks. In the event of flares, a moderately potent corticosteroid (prednicarbate 0.25% cream) was permitted as rescue medication in both groups. The percentage of days on which a topical corticosteroid was used to treat disease flares was the main outcome measure.. Corticosteroid medication was used on 14.2% (95% confidence interval, CI: 8.3-21.1) of the days of the 24-week treatment period in the pimecrolimus group and on 37.2% (95% CI: 30.4-44.0) of the days in the control group (p < 0.001). In total, 44.8% (43/96) of patients in the pimecrolimus group did not experience a flare compared with 18.8% (18/96) of patients in the control group. The median time to first flare was 144 days in the pimecrolimus group and 26 days in the control group (p < 0.001). Pimecrolimus treatment was also associated with improvement in signs and symptoms of AD, pruritus, patients' self-assessment and quality of life.. Pimecrolimus cream 1% b.i.d. is an effective, well-tolerated, long-term treatment for AD in adults, substantially reducing the number of flares compared to a conventional therapy and consequently reducing or eliminating the need for corticosteroid treatment.

Topics: Administration, Cutaneous; Adolescent; Adult; Aged; Dermatitis, Atopic; Dermatologic Agents; Disease-Free Survival; Double-Blind Method; Female; Humans; Male; Middle Aged; Ointments; Severity of Illness Index; Tacrolimus; Treatment Outcome

Two 26-week US clinical trials of identical design were conducted to evaluate the efficacy and safety of pimecrolimus (Elidel, SDZ ASM 981) cream 1% in pediatric atopic dermatitis (AD). A secondary aim of both trials, and the focus of this article, was to evaluate the quality-of-life (QoL) impact of pimecrolimus compared with its vehicle.. A 6-week randomized, double-blind treatment phase was followed by a 20-week open-label phase during which all patients received pimecrolimus (403 patients 2 to 17 years old with mild to moderate AD; 267 randomized to pimecrolimus and 136 to vehicle). QoL analyses were conducted on the intention-to-treat data and included patients 8 years old or younger. QoL was evaluated with the Parent's Index of Quality of Life in Atopic Dermatitis (PIQoL-AD) at baseline, 6 weeks, and 6 months. The PIQoL-AD is a 28-item measure completed by the parents of children with AD (0 to 8 years old).. PIQoL-AD scores were available for 241 cases at baseline (158 pimecrolimus, 83 vehicle), 193 at 6 weeks (132 pimecrolimus, 61 vehicle), and 161 at 6 months (113 pimecrolimus, 48 vehicle). Improvement in parents' QoL was seen for both groups between baseline and 6 weeks and 6 months. Analysis of covariance on PIQoL-AD scores at 6 weeks showed statistically significant superiority of pimecrolimus compared with vehicle. After all patients were switched to receive pimecrolimus at week 6, mean PIQoL-AD scores were the same across both groups at 6 months. Positive but low levels of association were observed between changes in PIQoL-AD scores and changes in severity of AD (Investigator's Global Assessment and parent-perceived severity of pruritus).. The results showed that pimecrolimus had a beneficial effect on parents' QoL in pediatric AD.

Topics: Adult; Child; Child, Preschool; Dermatitis, Atopic; Dermatologic Agents; Double-Blind Method; Female; Humans; Infant; Male; Parents; Quality of Life; Severity of Illness Index; Tacrolimus

Pimecrolimus is a cell-selective inhibitor of inflammatory cytokine release developed specifically for the treatment of inflammatory skin diseases.. The objective of this study was to evaluate blood concentrations and tolerability of pimecrolimus during topical treatment.. 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.. 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.. 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.

Topics: Administration, Topical; Adult; Biological Availability; Dermatitis, Atopic; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Male; Severity of Illness Index; Tacrolimus; Treatment Outcome

Vehicle-controlled studies have demonstrated the efficacy and safety of tacrolimus ointment in the treatment of patients with atopic dermatitis (AD).. This study was undertaken to compare 0.03% and 0.1% tacrolimus ointment with 1% hydrocortisone acetate ointment in children 2 to 15 years of age with moderate-to-severe AD.. Treatment was twice daily to affected areas for 3 weeks in this multicenter, randomized, double-blind, parallel-group study. The primary endpoint was the modified eczema area and severity index (mEASI) mean area under the curve (mAUC) as a percentage of baseline.. Five hundred sixty patients were randomized and received at least one application of ointment. Discontinuations included 21 of 189 patients from the 0.03% tacrolimus group, 13 of 186 patients from the 0.1% tacrolimus group, and 20 of 185 patients from the hydrocortisone acetate group. The median mEASI mAUC as a percentage of baseline showed 0.03% and 0.1% tacrolimus to be significantly more effective than 1% hydrocortisone acetate (P <.001) and 0.1% tacrolimus to be more effective than 0.03% tacrolimus (P =.006). The mEASI mAUC as a percentage of baseline was 44.8%, 39.8%, and 64.0% for patients who received 0.03% tacrolimus, 0.1% tacrolimus, and 1% hydrocortisone acetate, respectively. Transient skin burning was the only adverse event to show a higher incidence in the tacrolimus treatment groups than in the hydrocortisone acetate group (P <.05). Laboratory parameters showed no treatment differences and no marked changes over time.. Tacrolimus, 0.03% and 0.1%, was significantly more effective than 1% hydrocortisone acetate and 0.1% tacrolimus was more effective than 0.03% tacrolimus in the treatment of moderate-to-severe AD in children. No safety concerns were identified.

Topics: Administration, Topical; Adolescent; Child; Child, Preschool; Dermatitis, Atopic; Double-Blind Method; Female; Humans; Hydrocortisone; Immunosuppressive Agents; Male; Tacrolimus; Treatment Outcome

Vehicle-controlled studies have demonstrated the efficacy and safety of tacrolimus ointment for patients with atopic dermatitis.. This study was undertaken to compare 0.03% and 0.1% tacrolimus ointment with 0.1% hydrocortisone-17-butyrate ointment, a midpotent to potent topical corticosteroid, in the treatment of adult patients with moderate-to-severe atopic dermatitis.. Patients applied ointment twice daily to all affected areas for 3 weeks in this multicenter, randomized, double-blind, parallel-group study. The primary endpoint was the modified eczema area and severity index (mEASI) mean area under the curve as a percentage of baseline.. Five hundred seventy patients were randomized and received treatment. Discontinuations included 22 of 193 patients from the 0.03% tacrolimus group, 22 of 191 patients from the 0.1% tacrolimus group, and 17 of 186 patients from the hydrocortisone butyrate group. The median mEASI mean area under the curve as a percentage of baseline was 47.0%, 36.5%, and 36.1% for patients who received 0.03% tacrolimus, 0.1% tacrolimus, and 0.1% hydrocortisone butyrate, respectively. There was no statistically significant difference between 0.1% tacrolimus and 0.1% hydrocortisone butyrate; however, the lower improvement in mEASI for 0.03% tacrolimus was statistically significant when compared with 0.1% tacrolimus (P <.001) or hydrocortisone butyrate (P =.002). Skin burning and pruritus at the application site showed a higher incidence in the tacrolimus treatment groups than in the hydrocortisone butyrate group (P <.05). Laboratory parameters showed no treatment differences and no marked changes over time.. The efficacy of 0.1% tacrolimus ointment was similar to that of 0.1% hydrocortisone butyrate ointment and was lower for 0.03% tacrolimus ointment. No serious safety concerns were identified.

Topics: Administration, Topical; Adult; Dermatitis, Atopic; Double-Blind Method; Female; Humans; Hydrocortisone; Immunosuppressive Agents; Male; Ointments; Tacrolimus; Treatment Outcome

The ascomycin derivative pimecrolimus (ASM 981) is a cell-selective cytokine inhibitor, specifically developed for the treatment of inflammatory skin diseases.. When applied topically, pimecrolimus cream 1% has shown promise as a treatment for inflammatory skin conditions, including atopic dermatitis (AD) in children and adults, allergic contact dermatitis, and chronic contact irritant hand dermatitis in adults.. In two independent 6-week, randomized, multicenter studies of identical design, the efficacy and safety of pimecrolimus cream 1% in children with predominantly moderate AD were compared with vehicle. Pooled data from a total of 403 patients were used in the analysis. The primary efficacy parameter was the Investigator's Global Assessment (IGA) score. Secondary parameters included Eczema Area and Severity Index (EASI) and severity of pruritus scores. Subjects were also asked to assess their disease control as uncontrolled, limited, good, or complete.. Significant therapeutic benefits relative to vehicle were observed in the pimecrolimus-treated group at the first efficacy assessment, 8 days after initial application of the study medication (eg, relief of pruritus). At each subsequent postbaseline visit, pimecrolimus-treated patients showed significant improvement relative to controls in all efficacy measures. The medication was well tolerated.. Pimecrolimus cream 1% appears to be a safe and effective alternative to currently used therapies for AD.

Topics: Administration, Topical; Adolescent; Child; Child, Preschool; Dermatitis, Atopic; Double-Blind Method; Female; Humans; Immunosuppressive Agents; Infant; Male; Tacrolimus

Pimecrolimus cream (SDZ ASM 981), a nonsteroid inhibitor of inflammatory cytokines, is effective in atopic dermatitis (AD). We assessed whether early treatment of AD signs/symptoms with pimecrolimus could influence long-term outcome by preventing disease flares.. Early intervention with pimecrolimus was compared with a conventional AD treatment strategy (ie, emollients and topical corticosteroids). In this 1-year, controlled, double-blind study, 713 AD patients (2-17 years) were randomized 2:1 to a pimecrolimus-based or conventional regimen. Both groups used emollients for dry skin. Early AD signs/symptoms were treated with pimecrolimus cream or, in the conventional treatment group, vehicle to prevent progression to flares. If flares occurred, moderately potent topical corticosteroids were mandated. The primary efficacy endpoint was ranked flares at 6 months. Safety was monitored clinically, and a skin recall-antigen test was performed at study completion.. BASELINE CHARACTERISTICS OF THE PATIENTS: The mean age for both groups was approximately 8 years, and the majority of patients had moderate disease at baseline. PATIENT FOLLOW-UP AND EXPOSURE TO STUDY MEDICATION: The mean duration of follow-up (+/-standard error) was 303.7 (+/-5.30) days in the pimecrolimus group and 235.2 (+/-9.40) days in the control group. The discontinuation rate was significantly higher in the control group than in the pimecrolimus group (51.5% vs 31.6% at 12 months), and proportionately more patients with severe or very severe disease discontinued in the control group. The main reason for the higher discontinuation rate in the control group was unsatisfactory therapeutic effect (30.4% vs 12.4%). This resulted in a substantially higher mean number of study medication treatment days in the pimecrolimus group compared with the control group: 211.9 (69.8% of study days) versus 156.0 (66.3% of study days). Of those patients who completed 12 months on study, 14.2% and 7.0% of patients in the pimecrolimus and vehicle groups, respectively, used study medication continuously.. Patients in the pimecrolimus group experienced significantly fewer AD flares than those in the control group, according to the primary efficacy analysis on ranked flares of AD (Van Elteren test). The proportion of patients who completed 6 or 12 months with no flares was approximately twice as high in the pimecrolimus group compared with control (61.0% vs 34.2% at 6 months; 50.8% vs 28.3% at 12 months). Fewer flares were observed in the pimecrolimus group regardless of baseline disease severity, so even severe patients derived benefit from the treatment. The analysis of time to first flare showed that treatment with pimecrolimus was associated with a significantly longer flare-free period (log- rank test). Covariate analysis indicated a statistically significant effect on time to first flare of baseline Eczema Area and Severity Index score, and whether patients had "severe" or "very severe" disease at baseline according to the Investigators' Global Assessment, although patients in all baseline disease severity subgroups benefited from treatment. Age had no significant effect. Fewer patients in the pimecrolimus group required topical corticosteroid therapy compared with control (35.0% vs 62.9% at 6 months; 42.6% vs 68.4% at 12 months), and patients in the pimecrolimus group spent fewer days on topical corticosteroid therapy (57.4% vs 31.6% [pimecrolimus vs control, respectively] spent 0 days on topical corticosteroid therapy, 17.1% vs 27.5% 1-14 days, and 25.5% vs 41.0% >14 days over the 12 months of the study). This steroid-sparing effect of pimecrolimus was evident despite pimecrolimus-treated patients being on study longer than patients in the control group. The average proportion of study days spent on second-line corticosteroids was 4.08% in the pimecrolimus group and 9.10% in the control group. Analysis of Eczema Area and Severity Index over time showed significantly lower median scores, thus indicating better disease control in the pimecrolimus group compared with the control group. Similar results were obtained from analysis of the Investigators' Global Assessment (not shown). The treatment groups were well balanced with respect to the number of patients using antihistamines during the study (57.2% vs 62.9%, pimecrolimus vs control, respectively).. There were no appreciable differences between treatment groups in the overall incidence of adverse events. The most frequent adverse events were common childhood infections and ailments, including nasopharyngitis, headache, and cough. The incidence of suspected drug-related adverse events was not significantly different in the pimecrolimus group (24.7% vs 18.7%--pimecrolimus vs control), and the incidence of serious adverse events was low (8.3% vs 5.2%--pimecrolimus vs control). Life-table analysis of incidence of adverse events revealed no significant differences between the treatment groups, except for cough. Local tolerability was good in both treatment groups. The most common application site reaction reported was sensation of burning (10.5% vs 9.3%--pimecrolimus vs control). There were no major differences between treatment groups in the duration or severity of application site reactions, most of which were mild-to-moderate and transient, occurring within the first week of treatment. Skin infections were reported in both groups. There were no between-group differences in the life-table analysis of time to first occurrence of bacterial skin infections nor in the adjusted incidence of bacterial skin infections. Although there were no significant differences between treatment groups in the incidence of individual viral skin infections, the incidence of grouped viral skin infections (12.4% vs 6.3%--pimecrolimus vs control) showed a slightly higher incidence in the pimecrolimus group. Laboratory values and vital signs showed no significant between-group differences. There were no significant differences between treatment groups in response to recall antigens in those patients who remained on study for 12 months.. Treatment of early AD signs/symptoms with pimecrolimus was effective in preventing progression to flares in more than half the patients, reducing or eliminating the need for topical corticosteroids. The benefits were consistently seen at 6 months across important disease severity subgroups and with respect to the various predefined efficacy endpoints. Furthermore, these benefits were sustained for 12 months, providing evidence that long-term treatment with pimecrolimus leads to better control of AD. Treatment with pimecrolimus was well tolerated and was not associated with clinically relevant adverse events compared with the conventional treatment group. The results reported here offer the prospect of effective long-term management of AD with reduced need for topical corticosteroids.

Topics: Adolescent; Anti-Inflammatory Agents, Non-Steroidal; Child; Child, Preschool; Dermatitis, Atopic; Double-Blind Method; Emollients; Emulsions; Female; Follow-Up Studies; Headache; Humans; Infant; Life Tables; Male; Patient Dropouts; Pharyngitis; Severity of Illness Index; Tacrolimus; Treatment Outcome

A total of 632 adults with atopic dermatitis applied tacrolimus ointment (0.03% or 0.1%) or vehicle twice daily for up to 12 weeks in two randomized, double-blind studies. This report focuses on the efficacy of tacrolimus ointment in these studies. The mean percent body surface area (%BSA) affected at baseline was 45%, and 56% of patients had severe atopic dermatitis. Evaluations included a physician's global evaluation of clinical response, %BSA affected, individual signs of atopic dermatitis, the Eczema Area and Severity Index (EASI) score, and the patient's assessment of pruritus. A 90% or greater improvement from baseline in disease status was observed for 6.6%, 27.5%, and 36.8% of patients in the vehicle, 0.03% tacrolimus ointment, and 0.1% tacrolimus ointment groups, respectively (P<.001), and 50% or better improvement was observed for 19.8%, 61.6%, and 72.7% of patients, respectively. Tacrolimus ointment-treated patients showed significantly greater improvement than vehicle-treated patients for all efficacy parameters evaluated, including the %BSA affected, the total score and individual scores for signs of atopic dermatitis, the patient's assessment of pruritus, and EASI score. The 0.1% concentration was more effective than the 0.03% concentration, particularly in patients with severe disease and/or extensive BSA involvement at baseline and in African Americans. Tacrolimus ointment is an effective therapy for the treatment of adult patients with atopic dermatitis on all skin regions including the head and neck.

Topics: Adolescent; Adult; Aged; Dermatitis, Atopic; Double-Blind Method; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Ointments; Tacrolimus; Treatment Outcome

In two randomized, double-blind, multicenter studies, a total of 631 adult patients with moderate to severe atopic dermatitis applied tacrolimus ointment (0.03% or 0.1%) or vehicle twice daily for up to 12 weeks. The mean percent body surface area (%BSA) affected at baseline was 45%, and 56% of patients had severe atopic dermatitis. As previously reported, these studies showed that tacrolimus ointment was superior to vehicle for all efficacy parameters measured. This report focuses on the safety of tacrolimus ointment in these studies. The most common adverse events were the sensation of skin burning, pruritus, flu-like symptoms, skin erythema, and headache. Skin burning and pruritus were more common among patients with severe or extensive disease; these events were usually brief and were resolved during the first few days of treatment. Common adverse events with a significantly higher incidence in one or both of the tacrolimus ointment groups than in the vehicle group included skin burning, flu-like symptoms, and headache. More patients in the vehicle group discontinued the study because of an adverse event than in either of the tacrolimus ointment groups. There were no notable or consistent changes in any laboratory variables. Tacrolimus was not detected in 80% of blood samples collected. Measurable concentrations of tacrolimus were transitory and were not associated with adverse events. Tacrolimus ointment is a safe therapy for the treatment of adult patients with atopic dermatitis on the face, neck, or other body regions.

Topics: Adolescent; Adult; Aged; Dermatitis, Atopic; Double-Blind Method; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Ointments; Safety; Tacrolimus

The safety and efficacy of 0.03% and 0.1% tacrolimus ointment for the treatment of atopic dermatitis were evaluated in a 12-week, randomized, double-blind, vehicle-controlled study of 351 children 2 to 15 years of age with moderate to severe atopic dermatitis. The mean age of patients was 6.1 years. A total of 61.5% of patients had severe atopic dermatitis at baseline. The mean percentage of body surface area affected was 47.7%, and 83.5% of patients were affected on the head and/or neck. Significantly more patients (P<.001) achieved clinical improvement of 90% or better with 0.03% or 0.1% tacrolimus ointment compared with vehicle. Significant improvements in the signs and symptoms of atopic dermatitis, percent body surface area affected, and the patient's assessment of pruritus were also observed early in treatment and were maintained throughout the study. Adverse events with a statistically significantly greater incidence in the 0.03% tacrolimus ointment treatment group compared with vehicle were limited to the sensation of skin burning, pruritus, varicella, and vesiculobullous rash ("blisters"). Varicella and vesiculobullous rash occurred at a low incidence (<5%). No adverse event occurred at a statistically higher incidence in the 0.1% tacrolimus ointment-treated group compared with vehicle. Tacrolimus ointment was equally safe for younger (2-6 years) and older (7-15 years) children. Both tacrolimus ointment concentrations (0.03% and 0.1%) were safe and significantly more effective than vehicle for the treatment of atopic dermatitis in children.

Topics: Adolescent; Child; Child, Preschool; Dermatitis, Atopic; Double-Blind Method; Drug Administration Schedule; Female; Humans; Immunosuppressive Agents; Male; Ointments; Safety; Tacrolimus; Treatment Outcome

Tacrolimus ointment is a nonsteroidal topical immunomodulator that was formulated specifically for the treatment of atopic dermatitis. A total of 255 children, 2 to 15 years of age, with moderate to severe atopic dermatitis applied 0.1% tacrolimus ointment twice daily for up to 12 months to assess long-term safety and efficacy. Patients on average were treated with tacrolimus ointment for 279 days or 87% of study days. Substantial improvements in the signs and symptoms of atopic dermatitis, percent body surface area affected, and the patient's or parent's assessment of pruritus were observed during the first week of treatment and were maintained throughout the study. Transient skin burning and itching were the most common drug application site adverse events. Occurrence of these symptoms decreased after the first few days of treatment. There was no increased incidence of infections or other significant adverse events. Effectiveness of tacrolimus was maintained with prolonged daily use. Tacrolimus ointment (0.1%) is safe and effective for long-term treatment of atopic dermatitis in children.

Topics: Adjuvants, Immunologic; Adolescent; Child; Child, Preschool; Dermatitis, Atopic; Drug Evaluation; Female; Humans; Immunosuppressive Agents; Male; Ointments; Safety; Tacrolimus; Treatment Outcome

Atopic dermatitis can have detrimental effects on health-related quality of life (QOL).. Our purpose was to examine the QOL impact of tacrolimus ointment in patients with atopic dermatitis.. The Dermatology Life Quality Index (DLQI), Children's DLQI (CDLQI), and Toddler QOL Survey were used to assess QOL in adults (16 years or older), children (5-15 years), and toddlers (2-4 years) enrolled in 12-week, randomized, double-blind studies comparing two concentrations of tacrolimus ointment (0.03% and 0.1%) versus vehicle ointment for treatment of atopic dermatitis. QOL was assessed at baseline, week 3, and week 12/early discontinuation.. Of the 985 patients enrolled, 91.5% had evaluable QOL data. Among adults, both tacrolimus ointment groups experienced improved QOL relative to the vehicle control group for all QOL scales (P<.001). Among children and toddlers, both tacrolimus ointment groups demonstrated significant QOL improvements relative to the vehicle control group (P<.05) for all but the Personal Relationships scale in the 0.03% tacrolimus ointment group among children.. Tacrolimus ointment is associated with significant QOL benefits in adults, children, and toddlers with atopic dermatitis.

Topics: Adolescent; Adult; Child; Child, Preschool; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Ointments; Quality of Life; Tacrolimus

Atopic dermatitis (AD) is a chronic inflammatory skin disease in which antigen-presenting epidermal dendritic cells (DCs), ie, Langerhans cells and the so-called inflammatory dendritic epidermal cells (IDECs) expressing the high-affinity receptor for IgE (FcepsilonRI) may play a significant pathophysiologic role. Therapeutic efficacy of the immunosuppressive macrolide tacrolimus (FK506) in AD has been demonstrated in clinical trials, but little is known of its mode of action.. The present study focused on the effects of topical tacrolimus treatment on epidermal CD1a+/FcepsilonRI+ DC populations in lesional AD.. Immunohistological analysis, epidermal DC phenotyping, and functional studies were performed on skin biopsy specimens from treated and untreated lesional skin of 10 patients with AD participating in a clinical trial with tacrolimus.. Untreated lesional skin was characterized by a high proportion of CD1a+ cells, which was largely due to a high proportion of IDECs strongly expressing FcepsilonRI. Epidermal DCs isolated from untreated lesional skin exhibited high stimulatory activity toward autologous T cells, which was strongly reduced while clinical improvement was seen during application of tacrolimus. Concomitantly, a decreased FcepsilonRI expression was observed in both Langerhans cells and IDECs. Finally, topical tacrolimus led to a progressive decrease in the IDEC population within the pool of CD1a+ epidermal DCs and also to a decrease in their CD36 expression, which is indicative of lower local inflammation.. Epidermal CD1a+ DCs may represent a target for topical tacrolimus in the treatment of AD.

Topics: Administration, Topical; Adolescent; Adult; Antigen-Presenting Cells; Dendritic Cells; Dermatitis, Atopic; Flow Cytometry; Humans; Immunohistochemistry; Phenotype; Receptors, IgE; Skin; Tacrolimus

SDZ ASM 981 is a selective inhibitor of inflammatory cytokine release under development for the topical treatment of atopic dermatitis.. This first paediatric study was designed to measure the systemic exposure to SDZ ASM 981 in young children with atopic dermatitis treated on extensive skin areas.. Children 1-4 years of age referred to a tertiary care centre for their atopic dermatitis were treated twice daily for 3 weeks with 1% SDZ ASM 981 cream. SDZ ASM 981 blood concentrations were measured on day 4 and 22 (last day) of treatment, and 1 week after the last application, using a radioimmunoassay with a limit of quantification of 0.5 ng mL(-1). Efficacy was assessed by the Eczema Area Severity Index (EASI).. The 10 patients included had 23-69% of their body surface area (BSA) affected at baseline. Of the 63 SDZ ASM 981 blood concentrations measured, 63% were < 0.5 ng mL(-1); the maximum value observed was 1.8 ng mL-1. No accumulation was evidenced between days 4 and 22. The first two patients experienced a flare of atopic dermatitis that was not controlled by the study medication. In the other patients, the EASI improved by 8-89% at 3 weeks of treatment.. In these children 1-4 years of age, blood concentrations of SDZ ASM 981 during topical treatment with the 1% cream were consistently low even in the children with the most extensive areas treated (up to 69% of their BSA).

Topics: Administration, Cutaneous; Child, Preschool; Dermatitis, Atopic; Dermatologic Agents; Drug Administration Schedule; Female; Humans; Infant; Male; Severity of Illness Index; Tacrolimus; Treatment Outcome

SDZ ASM 981 is a selective inhibitor of the production of pro-inflammatory cytokines from T cells and mast cells in vitro. It is the first ascomycin macrolactam derivative under development for the treatment of inflammatory skin diseases.. This study was designed to determine the safety and efficacy of SDZ ASM 981 cream at concentrations of 0.05%, 0.2%, 0.6% and 1.0% in the treatment of patients with atopic dermatitis and to select the concentration to be used in phase III studies.. This was a double-blind, randomized, parallel-group, multicentre dose-finding study. A total of 260 patients were randomly assigned to treatment with SDZ ASM 981 cream at concentrations of 0.05%, 0.2%, 0.6%, or 1.0%, matching vehicle cream, or the internal control 0.1% betamethasone-17-valerate cream (BMV). Treatment was given twice daily for up to 3 weeks.. A clear dose-response relationship for SDZ ASM 981 was evident, with 0.2%, 0.6% and 1.0% SDZ ASM 981 creams all being significantly more effective than vehicle (P = 0.041, 0.001 and 0.008, respectively) in terms of baseline to end-point changes in the Eczema Area Severity Index (EASI) and pruritus score. The 1.0% cream was the most effective SDZ ASM 981 concentration. BMV was more effective than the SDZ ASM 981 creams tested in this study. It appears that the efficacy plateau was not reached with the SDZ ASM 981 creams within 3 weeks treatment. SDZ ASM 981 was well tolerated. Burning or a feeling of warmth were the only adverse events reported more frequently in the 0.6% and 1.0% SDZ ASM 981 treatment groups than in the vehicle treatment group (42.9%, 48.9% and 34.9%, respectively). Few systemic adverse events were reported during the study (headache was the most frequent systemic event reported by 15 of 252 patients) and none was considered to be related to treatment. The local tolerability profile of the 1.0% cream was similar to that of the lower concentrations.. 1.0% SDZ ASM 981 cream, which was shown to be safe, well tolerated and the most effective concentration in this study, was selected as the concentration to be further developed in phase III studies.

Topics: Adolescent; Adult; Aged; Dermatitis, Atopic; Dermatologic Agents; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Middle Aged; Severity of Illness Index; Tacrolimus; Treatment Outcome

Severe atopic blepharitis is difficult to treat, as topical steroids offer only a limited therapeutic benefit with increasing side effects by time. Topical FK 506 was found to be efficient and safe for treatment of atopic dermatitis in dermatologic studies. The use of topical FK 506 in atopic blepharitis has not been reported so far.. Fourteen patients with severe atopic blepharitis were treated with topical FK 506 0.1 %. The ointment was applied twice daily on the eye lids. Ophthalmologic examinations were scheduled at two weeks, two months and five months after onset of treatment. A score was defined for the skin of the lid (edema, erythema, lichenification, oozing, excoriation and crusting) and for the eye lid margin (erythema, thickening, crusting) respectively. Every patient graded pruritus on a visual analogue scale.. The mean skin score prior to treatment was 25.6 +/- 5.8, after two weeks 7.9 +/- 4.8 (p < 0.001), after two months 5.8 +/- 5.0 (p < 0.001) and after five months 5.3 +/- 5.3 (p < 0.001). The mean score for the eye lid margin prior to treatment was 12.3 +/- 4.0, after two weeks 4.6 +/- 2.7 (p < 0.001), after two months 3.8 +/- 2.4 (p < 0.001) and after five months 4.3 +/- 2.6 (p < 0.001). The mean score for pruritus prior to treatment was 8.1 +/- 1.3, after two weeks 2.0 +/- 1.4 (p < 0.001), after two months 1.3 +/- 0.8 (p < 0.001) and after five months 0.8 +/- 0.7 (p < 0.001). All patients assessed the overall situation under therapy as markedly improved.. Topical FK 506 0.1 % ointment turns out to be an excellent therapeutic option for treatment of severe atopic blepharitis. Long-term efficacy and safety have to be evaluated in long-term follow-up studies.

Topics: Administration, Topical; Adult; Blepharitis; Cross-Over Studies; Dermatitis, Atopic; Dose-Response Relationship, Drug; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Ointments; Patient Satisfaction; Severity of Illness Index; Tacrolimus; Treatment Outcome

We identified 19 patients with facial atopic eczema who failed to respond to tacrolimus (FK506) ointment, although tacrolimus ointment has shown excellent benefit for the treatment of recalcitrant facial erythema in most patients with atopic dermatitis.. We attempted to determine the efficacy of an original lotion formulation of tacrolimus for facial atopic dermatitis resistant to tacrolimus ointment.. Recalcitrant facial erythema of these 19 patients was treated with an original tacrolimus lotion preparation for 6 months. Patch testing with white petrolatum was performed in both the 19 patients and in 30 other atopic dermatitis patients who had experienced excellent results with tacrolimus ointment.. Of the 19 resistant patients, those whose symptoms were greatly or moderately improved by the lotion were 95%, 89% and 89% after 2 weeks, 3 months and 6 months of treatment, respectively. Further, patch testing to petrolatum showed positive reactions in several (six of 19) patients, compared with none of 30 controls with atopic eczema that had responded to topical tacrolimus ointment.. The tacrolimus lotion had a significant effect on the recalcitrant facial erythema in adult patients with atopic dermatitis who were resistant to tacrolimus ointment. We suggest that one reason for the unresponsiveness to tacrolimus ointment may be because of contact sensitivity to white petrolatum.

Topics: Adolescent; Adult; Dermatitis, Atopic; Dermatitis, Contact; Dosage Forms; Drug Carriers; Drug Eruptions; Drug Resistance; Facial Dermatoses; Follow-Up Studies; Humans; Immunosuppressive Agents; Ointments; Patch Tests; Petrolatum; Tacrolimus

To investigate the safety and efficacy of using 0.1% tacrolimus ointment for long-term treatment of atopic dermatitis.. Open-label, noncomparative study with 6 to 12 months of follow-up.. Outpatient departments in 30 study centers in 11 European countries.. We enrolled 316 patients aged 18 years and older with moderate to severe atopic dermatitis, 200 for 6 months and 116 for 12 months; 77.5% of patients completed the study.. Twice-daily application of 0.1% tacrolimus ointment on all affected skin. Visits were scheduled on day 1; after 1, 2, and 4 weeks of treatment; and monthly thereafter.. Safety assessments included monitoring of adverse events, clinical laboratory values, and tacrolimus blood concentrations. Efficacy end points included a combined score (modified Eczema Area and Severity Index) and an investigator's global assessment.. Local irritation, adverse events such as burning sensation (47% of patients), pruritus (24% of patients), and erythema (12% of patients) were common but tended to occur only when initiating treatment. Laboratory values showed no marked changes over time. Systemic absorption was minimal, with the maximum tacrolimus blood concentration being less than 1 ng/mL in 76% of patients. All efficacy end points showed improvement. The mean (SD) modified Eczema Area and Severity Index score was 23.7 (12.6) at day 1, 13.5 (11.3) at week 1, 6.1 (9.2) at month 6, and 6.1 (8.1) at month 12. Marked or excellent improvement or clearance of disease was reported in 54%, 81%, and 86% of patients at week 1, month 6, and month 12, respectively.. Up to 1 year of tacrolimus ointment use was safe and effective in patients with atopic dermatitis. Arch Dermatol. 2000;136:999-1006

Topics: Administration, Topical; Adolescent; Adult; Aged; Dermatitis, Atopic; Europe; Facial Dermatoses; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Leg; Male; Middle Aged; Neck; Ointments; Tacrolimus; Treatment Outcome

Tacrolimus is a potent immunosuppressant used in organ transplant recipients; an ointment formulation is being developed as a therapeutic agent for atopic dermatitis.. Our purpose was to define the pharmacokinetics and evaluate tacrolimus 0.3% ointment as therapy for moderate to severe atopic dermatitis.. Thirty-nine patients, 5 to 75 years of age, received 14 applications over 8 days. Serial blood samples were collected on days 1 and 8, with predose samples collected on days 2 through 7. Overall response and signs/symptoms were rated daily on days 1 through 11. Incidence of adverse events and laboratory profile were determined.. Mean area under the curve (0.9 to 42.5 ng x hr/ml) was highly variable and appeared to be related to size of application area. No systemic accumulation of tacrolimus was observed. Comparison to historical intravenous data indicates that absolute bioavailability of topical tacrolimus was less than 0.5%. Ninety-five percent of patients showed at least good improvement. All adverse events were transient. Burning was the most common application site adverse event and vasodilatation ("flushing/warmth") was the most common nonapplication site adverse event. No drug-related changes in laboratory profile were observed.. The results of this study suggest that tacrolimus 0.3% ointment may be a safe and effective therapy for atopic dermatitis.

Topics: Administration, Cutaneous; Adolescent; Adult; Aged; Area Under Curve; Biological Availability; Child; Child, Preschool; Dermatitis, Atopic; Female; Flushing; Follow-Up Studies; Humans; Immunosuppressive Agents; Incidence; Injections, Intravenous; Male; Middle Aged; Ointments; Remission Induction; Sensation Disorders; Tacrolimus; Vasodilation

To compare the safety and efficacy of 1% SDZ ASM 981 cream and a matching placebo cream in the treatment of patients with moderate atopic dermatitis.. A randomized, double-blind, placebo-controlled, right-and-left comparison study.. Academic referral center.. Thirty-four adult patients with moderate atopic dermatitis.. Topical 1% SDZ ASM 981 cream was applied twice daily (n=16) or once daily (n=18) and compared with a corresponding placebo cream base.. Efficacy was measured using a 4-point (0-3) scale for erythema, pruritus, exudation, excoriation, and lichenification (Atopic Dermatitis Severity Index [ADSI]). The ADSI score was defined as the sum of these 5 ratings (range, 0-15) and was determined on the pretreatment day (1 to 14 days before day 0) and on days 0, 2, 4, 7, 9, 11, 14, 16, 18, and 21. The percentage change from baseline (day 0) in the ADSI score was calculated on each of these days. Safety was evaluated by monitoring of adverse events, physical examination, hematologic examination, clinical chemistry studies, urinalysis, and measurement of blood levels of SDZ ASM 981.. Of the 38 patients recruited, 34 started and 28 completed treatment according to the protocol. Sixteen patients used the cream twice daily, with significant improvement after 2 days of treatment. Within 3 weeks of topical therapy with 1% SDZ ASM 981 cream twice daily, a mean reduction of 71.9% in the ADSI score was observed at the actively treated test sites compared with a mean reduction of 10.3% at the placebo-treated test sites (P<.001). Efficacy was significantly less in the group treated once daily (n=18), with mean reductions of 37.7% and 6.2%, respectively. The efficacy was especially apparent for pruritus and excoriation. There were no clinically relevant drug-related adverse effects.. Treatment with 1% SDZ ASM 981 cream was well tolerated. Twice-daily application of 1% SDZ ASM 981 cream was significantly more effective than use of the corresponding placebo and more effective than once-daily treatment. The new macrolactam ascomycin derivative SDZ ASM 981 is a promising agent for the treatment of patients with atopic dermatitis. More elaborate phase 2 and 3 trials are under way to fully investigate the potential of this medication.

Topics: Administration, Topical; Adolescent; Adult; Dermatitis, Atopic; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Severity of Illness Index; Tacrolimus; Time Factors; Treatment Outcome

We conducted a randomized, double-blind, placebo-controlled trial to assess the atrophogenicity of tacrolimus ointment. In a combined group of atopic dermatitis patients (n = 14) and healthy volunteers (n = 12), 0.3% tacrolimus, 0.1% tacrolimus, betamethasone-valerate, and a vehicle control were applied in a randomized order to nonsymptomatic, 4 cm x 4 cm regions of abdominal skin. After 7 d of treatment under occlusion, the carboxy- and amino-terminal propeptides of procollagen I (PICP, PINP) and the amino-terminal propeptide of procollagen III (PIIINP) were measured from suction blister fluid with specific radioimmunoassays. In addition, ultrasound measurements of skin thickness were taken. Betamethasone-treated areas showed median PICP, PINP, and PIIINP concentrations of 17.0%, 17.6%, and 39.5% of the vehicle control at the end of the treatment period, respectively, whereas the 0.1% and 0.3% tacrolimus-treated areas showed median concentrations of approximately 100% of the vehicle control (p < 0.001). Betamethasone was also the only treatment to reduce skin thickness; the median decrease in skin thickness was 7.4% relative to 0.1% tacrolimus, 7.1% relative to 0.3% tacrolimus, and 8.8% relative to the vehicle control (p < 0.01). Results for atopic dermatitis patients and healthy volunteers were similar. These findings suggest that tacrolimus does not cause skin atrophy.

Topics: Adolescent; Adult; Collagen; Dermatitis, Atopic; Double-Blind Method; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Ointments; Peptide Fragments; Procollagen; Reference Values; Tacrolimus

A topical formulation of tacrolimus, an immunosuppressant currently marketed for the prevention of rejection after solid organ transplant, is a potential therapeutic agent for atopic dermatitis.. We sought to determine the safety and efficacy of tacrolimus ointment in pediatric patients with moderate-to-severe atopic dermatitis.. In this double-blind, vehicle-controlled multicenter trial, children ages 7 to 16 years were treated with twice daily application of tacrolimus ointment at 1 of 3 concentrations (0.03% [n = 43], 0.1% [n = 49], or 0.3% [n = 44]) or vehicle (n = 44) for up to 22 days, with a 2-week follow-up period.. The Physician's Global Evaluation of clinical response showed that 69% (95% confidence interval: 53-82) of patients in the 0.03% tacrolimus ointment group, 67% (95% confidence interval: 52-81) in the 0.1% tacrolimus ointment group, and 70% (95% confidence interval: 54-83) in the 0.3% tacrolimus ointment group, compared with 38% (95% confidence interval: 24-54) in the vehicle group, had a marked to excellent (> or =75%) improvement or clearing of their atopic dermatitis (P =.005, .007, and .004, respectively for the 3 tacrolimus groups compared with the vehicle group). The mean percent improvement for a modified Eczema Area and Severity Index at end of treatment for each of the 3 tacrolimus groups (0.03%, 72%; 0.1%, 77%: and 0.3%, 81%) was significantly better than that of the vehicle group (26%; P <.001). The median percent reduction in pruritus was significantly greater for tacrolimus-treated patients (74% to 89%) than for vehicle-treated patients (51%, P = .027). No serious systemic adverse events were noted, and systemic absorption was minimal.. Tacrolimus ointment appears to be safe and effective in children with atopic dermatitis.

Topics: Administration, Topical; Adolescent; Child; Dermatitis, Atopic; Double-Blind Method; Female; Humans; Immunosuppressive Agents; Male; Tacrolimus; Treatment Outcome

A highly sensitive enzyme-linked immunosorbent assay method has been developed for the determination of tacrolimus in human blood samples. The assay is a modification of the previously published assay with improved sensitivity. Following extraction of tacrolimus with methanol and sulfosalicylic acid, the samples are incubated for 2 h at room temperature on a Nunc Maxisorb plate that has been treated for nonspecific binding by precoating with polyclonal antibody. The analysis of human blood following the standard addition of tacrolimus (0.02-5.0 ng/ml) demonstrated excellent precision and accuracy over a 6-day period. The interday and intraday co-efficients of variation were 6.0-28.9 and 3.9-15.2%, respectively. The limit of quantitation was 0.05 ng/ml. The method was used to quantitate blood concentration of tacrolimus in patients following the administration of tacrolimus ointment.

Topics: Adult; Child; Dermatitis, Atopic; Enzyme-Linked Immunosorbent Assay; Humans; Immunosuppressive Agents; Ointments; Reproducibility of Results; Sensitivity and Specificity; Tacrolimus

Tacrolimus (FK 506) is an effective immunosuppressant drug for the prevention of rejection after organ transplantation, and preliminary studies suggest that topical application of tacrolimus is effective in the treatment of atopic dermatitis.. We conducted a randomized, doubleblind, multicenter study that compared 0.03 percent, 0.1 percent, and 0.3 percent tacrolimus ointment with vehicle alone in patients with moderate to severe atopic dermatitis. The ointment was applied twice daily to a defined, symptomatic area of 200 to 1000 cm2 of skin for three weeks. The primary end point was the change in the summary score for erythema, edema, and pruritus between the first and last days of treatment.. After three weeks of treatment, the median percentage decrease in the summary score for dermatitis on the trunk and extremities was 66.7 percent for the 54 patients receiving 0.03 percent tacrolimus, 83.3 percent for the 54 patients receiving 0.1 percent tacrolimus, 75.0 percent for the 51 patients receiving 0.3 percent tacrolimus, and 22.5 percent for the 54 patients receiving vehicle alone (P<0.001). The results for the face and neck were similar. The differences among the three tacrolimus groups were not statistically significant. A sensation of burning at the site of application was the only adverse event that was significantly more frequent with tacrolimus than with vehicle alone (P<0.001). Throughout the study, most patients in all three tacrolimus groups had blood concentrations of tacrolimus below 0.25 ng per milliliter. The highest concentration was 4.9 ng per milliliter, which was reported in the group receiving 0.3 percent tacrolimus.. The short-term application of tacrolimus ointment is effective in the treatment of atopic dermatitis, with the sensation of burning being the main side effect.

Topics: Administration, Cutaneous; Adult; Dermatitis, Atopic; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Immunosuppressive Agents; Male; Ointments; Tacrolimus; Treatment Outcome

Topics: Administration, Topical; Adult; Dermatitis, Atopic; Drug Administration Schedule; Humans; Immunosuppressive Agents; Tacrolimus

Topics: Adult; Dermatitis, Atopic; Humans; Ointments; Tacrolimus

Topics: Administration, Topical; Dermatitis, Atopic; Humans; Scleroderma, Localized; Tacrolimus

Topics: Administration, Topical; Dermatitis, Atopic; Dermatologic Agents; Humans; Irritants; Sensation; Tacrolimus; Treatment Outcome

Topics: Dermatitis, Atopic; Humans; Ownership; Patient Selection; Severity of Illness Index; Tacrolimus; Treatment Outcome

Nonsteroidal topicals and systemic therapies are often utilized for atopic dermatitis (AD) in children with inadequate response to topical corticosteroids. We sought to characterize patient factors associated with prescriptions for nonsteroidal topical (tacrolimus, pimecrolimus, crisaborole), systemic immunosuppressant (methotrexate, mycophenolate, cyclosporine, azathioprine), and systemic corticosteroid therapy among children with AD. In a cross-sectional study of patients <18 years old with AD seen at a large children's hospital between 2009 and 2017, we found that nonsteroidal topical and systemic medication prescriptions were associated with older age of the patient, male sex, comorbid atopy, greater healthcare utilization, specialist care, and race/ethnicity. Compared to White patients, Black and Hispanic patients were less likely to be prescribed nonsteroidal topicals and non-White patients were less likely to be prescribed systemic medications, suggesting that further examination of potential disparities in pediatric AD treatment is needed.

Topics: Adolescent; Child; Cross-Sectional Studies; Cyclosporine; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Male; Prescriptions; Tacrolimus

The cancer risks associated with treatment with topical calcineurin inhibitors (TCIs) in patients with atopic dermatitis (AD) remain controversial, and limited evidence exists regarding the cancer risks among patients with AD treated with TCIs in Asian populations.. This study identified the association between TCI use and the risks of developing all cancers, lymphoma, skin cancers, and other cancers.. This study was a nationwide, population-based, retrospective cohort study.. Taiwan's National Health Insurance Research Database.. Patients diagnosed at least twice with ICD-9 code 691 or at least one time with ICD-9 codes 691 or 692.9 within 1 year between 1 January 2003 and 31 December 2010 were included and followed until 31 December 2018. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using the Cox proportional hazard ratio model.. Patients using tacrolimus or pimecrolimus were identified in the National Health Insurance Research Database and compared with patients using topical corticosteroids (TCSs).. The main outcomes were hazard ratios (HRs) of cancer diagnoses and associated outcomes obtained from the Taiwan Cancer Registry database.. After propensity score (PS) matching, the final cohort included 195,925 patients with AD, including 39,185 who were initial TCI users and 156,740 who were TCS users. Propensity score matching was performed according to age, sex, index year, and Charlson Comorbidity Index using a ratio of 1:4. Except for leukemia, HR and 95% CI showed no significant associations between TCI use and the risk of developing all cancer, lymphoma, skin cancers, and other cancers. Sensitivity analysis showed that the lag time HRs for every cancer subtype continued to show no significant association between TCI use and cancer risk, except for leukemia.. Our study found no evidence to support an association between TCI use and the risks of almost all cancers compared with TCS use in patients with AD, but physicians should be aware of potentially higher risks of leukemia with TCI use. This study represents the first population-based study focused on the cancer risk of TCI use among patients with AD in an Asian population.

Topics: Calcineurin Inhibitors; Dermatitis, Atopic; Humans; Leukemia; Lymphoma; Retrospective Studies; Skin Neoplasms; Tacrolimus

The aim of this study was to evaluate the efficacy and safety of combining dupilumab with topical tacrolimus for the treatment of atopic dermatitis (AD) in children aged 6 to 12 years.. A total of 168 pediatric (aged 6 to 12 years) patients with severe AD admitted to our hospital between April 2022 and April 2023 were included in this retrospective study. These patients are grouped according to different medication methods, assigned them to receive either tacrolimus plus topical corticosteroids (control group) or dupilumab combined with tacrolimus and topical corticosteroids (study group), with 84 patients in each group. Clinical efficacy and adverse reactions were primary clinical endpoints.. The use of dupilumab significantly increased the total effective rate for the patients by 14.29%, from 77.38% (65/84) in the control group to 91.67% (77/84) in the study group. Following treatment, patients given dupilumab showed a more significantly decreased peripheral blood eosinophils (EOS) and immunoglobulin E (IgE) levels than those without dupilumab treatment. Patients administered with dupilumab exhibited markedly lower scores on the Patient-oriented Eczema Measure (POEM) at weeks 12 and 16 and lower Eczema Area and Severity Index (EASI) scores at weeks 8, 12, and 16 when compared to those patients who did not receive dupilumab therapy. At the 16-week, 37 patients in the study group obtained a score of 1/0 on the Verified Investigator's Global Assessment (v-IGA) scale, whereas the control group had 24 such cases, indicating a significantly higher response rate provided by the protocol incorporating dupilumab. After 16 weeks of treatment, both groups demonstrated a marked decrease in itch numeric rating scale (NRS) scores and Dermatology Life Quality Index (DLQI) scores, with lower scores observed in the study group than in the control group. The absence of a significant difference in the incidence of adverse reactions between the two groups suggested a high safety profile of dupilumab.. The combination of dupilumab with topical tacrolimus demonstrated favorable efficacy in the management of AD in children aged 6 to 12 years. This treatment protocol effectively alleviates symptoms, enhances the quality of life of patients, and shows no increased risk of adverse reactions.

Topics: Child; Dermatitis, Atopic; Double-Blind Method; Eczema; Glucocorticoids; Humans; Quality of Life; Retrospective Studies; Severity of Illness Index; Tacrolimus; Treatment Outcome

Topics: Administration, Topical; Dermatitis, Atopic; Hand; Humans; Immunosuppressive Agents; Ointments; Tacrolimus; Treatment Outcome

Topical tacrolimus is used off-label in young children, but data are limited on its use in children under 2 years of age and for long-term treatment.. To compare safety differences between topical tacrolimus (0.03% and 0.1% ointments) and topical corticosteroids (mild and moderate potency) in young children with atopic dermatitis (AD).. We conducted a 36-month follow-up study with 152 young children aged 1-3 years with moderate to severe AD. The children were followed up prospectively, and data were collected on infections, disease severity, growth parameters, vaccination responses and other relevant laboratory tests were gathered.. There were no significant differences between the treatment groups for skin-related infections (SRIs) (P = 0.20), non-SRIs (P = 0.20), growth parameters height (P = 0.60), body weight (P = 0.81), Eczema Area and Severity Index (EASI) (P = 0.19), vaccination responses (P = 0.62), serum cortisone levels (P = 0.23) or serum levels of interleukin (IL)-4, IL-10, IL-12, IL-31 and interferon-γ. EASI decreased significantly in both groups (P < 0.001). In the tacrolimus group, nine patients (11.68%) had detectable tacrolimus blood concentrations at the 1-week visit. There were no malignancies or severe infections during the study, and blood eosinophil counts were similar in both groups.. Topical tacrolimus (0.03% and 0.1%) and topical corticosteroids (mild and moderate potency) are safe to use in young children with moderate to severe AD, and have comparable efficacy and safety profiles.

Topics: Administration, Topical; Child; Child, Preschool; Dermatitis, Atopic; Dermatologic Agents; Follow-Up Studies; Glucocorticoids; Humans; Immunosuppressive Agents; Infant; Ointments; Tacrolimus; Treatment Outcome

To evaluate the role of tacrolimus ointment in the management of patients on dupilumab therapy for severe atopic dermatitis, in a real-life setting.. Consecutive patients with severe AD treated with dupilumab were enrolled. Topical treatment was associated according to the clinical practice. Eczema Area and Severity Index (EASI), itching and sleep Numerical Rating Scale (NRS) and Dermatologic quality of Life (DLQI) were recorded at baseline and after 4, 16 and 52 weeks of treatment with dupilumab.. Overall, 342 patients were enrolled, and 307 were evaluable. Tacrolimus was used by 6.5% (n=20) of patients at baseline, 11%, 13.5%, and 11.3% after 1, 4 and 12 months, respectively; the mean time to introduce tacrolimus after initiation of dupilumab was 8.3 ± 0.3 months. Low EASI score (<7; mild disease) after 1 month of systemic therapy was more frequent in patients who applied tacrolimus at baseline than in patients who did not (72.2% vs. 55.8%, p=0.027). Female sex, low DLQI scores, low age at dupilumab initiation, and non-generalized AD were correlated with an increased probability to start tacrolimus at any time during the study.. Data suggested that early treatment of localized areas with tacrolimus improves systemic treatment efficacy.

Topics: Dermatitis, Atopic; Eczema; Female; Humans; Pruritus; Quality of Life; Severity of Illness Index; Tacrolimus; Treatment Outcome

Localized flushing after alcohol ingestion is a reported adverse effect of 2 topical calcineurin inhibitors, tacrolimus and pimecrolimus, which are approved to treat atopic dermatitis and used off label for other dermatologic conditions. We propose techniques for alleviating this phenomenon.

Topics: Administration, Topical; Calcineurin Inhibitors; Dermatitis, Atopic; Drug-Related Side Effects and Adverse Reactions; Humans; Tacrolimus

Topics: Blepharitis; Dermatitis, Atopic; Eczema; Eyelids; Humans; Immunosuppressive Agents; Tacrolimus; Treatment Outcome

Topical calcineurin inhibitors are a family of drugs that have been touted for having high efficacy without the risks of cutaneous atrophy and systemic absorption seen with topical corticosteroids. They may play an important role in the elderly population, where preexisting cutaneous atrophy increases susceptibility to these adverse effects.

Topics: Administration, Topical; Aged; Atrophy; Calcineurin Inhibitors; Dermatitis, Atopic; Dermatologic Agents; Humans; Medicare; Tacrolimus; United States

This is the English version of the Clinical Practice Guidelines for the Management of Atopic Dermatitis 2021. Atopic dermatitis (AD) is a disease characterized by relapsing eczema with pruritus as a primary lesion. In Japan, from the perspective of evidence-based medicine, the current strategies for the treatment of AD consist of three primary measures: (i) use of topical corticosteroids, tacrolimus ointment, and delgocitinib ointment as the main treatment of the inflammation; (ii) topical application of emollients to treat the cutaneous barrier dysfunction; and (iii) avoidance of apparent exacerbating factors, psychological counseling, and advice about daily life. In the present revised guidelines, descriptions of three new drugs, namely, dupilumab, delgocitinib, and baricitinib, have been added. The guidelines present recommendations to review clinical research articles, evaluate the balance between the advantages and disadvantages of medical activities, and optimize medical activity-related patient outcomes with respect to several important points requiring decision-making in clinical practice.

Topics: Dermatitis, Atopic; Emollients; Glucocorticoids; Humans; Ointments; Tacrolimus

A 15-year-old Asian girl with severe atopic dermatitis was referred for dupilumab-associated blepharoconjunctivitis. Medical history was significant for severe atopic dermatitis. She was started on prednisolone acetate 1% ophthalmic suspension three times daily, and dupilumab injections were withheld after the initial visit. The patient was noted to have right lower eyelid ectropion, cicatricial occlusion, and severe punctal stenosis 6 weeks later. She was started on 0.03% tacrolimus ointment to the eyelid margin. Resolution of ectropion and restoration of punctal patency with residual stenosis were observed 4 weeks later. This is the first reported adolescent case of dupilumab-associated ectropion and punctal stenosis successfully treated with topical tacrolimus ointment.

Topics: Adolescent; Constriction, Pathologic; Dermatitis, Atopic; Ectropion; Female; Humans; Immunosuppressive Agents; Lacrimal Apparatus Diseases; Ointments; Tacrolimus; Treatment Outcome

Topics: Administration, Topical; Calcineurin Inhibitors; Dermatitis, Atopic; Humans; Tacrolimus

Topics: Animals; Dermatitis, Atopic; Hydrogels; Mice; Nanoparticles; Porosity; Rats; Silicon Dioxide; Tacrolimus

Topical calcineurin inhibitors (TCIs) are an important anti-inflammatory drug for treating atopic dermatitis (AD). However, those treatment responses are variable. In this study, we stratified AD patients by patterns of response to remission maintenance therapy (proactive therapy) with topical tacrolimus, a typical TCI. Thereafter, we explored patient features that predict the success or failure of proactive therapy using TCI (TCI proactive therapy).. A single-arm open-label clinical study aimed to evaluate the efficacy of TCI proactive therapy was conducted in 31 patients with AD. Patients were treated with TCS to induce remission (remission-induction period) followed by daily TCI ointment (0.1% tacrolimus) application for 4 weeks (maintenance therapy period), and twice-weekly application for 12 weeks (proactive therapy period). Based on its results, treatment outcomes were correlated with the patients' clinical and laboratory findings.. Of the 31 patients enrolled in the study, 21 successfully completed maintenance therapy (TCI responders). Among them, 13 completed (proactive-completed group) and 8 failed proactive therapy (proactive-dropout group). At the beginning of maintenance therapy, the serum IgE level was significantly higher in the TCI responders than in those who failed maintenance therapy (. AD patients were stratified into three different response patterns to TCI proactive therapy. Patients with less involvement of IgE in the pathogenesis and inadequate remission induction by TCS may not be expected to respond well to TCI proactive therapy.Key messagesAD patients can be stratified into three types according to their pattern of responsiveness to TCI proactive therapy.The efficacy of TCI proactive therapy is lower in AD patients with lower serum IgE levels.TCI proactive therapy should be done after the achievement of adequate remission induction by TCS.

Topics: Administration, Topical; Adult; Calcineurin Inhibitors; Dermatitis, Atopic; Dermatologic Agents; Female; Humans; Immunoglobulin E; Male; Ointments; Prospective Studies; Tacrolimus; Treatment Failure

Atopic dermatitis (AD) has a severe impact on quality of life (QoL).. To analyze the impact of AD on QoL of small children with moderate-to-severe AD in a tertiary health care hospital in Helsinki, Finland.. Based on interim analysis of this longitudinal follow-up study, we investigated treatment response (topical corticosteroids vs. tacrolimus) and QoL of 152 small children with moderate-to-severe AD.. The tacrolimus group had a significantly better treatment response at 12 months visit, but thereafter no differences were observed (p = 0.029; Mann-Whitney U test). The odds ratio for group comparisons was 2.258 (CI: 1.151-4.431). There was a significant improvement in QoL during follow-up in both treatment groups. Our study showed substantial improvements in disease severity and QoL based on active management and effective treatments in small children with AD. The main improvement was seen during the first year in both treatment groups with a lasting response.. Effective treatment has a significant positive impact on the QoL of small children with AD and their families.

Topics: Administration, Topical; Dermatitis, Atopic; Dermatologic Agents; Family; Female; Follow-Up Studies; Humans; Hydrocortisone; Immunosuppressive Agents; Infant; Longitudinal Studies; Male; Ointments; Pruritus; Quality of Life; Severity of Illness Index; Tacrolimus

Topics: Dermatitis, Atopic; Eczema; Humans; Pharmacies; Pharmacy; Tacrolimus

The epidermal skin barrier and lipids that are integral to its structure are impaired in atopic dermatitis (AD). Current treatment guidelines include proactive therapy.. This study assessed the effect of 12 weeks of proactive treatment with tacrolimus ointment 0.1% (TAC) compared with mometasone furoate cream (MF) on specific skin barrier lipids in patients with AD who previously received 10 days of reactive treatment with either agent.. This was an open-label, non-interventional study. In the reactive phase, forearm lesions in 20 patients were treated with either TAC or MF twice daily for 10 days. In the subsequent proactive phase, patients applied TAC or MF twice weekly for 12 weeks (. Over the 12-week proactive treatment period, the mean local SCORAD significantly decreased in the TAC and MF treatment group. Levels of total and individual ceramides increased in both groups. Normalized intercellular lipid lamellae values were significantly higher with proactive TAC treatment than MF and undistinguishable from healthy skin.. The results show that proactive treatment with TAC is superior in restoring the skin barrier.

Topics: Ceramides; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Mometasone Furoate; Ointments; Tacrolimus; Treatment Outcome

A consecutive case series of patients with dupilumab-associated ocular surface disease (DAOSD) that describes common ocular symptoms and signs, proposes a symptom disease severity grading system, and describes treatment strategies of DAOSD patients was evaluated.. A retrospective chart review of patients with concomitant dupilumab-treated atopic dermatitis and DAOSD with ophthalmic evaluation between January 2014 and May 2019 was conducted.. Twenty-nine patients (mean age 46 years, M/F: 12/17) with 57 ophthalmic exams were identified. The most common ocular symptoms included irritation/pain (n = 28, 97%), redness (n = 24, 83%), pruritus (n = 18, 62%), discharge (n = 18, 62%), and light sensitivity (n = 6, 21%). The most frequent signs included conjunctival injection (n = 18, 62%), superficial punctate keratitis (n = 16, 55%), and papillary reaction (n = 8, 28%). Topical corticosteroids (TCS) (n = 23, 79%), tacrolimus (n = 6, 21%), and artificial tears (n = 7, 24%) were the most commonly used therapies. Of those with follow-up documentation (n = 21), 20 were noted to have partial or complete response with TCS based on symptoms and reduction of signs. Using our proposed symptom-based grading scale, scaled 1 to 5 based on the presence of common symptoms listed above, 66% (n = 19) requiring topical immunomodulating therapy were found in the 'severe' group (≥3 symptoms) and 17% (n = 5) were found in the 'mild' group (≤2 symptoms).. This study provides insight into the commonly presenting ocular signs and symptoms associated with DAOSD and highlights the efficacy of TCS and other immunomodulators in improving symptoms associated with DAOSD. Based on our findings, we propose a symptom-based grading system that can guide nonophthalmic physicians regarding ophthalmology consult.

Topics: Adolescent; Adult; Aged; Anti-Allergic Agents; Antibodies, Monoclonal, Humanized; Child; Conjunctivitis; Dermatitis, Atopic; Eye Pain; Female; Follow-Up Studies; Glucocorticoids; Humans; Keratitis; Male; Middle Aged; Retrospective Studies; Severity of Illness Index; Tacrolimus; Treatment Outcome

To describe the clinical and laboratory profile, natural course, treatment outcome, and risk factors of posttransplant esophageal and nonesophageal eosinophilic gastrointestinal disorders (EGIDs).. All children (aged <18 years) who underwent liver transplantation, between 2011 and 2019, in a single transplant center with a follow-up period of 1 year or more posttransplant and with a history of posttransplant endoscopic evaluation were included in this study.. During the study period, 89 children met the inclusion criteria. Patients were followed for a median of 8.0 years. A total of 39 (44%) patients were diagnosed with EGID after transplantation. Of these, 29 (33%) had eosinophilic esophagitis (EoE), and 10 (11%) had eosinophilic gastritis, gastroenteritis or enterocolitis. In comparison with the non-EGID group, patients with EGID were younger at transplant (P ≤ 0.0001), transplanted more frequently due to biliary atresia (P ≤ 0.0001), and had higher rates of pretransplant allergy (P = 0.019). In the posttransplant period, they had higher rates of mammalian Target of Rapamycin inhibitor use (P = 0.006), Epstein-Barr virus viremia (P = 0.03), post-transplant lymphoproliferative disease (P = 0.005), and allergen sensitization (P ≤ 0.0001). In regression analysis, young age at transplant, age at diagnosis, pretransplant atopic dermatitis, and post-transplant lymphoproliferative disease were associated with an increased risk of EGID or EoE. Laboratory abnormalities such as anemia (P = 0.007), thrombocytosis (P = 0.012), and hypoalbuminemia (P = 0.031) were more commonly observed in the eosinophilic gastritis, gastroenteritis or enterocolitis group than in the EoE group. Following treatment, most patients had symptomatic resolution at 3 months and histologic resolution at 6 months postdiagnosis. Among the patients who had 5 years of follow-up, none recurred.. EGID is a common posttransplant diagnosis, which seems to affect patients who are transplanted earlier and who have pretransplant atopy. Posttransplant EGID is responsive to treatment, but as histologic remission occurs after symptomatic resolution, the decision to perform control endoscopy should be delayed.

Topics: Age Factors; Anti-Allergic Agents; Biliary Atresia; Budesonide; Child; Child, Preschool; Cholestasis, Intrahepatic; Dermatitis, Atopic; Disease Progression; Drug Tapering; Enteritis; Enterocolitis; Eosinophilia; Eosinophilic Esophagitis; Epstein-Barr Virus Infections; Female; Follow-Up Studies; Gastritis; Glucocorticoids; Graft Rejection; Humans; Hypersensitivity; Immunosuppressive Agents; Infant; Ketotifen; Liver Failure, Acute; Liver Transplantation; Lymphoproliferative Disorders; Male; Postoperative Complications; Prevalence; Retrospective Studies; Risk Factors; Tacrolimus; TOR Serine-Threonine Kinases; Treatment Outcome; Viremia

Atopic dermatitis (AD) is a common skin disease during infancy, which imposes a considerable burden on patients, their families, and the society, requiring effective treatment options that result in rapid and sustained symptom relief. Additionally, early treatment may prevent the development of atopic comorbidities by restoring the skin barrier. Currently, topical standard-of-care for AD in infants includes emollients and topical corticosteroids (TCS) to treat and reduce the risk of flares. However, only few have been approved for infants and long-term maintenance therapy with TCS is not indicated due to potential local and systemic side effects, including skin atrophy. Accordingly, the recently updated European guidelines for treatment of AD recommend topical calcineurin inhibitors (TCIs) for long-term use, treatment of sensitive skin areas, and for use in the pediatric population. Evidence on the use of TCIs for infants has almost been exclusively collected for pimecrolimus, with >4000 infants evaluated in clinical trials, consistently confirming that pimecrolimus is a safe and effective treatment for infants with AD. Nevertheless, its use is still restricted in most countries to children above the age of 2 years due to initial and mostly theoretical safety concerns. Based on a careful review of the available evidence of clinical trials, post-marketing surveillance, and epidemiological studies, an Expert Panel of European dermatologists and pediatric allergologists concluded that these safety concerns are no longer valid. Therefore, pimecrolimus offers a safe and effective alternative to TCS in infants aged 3 months and above, and labeling restrictions in this age group are no longer justified.

Topics: Calcineurin Inhibitors; Child; Consensus; Dermatitis, Atopic; Humans; Infant; Infant, Newborn; Tacrolimus; Treatment Outcome

Topics: Adrenal Cortex Hormones; Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; COVID-19; Dermatitis, Atopic; Female; Humans; Immunosuppressive Agents; Lichen Planus; Male; Middle Aged; Pemphigus; Psoriasis; SARS-CoV-2; Tacrolimus

Topics: Calcineurin Inhibitors; Child; Dermatitis, Atopic; Humans; Tacrolimus

Atopic dermatitis (AD) is one of the most common inflammatory skin diseases and has aesthetic, physical, and emotional-social sequelae when left untreated.. To classify the most common adverse reactions associated with dupilumab treatment in patients with AD.. The United States Food and Drug Administration Adverse Event Reporting (FAERS) database was analyzed for common adverse reactions associated with dupilumab, topical pimecrolimus, and topical tacrolimus. Phase III clinical trial data were used to compare the rate of herpes infections between the treatment group and placebo group.. The most common adverse reaction associated with dupilumab was ocular complications. Herpes infections were extremely rare in the patients with AD being treated with dupilumab.. Prescribing information for dupilumab, topical pimecrolimus, and topical tacrolimus is not available. Adverse effects are reported by patients, health care providers, and pharmaceutical companies, they have not been corroborated.. Ocular complications are the most common complication associated with dupilumab. The rate of herpes infection is low in patients being treated with dupilumab, topical pimecrolimus, and topical tacrolimus. There is no significant difference for the rate of herpes infection between, placebo, dupilumab, topical pimecrolimus, and the topical tacrolimus treatment group, suggesting that dupilumab does not affect herpes infection rates.

Topics: Antibodies, Monoclonal, Humanized; Blepharitis; Clinical Trials as Topic; Conjunctivitis; Dermatitis, Atopic; Dry Eye Syndromes; Eye Diseases; Herpesviridae Infections; Humans; Hyperemia; Interleukin-13; Interleukin-4; Retrospective Studies; Tacrolimus; United States; United States Food and Drug Administration; Virus Activation

Atopic dermatitis is a chronic relapsing, inflammatory skin disorder associated with skin barrier dysfunction, the prevalence of which has increased dramatically in developing countries. In this article, we propose a treatment algorithm for patients with mild-to-moderate and severe atopic dermatitis flares in daily clinical practice. An international panel of 15 dermatology and allergy experts from eight countries was formed to develop a practical algorithm for the treatment of patients with atopic dermatitis, with a particular focus on topical therapies. In cases of mild-to-moderate atopic dermatitis involving sensitive skin areas, the topical calcineurin inhibitor pimecrolimus should be applied twice daily at the first signs of atopic dermatitis. For other body locations, patients should apply a topical calcineurin inhibitor, either pimecrolimus or tacrolimus, twice daily at the first signs of atopic dermatitis, such as pruritus, or twice weekly in previously affected skin areas. Emollients should be used regularly. Patients experiencing acute atopic dermatitis flares in sensitive skin areas should apply a topical corticosteroid twice daily or alternate once-daily topical corticosteroid/topical calcineurin inhibitor until symptoms improve. Following improvement, topical corticosteroid therapy should be discontinued and patients switched to a topical calcineurin inhibitor. Maintenance therapy should include the use of pimecrolimus once daily for sensitive areas and tacrolimus for other body locations. This treatment algorithm can help guide clinical decision-making in the treatment of atopic dermatitis.

Topics: Administration, Topical; Algorithms; Calcineurin Inhibitors; Clinical Decision-Making; Dermatitis, Atopic; Humans; Tacrolimus; Treatment Outcome

Atopic dermatitis (AD) is the most common inflammatory skin disease affecting people of all age groups worldwide. To our knowledge, there are currently no studies estimating the effectiveness of tacrolimus ointment and dupilumab as a combination therapy for AD. Thus, here we describe the effectiveness and safety of tacrolimus ointment in combination with dupilumab for facial rashes in patients with AD. Overall, we included 109 patients who newly received dupilumab from April 2018 to July 2020 in the Dermatology Department of Hyogo College of Medicine Hospital. Of them, 60 patients were treated with tacrolimus ointment. Specifically, of the 60 patients, 40 were treated with dupilumab in combination with tacrolimus ointment and topical steroids, whereas the remaining 20 were prescribed tacrolimus ointment alone and were further analyzed. The analysis showed that the combination does not cause serious side-effects at high frequency. The patients showed rapid improvement of facial dermatitis along with systemic dermatitis, and the rate of improvement of head/neck Eczema Area and Severity Index (EASI) score significantly correlated with the rate of improvement of overall EASI score. In addition, there was no complication of herpes simplex observed in these 20 patients. Thus, tacrolimus ointment combined with dupilumab is an effective and safe treatment option for facial AD.

Topics: Antibodies, Monoclonal, Humanized; Dermatitis, Atopic; Eczema; Humans; Immunosuppressive Agents; Ointments; Tacrolimus; Treatment Outcome

Human mesenchymal stem cells (hMSCs) therapy has recently been considered a promising treatment for atopic dermatitis (AD) due to their immunomodulation and tissue regeneration ability. In our previous studies, we demonstrated that hMSCs alleviate allergic inflammation in murine AD model by inhibiting the activation of mast cells and B cells. Also our phase I/IIa clinical trial showed clinical efficacy and safety of hMSCs in moderate-to-severe adult AD patients. However, hMSCs therapy against atopic dermatitis have had poor results in clinical field. Therefore, we investigated the reason behind this result. We hypothesized that drug-cell interaction could interfere with the therapeutic efficacy of stem cells, and investigated whether coadministration with pimecrolimus, one of the topical calcineurin inhibitors, could influence the therapeutic potential of human umbilical cord blood mesenchymal stem cells (hUCB-MSCs) in AD.. hUCB-MSCs were subcutaneously injected to AD-induced mice with or without pimecrolimus topical application. To examine whether pimecrolimus influenced the immunomodulatory activity of hUCB-MSCs, hUCB-MSCs were treated with pimecrolimus.. Pimecrolimus disturbed the therapeutic effect of hUCB-MSCs when they were co-administered in murine AD model. Moreover, the inhibitory functions of hUCB-MSCs against type 2 helper T (Th2) cell differentiation and mast cell activation were also deteriorated by pimecrolimus treatment. Interestingly, we found that pimecrolimus decreased the production of PGE. Coadministration of pimecrolimus with hMSCs could interfere with the therapeutic efficacy of hMSCs in atopic dermatitis, and this is the first study that figured out the interaction of hMSCs with other drugs in cell therapy of atopic dermatitis. Therefore, this study might give rise to improvement of the clinical application of hMSCs therapy and facilitate the widespread application of hMSCs in clinical field.

Topics: Animals; Cyclooxygenase 2; Dermatitis, Atopic; Humans; Mesenchymal Stem Cells; Mice; Tacrolimus

To identify risk factors for the development of dupilumab-induced ocular surface disease (DIOSD) in adult patients with atopic dermatitis (AD) and describe outcomes of treatment.. A retrospective institutional cohort study performed at the Rabin Medical Center, Petach Tikva, Israel. Adult patients with AD who received dupilumab from March 2018 to June 2019 were included. Demographics, AD severity scores, blood IgE levels, previous atopic keratoconjunctivitis (AKC), dermatological response to dupilumab, ophthalmological evaluation and treatment were noted. Univariate and multivariate analyses were used to identify risk factors for DIOSD.. Sixteen of 37 patients who were included in the study (43%) had new or exacerbated symptoms of ocular surface disease starting at 2 weeks following the first treatment. Three patients reported transient dry eye sensation which lasted 2 weeks; nine patients reported chronic dry eye sensation, and four patients (25%) had marked blepharoconjunctivitis. The presence of severe AD was the strongest predictor of DIOSD. Not a single patient with moderate AD had DIOSD. In multivariate analysis, prior AKC was a risk factor for DIOSD (R. DIOSD is common in patients with AD receiving dupilumab. While most cases are mild, some patients can develop blepharoconjunctivitis which responds well to tacrolimus ointment. AD severity, and previous AKC are risk factors for DIOSD.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Dermatitis, Atopic; Female; Humans; Immunosuppressive Agents; Interleukin-4 Receptor alpha Subunit; Keratoconjunctivitis; Male; Middle Aged; Ointments; Retrospective Studies; Tacrolimus; Treatment Outcome; Young Adult

Topics: Dermatitis, Atopic; Eczema; Humans; Severity of Illness Index; Tacrolimus

Atopic dermatitis (AD) is one of the most common cutaneous inflammatory diseases both in adults and in children. It is a chronic, remitting-relapsing dermatitis, primarily managed by dermatologists, but also by allergists and primary care physicians. Due to coexistence of comorbidities, often a multidisciplinary team is required. Topical calcineurin inhibitors (TCIs - i.e. tacrolimus and pimecrolimus) are a class of steroid-sparing, anti-inflammatory agents that have been shown to be efficacious for the treatment of AD acute flares and in maintenance therapy. In particular, the application of tacrolimus ointment twice daily reduces AD severity and pruritus. Moreover, maintenance therapy with an intermittent application of tacrolimus to recurrent skin sites (proactive therapy) decreases frequency and severity of relapses. Many studies have also assessed the efficacy of TCIs in disorders other than AD. Although US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) issued a "black box warning" regarding the possible cancerogenic activity of these drugs, there is currently no strong evidence of an increased rate of malignancy in treated patients, and observational data from postmarketing surveillance studies have shown no safety concerns. A panel of dermatologists have thoroughly discussed the use of tacrolimus in AD after 15-year experience. The experts focused on AD flare treatment, maintenance therapy and management of side effects. Consensus was reached on some areas of interest, namely the stages of AD in which tacrolimus is recommended, the amount of drug to be applied, how to manage side effects, and how to improve patient's compliance. Moreover, the panel of experts recommended to perform randomized clinical trials to confirm the efficacy of tacrolimus off-label use, which led to successful outcomes in other skin diseases.

Topics: Administration, Cutaneous; Adult; Calcineurin Inhibitors; Consensus; Dermatitis, Atopic; Dermatologists; Humans; Immunosuppressive Agents; Medication Adherence; Severity of Illness Index; Tacrolimus

Topics: Adult; Antibodies, Monoclonal, Humanized; Conjunctivitis; Dermatitis, Atopic; Female; Humans; Immunocompromised Host; Immunosuppressive Agents; Interleukin-4 Receptor alpha Subunit; Liver Function Tests; Liver Transplantation; Tacrolimus

Fucoxanthin (FX) is a xanthophyll that is contained abundantly in marine plants. The biological action of FX includes its antioxidant and anti-lipogenic activities, while the precise action of its mechanisms on skin cells has not yet been clarified. The current study examined the effect of FX in comparison with tacrolimus (TAC) on NC/Nga mice, which are an atopic dermatitis (AD) model. FX topical treatment dramatically ameliorated itching behavior over the TAC treatment, which was insufficient for improvement of AD symptoms. In Nc/Nga mice, FX or TAC applied to the skin inhibited eosinophil infiltration with decreased expression of Il-33. FX also stimulated Il-2, Il-5, Il-13, Il-10, and TGF-β expression levels, and Sca1

Topics: Animals; Anti-Inflammatory Agents; Cells, Cultured; Dermatitis, Atopic; Immunity, Innate; Keratinocytes; Lymphocytes; Mice; Tacrolimus; Xanthophylls

Long-term safety of topical calcineurin inhibitors is not well understood. APPLES (A Prospective Pediatric Longitudinal Evaluation to Assess the Long-Term Safety of Tacrolimus Ointment for the Treatment of Atopic Dermatitis; NCT00475605) examined incidence of lymphoma and other cancers in a pediatric population with atopic dermatitis.. To quantify incident malignancies during 10 years in children with atopic dermatitis who used topical tacrolimus for ≥6 weeks.. Standardized incidence ratios for cancer events were analyzed relative to sex-, age-, and race-matched control data from national cancer registries.. There were 7954 eligible patients enrolled at 314 sites in 9 countries. During 44,629 person-years, 6 confirmed incident cancers occurred (standardized incidence ratio, 1.01; 95% confidence interval, 0.37-2.20). No lymphomas occurred.. Observational prospective cohort study.. The cancer incidence was as expected, given matched background data. This finding provides no support for the hypothesis that topical tacrolimus increases long-term cancer risk in children with atopic dermatitis.

Topics: Administration, Topical; Adolescent; Age Factors; Calcineurin Inhibitors; Child; Child, Preschool; Dermatitis, Atopic; Female; Humans; Incidence; Infant; Longitudinal Studies; Male; Neoplasms; Prospective Studies; Registries; Risk Assessment; Risk Factors; Sex Factors; Tacrolimus

Topics: Calcineurin Inhibitors; Child; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Incidence; Neoplasms; Tacrolimus

Topics: Administration, Topical; Adult; Calcineurin Inhibitors; Carcinoma; Dermatitis, Atopic; Humans; Keratinocytes; Skin Neoplasms; Tacrolimus

Atopic dermatitis (AD) is a highly pruritic, chronic inflammatory skin disease. The diagnosis is made using evaluated clinical criteria. Disease activity and burden are best measured with a composite score, assessing both objective and subjective symptoms, such as SCORing Atopic Dermatitis (SCORAD). AD management must take into account clinical and pathogenic variabilities, the patient's age and also target flare prevention. Basic therapy includes hydrating and barrier-stabilizing topical treatment universally applied, as well as avoiding specific and unspecific provocation factors. Visible skin lesions are treated with anti-inflammatory topical agents such as corticosteroids and calcineurin inhibitors (tacrolimus and pimecrolimus), which are preferred in sensitive locations. Topical tacrolimus and some mid-potency corticosteroids are proven agents for proactive therapy, which is defined as the long-term intermittent anti-inflammatory therapy of frequently relapsing skin areas. Systemic anti-inflammatory or immunosuppressive treatment is a rapidly changing field requiring monitoring. Oral corticosteroids have a largely unfavourable benefit-risk ratio. The IL-4R-blocker dupilumab is a safe, effective and licensed, but expensive, treatment option with potential ocular side-effects. Other biologicals targeting key pathways in the atopic immune response, as well as different Janus kinase inhibitors, are among emerging treatment options. Dysbalanced microbial colonization and infection may induce disease exacerbation and can justify additional antimicrobial treatment. Systemic antihistamines (H1R-blockers) only have limited effects on AD-related itch and eczema lesions. Adjuvant therapy includes UV irradiation, preferably narrowband UVB or UVA1. Coal tar may be useful for atopic hand and foot eczema. Dietary recommendations should be patient-specific, and elimination diets should only be advised in case of proven food allergy. Allergen-specific immunotherapy to aeroallergens may be useful in selected cases. Psychosomatic counselling is recommended to address stress-induced exacerbations. Efficacy-proven 'Eczema school' educational programmes and therapeutic patient education are recommended for both children and adults.

Topics: Adult; Anti-Inflammatory Agents; Calcineurin Inhibitors; Child; Dermatitis, Atopic; Eczema; Humans; Pruritus; Tacrolimus

Atopic eczema (AE) is a chronic, highly pruritic, inflammatory skin condition with increasing prevalence worldwide. Atopic eczema mostly affects children, impairing quality of life with poor disease control leading to progression of other atopic disorders. As most patients in South Africa have no access to specialist healthcare, a practical approach is needed for the management of mild-to-moderate AE in paediatric patients for daily clinical practice.. A panel of experts in AE convened to develop a practical algorithm for the management of AE for children and adolescents in South Africa.. Regular moisturising with an oil-based emollient remains the mainstay of AE treatment. Severe AE flares should be managed with topical corticosteroids (TCSs). For mild-to-moderate AE flares in sensitive skin areas, a topical calcineurin inhibitor (TCI) should be applied twice daily from the first signs of AE until complete resolution. Topical corticosteroids may be used when TCIs are unavailable. In non-sensitive skin areas, TCSs should be used for mild-to-moderate AE, but TCIs twice daily may be considered. Proactive maintenance treatment with low-dose TCI or TCS 2-3 times weekly and the liberal use of emollients is recommended for patients with recurrent flares.. This algorithm aims to simplify treatment of paediatric AE, optimising clinical outcomes and reducing disease burden. This approach excludes treatment of patients with severe AE, who should be referred to specialist care. Emphasis has been given to the importance of general skincare, patient education and the topical anti-inflammatory medications available in South Africa (TCSs and TCIs).

Topics: Adolescent; Algorithms; Child; Dermatitis, Atopic; Humans; Quality of Life; South Africa; Tacrolimus

Patients with atopic dermatitis commonly experience ophthalmic complications, and a higher incidence of conjunctivitis has been observed during treatment with dupilumab. We present the case of a 49-year-old woman with persistent severe atopic dermatitis who complained of refractory conjunctivitis associated with dupilumab. Ocular examination showed features of atopic conjunctivitis for which an external topical application to the eyelids of pimecrolimus 10 mg/g cream was prescribed. The patient showed substantial clinical remission after only 12 days. This case was remarkable as the medication applied externally to the eyelid skin was effective in treating the conjunctival involvement possibly due to penetration of pimecrolimus through the eyelid layers. Further studies are needed to support the use of this drug for dupilumab-related conjunctivitis.

Topics: Administration, Topical; Antibodies, Monoclonal, Humanized; Conjunctivitis; Dermatitis, Atopic; Dermatologic Agents; Eyelids; Female; Humans; Middle Aged; Tacrolimus; Treatment Outcome

Plants of the genus

Topics: Administration, Topical; Animals; Anti-Allergic Agents; beta-N-Acetylhexosaminidases; Biflavonoids; Cell Line; Dermatitis, Atopic; Dinitrochlorobenzene; Disease Models, Animal; Immunoglobulin E; Interleukin-4; Mice; Mice, Hairless; Plant Extracts; Tacrolimus; Wikstroemia

Topics: Administration, Topical; Adult; Algorithms; Calcineurin Inhibitors; Child; Child, Preschool; Dermatitis, Atopic; Emollients; Europe; Humans; Middle East; Ointments; Tacrolimus; Treatment Outcome

Topics: Biodiversity; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Microbiota; Skin; Tacrolimus; Treatment Outcome

Atopic keratoconjunctivitis is frequently associated with atopic eyelid dermatitis. It may require topical steroids, the prolonged use of which may cause ocular complications. Tacrolimus is an immunosuppressant used topically on the skin in atopic dermatitis. The purpose of this study is to evaluate the efficacy and tolerability of tacrolimus 0.1% ointment applied to the eyelids in atopic keratoconjunctivitis.. This is a single center, retrospective study carried out between June 2014 and February 2017. Patients presenting with atopic keratoconjunctivitis uncontrolled by first-line medical treatment were included. The main outcome was change in functional symptoms as evaluated by the NEI-VFQ25 and OSDI quality of life scores. Secondary criteria were visual acuity and topical steroids use.. Among the 18 patients included, the mean age was 37.9±16.8years. The first follow-up visit occurred on average 68.3±55.3 days after initiation of treatment. The NEI-VFQ25 score improved significantly for seven of the sub-scores (P<0.05), and the mean OSDI decreased significantly from 52.3±26.2 to 22.0±27.0 (P<0.001), demonstrating a decrease in ocular symptoms. A significant reduction in the number of patients requiring topical steroid treatment was observed. There was no significant change in visual acuity.. Tacrolimus 0.1% ointment applied to the eyelids appears to be an effective treatment in the management of atopic keratoconjunctivitis.

Topics: Administration, Topical; Adult; Conjunctivitis, Allergic; Dermatitis, Atopic; Female; Humans; Keratoconjunctivitis; Male; Middle Aged; Ointments; Retrospective Studies; Tacrolimus; Treatment Outcome; Young Adult

This study is aimed to further investigate the anti-atopic dermatitis (AD) activities of dehydroxymethylepoxyquinomicin (DHMEQ) ointment and compare its effect with that of tacrolimus ointment based on the previous study that DHMEQ improves AD-like lesions. AD were induced by 2,4-dinitroclilorobenzene/oxazolone (DNCB/OX) repeatedly on the ears of BABL/C mice while medical tape was additionally used to disrupt stratum corneum in order to exacerbate the lesions. The mice were randomly divided into groups, which are normal, vehicle, DHMEQ (0.1%) and tacrolimus (0.1%). Those in the last two groups were externally applied with DHMEQ ointment and tacrolimus ointment, respectively. The results showed that both of them significantly improved dermatitis symptoms of DNCB/OX-induced AD-like lesions, such as redness, itching, weeping, scaling and thickening of the skin, while reducing epidermis thickness, dermis thickness and the number of mast cells as well, which were examined histopathologically. In contrast with DHMEQ, tacrolimus led to a significant decrease in body weight after long-term application. Both DHMEQ and tacrolimus suppress DNCB-induced increase of serum total IgE and attenuate expression of inflammatory factors IL-4, IL-6, IL-13, IL-1β and interferon (IFN)-γ in the disrupted ear tissues. On the other hand, the mice applied with tacrolimus became obviously irritable, jumping up and down, and inflammatory exudation on the lesioned-skin surface of the mice was remarkably observed. Contrary to the side effects made by tacrolimus, DHMEQ didn't cause any adverse stimulus response. As a conclusion, DHMEQ is safer, milder and more suitable for long-term use than tacrolimus for the treatment of AD-like lesions.

Topics: Animals; Benzamides; Cyclohexanones; Cytokines; Dermatitis, Atopic; Dinitrochlorobenzene; Disease Models, Animal; Epidermis; Female; Humans; Immunoglobulin E; Immunosuppressive Agents; Inflammation Mediators; Mast Cells; Mice; Mice, Inbred BALB C; Ointments; Oxazolone; Tacrolimus

Atopic keratoconjunctivitis is associated with eyelid eczema. It may require the use of local corticosteroids which if prolonged can be a source of ocular complications. Tacrolimus is an immunosuppressant used in cutaneous application in atopic dermatitis. The aim of this study was to measure the efficacy and tolerance of tacrolimus 0.1% ointment in palpebral application in atopic keratoconjunctivitis.. This retrospective, single-center study was conducted between June 2014 and February 2017. Patients with atopic keratoconjunctivitis not controlled by first-line medical treatments were included. The primary endpoint was the evolution of functional signs as assessed by the NEI-VFQ25 and OSDI quality of life scores. Secondary endpoints were visual acuity and local corticosteroid use.. Among the 18 patients included, the mean age was 37.9±16.8 years. The first follow-up visit was on average 68.3±55.3 days after initiation of treatment. The NEI-VFQ25 score was significantly improved for seven of its sub-scores (P<0.05) and the mean OSDI decreased significantly from 52.3±26.2 to 22.0±27.0 (P<0.001) showing a decrease in eye discomfort. A significant reduction was observed in the number of patients using local corticosteroids. There was no significant change in visual acuity.. Tacrolimus ointment 0.1% in palpebral application appears to be an effective treatment for the management of atopic keratoconjunctivitis.

Topics: Administration, Topical; Adult; Conjunctivitis, Allergic; Dermatitis, Atopic; Female; Humans; Immunosuppressive Agents; Keratoconjunctivitis; Male; Middle Aged; Ointments; Retrospective Studies; Tacrolimus; Treatment Outcome; Young Adult

Topics: Administration, Ophthalmic; Adolescent; Adult; Chronic Disease; Conjunctivitis, Allergic; Dermatitis, Atopic; Female; Humans; Immunosuppressive Agents; Male; Ophthalmic Solutions; Prospective Studies; Tacrolimus; Treatment Outcome; Young Adult

The present study examined the efficacy of the topical 15d‑PGJ2‑poloxamer 407 hydrogel in an atopic dermatitis (AD) animal model. The 15d‑PGJ2 hydrogel was prepared and characterized. The examined rats possessed AD‑Like cutaneous lesions, which were induced using 2,4‑dinitrochlorobenzene, the rats were then treated with a hydrogel vehicle, 15d‑PGJ2 hydrogel or tacrolimus for 14 days. The rats were sacrificed and blood samples were collected to quantify the IgE levels. Subsequently, skin biopsies were stained with toluidine blue to identify mast cells and immunohistochemistry was performed for ROR‑γt and TNF‑α. Histological analyses demonstrated that 15d‑PGJ2 hydrogel significantly decreased mast cell infiltration (P<0.05) when compared with the AD‑group. Tacrolimus at 0.1% exhibited decreased mast cell infiltration; however, this difference was not statistically significant from the AD‑group. Topical 15d‑PGJ2 hydrogel and Tacrolimus 0.1% significantly reduced the serum levels of IgE (P<0.05) compared with the AD‑group. Immunohistochemistry revealed a significant decrease in ROR‑γt and TNF‑α positive cell expression (P<0.05) in the 15d‑PGJ2 hydrogel group compared with the AD‑group. In summary, topical administration of 15d‑PGJ2 hydrogel had a beneficial effect on AD symptoms, suggesting that this formulation may be a useful strategy for the treatment of AD.

Topics: Administration, Topical; Animals; Dermatitis, Atopic; Dinitrochlorobenzene; Hydrogels; Immunoglobulin E; Immunohistochemistry; Immunosuppressive Agents; Male; Mast Cells; Nuclear Receptor Subfamily 1, Group F, Member 3; Prostaglandin D2; Rats; Rats, Wistar; Skin; Tacrolimus; Tumor Necrosis Factor-alpha

Using large-scale receipt data, we analyzed the differences in the prescription of drugs and their costs between dermatology and pediatrics in the treatment of atopic dermatitis (AD) in children. Between August 2010 and July 2011, 50 706 patients were diagnosed as having AD, and the data of 21 075 (15 257 dermatology, 5818 pediatric) patients aged 0-14 years were included in this study. The use of classes I (strongest), II (very strong), and III (strong) topical corticosteroids and tacrolimus was significantly higher in dermatology than in pediatrics (class I, 2.88% vs 0.76%; class II, 27.68% vs 8.32%; class III, 52.53% vs 39.88%; tacrolimus, 5.05% vs 2.82%; all P < 0.05). Although total drug costs were higher in dermatology than in pediatrics, mean drug costs per person were significantly higher in pediatrics. Moisturizers and protective agents had the highest cost (~ ¥690 million). The introduction rate of generic drugs was low at 8.3% among classes I-V. The introduction rate of moisturizers and protective agents, for which costs were the highest, was approximately 9%. The prescription of generic classes II-V topical corticosteroids and moisturizers and protective agents was also significantly higher in dermatology than in pediatrics (P < 0.05). Among patients younger than 2 years, 4405 received drugs for AD; classes I and II topical corticosteroids and tacrolimus (against the guidelines) were administrated in 35 (0.8%), 474 (10.8%) and 29 patients (0.7%), respectively. The introduction of generic drugs is still low, and the use of generic moisturizers and protective agents should be addressed further.

Topics: Adolescent; Adult; Aged; Child; Child, Preschool; Dermatitis, Atopic; Dermatologic Agents; Dermatology; Drugs, Generic; Female; Glucocorticoids; Humans; Infant; Infant, Newborn; Japan; Male; Middle Aged; Pediatrics; Prescription Drugs; Prescription Fees; Protective Agents; Tacrolimus; Young Adult

Topical application of tacrolimus (FK506) was effective in the treatment of atopic dermatitis (AD); however, adverse effects frequently occurred with the increase of FK506 dose during long-term treatment.. The objective of this project was to develop a hybrid skin targeting system encapsulating FK506 based on nicotinamide (NIC) and chitosan nanoparticles (CS-NPs), ie, FK506-NIC-CS-NPs, which took advantages of both of NIC and CS-NPs to obtain the synergetic effects of percutaneous delivery and treatment efficacy enhancement along with dose reduction.. The formulation of FK506-NIC-CS-NPs was optimized and characterized. In vitro and in vivo skin permeation studies were performed. AD-like skin lesions were constructed with BALB/c mice by 1-chloro-2, 4-dinitrobenzene (DNCB)-induced, and FK506-NIC-CS-NPs containing different dose of FK506 were topically administered to treat AD-like skin lesions in comparison with Protopic.. NIC was found to significantly increase the FK506 EE to 92.2% by CS-NPs. In comparison with commercial FK506 ointment (Protopic), in vitro and in vivo skin permeation studies demonstrated that NIC-CS-NPs system significantly enhanced FK506 permeation through and into the skin, and deposited more FK506 into the skin. The treatment efficacy on clinical symptoms, histological analysis, and molecular biology of the AD-mice demonstrated that NIC-CS-NPs with ~1/3 dose of FK506 of Protopic was superior to that of Protopic, and NIC-CS-NPs vehicle exhibited the adjuvant therapy and moderate anti-AD effects.. The system of NIC-CS-NPs enhances the permeability of FK506, plays an adjuvant role in anti-AD, reduces the dose of FK506 in treating AD, and is therefore a promising nanoscale system of FK506 for the effective treatment of AD.

Topics: Administration, Cutaneous; Animals; Chitosan; Dermatitis, Atopic; Dinitrochlorobenzene; Drug Delivery Systems; Male; Mice; Mice, Inbred BALB C; Nanoparticles; Niacinamide; Ointments; Rats, Sprague-Dawley; Skin; Skin Absorption; Tacrolimus; Treatment Outcome

Topical Betamethasone (BM) and Pimecrolimus (PC) are widely used drugs in the treatment of atopic dermatitis (AD). Though the biomolecules and biological pathways affected by the drugs are known, the causal inter-relationships among these pathways in the context of skin is not available. We aim to derive this insight by using transcriptomic data of AD skin samples treated with BM and PC using systems biology approach.. Transcriptomic datasets of 10 AD patients treated with Betamethasone and Pimecrolimus were obtained from GEO datasets. We used a novel computational platform, eSkIN ( www.persistent.com/eskin ), to perform pathway enrichment analysis for the given datasets. eSkIN consists of 35 skin specific pathways, thus allowing skin-centric analysis of transcriptomic data. Fisher's exact test was used to compute the significance of the pathway enrichment. The enriched pathways were further analyzed to gain mechanistic insights into the action of these drugs.. Our analysis highlighted the molecular details of the mechanism of action of the drugs and corroborated the known facts about these drugs i.e. BM is more effective in triggering anti-inflammatory response but also causes more adverse effect on skin barrier than PC. In particular, eSkIN helped enunciate the biological pathways activated by these drugs to trigger anti-inflammatory response and its effect on skin barrier. BM suppresses pathways like TNF and TLRs, thus inhibiting NF-κB while PC targets inflammatory genes like IL13 and IL6 via known calcineurin-NFAT pathway. Furthermore, we show that the reduced skin barrier function by BM is due to the suppression of activators like AP1 transcription factors, CEBPs.. We thus demonstrate the detailed mechanistic insight into drug action of AD using a novel computational approach.

Topics: Administration, Topical; Betamethasone; Dermatitis, Atopic; Dermatologic Agents; Humans; Systems Biology; Tacrolimus; Transcriptome

Allergies are frequently implicated in ophthalmologic practice. These typically benign allergies can be potentially severe for the ocular surface and have an impact in everyday life. We relate, through a case of keratoconjunctivitis involving 2 types of hypersensitivity, the various triggers and therapeutic choices to allow a more effective treatment.

Topics: Adult; Allergens; Animals; Azithromycin; Blepharitis; Cats; Dermatitis, Atopic; Desensitization, Immunologic; Dogs; Drug Therapy, Combination; Eosinophilia; Histamine Antagonists; Humans; Hypersensitivity, Immediate; Immunoglobulin E; Intradermal Tests; Keratoconjunctivitis; Lubricant Eye Drops; Male; Pyroglyphidae; Rhinitis, Allergic, Seasonal; Tacrolimus

Topics: Administration, Topical; Adult; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Child; Dermatitis, Atopic; Eczema; Humans; Tacrolimus

Atopic keratoconjunctivitis (AKC) remains a difficult diagnosis despite advances in imaging technologies. This is a case study of the diagnostic and treatment course for a patient with AKC.. A 15-year-old male complained of progressively increasing pain, redness, watering and blurred vision in the right eye. The medical history showed that the patient suffered from itching on the hands, knees, neck and the eye skin one year before the onset of initial symptoms in the affected eye.. A final diagnosis of stage III AKC with atopic dermatitis (AD) was reached.. The patient was used 0.1% tacrolimus eye drops and 0.3% gatifloxacin eye gel after antimicrobial susceptibility test was performed. In the presence of AD, 0.1% mometasone furoate cream and 0.03% tacrolimus ointment were applied twice daily.. One month after starting treatment, the conjunctivitis and corneal ulcer rapidly improved along with reduced lid papillae. Macular grade corneal opacity was noticed with minimal thinning. The AD also rapidly improved. At the end of two months patient was asymptomatic with a significant improvement in his quality of life.. Proper diagnosis of AKC especially when associated with dermatological signs along with management of AD in conjunction with dermatologist is necessary to prevent corneal involvement which can cause permanent visual disability is of utmost importance. We also noticed that topical tacrolimus is a good option for the treatment of severe AKC with AD along with systemic immunosupressants.

Topics: Administration, Topical; Adolescent; Anti-Allergic Agents; Anti-Bacterial Agents; Conjunctivitis, Allergic; Corneal Ulcer; Dermatitis, Atopic; Fluoroquinolones; Gatifloxacin; Humans; Immunosuppressive Agents; Male; Mometasone Furoate; Ophthalmic Solutions; Tacrolimus; Treatment Outcome

Tacrolimus ointment is used worldwide to treat atopic dermatitis. Although tacrolimus ointment is not suitable for clinical admixtures, it is often mixed with various ointments or creams, such as corticosteroids, antibacterial agents, and moisturizing agents. There is only one report of quality testing of admixtures of tacrolimus ointment with adaparene gel (Differin

Topics: Adrenal Cortex Hormones; Dermatitis, Atopic; Drug Compounding; Drug Stability; Humans; Immunosuppressive Agents; Ointments; Tacrolimus

Atopic dermatitis (AD) is the most frequent chronic inflammatory skin disorder in children and is usually accompanied by genetic and environmental factors. Effective management and treatment of AD is challenging and often requires systemic immunosuppressive therapy when refractory to topical treatments. We report a rare association between chronic hepatitis C virus (HCV) and severe AD, management of which required systemic cyclosporine because of its favorable effects on inflammatory and viral-related clinical outcomes.

Topics: Adolescent; Cyclosporine; Dermatitis, Atopic; Hepatitis C, Chronic; Humans; Immunosuppressive Agents; Male; Tacrolimus

Topics: Administration, Cutaneous; Adolescent; Adult; Dermatitis, Atopic; Emollients; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Pain; Pain Measurement; Prospective Studies; Pruritus; Skin; Tacrolimus; Treatment Outcome; Water Loss, Insensible; Young Adult

Seborrheic dermatitis (SD) is a common inflammatory skin condition. The etiology is unclear, although overgrowth of Malassezia on the skin has been suggested to cause SD. This study investigated whether colonization with Staphylococcus plays a role in facial SD, which was not well addressed previously.. The study was conducted from September 1, 2011 to February 20, 2012 in the First Hospital of China Medical University. In the first phase, the study evaluated the level of transepidermal water loss (TEWL) and the number of colony-forming units (CFU) of Staphylococcus in defined skin areas of SD patients who were human immunodeficiency virus (HIV) seropositive (HIV [+] SD [+] group, n = 13), classical SD (HIV [-] SD [+] group, n = 24) patients, HIV seropositive-non-SD (HIV [+] SD [-] group, n = 16) patients, and healthy volunteers (HIV [-] SD [-] group, n = 16). In the second phase, we enrolled another cohort of HIV (-) SD (+) patients who applied topical fusidic acid (n = 15), tacrolimus (n = 16), or moisturizer (n = 12). Changes in the Seborrheic Dermatitis Area Severity Index (SDASI), TEWL, and Staphylococcus density were evaluated 2 weeks later. Comparisons of each index were performed using analysis of variance (ANOVA) and least significant difference method.. The level of TEWL was greater through lesional sites in the HIV (+) SD (+) group than that in HIV (+) SD (-) and HIV (-) SD (-) groups (95% confidence interval [CI]: 18.873-47.071, P < 0.001 and 95% CI: 28.755-55.936, P < 0.001, respectively). The number of CFU of Staphylococcus was greater in the HIV (+) SD (+) group than that in HIV (+) SD (-) and HIV (-) SD (-) groups (95% CI: 37.487-142.744, P = 0.001 and 95% CI: 54.936-156.400, P < 0.001, respectively). TEWL was significantly more improved in patients treated with tacrolimus and fusidic acid than that in those treated with moisturizers (95% CI: 7.560-38.987, P = 0.004 and 95% CI: 4.659-37.619, P = 0.011, respectively). Topical tacrolimus and fusidic acid were significantly associated with decreased SDASI as compared with moisturizer (95% CI: 0.03-0.432, P = 0.025 and 95% CI: 0.033-0.44, P = 0.024, respectively).. High colonization with Staphylococcus epidermidis, along with impaired skin permeability barrier function, contributes to the occurrence of SD.

Topics: Dermatitis, Atopic; Dermatitis, Seborrheic; Fusidic Acid; HIV; Humans; Skin; Staphylococcus epidermidis; Tacrolimus

Topics: Dermatitis, Atopic; Dermatologic Agents; Double-Blind Method; Eczema; Humans; Tacrolimus; Treatment Outcome

In this paper, we aimed to explore the potential mechanism underlying atopic dermatitis (AD) and its association with asthma. The BALB/c mice were randomly assigned to three groups, including the vehicle control (VD) group, the AD group, and the treatment (TR) group. The AD mice model was successfully constructed in the AD and TR group. The dermatitis severity scores and skin lesions were significantly increased in AD mice after DNCB application. Airway responsiveness in the AD group was significantly higher than in the TR group. The number of inflammatory cells was increased in skin lesions and bronchoalveolar lavage fluid (BALF) of AD mice. The levels of IL-4, IL-5, IFN-γ, and OVA-IgE in BALF supernatants of mice in the AD group were higher than those in the VC group. All the changes in AD mice were decreased by tacrolimus. These results indicate that AD may be a significant risk factor for atopic asthma development.

Topics: Animals; Asthma; Bronchoalveolar Lavage Fluid; Dermatitis, Atopic; Dinitrochlorobenzene; Eczema; Mice; Mice, Inbred BALB C; Tacrolimus

Topical corticosteroid and calcineurin inhibitor have similar therapeutic benefits in atopic dermatitis (AD), but the differences in therapeutic mechanisms of action of these agents against AD symptoms are not fully understood.. This study was performed to examine the different effects of topical betamethasone valerate (BMV), clobetasol propionate (CBP), and tacrolimus (TAC) on itch-related behavior and dermatitis in NC/Nga mice with AD-like symptoms.. AD-like dermatitis was induced in the dorsal skin of NC/Nga mice by repeated topical application of Dermatophagoides farinae body (Dfb) ointment twice weekly for three weeks. Mice with dermatitis scores over 5 were divided into five groups with equal dermatitis scores and treated with BMV, CBP, TAC, or Vaseline (Vas) once daily for two consecutive days, or were not treated (NT). Scratching behavior was analyzed using a SCLABA. After the second treatment, dermatitis showed significantly greater improvement in the CBP and TAC-treated groups than in the Vas-treated and NT groups. The numbers of scratching bouts were significantly lower in CBP and TAC-treated mice than in Vas-treated mice. TEWL was significantly lower in TAC-, but not in CBP-, treated mice than in Vas-treated mice. Immunohistochemical examination showed that BMV, CBP and TAC did not reduce the increased densities of epidermal protein gene product 9.5- and substance P-immunoreactive fibers. The numbers of dermal CD4-immunoreactive T cells were significantly lower in BMV and CBP-treated mice than in Vas-treated and NT mice. The numbers of dermal eosinophils were significantly lower in BMV, CBP and TAC-treated mice than in Vas-treated and NT mice, with CBP showing the strongest effect. CBP significantly reduced epidermal thickness compared with Vas and NT. There were no significant differences in the numbers of interleukin-31-immunoreactive cells and mast cells, or in expression of epidermal thymic stromal lymphopoietin among all five groups.. The therapeutic potency of TAC against AD-like symptoms, including pruritus, is equal to that of the corticosteroid CBP. Epidermal innervation of sensory nerves itself might not be related to the therapeutic effects of topical tacrolimus and corticosteroids in its early phase.

Topics: Administration, Topical; Adrenal Cortex Hormones; Animals; Betamethasone Valerate; Clobetasol; Cytokines; Dermatitis, Atopic; Dermatophagoides farinae; Disease Models, Animal; Emollients; Epidermis; Humans; Immunosuppressive Agents; Male; Mast Cells; Mice; Ointments; Petrolatum; Pruritus; Tacrolimus; Thymic Stromal Lymphopoietin; Treatment Outcome; Ubiquitin Thiolesterase

Topics: Dermatitis, Atopic; Eczema; Humans; Tacrolimus

We have designed and efficiently synthesized novel 1-phenyl-6-aminouracils by replacing the chroman moiety in CX-659S, a nonsteroidal dermatologic candidate, with dimethyldihydrobenzofuranol to cancel CX-659S asymmetric center. Medicinal chemistry effort culminated in the discovery of 13d bearing a 3-methyl group at the 1-phenyl group as a promising compound. Compound 13d, having good in vitro ADME profile and moderate oral bioavailability in mice, showed potent anti-inflammatory activity against hapten-induced contact hypersensitivity reaction in mice following topical and oral administration. The effects of 13d were equipotent to that of tacrolimus or prednisolone. In addition, compound 13d, having potent hydroxyl radical-scavenging activity, showed more potent suppressive effect on substance P-induced pruritus in mice than oxatomide.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents; Benzofurans; Cell Line, Tumor; Cell Membrane Permeability; Dermatitis, Atopic; Half-Life; Humans; Mice; Microsomes; Pruritus; Rats; Uracil

Calcineurin inhibitors (CNIs) exhibit remarkable efficacy in atopic dermatitis (AD). Tacrolimus, one type of CNI, is prevalently used to treat AD. AD is a chronic inflammatory disease that exhibits predominant infiltration of T-helper type 2 (Th2) cell in the acute phase and a mixed Th1 and Th0 cell pattern in chronic lesions. Cytokines such as tumor necrosis factor-α (TNF-α), Th2-related chemokines [e.g., macrophage-derived chemokine (MDC)/CCL22 and I-309/CCL1], Th1-related chemokines [e.g., interferon γ-induced protein 10 (IP-10)/CXCL10], and neutrophil chemoattractant growth-related oncogene-α (GRO-α)/CXCL1 are involved in the pathogenesis of AD. However, whether tacrolimus modulates the expression of AD-associated cytokines and chemokines remains unknown. The intracellular mechanisms of tacrolimus are also unclear.. Human monocytic cell line THP-1 cells were pretreated with tacrolimus and stimulated with lipopolysaccharide (LPS). The MDC, I-309, IP-10, GRO-α, and TNF-α concentrations of the cell supernatants were measured using enzyme-linked immunosorbent assay. Intracellular signaling was investigated using the Western blot analysis.. Tacrolimus suppressed the expression of MDC, IP-10, I-309, GRO-α, and TNF-α in LPS-stimulated THP-1 cells in a dose- and time-dependent manner. All three mitogen-activated protein kinase (MAPK) inhibitors and the nuclear factor-κB inhibitor suppressed LPS-induced MDC, I-309, and TNF-α expressions in THP-1 cells. Only MAPK inhibitors suppressed LPS-induced expression of IP-10 and GRO-α. Tacrolimus suppressed the LPS-induced phosphorylation of MAPK-extracellular signal-related kinase (ERK).. Tacrolimus suppressed LPS-induced MDC, I-309, IP-10, GRO-α, and TNF-α expressions in monocytes through the MAPK-ERK pathway; thus, tacrolimus may yield therapeutic efficacy by modulating AD-associated cytokines and chemokines.

Topics: ADAM Proteins; Calcineurin Inhibitors; Cell Line; Chemokine CCL1; Chemokine CCL22; Chemokine CXCL1; Chemokine CXCL10; Cytokines; Dermatitis, Atopic; Humans; Lipopolysaccharides; Monocytes; Tacrolimus; Tumor Necrosis Factor-alpha; Tumor Suppressor Proteins

Topics: Adolescent; Adult; Aged; Calcineurin Inhibitors; Cyclosporine; Delayed-Action Preparations; Dermatitis, Atopic; Drug Evaluation; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Tacrolimus; Treatment Outcome; Young Adult

Topics: Administration, Cutaneous; Adult; Alcohol Drinking; Calcineurin Inhibitors; Dermatitis, Atopic; Drug Interactions; Erythema; Eyelid Diseases; Facial Dermatoses; Humans; Male; Tacrolimus

The discrepancy in drug absorption between healthy and diseased skins is an issue that needs to be elucidated. The present study attempted to explore the percutaneous absorption of drugs via lesional skin by using atopic dermatitis (AD) as a model. Tape-stripping and ovalbumin (OVA) sensitization induced AD-like skin. The lesions were evaluated by physiological parameters, histology, cytokines, and differentiation proteins. The permeants of tacrolimus, 8-methoxypsoralen, methotrexate, and dextran were used to examine in vitro and in vivo cutaneous permeation. Transepidermal water loss (TEWL) increased from 5.2 to 27.4 g/m(2)/h by OVA treatment. AD-like lesions were characterized by hyperplasia, skin redness, desquamation, and infiltration of inflammatory cells. Repeated OVA challenge produced a T-helper 2 (Th2) hypersensitivity accompanied by downregulation of filaggrin, involucrin, and integrin β. Tacrolimus, the most lipophilic permeant, revealed an increase of cutaneous deposition by 2.7-fold in AD-like skin compared to intact skin. The transdermal flux of methotrexate and dextran, the hydrophilic permeants, across AD-like skin increased about 18 times compared to the control skin. Surprisingly, AD-like skin showed less skin deposition of 8-methoxypsoralen than intact skin. This may be because the deficient lipids in the atopic-affected stratum corneum (SC) diminished drug partitioning into the superficial skin layer. The fluorescence and confocal microscopic images demonstrated a broad and deep passage of small-molecular and macromolecular dyes into AD-like skin. The results obtained from this report were advantageous for showing how the lesional skin influenced percutaneous absorption.

Topics: Animals; Cytokines; Dermatitis, Atopic; Dextrans; Filaggrin Proteins; Methotrexate; Methoxsalen; Mice; Models, Biological; Ovalbumin; Pharmaceutical Preparations; Skin; Skin Absorption; Tacrolimus; Water Loss, Insensible

The increasing incidence and prevalence of atopic dermatitis (AD) demands new therapeutic approaches for treating the disease. We investigated the therapeutic efficacy of immunomodulator FTY720 ointment (fingolimod) for mite-induced intractable AD using an NC/Nga mouse model.. Female NC/Nga mice that developed severe AD were divided into four groups: (1) FTY720 (0.001% FTY720 ointment), (2) tacrolimus (tacrolimus hydrate ointment) (3) betamethasone (betamethasone ointment), and (4) ointment base (hydrophilic petrolatum), all of which received treatment six times per week. Therapeutic efficacy after two weeks was evaluated in terms of AD severity, histochemical observations (epidermal hypertrophy, mast cell accumulation, and CD3(+) T cell infiltration), transepidermal water loss (TEWL), and epidermal barrier function (filaggrin expression).. Betamethasone treatment showed little effect, confirming that the AD was intractable. In the FTY720 group, AD improved significantly compared with the ointment base group, as did epidermal hypertrophy, mast cell accumulation, and CD3(+) T cell infiltration. In contrast, AD in the tacrolimus and betamethasone groups did not improve significantly, nor did epidermal hypertrophy or mast cell accumulation. Furthermore, in the FTY720 group, TEWL decreased significantly compared with the ointment base group, and filaggrin expression significantly increased compared with the betamethasone and ointment base groups.. FTY720 ointment is a promising candidate for treatment of intractable AD. These findings also provide the first evidence that FTY720 ointment ameliorates epidermal barrier function.

Topics: Animals; Dermatitis, Atopic; Dermatophagoides farinae; Disease Models, Animal; Female; Filaggrin Proteins; Fingolimod Hydrochloride; Immunoglobulin E; Immunologic Factors; Immunosuppressive Agents; Intermediate Filament Proteins; Mice; Ointments; Tacrolimus

Topics: Child; Child, Preschool; Dermatitis, Atopic; Dermatologic Agents; Humans; Immunosuppressive Agents; Infant; Lymphoma; Skin Neoplasms; Sunlight; Tacrolimus

Atopic dermatitis (AD) is a multifactorial inflammatory skin disease with release of distinct inflammatory signals. This study investigated the presence of eicosanoids in AD skin and the effect of topical agents with potential to suppress inflammation. Twelve patients with moderate AD received topical treatment on either arm with tacrolimus 0.1% ointment or a lotion containing 12% ω-6 fatty acids (polyunsaturated fatty acids; PUFA) twice daily for 5 consecutive days. Interstitial fluid was collected in vivo via dermal microdialysis from 4 defined skin areas: lesional, non-lesional and topically treated skin (tacrolimus or PUFA). Markers of oxidative stress (F2-isoprostanes; 5- and 8-prostaglandin F2α) and inflammation (9α,11α-prostaglandin F2α; and prostaglandin E2) were determined by gas chromatography-mass spectrometry. All eicosanoid levels were reduced in non-lesional and tacrolimus-treated skin. A significant reduction was observed in total F2-isoprostanes; 9α,11α-prostaglandin F2α; and prostaglandin E2 in non-lesional skin and in 9α,11α-prostaglandin F2α in tacrolimus-treated compared with untreated AD skin. In conclusion, treatment with tacrolimus compared with PUFA appears to suppress eicosanoids more efficiently in AD skin.

Topics: Administration, Topical; Animals; Biomarkers; Dermatitis, Atopic; Eicosanoids; Fatty Acids, Unsaturated; Female; Gas Chromatography-Mass Spectrometry; Humans; Immunosuppressive Agents; Male; Microdialysis; Oxidative Stress; Swine; Tacrolimus; Young Adult

Tacrolimus (TAC), a non-steroidal anti-inflammatory and immunosuppressive agent, is used for the treatment of atopic dermatitis (AD) and skin immune diseases. TAC-loaded topical hydrogel formulations composed of carbomer, carnosine, transcutol P (diethylene glycol monoethyl ether) and humectant were prepared. For comparison, TAC-loaded topical cream-type formulations were also prepared and commercially available TAC ointment was used as a reference. A drug release study in vitro revealed that the total amount of TAC released from hydrogels over 24 h was approximately 30 times greater than that for the reference formulation. Compared to the reference ointment and creams, carbomer gel formulations showed higher skin permeation and retention of TAC (significantly different at p < 0.05), especially those with more than 10% of transcutol P. Therefore, carbomer gel formulations with sufficient levels of transcutol P are good candidates for skin delivery of TAC and have potential as therapeutic agents for the treatment of AD or immune skin disorders.

Topics: Acrylic Resins; Administration, Topical; Dermatitis, Atopic; Drug Liberation; Ethylene Glycols; Humans; Hydrogel, Polyethylene Glycol Dimethacrylate; Immunosuppressive Agents; Skin Absorption; Tacrolimus

Atopic dermatitis (AD) is a disease characterized by relapsing eczema with pruritus as a primary lesion. Most patients have an atopic predisposition. The definitive diagnosis of AD requires the presence of all three features: (i) pruritus; (ii) typical morphology and distribution of the eczema; and (iii) chronic and chronically relapsing course. The current strategies to treat AD in Japan from the perspective of evidence-based medicine consist of three primary measures: (i) the use of topical corticosteroids and tacrolimus ointment as the main treatment for the inflammation; (ii) topical application of emollients to treat the cutaneous barrier dysfunction; and (iii) avoidance of apparent exacerbating factors, psychological counseling and advice about daily life. The guidelines present recommendations to review clinical research articles, evaluate the balance between the advantages and disadvantages of medical activities, and optimize medical activity-related patient outcomes with respect to several important points requiring decision-making in clinical practice.

Topics: Administration, Cutaneous; Administration, Oral; Anti-Inflammatory Agents; Dermatitis, Atopic; Dermatologic Agents; Diet Therapy; Evidence-Based Medicine; Glucocorticoids; Histamine Antagonists; Humans; Immunosuppressive Agents; Japan; Ointments; Patient Compliance; Patient Education as Topic; Pruritus; Quality of Life; Severity of Illness Index; Tacrolimus; Ultraviolet Therapy

We sought to explore the architecture of trials of calcineurin inhibitors for atopic eczema to document the extent to which comparisons with active treatments such as topical corticosteroids might have been included or avoided. We identified all eligible randomized controlled trials using the Global Resource for EczemA Trials (GREAT) database. Network plots were produced where the nodes represented a treatment type and the lines between the nodes represented the number of trials or participants involved in the various treatment comparisons. A total of 174 randomized controlled trials for atopic eczema treatments were identified in which pimecrolimus, tacrolimus, or topical corticosteroids were compared with another intervention or a vehicle/emollient. Of 39 trials involving pimecrolimus and 41 trials involving tacrolimus, 8 (20.5%) and 13 (31.7%), respectively, made comparisons with topical corticosteroids, and 25 (64.1%) and 15 (36.6%), respectively, were vehicle-controlled studies. The high rate of comparisons with vehicle controls in randomized controlled trials that assessed the efficacy of pimecrolimus or tacrolimus long after efficacy had been established is a matter of concern. Active comparators (mild topical corticosteroids for pimecrolimus and moderate to potent topical corticosteroids for tacrolimus) are best placed to determine how topical calcineurin inhibitors compare with established clinical practice.

Topics: Administration, Cutaneous; Adrenal Cortex Hormones; Calcineurin Inhibitors; Dermatitis, Atopic; Dermatologic Agents; Humans; Immunosuppressive Agents; Randomized Controlled Trials as Topic; Research Design; Tacrolimus; Treatment Outcome

Interest is increasing in the potentially beneficial role of probiotics in the prevention and treatment of atopic diseases. In this study, we investigated the protective effects of Lactococcus chungangensis CAU 28(T) against atopic dermatitis using murine macrophage RAW 264.7 cells, human keratinocyte HaCaT cells, human mast cell line HMC-1 cells, and a 2,4-dinitrochlorobenzene-induced atopic dermatitis model (NC/Nga mice). The results showed that L. chungangensis CAU 28(T) exhibited potent antiinflammatory activity by inhibiting the production of the proinflammatory mediators nitric oxide and prostaglandin E2 in lipopolysaccharide-stimulated RAW 264.7 cells. Treatment with L. chungangensis CAU 28(T) reduced the release of β-hexosaminidase and histamine in HMC-1 cells stimulated with mast cell activator compound 48/80. In addition, the back skin and ears of NC/Nga mice exhibited reduced histological manifestations of atopic skin lesions such as erosion, hyperplasia of the epidermis and dermis, and inflammatory cell infiltration. Oral administration of L. chungangensis CAU 28(T) suppressed the production of IL-4, IL-5, IL-12, IFN-γ, tumor necrosis factor-α, and thymus- and activation-regulated chemokine (TARC) in skin lesions, indicating that it strongly drives the local immune system with efficacy comparable to that of tacrolimus, a topical immunomodulatory drug used for the treatment of atopic dermatitis. The findings indicate that L. chungangensis CAU 28(T) could be a novel probiotic candidate for controlling the symptoms of atopic dermatitis.

Topics: Administration, Oral; Animals; beta-N-Acetylhexosaminidases; Cell Line, Tumor; Cell Survival; Chemokine CCL17; Dermatitis, Atopic; Dinitrochlorobenzene; Dinoprostone; Female; Histamine; Humans; Immunoglobulin E; Interferon-gamma; Interleukin-12; Interleukin-4; Interleukin-5; Lactococcus; Lipopolysaccharides; Mast Cells; Mice; Nitric Oxide; Probiotics; RAW 264.7 Cells; RNA, Messenger; Skin; Tacrolimus; Tumor Necrosis Factor-alpha

Atopic dermatitis (AD) is caused by both dysregulated immune responses and an impaired skin barrier. Although leukotriene B4 (LTB4) is involved in tissue inflammation that occurs in several disorders, including AD, therapeutic strategies based on LTB4 inhibition have not been explored. Here we demonstrate that progression of an AD-like skin disease in NC/Nga mice is inhibited when docosahexaenoic acid (DHA)/eicosapentaenoic acid (EPA) is administered together with FK506. Treatment with DHA/EPA and FK506 decreases the clinical score of dermatitis in NC/Nga mice and lowers local LTB4 concentrations. The treatment also suppressed the infiltration of T cells, B cells, eosinophils and neutrophils, and promoted reduced serum IgE levels. Secretion of IL-13 and IL-17A in CD4(+) T cells was lower in DHA/EPA- and FK506-treated mice than in mice treated with FK506 alone. The inhibition of disease progression induced by DHA/EPA was reversed by local injection of LTB4, suggesting that the therapeutic effect of DHA/EPA is LTB4-dependent. Our results demonstrate that treatment of AD with DHA/EPA is effective for allergic skin inflammation and acts by suppressing LTB4 production. J. Med. Invest. 63: 187-191, August, 2016.

Topics: Animals; Dermatitis, Atopic; Docosahexaenoic Acids; Eicosapentaenoic Acid; Immunoglobulin E; Leukotriene B4; Mice; Tacrolimus

Topics: Administration, Topical; Dermatitis, Atopic; Eczema; Humans; Immunosuppressive Agents; Tacrolimus

Topics: Activities of Daily Living; Adolescent; Adrenal Cortex Hormones; Adult; Aged; Antipruritics; Child; Dermatitis, Atopic; Emollients; Female; Histamine Antagonists; Humans; Internet; Male; Middle Aged; Pruritus; Surveys and Questionnaires; Tacrolimus; Young Adult

A black box warning describes a potential risk of malignancy associated with topical use of pimecrolimus to treat atopic dermatitis due to its similarity to oral calcineurin inhibitors used in solid-organ transplantation and spontaneous reporting of malignancies, including lymphomas and cutaneous malignancies.. To evaluate the risk of malignancy in a postmarketing study of children exposed to pimecrolimus.. A longitudinal cohort study among a nationwide ongoing long-term cohort of children enrolled in the Pediatric Eczema Elective Registry (PEER) who had a history of atopic dermatitis and pimecrolimus use with data available up through May 2014.. Reports of malignancy among those in the PEER compared with expected rates from the Surveillance, Epidemiology, and End Results (SEER) program.. Overall, 7457 children were enrolled in the PEER, for a total of 26,792 person-years. Children used a mean (SD) of 793 (1356) g of pimecrolimus when enrolled in the study. As of May 2014, five malignancies had been reported. These include 2 leukemias, 1 osteosarcoma, and 2 lymphomas. No skin cancers were reported. The standardized incidence ratio for all malignancies (primary outcome) based on the age-standardized SEER population was 1.2 (95% CI, 0.5-2.8). As secondary analyses, the standardized incidence ratios (based on 2 cases for each) were 2.9 (95% CI, 0.7-11.7) for lymphoma and 2.0 (95% CI, 0.5-8.2) for leukemia. None of these findings were statistically significant.. Based on more than 25,000 person-years of follow-up, it seems unlikely that topical pimecrolimus as it was used in the PEER cohort to treat atopic dermatitis is associated with an increased risk of malignancy.

Topics: Administration, Cutaneous; Adolescent; Child; Child, Preschool; Cohort Studies; Dermatitis, Atopic; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Longitudinal Studies; Male; Neoplasms; Registries; Risk; SEER Program; Tacrolimus

Topics: Dermatitis, Atopic; Female; Humans; Immunosuppressive Agents; Male; Neoplasms; Tacrolimus

There is a lack of information on the use oral immunosuppressive drugs in atopic dermatitis (AD) daily practice.. A 10-years overview of the use of oral immunosuppressive drugs in patients with severe AD.. Medical charts of patients with AD, who received oral immunosuppressive drugs at the Academic Medical Center Amsterdam and in the University Medical Center Utrecht between January 2001 and January 2011, were analysed. Particular attention was paid to patient characteristics, prior treatment, prescribed oral immunosuppressive drugs, the order of use, doses and treatment durations and reasons for discontinuation of treatment.. Of 334 patients [53% male, mean age at start of an oral immunosuppressive drug 36.9 years (SD 13.6)] with AD received oral immunosuppressive treatment of which 102 (31%) participated in clinical trials. Cyclosporine A (CyA) was given in 80% of the patients, mycophenolate mofetil or enteric-coated mycophenolate (MMF/EC-MPS) in 31%, azathioprine (AZA) in 14%, methotrexate (MTX) in 11%, systemic glucocorticosteroids in 7% and systemic tacrolimus in 5%. In these academic centra, CyA was the first choice oral immunosuppressive in 252 patients. Reasons for discontinuation of oral immunosuppressive drugs were controlled AD disease, ineffectiveness and adverse events.. Various types of oral immunosuppressive drugs have been used over the past 10 years for the treatment of severe AD with a prominent first choice for CyA. Adverse events and ineffectiveness were frequent reasons for discontinuation. A prospective database of patients using oral immunosuppressive treatments in daily practice will give more insight in the effectiveness and safety and may help to formulate future recommendations.

Topics: Academic Medical Centers; Administration, Oral; Adult; Azathioprine; Cyclosporine; Dermatitis, Atopic; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Male; Methotrexate; Middle Aged; Mycophenolic Acid; Tacrolimus; Young Adult

Topics: Administration, Topical; Adolescent; Adult; Age Factors; Child; Child, Preschool; Cohort Studies; Dermatitis, Atopic; Disease Progression; Disease-Free Survival; Drug Prescriptions; Female; Humans; Immunosuppressive Agents; Male; Ointments; Practice Patterns, Physicians'; Self Report; Skin Cream; Tacrolimus; Young Adult

Topical tacrolimus has been observed to induce granulomatous rosacea (GR) in prior case reports and series. In most cases, patients recover fully after withdrawing tacrolimus and initiating doxycycline or minocycline. Herein, we describe a case of severe GR, which required further therapy. Clinicians should be aware of this rare complication because of the frequent use of topical tacrolimus.

Topics: Anti-Bacterial Agents; Dermatitis, Atopic; Female; Humans; Rosacea; Tacrolimus; Tetracycline; Young Adult

Thymic stromal lymphopoietin (TSLP) initiates the Th2-type allergic inflammation, and is thought to play an important role in the pathogenesis of atopic dermatitis (AD). TNF-α is a key cytokine which is involved in the pathophysiology of various inflammatory diseases, and the expression level is elevated in the sera and skin of patients with AD. In addition, TNF-α has been reported to induce TSLP expression in epidermal keratinocytes. Topical glucocorticoids and calcineurin inhibitors are safe and effective agents for AD, but the effects of these agents on TNF-α-induced TSLP expression are not fully understood.. To investigate whether the glucocorticosteroid dexamethasone and the calcineurin inhibitor tacrolimus could affect TSLP expression induced by TNF-α in lesional keratinocytes of AD.. The effects of topical dexamethasone and tacrolimus on TSLP expression were evaluated in an AD mouse model induced by repeated 2,4,6-trinitro-1-chlorobenzene application. Co-immunostaining for TSLP and TNF-α was performed using skin samples from AD patients and the mouse model. Normal human epidermal keratinocytes (NHEKs) were cultured with dexamethasone or tacrolimus in the presence of TNF-α to analyze TSLP expression.. Topical application of dexamethasone but not tacrolimus repressed TSLP expression in the mouse model. TSLP and TNF-α showed similar distribution pattern in epidermal keratinocytes of AD lesions and the mouse model. TSLP expression was induced by TNF-α via NF-κB in a dose-dependent and an autocrine and/or paracrine manner in NHEKs, which was significantly suppressed by dexamethasone but not by tacrolimus. Similarly to TSLP expression, IL-6, TNF-α, IL-8, and IL-36γ expression induced by TNF-α were significantly suppressed by dexamethasone but not by tacrolimus in NHEKs.. Dexamethasone but not tacrolimus suppresses the TSLP expression induced by TNF-α in lesional keratinocytes of AD model. Our observations uncover the unreported functional difference between topical glucocorticosteroids and calcineurin inhibitors in cutaneous inflammatory diseases.

Topics: Animals; Cytokines; Dermatitis, Atopic; Dexamethasone; Disease Models, Animal; Keratinocytes; Male; Mice, Inbred BALB C; Tacrolimus; Thymic Stromal Lymphopoietin; Tumor Necrosis Factor-alpha

Topics: Dermatitis, Atopic; France; Humans; Immunosuppressive Agents; Reimbursement Mechanisms; Tacrolimus

Topics: Dermatitis, Atopic; Dermatologic Agents; Humans; Tacrolimus

Topics: Animals; Anti-Allergic Agents; Dermatitis, Atopic; Dibenzoxepins; Disease Models, Animal; Immunosuppressive Agents; Interleukins; Mice; Olopatadine Hydrochloride; Pruritus; Tacrolimus

Ginseng and ginsenosides are frequently used in the treatment of chronic inflammatory diseases. Recently, 20-O-β-d-glucopyranosyl-20(S)-protopanaxadiol (GPD), the main metabolite of ginsenosides, was reported to have both anti-allergic and anti-pruritic effects. The immunomodulatory effects of GPD-fortified ginseng extract (GFGE) on atopic dermatitis (AD)-like symptoms in mice were investigated. This study was designed to investigate the preventive effect of GFGE on AD-like symptoms.. The effects of orally administered GFGE on Dermatophagoides farinae body extract (DFE)-induced AD-like symptoms in NC/Nga mice were assessed by analyzing dermatitis score, ear thickness, scratching time, skin histological changes, and serum level of macrophage-derived chemokine (MDC). In addition, splenocytes were isolated from the mice and stimulated with anti-CD3 and anti-CD28 monoclonal antibodies to produce cytokines.. Oral administration of GFGE significantly attenuated DFE-induced increases in dermatitis score, ear thickness, scratching time, and severity of skin lesions in NC/Nga mice. GFGE treatment also reduced level of MDC in serum, infiltration of eosinophils and mast cells in skin, and production of cytokines in splenocytes.. These results suggest that GFGE might ameliorate DFE-induced AD-like symptoms and be an alternative therapeutic agent for the prevention of AD.

Topics: Administration, Oral; Animals; Anti-Allergic Agents; Antigens, Dermatophagoides; Cytokines; Dermatitis, Atopic; Female; Ginsenosides; Immunosuppressive Agents; Mice; Mice, Inbred Strains; Panax; Plant Extracts; Skin; Spleen; Tacrolimus

Topics: Dermatitis, Atopic; Female; Humans; Hydrocortisone; Male; Tacrolimus

Topical calcineurin inhibitors are widely used to treat inflammatory dermatoses for their steroid-sparing advantage. Herein, we report a patient with chronic lip dermatitis who developed multiple labial melanotic macules after application of tacrolimus 0.1% ointment and pimecrolimus 1% cream. Prior and current reports raise concerns for potential development of pigmented lesions associated with topical calcineurin inhibitor use. These reports highlight the need for careful risk-benefit assessment when prescribing topical calcineurin inhibitors for inflammatory dermatoses, especially when used on sun-exposed sites.

Topics: Administration, Cutaneous; Adult; Biopsy; Calcineurin Inhibitors; Dermatitis, Atopic; Diagnosis, Differential; Female; Humans; Lentigo; Lip Diseases; Peptidylprolyl Isomerase; Tacrolimus

Atopic dermatitis (AD) is a commonly encountered inflammatory skin disease. Although acute lesions of acute AD are characterized by intense inflammation, the hallmarks of chronic AD lesions include lichenified fibrosis and thickening of the upper dermis. The increased expression of transforming growth factor beta 1 (TGF-β1), a well-known fibrogenic cytokine, is observed in chronic AD lesions. Tacrolimus (FK506) ointment has been reported to be effective for treating AD as well as some TGF-β1-induced fibrotic diseases.. To evaluate the effect of tacrolimus on TGF-β1-stimulated cultured normal human dermal fibroblasts and explore the potential signalling pathways involved.. Fibroblasts cultured from healthy adult human foreskins were treated with TGF-β1 with or without tacrolimus. The impact on cell viability and proliferation were assessed by [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] (MTT) assay and BrdU incorporation assay respectively. Reverse transcription-polymerase chain reaction (RT-PCR), quantitative real-time PCR, enzyme-linked immunosorbent assay (ELISA) and western blotting were performed to evaluate the relevant expressions of mRNA or proteins in fibroblasts.. Our results revealed that the increased expressions of transforming growth factor-β receptor I (TGF-βRI) and TGF-βRII in TGF-β1-treated fibroblasts were suppressed by tacrolimus treatment. In addition, tacrolimus significantly inhibited fibroblast proliferation enhanced by TGF-β1. TGF-β1 increased type I collagen production, and this enhancing effect was suppressed by tacrolimus. The down-regulation of MMP-1 and up-regulation of TIMP-1 induced by TGF-β1 were reversed by tacrolimus. The increase in phosphorylated p38 mitogen-activated protein kinase (p38MAPK) expression stimulated by TGF-β1 was down-regulated by tacrolimus. Moreover, the fibroblasts treated with p38MAPK inhibitor significantly reduced type I collagen expression induced by TGF-β1.. The present results demonstrated that tacrolimus significantly inhibited physiological functions of fibroblasts enhanced by TGF-β1 in vitro. Clinically, we propose that topical tacrolimus may not only reduce AD recurrence but also ameliorate dermal fibrosis often seen in chronic AD lesions.

Topics: Cell Proliferation; Cell Survival; Cells, Cultured; Chronic Disease; Collagen Type I; Dermatitis, Atopic; Down-Regulation; Fibroblasts; Humans; Immunosuppressive Agents; MAP Kinase Signaling System; Matrix Metalloproteinase 1; p38 Mitogen-Activated Protein Kinases; Protein Serine-Threonine Kinases; Receptor, Transforming Growth Factor-beta Type I; Receptor, Transforming Growth Factor-beta Type II; Receptors, Transforming Growth Factor beta; RNA, Messenger; Tacrolimus; Tissue Inhibitor of Metalloproteinase-1; Transforming Growth Factor beta1; Up-Regulation

Light emitting diode (LED) phototherapy is an effective alternative for the treatment of inflammatory skin disorders. Tacrolimus (FK-506) is a potent immunomodulating agent, which has been used to treat AD. Combination therapy is often used in the treatment of AD to improve therapeutic efficacy or to reduce the dose of each drug.. To investigate the therapeutic efficacy of monotherapy with either 850nm LED phototherapy or low-dose FK-506, and combination therapy in Dermatophagoides farina (Df)-induced AD-like skin lesions in NC/Nga mice.. The Df-induced NC/Nga mice with a clinical score of 7 were used for treatment with LED (10 and 25J/cm(2)) alone, low-dose FK-506 (1mg/kg) or in combination. The synergistic effects of combined therapy were evaluated by dermatitis scores, skin histology, skin barrier function, and immunological parameters, such as IgE, NO, Th2-mediated cytokines and chemokines.. Combination therapy with 850nm (25J/cm(2)) LED and low-dose FK-506 showed a significant reduction in the severity of skin lesions. Combined therapy decreased in the serum level of IgE, NO, and in the splenic level of Th2-mediated cytokines and chemokines. Combination therapy significantly also reduced the inflammatory cellular infiltrate into the skin lesions. Moreover, combination therapy led to recovery of skin barrier function in the skin lesions.. The use of combination of LED phototherapy and low-dose immunosuppressant improved Df-induced AD-like skin lesions in an NC/Nga mouse model by dominantly reducing IgE, NO, suppressing Th2-mediated immune responses, and inhibiting inflammatory cells, as well as improving skin barrier function.

Topics: Animals; Chemokines; Combined Modality Therapy; Cytokines; Dermatitis, Atopic; Dermatophagoides farinae; Humans; Immunoglobulin E; Immunosuppressive Agents; Inflammation; Light; Male; Mice; Nitric Oxide; Phototherapy; Skin; Spleen; Tacrolimus; Th2 Cells

Type I hypersensitivity reactions have been described after solid organ transplantation despite T cell targeted immunosuppressive therapy. There are several reports of food allergy, asthma and eosinophilic colitis in pediatric transplant recipients under Tacrolimus immunosuppression, but not Cyclosporine A. We present the case of a 6 year old patient that developed de novo atopic dermatitis, eosinophilia and high levels of total IgE under systemic treatment with tacrolimus.

Topics: Child, Preschool; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Male; Tacrolimus

To assess off-label use of the topical calcineurin inhibitors (TCIs), tacrolimus and pimecrolimus, in children during periods before and after regulatory action by the US Food and Drug Administration (FDA) in 2005.. We identified new pediatric (age <20 years) users of topical tacrolimus or pimecrolimus in US Medicaid from 2001 to 2009, and examined the annual rate of drug use (pre- and postregulatory action) by age. We assessed medical claims for diagnoses consistent with an indication for a TCI, and assessed prescriptions for evidence of first-line atopic dermatitis therapy use before TCI initiation.. There were 57,664 eligible pediatric tacrolimus users and 425,242 eligible pediatric pimecrolimus users at baseline. The rate of TCI use decreased substantially after FDA regulatory action. The proportion of new users younger than 2 years of age significantly decreased for both tacrolimus (36.7% to 22.5%, P < .001) and pimecrolimus (47.0% to 33.7%, P < .001) after regulatory actions. Previous use of topical corticosteroids increased by ≈ 7% for both TCIs from the pre- to postregulatory period. However, after regulatory actions, there was only a small increase in the proportion of tacrolimus or pimecrolimus users with an atopic dermatitis or eczema diagnosis before drug initiation, and high strength use of tacrolimus was unchanged.. The rate of TCI use in children younger than 2 years of age fell substantially after FDA regulatory action in 2005. Off-label use of TCI as first-line therapy changed little.

Topics: Administration, Topical; Adolescent; Calcineurin Inhibitors; Child; Child, Preschool; Cohort Studies; Dermatitis, Atopic; Dermatologic Agents; Eczema; Female; Humans; Infant; Male; Medicaid; Off-Label Use; Tacrolimus; United States; Young Adult

Topics: Administration, Topical; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Keratoconjunctivitis; Tacrolimus

In atopic dermatitis (AD), topical anti-inflammatory therapy with skin barrier restoration to prevent repeated inflammatory episodes leads to long-term therapeutic success. Tacrolimus, although effective against AD, is a challenging molecule due to low solubility, low-penetration, poor-bioavailability, and toxicity. Part I of this paper, reported novel modified nanolipid carrier system for topical delivery of tacrolimus (T-MNLC), offering great opportunity to load low-solubility drug with improved entrapment efficiency, enhanced stability and improved skin deposition. Present investigation focused on restoration of skin barrier, site-specific delivery, therapeutic effectiveness, and safety of novel T-MNLC. T-MNLC greatly enhanced occlusive properties, skin hydration potential and reduced transepidermal water loss. This might help to reduce the number of flares and better control the disease. Cutaneous uptake and drug deposition in albino rats by HPLC and confocal laser scanning microscopy revealed prominently elevated drug levels in all skin strata with T-MNLC as compared to reference. T-MNLC demonstrated efficient suppression of inflammatory responses in BALB/c mice model of AD. Safety assessment by acute and repeated-dose dermal toxicity demonstrated mild keratosis and collagenous mass infiltration at the treatment area with repeated application of reference. Interestingly, T-MNLC showed no evident toxicity exhibiting safe drug delivery. Thus, novel T-MNLC would be a safe, effective, and esthetically appealing alternative to conventional vehicles for treatment for AD.

Topics: Administration, Cutaneous; Animals; Colloids; Dermatitis, Atopic; Drug Carriers; Drug Delivery Systems; Drug Evaluation, Preclinical; Mice; Mice, Inbred BALB C; Nanoparticles; Organ Culture Techniques; Rats; Rats, Wistar; Skin Absorption; Swine; Tacrolimus; Treatment Outcome

Topics: Dermatitis, Atopic; Dermatologic Agents; Humans; Immunity, Innate; Tacrolimus

Tacrolimus (FK-506) has been found to exhibit potent inhibitory effects on spontaneously developed dermatitis. We previously showed that glucosamine prevents the development of Atopic dermatitis (AD)-like skin lesions in NC/Nga mice. The aims of our study were to investigate the synergistic therapeutic efficacy of combination of glucosamine plus FK-506 in dermatophagoides farina (Df)-induced AD-like skin lesions in NC/Nga mice and to determine the underlying therapeutic mechanisms. The Df-induced NC/Nga mice with a clinical score of 8 were used for treatment with glucosamine (500 mg/kg) alone, FK-506 (1.0 mg/kg) or in combination. The synergistic effects of combination therapy were evaluated by dermatitis scores, skin histology and immunological parameters such as IgE, Th2-mediated cytokines and chemokines, CD3(+) T cells and CLA(+) T cells. Combined therapy using glucosamine plus FK-506 improved the development of AD-like skin lesions as exemplified by a significant decrease in total skin symptom severity scores. The suppression of dermatitis by combined therapy was accompanied by a decrease in the plasma level of IgE and in the splenic level of IL-5, IL-13, TARC and eotaxin. Histological finding indicated that the dermal infiltration of inflammatory cells including mast cells and eosinophils was greatly reduced. Particularly, immunohistological evaluation reveals a reduction in CD3(+) T cells and CLA(+) cells in the combined therapy. Our findings suggest that combination therapy of glucosamine plus FK-506 was more synergistic efficacy than single-modality treatment with either alone to improve the development of established dermatitis in NC/Nga mice model. This combined immunosuppressive therapy may provide an effective therapeutic strategy for the treatment of AD.

Topics: Animals; CD3 Complex; Chemokine CCL11; Chemokine CCL17; Chemokines; Cytokines; Dermatitis, Atopic; Dermatophagoides farinae; Disease Models, Animal; Drug Therapy, Combination; Eosinophils; Glucosamine; Immunoglobulin E; Immunosuppressive Agents; Interleukin-13; Interleukin-5; Male; Mast Cells; Mice; Scavenger Receptors, Class B; Skin; Tacrolimus; Th2 Cells

The mechanism of action of pimecrolimus (PIM) on atopic lesions is still under consideration. Thus far, we have evidence of its anti-inflammatory and immunomodulatory activity, and recent papers focus on its effect on epidermal barrier function. This study analysed changes in the expression of genes associated with skin barrier dysfunction in atopic dermatitis (AD) skin lesions after 2 weeks of exposure to PIM 1% cream. A real-time quantitative PCR analysis of selected epidermal differentiation complex genes and three alternative pathway keratins was performed in skin biopsies from 11 individuals with AD before and after PIM exposure. The real-time quantitative PCR analysis was compared to non-lesional skin in the same patients. Involucrin, a small proline-rich region (SPRR) 2C gene, and alternative pathway keratin 16 showed significant over-expression in lesional skin followed by significant decrease after PIM therapy. The SPRR1A gene, S100A9, and keratin 6A were also increased; however, the decrease after PIM treatment was not significant. The changes in S100 A2, A7 and A8 followed a similar course with borderline significance. SPRR4 had a significant decrease in expression in lesional versus non-lesional skin, which persisted after PIM treatment. No significant changes were detected in mRNA expression levels of filaggrin and loricrin. Our results suggest that PIM can be effective in restoring the epidermal barrier in patients with AD at least in part by its impact on expression of genes, which are important for the normal barrier function of skin.

Topics: Adult; Cornified Envelope Proline-Rich Proteins; Dermatitis, Atopic; Dermatologic Agents; Female; Filaggrin Proteins; Gene Expression; Gene Expression Profiling; Humans; Keratin-16; Keratin-6; Male; Middle Aged; Ointments; Protein Precursors; RNA, Messenger; Skin; Tacrolimus; Treatment Outcome; Young Adult

In the acute phase of atopic dermatitis (AD), T-helper type 2 (Th2) cytokines characterize the inflammatory response in the skin. IL-33 is a new tissue-derived cytokine, which is mainly expressed by cells of barrier tissues, and is known to activate Th2 lymphocytes, mast cells, and eosinophils. IL-33 signals through a receptor complex consisting of IL-33-specific receptor ST2 and a co-receptor IL-1RAcP. As IL-33 is known to promote Th2-type immunity, we examined expression profiles of IL-33 and its receptor components in human AD skin, in the murine model of AD, and in various cell models. We found increased expression of IL-33 and ST2 in AD skin after allergen or staphylococcal enterotoxin B (SEB) exposure, as well as in the skin of 22-week-old filaggrin-deficient mice. In addition, skin fibroblasts, HaCaT keratinocytes, primary macrophages, and HUVEC endothelial cells efficiently produced IL-33 in response to the combined stimulation of tumor necrosis factor-α and IFN-γ, which was further enhanced by a mimetic of double-stranded RNA. Finally, the increased expression of IL-33 and ST2 caused by irritant, allergen, or SEB challenge was suppressed by topical tacrolimus treatment. These results suggest an important role for IL-33-ST2 interaction in AD and highlight the fact that bacterial and viral infections may increase the production of IL-33.

Topics: Allergens; Animals; Cells, Cultured; Dermatitis, Atopic; Disease Models, Animal; Enterotoxins; Female; Fibroblasts; Filaggrin Proteins; Human Umbilical Vein Endothelial Cells; Humans; Immunosuppressive Agents; Interferon-gamma; Interleukin-1 Receptor-Like 1 Protein; Interleukin-33; Interleukins; Intermediate Filament Proteins; Keratinocytes; Macrophages; Mice; Mice, Inbred BALB C; Pyroglyphidae; Receptors, Cell Surface; RNA, Messenger; Tacrolimus; Tumor Necrosis Factor-alpha; Up-Regulation

Epidermal hyperinnervation in atopic dermatitis (AD) is activated directly by various external stimuli, causing enhanced itching. Nerve density is regulated by the nerve repulsion factor semaphorin 3A (Sema3A), along with nerve elongation factors.. To investigate the effects of Sema3A ointment in the NC/Nga mouse model of AD.. An AD-like phenotype was induced by repeated application of Dermatophagoides farinae body (Dfb) ointment to the dorsal skin of NC/Nga mice. Vaseline, heparinoid, betamethasone, tacrolimus and recombinant Sema3A ointments were applied to the lesional skin once a day for 4 days. Transepidermal water loss (TEWL) was measured before and after each treatment. We also scored the degree of dermatitis and recorded videos to observe scratching behavior. Subsequently, we collected skin samples from these mice for histological analyses.. Topical application of Sema3A, betamethasone and tacrolimus ointments significantly inhibited scratching behavior and improved dermatitis scores in Dfb-treated mice compared with control mice, whereas vaseline and heparinoid had no effects. A significant improvement of TEWL was observed only in Sema3A ointment-treated mice. Moreover, Sema3A ointment reduced the densities of PGP9.5- and substance P-immunoreactive nerve fibers in the epidermis and the numbers of inflammatory cells, such as CD4 immunoreactive T cells and eosinophils, and improved acanthosis in the Dfb-treated mice compared with controls.. Sem3A ointment may have therapeutic efficacy in patients with pruritus and dermatitis of AD.

Topics: Administration, Topical; Animals; Anti-Inflammatory Agents; Behavior, Animal; Betamethasone; Dermatitis, Atopic; Dermatophagoides farinae; Drug Therapy, Combination; Epidermis; Immunosuppressive Agents; Male; Mice; Mice, Inbred Strains; Nerve Endings; Ointments; Pruritus; Semaphorin-3A; Specific Pathogen-Free Organisms; Tacrolimus

In recent years, pimecrolimus 1% cream has been demonstrated to reduce symptoms of atopic dermatitis in patients when applied topically.. In our study we compared the therapeutic effects of local 1% pimecrolimus to 1% hydrocortisone, and to a control group in a mouse model with atopic dermatitis in the external ear canals. Atopic dermatitis was created by application of Dinitrochlorobenzene in the external ear canals of mice. The development of atopic dermatitis was detected by clinical observation score and determination of total serum IgE levels. Pimecrolimus and hydrocortisone cream were topically applied to the external ear canal skin once a day for 14 days.. There was no significant difference between the hydrocortisone and the pimecrolimus therapy groups, while there was a statistically significant difference between these 2 groups and the control group (p<0.05) Assessment of the clinical observation scoring carried out on the 14th day of therapy revealed that there was no difference between the hydrocortisone and pimecrolimus groups. Biopsies were taken on the 14th day following treatment. Tissue samples were histologically evaluated; contact dermatitis was observed microscopically in the control group, but in the therapy groups only minimal evidence of contact dermatitis was found.. The results of our study reveal that the therapeutic efficacy of 1% pimecrolimus was equivalent to 1% hydrocortisone treatment in the artificially developed atopic dermatitis model in external ear canals of mice. These results clearly demonstrate that 1% pimecrolimus cream can be an effective alternative therapeutic agent in cases where steroid treatment proves to be insufficient or in cases where treatment must be discontinued due to its adverse effects.

Topics: Animals; Dermatitis, Atopic; Dermatologic Agents; Ear, External; Emollients; Female; Hydrocortisone; Immunoglobulin E; Mice; Tacrolimus

Topics: Acyclovir; Adrenal Cortex Hormones; Antiviral Agents; Dermatitis, Atopic; Diagnosis, Differential; Humans; Immunosuppressive Agents; Kaposi Varicelliform Eruption; Male; Middle Aged; Simplexvirus; Skin; Tacrolimus; Valacyclovir; Valine

We describe the case of a boy who presented with abdominal Burkitt lymphoma; he had been regularly using tacrolimus ointment 0.1% for severe recurrent atopic dermatitis for 7 years immediately prior to developing cancer. We present his medical history and review the current knowledge regarding a link between topical tacrolimus and malignancy risk.

Topics: Administration, Cutaneous; Burkitt Lymphoma; Child; Dermatitis, Atopic; Diagnosis, Differential; Humans; Ileal Diseases; Ileal Neoplasms; Ileocecal Valve; Immunosuppressive Agents; Intussusception; Male; Tacrolimus; Tomography, X-Ray Computed

The objective of present investigation was to study in vivo behavior of tacrolimus-loaded lipid-nanoparticles (T-LN) to understand its targeting potential for treatment of atopic-dermatitis-(AD). T-LN have shown significantly improved drug penetration to deeper epidermal and dermal skin-layers than commercial ointment-Protopic(®) and effectively reached target dendritic-immune-cells, responsible for immunopathogenesis of AD. Due to enhanced penetrability of T-LN, it became necessary to evaluate the toxicity of the nanocarrier and the drug at non-target tissues. This paper evaluates dermatopharmacokinetics (DPK), biodistribution, efficacy and safety of T-LN in comparison to Protopic(®) as reference. In vivo DPK in guinea pigs showed 3.02-fold higher bioavailability while γ-scintigraphy in albino-rats demonstrated 1.5-fold rapid penetration of radioactivity in skin for T-LN. Biodistribution in albino-rats revealed restricted localization at the target-skin-area with no general spreading to other body organs suggesting targeting potential of T-LN. In vivo efficacy studies in BALB/c mice showed highly efficient suppression of inflammatory AD-like skin-lesions with T-LN than reference and placebo. Dermal toxicity-studies revealed keratosis and collagenous mass-infiltration with repeated application of reference however interestingly, T-LN treated group showed no evident toxicity demonstrating significantly improved safety. Thus T-LN offered improved penetration to the target site without any toxic-effects and would represent an efficient and commercially viable alternative for AD treatment.

Topics: Administration, Cutaneous; Animals; Biological Availability; Dendritic Cells; Dermatitis, Atopic; Disease Models, Animal; Drug Delivery Systems; Female; Guinea Pigs; Immunosuppressive Agents; Lipids; Mice; Mice, Inbred BALB C; Nanoparticles; Ointments; Rats; Rats, Wistar; Skin Absorption; Species Specificity; Tacrolimus; Tissue Distribution; Toxicity Tests

The purpose of this work was to prepare and characterize a novel ethosomal carrier for tacrolimus, an immunosuppressant treating atopic dermatitis (AD), and to investigate inhibition action upon allergic reactions of mice aiming at improving pharmacological effect for tacrolimus in that commercial tacrolimus ointment (Protopic®) with poor penetration capability exhibited weak impact on AD compared with common glucocorticoid. Results indicated that the ethosomes showed lower vesicle size and higher encapsulation efficiency (EE) as compared with traditional liposomes with cholesterol. In addition, the quantity of tacrolimus remaining in the epidermis at the end of the 24-h experiment was statistically significantly greater from the ethosomal delivery system than from commercial ointment (Protopic®) (p<0.01), suggesting the greater penetration ability to the deep strata of the skin for ethosomes. Interestingly, tacrolimus-loaded ethosomes with ethanol, in contrast to that with propylene glycol, showed relatively higher penetration activity except insignificant differences in EE and polydispersity index. Topical application of ethosomal tacrolimus displayed the lowest ear swelling in BALB/c mice model induced by repeated topical application of 2,4-dinitrofluorobenzene compared to traditional liposomes and commercial ointment and effectively impeded accumulation of mast cells in the ear of the mice, suggesting efficient suppression for the allergic reactions. In conclusion, the ethosomal tacrolimus delivery systems may be a promising candidate for topical delivery of tacrolimus in treatment of AD.

Topics: Administration, Cutaneous; Animals; Cholesterol; Dermatitis, Atopic; Disease Models, Animal; Drug Delivery Systems; Ethanol; Immunosuppressive Agents; Liposomes; Male; Mast Cells; Mice; Mice, Inbred BALB C; Particle Size; Propylene Glycol; Rats; Rats, Wistar; Skin Absorption; Tacrolimus; Time Factors

Effects of probiotics on the prevention of atopic diseases have been proposed recently. Although we have already reported the suppressive effects of the probiotic, ImmuBalance™, on a mouse model for peanuts allergy, its influence on atopic diseases remains unclear.. Potential efficacy of ImmuBalance™, which is the fermented soy product, on treatment of atopic dermatitis (AD) was investigated using a mouse model for human AD, NC/Tnd mice.. For in vivo study, ImmuBalance containing chow or a control diet were fed to NC/Tnd mice with moderate dermatitis for 2 weeks. Topical application of FK506 ointment was used as a positive control. Clinical skin severity scores, scratching behaviors, trans-epidermal water loss (TEWL), and histological features were analyzed. For in vitro study, suppressive effect of ImmuBalance™ on nerve growth factor (NGF)-activated neurite outgrowth of PC12 cells was examined.. Clinical skin severity scores of the mice fed with ImmuBalance containing chow were gradually reduced as well as the mice treated with FK506. Feeding with ImmuBalance completely inhibited the increase in scratching behavior of NC/Tnd mice. The value of TEWL of NC/Tnd mice fed with ImmuBalance was significantly decreased. In addition, histological examination revealed that application of ImmuBalance decreased the number of PGP9.5-positive neuronal fibers in the lesional skin. When ImmuBalance extract was added to the culture, NGF-activated neurite outgrowth of PC12 cells was diminished through the inhibition of the phosphatidylinositol 3-kinase phosphorylation.. ImmuBalance could exhibit favorable alterations on AD symptoms, particularly through down regulation of the itch sensation.

Topics: Administration, Oral; Administration, Topical; Animals; Dermatitis; Dermatitis, Atopic; Down-Regulation; Fermentation; Glycine max; Hydrolysis; Male; Mice; Nerve Growth Factor; PC12 Cells; Phosphatidylinositol 3-Kinases; Phosphorylation; Pruritus; Rats; Skin; Tacrolimus; Time Factors; Water

Topics: Adrenal Cortex Hormones; Allergens; Animals; Child; Dermatitis, Atopic; Desensitization, Immunologic; Emollients; Humans; Skin; Tacrolimus

Atopic dermatitis (AD), or atopic eczema, is a pruriginous inflammatory dermatosis with a genetic predisposition evolving in recurrent flare-ups on a background of chronicity, affecting essentially infants and small children. The clinical phenotype of AD results from interactions between genes and susceptibility, a defect in the cutaneous barrier function (abnormalities in filaggrin and the proteins of the epidermic differentiation complex) and dysfunction of the innate and/or adaptive immune response. With its multifactorial origin, it is dependent on the TH2 lymphocyte system, with a tendency to produce immunoglobulin E (IgE) and the risk of asthma, rhinitis, or allergic conjunctivitis define an atopic susceptibility. Staphylococcus aureus colonization plays a vital role in the perpetuation of the inflammatory phenomena. The disease often regresses in older children. Its prevalence is on the rise in industrialized countries. Diagnosis is clinical, facilitated by certain criteria initially proposed by Hanifin and Rajka and then simplified by Williams. The allergological investigation is reserved for cases that are stubborn, severe, or associated with respiratory symptoms. AD is a dermatosis that evolves in erratic and often unpredictable flare-ups. AD flare-up treatment is based on local corticosteroid therapy. Maintenance therapy attempts to correct the cutaneous dryness with hydrating products whose efficacy has now been proven. Optimal management includes the family's and/or the child's comprehension of the treatment, explaining to them that the goal to reach is not only to relieve the child, but also to attempt to modify the course of the disease. AD is thus a star disease and a public health problem. The major progress made in the comprehension of the physiopathological mechanisms of AD promise targeted therapies from new biotechnologies.

Topics: Adolescent; Child; Child, Preschool; Dermatitis, Atopic; Filaggrin Proteins; Glucocorticoids; Humans; Immunoglobulin E; Immunosuppressive Agents; Infant; Prognosis; Remission, Spontaneous; Tacrolimus

To investigate the effectiveness of pimecrolimus cream 1% for sensitive skin in adult women and its underlying mechanisms.. The changes of subjective symptoms and signs were evaluated before and after the application of pimecrolimus cream 1% based on the severity of pruritus (SP) and severity of burning sensation (SB) scores, and on a basic syntax and molecular substrate (molecular psychophysics) of nociception and proprioception established by temperature-sensitive transient receptor potential (TRP) channels.. The SP and SB scores were significantly decreased in 32 patients with sensitive skin after using topical pimecrolimus cream 1% (P<0.05). Twenty (62.5%) patients showed positive capsaicin-like response (i.e. burning with consequent rapid amelioration of pruritus or burning sensation) and 6 (18.8%) showed positive camphor-like response (i.e. warming with consequent rapid amelioration of pruritus) on application sites after using the topical pimecrolimus cream 1%, and 6 (18.8%) showed negative capsaicin-like response and/or negative camphor-like response.. Pimecrolimus may rapidly inhibit or alleviate itch or burning sensation of patients with sensitive skin. The therapeutic effect of pimecrolimus is relevant to the mechanisms that activate or sensitize transient receptor potential vanilloid 1 (TRPV1) and desensitizes TRPV1 in the skin sensory afferents.

Topics: Adolescent; Adult; Dermatitis, Atopic; Female; Humans; Male; Middle Aged; Pruritus; Skin; Tacrolimus; TRPV Cation Channels; Young Adult

We report a small, but novel case series of four adults with severe generalized atopic eczema (AE) not responsive to several other immunomodulatory therapies, who were treated with oral tacrolimus (5 mg twice-daily). Three of the four patients failed therapy with systemic tacrolimus, despite two of these showing an initial clinical response; the fourth patient remains on tacrolimus monotherapy with good control of skin disease. Although oral tacrolimus was well-tolerated in this small group of adults, the clinical efficacy in this series for severe AE was poor. Tacrolimus may yet have a role in less severe disease, but larger prospective studies are required to qualify its place as a treatment option in AE.

Topics: Adult; Dermatitis, Atopic; Female; Humans; Immunosuppressive Agents; Middle Aged; Retrospective Studies; Tacrolimus

A twice-weekly maintenance treatment regimen with tacrolimus ointment for atopic dermatitis (AD) significantly delayed and reduced the number of disease exacerbations over a 12-month period compared with the standard reactive treatment regimen.. To determine the cost-effectiveness of tacrolimus ointment used in the maintenance treatment regimen vs. the standard reactive treatment regimen for the management of moderate and severe AD in adults and children.. Data from two pivotal phase III studies conducted in adults and children receiving 0·1% and 0·03% tacrolimus ointment, respectively, were used to populate a decision-analytic model. The costs and benefits associated with maintenance vs. reactive use of tacrolimus ointment were calculated over a 12-month period based on the clinical and quality of life data from the clinical trials. The analysis was conducted from the perspective of the U.K. National Health Service. Sensitivity analyses were conducted to assess the degree of uncertainty surrounding the results.. For both adults and children with moderate and severe AD, twice-weekly maintenance treatment with tacrolimus ointment was shown to be a more effective and less costly (dominant) treatment regimen than the standard treatment regimen. Sensitivity analyses demonstrated that the model was robust and largely insensitive to changes in model parameters.. Maintenance treatment with tacrolimus ointment for the management of moderate and severe AD provides incremental health benefits at a lower cost compared with the reactive treatment regimen.

Topics: Adult; Child; Child, Preschool; Cost-Benefit Analysis; Dermatitis, Atopic; Drug Administration Schedule; Drug Costs; Female; Humans; Immunosuppressive Agents; Male; State Medicine; Tacrolimus; United Kingdom

Topically applied calcineurin inhibitors have been shown to be effective in the treatment of atopic dermatitis. When systemically administered, these agents cause immunosuppression via inhibition of calcineurin in lymphocytes. As topical agents, the mechanism of action is poorly defined.. To test the hypothesis that skin-infiltrating lymphocytes are directly targeted when calcineurin inhibitors are applied to the skin.. Ten patients with atopic dermatitis were treated with 1% pimecrolimus cream twice daily to target lesions. Skin biopsies were performed before and 48 h after beginning therapy. We assessed the cellular localization of NFAT1 and NFAT2 as a surrogate measure of intracellular calcineurin activity (e.g. increasing cytoplasmic localization with increasing calcineurin inhibition).. All patients showed a clinical response, at both 48 h and 2 weeks. As previously described, NFAT2 localized to the follicular keratinocytes, and its activation was partially inhibited by topical pimecrolimus. NFAT1 was found to be expressed by follicular and interfollicular keratinocytes, and its mostly nuclear localization was not affected by topical pimecrolimus therapy. Both NFAT1 and NFAT2 were found in the infiltrating lymphocytes. However, using both manual counting as well as an automated method to assess nuclear intensity of NFAT staining, we found that the proportion of infiltrating leucocytes with nuclear ('activated') NFAT did not change following therapy with pimecrolimus.. Our results suggest that topical pimecrolimus does not act primarily by inhibiting the calcineurin/NFAT axis in lymphocytes but may instead act by other mechanisms, possibly by decreasing NFAT2 activity in follicular keratinocytes.

Topics: Administration, Topical; Biopsy; Calcineurin Inhibitors; Dermatitis, Atopic; Fluorescent Antibody Technique; Humans; Immunohistochemistry; Immunosuppressive Agents; Lymphocytes; NFATC Transcription Factors; Tacrolimus

Topics: Aminoquinolines; Animals; Antimicrobial Cationic Peptides; beta-Defensins; Cathelicidins; Cell Membrane; Cell Membrane Permeability; Dermatitis, Atopic; Epidermal Cells; Epidermis; Humans; Imiquimod; Immunosuppressive Agents; Interleukin-1alpha; Lipid Metabolism; Mice; Mice, Transgenic; Models, Animal; Receptors, Interleukin-1; Signal Transduction; Tacrolimus

Atopic dermatitis (AD) is a skin disorder having significant impact worldwide, characterized by itchy, erythematous and intensely pruritic rash with periods of remission. Tacrolimus is the drug-of-choice in treatment of many immune mediated dermatoses including AD. Despite being effective, most common adverse events of tacrolimus are burning sensation and pruritus at the application site prompting for development of novel carrier that could effectively target tacrolimus to site-of-action without producing undesirable toxic-effects. Tacrolimus loaded lipid nanoparticles (T-LN) were developed and evaluated comparatively for enhanced targeting potential to site of action and improved safety with commercially available ointment product, Protopic as reference. T-LN was successfully developed by high pressure homogenization technique. Significantly higher drug release and skin permeating properties were observed for T-LN as compared to reference. T-LN suppressed inflammatory response in vivo by 3.5 times more efficiently than reference, demonstrating its improved efficacy. Entrapment of tacrolimus in lipid nanoparticles avoided direct contact of drug with skin; alleviating drug related local side effects.

Topics: Animals; Dermatitis, Atopic; Immunosuppressive Agents; Lipids; Nanocapsules; Rats; Tacrolimus; Treatment Outcome

It has been suggested that the increased rate of bacterial infection in atopic dermatitis (AD) may be caused by reduced antimicrobial protein (AMP) expression. We were interested whether common treatments in AD affect antimicrobial defense. We investigated the effects of topically applied corticosteroids betamethasone valerate (BV) and triamacinolone acetonide (TA) and those of the calcineurin inhibitor pimecrolimus for 3 weeks on AMP expression in AD. BV and TA treatment in AD led to a significant reduction in AMP expression; protein expression of human beta-defensins (hBD)-2 and hBD-3, psoriasin, RNase 7 and cathelicidin LL-37 was below the level in skin of healthy controls. After pimecrolimus treatment, AMP expression was also reduced but less compared to BV and TA; the expression levels of hBD-2, psoriasin and RNase 7 still remained above the control levels. In essential fatty acid-deficient (EFAD) mice, a model of chronic skin barrier disease with inflammation, expression of the mouse beta-defensins mBD-1, mBD-3 and mBD-14 (orthologues for hBD-1, hBD-2 and hBD-3, respectively), was reduced by both treatments, again more pronounced by BV compared to pimecrolimus. In summary, we found that treatment for AD with corticosteroids in human skin and EFAD mice caused a strong reduction in AMPs; reduction was less with pimecrolimus. This result may explain the clinical observation that prolonged treatment with topical corticosteroids sometimes leads to bacterial infection.

Topics: Adrenal Cortex Hormones; Animals; Antimicrobial Cationic Peptides; Base Sequence; beta-Defensins; Betamethasone Valerate; Calcineurin Inhibitors; Case-Control Studies; Dermatitis, Atopic; Disease Models, Animal; DNA Primers; Fatty Acids, Essential; Gene Expression; Humans; Male; Mice; Mice, Hairless; RNA, Messenger; Skin Diseases, Bacterial; Tacrolimus; Triamcinolone Acetonide

Topics: Adrenal Cortex Hormones; Adult; Cyclosporine; Dermatitis, Allergic Contact; Dermatitis, Atopic; Dermatitis, Occupational; Dietary Proteins; Drug Resistance; Facial Dermatoses; Female; Food Hypersensitivity; Hand Dermatoses; Histamine Antagonists; Humans; Immunosuppressive Agents; Methotrexate; Patch Tests; Skin Tests; Tacrolimus

Tacrolimus ointment 0.1 percent is a well-established topical therapy for treating atopic dermatitis. Efficacy and safety have been described in several trials. Here, we present a patient with rapid onset of extensive varicella zoster infection in tacrolimus-treated skin: a side effect that has only occasionally been reported. Early recognition is important because rapid treatment for herpes zoster may lead to less frequent post-herpetic neuralgia and serious complications.

Topics: Acyclovir; Antiviral Agents; Dermatitis, Atopic; Dermatologic Agents; Drug Therapy, Combination; Female; Fusidic Acid; Herpes Zoster; Herpesvirus 3, Human; Humans; Middle Aged; Ointments; Tacrolimus; Treatment Outcome; Valacyclovir; Valine

Itching is the most important problem in atopic dermatitis and tacrolimus has been suggested to attenuate the itching by topical application. However, the anti-itch mechanism of tacrolimus has not been well elucidated. In the present study, an allergic dermatitis accompanied by frequent scratching behaviors was induced by repeated paintings with 2,4-dinitrofluorobenzene (DNFB) acetone solution onto the mouse ear and the effects of tacrolimus and dexamethasone on the dermatitis and associated scratching behavior were comparatively examined. Repeated DNFB paintings caused a typical dermatitis accompanied by elevated serum immunoglobulin E (IgE) and frequent scratching behaviors. Both tacrolimus and dexamethasone given topically for 10 days before the final challenge significantly inhibited the ear swelling and reduced the expression of interferon-gamma mRNA. Dexamethasone inhibited the accumulation of eosinophils completely, although tacrolimus did not. Both drugs did not affect the elevation of serum IgE levels. Tacrolimus significantly inhibited the scratching behavior, whereas dexamethasone failed to affect it. Repeated DNFB challenge depleted substance P in the dermis. Treatment with tacrolimus before the final challenge completely inhibited the recovery of substance P content, whereas dexamethasone facilitated the recovery. DNFB-induced ear swelling and scratching behavior were significantly inhibited by FK888, a tachykinin NK(1) receptor antagonist. Therefore, substance P seems to participate in the induction of ear swelling and scratching behavior upon final challenge with DNFB, and depletion of substance P by tacrolimus in the dermis contributes to its inhibition of ear swelling and scratching behavior at least in part.

Topics: Animals; Behavior, Animal; Dermatitis, Atopic; Dexamethasone; Ear; Male; Mice; Mice, Inbred BALB C; Pruritus; Substance P; Tacrolimus

We studied the suitability of our murine model for the treatment trials of atopic dermatitis (AD). In this model topical application of ovalbumin (OVA) together with bacterial superantigen, staphylococcal enterotoxin B (SEB) induces a cutaneous disease resembling AD. Injured mouse skin was treated with three different drugs: a class III corticosteroid, a calcineurin inhibitor and a type 4 phosphodiesterase inhibitor. One-week treatment with corticosteroid and phosphodiesterase inhibitor remarkably decreased both epidermal and dermal thickness, whereas the calcineurin inhibitor affected only the epidermal thickness. All investigated drugs reduced the infiltration of eosinophils and mast cells onto OVA/SEB sensitized skin areas, whereas CD4+ and CD8+ T cells as well as CD11c+ dendritic cells variously diminished after corticosteroid and calcineurin inhibitor treatments. Cutaneous expression of interleukin -4, -13, -10 and interferon-gamma also decreased differently depending on drug type. Interestingly, the calcineurin inhibitor and phosphodiesterase inhibitor increased total IgE antibodies and decreased SEB-specific IgG2a antibodies in OVA/SEB sensitized mice. All these drugs can ameliorate cutaneous inflammation, although the degree of recovery depends on the type of the drug. In summary, our results show that this mouse model can be used to test new topical treatments for AD.

Topics: Administration, Topical; Animals; Anti-Allergic Agents; Anti-Inflammatory Agents; Betamethasone Valerate; Calcineurin Inhibitors; Cytokines; Dermatitis, Atopic; Disease Models, Animal; Enterotoxins; Female; Immunoglobulin A; Immunoglobulin E; Immunohistochemistry; Immunosuppressive Agents; Mice; Mice, Inbred BALB C; Ovalbumin; Phosphodiesterase Inhibitors; Proteins; Reverse Transcriptase Polymerase Chain Reaction; Skin; Tacrolimus; Xanthines

Tinea incognito was first described 50 years ago. It is a dermatophytic infection with a clinical presentation modified by previous treatment with topical or systemic corticosteroids, as well as by the topical application of immunomodulators such as pimecrolimus and tacrolimus. Tinea incognito usually resembles neurodermatitis, atopic dermatitis, rosacea, seborrheic dermatitis, lupus erythematosus, or contact dermatitis, and the diagnosis is frequently missed or delayed.

Topics: Administration, Cutaneous; Antifungal Agents; Dermatitis, Atopic; Dermatitis, Contact; Dermatitis, Seborrheic; Dermatologic Agents; Diagnosis, Differential; Humans; Immunosuppressive Agents; Lupus Erythematosus, Discoid; Neurodermatitis; Ointments; Rosacea; Tacrolimus; Tinea; Trichophyton

Thymic stromal lymphopoietin (TSLP), highly expressed by keratinocytes in skin lesions in atopic dermatitis and bronchial epithelial cells in asthma, plays a key role in allergic diseases. Double-stranded RNA (dsRNA) stimulates keratinocytes to release TSLP in vitro.. To examine the potential of glucocorticoids and calcineurin inhibitors to suppress dsRNA-induced release of TSLP from keratinocytes.. Primary human kerarinocytes were stimulated with dsRNA in the presence of IL-4, IL-13 and TNF-alpha. TSLP release was measured by ELISA. The effects of glucocorticoids and 2 calcineurin inhibitors, cyclosporin A and FK506/tacrolimus, were analyzed.. The glucocorticoids inhibited dsRNA-induced release of TSLP. The inhibitory effect became saturated (50-70% reduction) at concentrations higher than 10(-10)M. Cyclosporin A inhibited the release of TSLP by 50-60% at 10(-5) and 10(-4)M. FK506 had no effect at 10(-5)M or less, but almost completely inhibited the release of TSLP at 10(-4)M. No synergistic effect was obtained with a glucocorticoid plus either of the calcineurin inhibitors. An additive inhibitory effect was obtained with a glucocorticoid plus 10(-5)M cyclosporin A. Glucocorticoid inhibited dsRNA-induced TSLP transcription in the absence of Th2/TNF cytokines.. Glucocorticoids inhibited the dsRNA-induced release of TSLP in the atopic cytokine milieu at much lower concentrations than calcineurin inhibitors, suggesting that they could be effective in the treatment of atopic dermatitis when exogenous or endogenous dsRNA is involved in the pathogenesis. In addition, the in vitro system established in this study would be useful for screening of therapeutic reagents which target TSLP expression.

Topics: Calcineurin Inhibitors; Cells, Cultured; Cytokines; Dermatitis, Atopic; Glucocorticoids; Humans; Immunosuppressive Agents; Keratinocytes; RNA, Double-Stranded; Tacrolimus; Thymic Stromal Lymphopoietin

To examine the 10-year outcome of affected body surface area (BSA), respiratory symptoms, and serum IgE in adult AD patients 6 years after a 4-year intervention with topical tacrolimus.. Patients who 10 years ago participated in a 4-year, open tacrolimus study (n = 65) were contacted for assessment of affected BSA, bronchial hyper-reactivity (BHR), respiratory symptoms, skin prick tests and serum IgE.. Altogether, 50 (77%) patients attended the follow-up visit. The median affected BSA decreased from 19% to 1.6% during the 10-year follow-up (p < 0.0001). Patients with active asthma and rhinitis symptoms at baseline reported a significant decrease at the follow-up (p = 0.02 andp = 0.01). In patients with BHR at baseline, the provocative dose of inhaled histamine producing a 15% decrease in FEV(1) increased. Responders (>or= 60% improvement of affected BSA) to tacrolimus treatment at the 1-year visit had a significantly smaller affected BSA at the 4- and 10-year visits than non-responders (< 60% improvement). Responders also showed a significant decrease in serum IgE at the follow-up visit compared to baseline (p = 0.002).. The long-term, effective treatment of patients with AD may have a beneficial effect on affected BSA, respiratory symptoms, and serum IgE.

Topics: Administration, Topical; Adolescent; Adult; Asthma; Body Surface Area; Bronchial Hyperreactivity; Cohort Studies; Dermatitis, Atopic; Dose-Response Relationship, Drug; Drug Administration Schedule; Eczema; Female; Follow-Up Studies; Humans; Immunoglobulin E; Male; Middle Aged; Respiratory Function Tests; Retrospective Studies; Risk Assessment; Skin Tests; Tacrolimus; Time Factors; Young Adult

Burning sensation at the site of application is the most common side effect of topical calcineurin inhibitors and is considered the most common reasons for premature discontinuation. Here, we analyze the possible mechanism(s) and offer a simple practical tip to mitigate this adverse effect. Simple cooling of the tube, immediately before use, does reduce the burning sensation and enable most intolerant patients to use the medication comfortably. We also discuss the possible explanation(s) for the success of this maneuver.

Topics: Administration, Topical; Calcineurin Inhibitors; Cold Temperature; Dermatitis, Atopic; Dermatologic Agents; Humans; Pain; Tacrolimus

Atopic dermatitis (AD) is a common chronic relapsing pruritic skin disease of dogs for which treatment has varied over time and geographical location. Recent high quality randomized controlled trials and systematic reviews have established which drugs are likely to offer consistent benefit. The International Task Force for Canine AD currently recommends a multi-faceted approach to treat dogs with AD. Acute flares should be treated with a combination of nonirritating baths and topical glucocorticoids, once an attempt has been made to identify and remove the suspected causes of the flare. Oral glucocorticoids and antimicrobial therapy must be added when needed. In dogs with chronic AD, a combination of interventions should be considered. Again, factors that trigger flares of AD must be identified and, if possible, avoided. Currently recognized flare factors include food, flea and environmental allergens, Staphylococcus bacteria and Malassezia yeast. Skin and coat hygiene and care must be improved by bathing with nonirritating shampoos and dietary supplementation with essential fatty acids. The severity of pruritus and skin lesions can be reduced with a combination of anti-inflammatory drugs. Currently, medications with good evidence of high efficacy include topical and oral glucocorticoids, and calcineurin inhibitors such as oral ciclosporin and topical tacrolimus. The dose and frequency of administration of these drugs should be tailored to each patient considering each drug's efficacy, adverse effects and cost. Allergen-specific immunotherapy should be offered, whenever feasible, in an attempt to prevent recurrence of clinical signs upon further exposure to environmental allergens to which the patient is hypersensitive.

Topics: Acute Disease; Administration, Oral; Administration, Topical; Animals; Anti-Infective Agents; Anti-Inflammatory Agents; Baths; Chronic Disease; Cyclosporine; Dermatitis, Atopic; Dermatologic Agents; Dog Diseases; Dogs; Drug Therapy, Combination; Glucocorticoids; Tacrolimus

Topical pimecrolimus 1% cream (Elidel) [hereafter referred to as topical pimecrolimus] is a nonsteroidal alternative in the treatment of pediatric atopic dermatitis. In vehicle-controlled, short-term, continuous-use trials in pediatric patients with mild to moderate atopic dermatitis, topical pimecrolimus was effective in treating disease symptoms. Topical pimecrolimus was effective in preventing disease flares and reducing the need for topical corticosteroids in longer term, intermittent-use trials. In addition, topical pimecrolimus was associated with improvements in the health-related quality of life of pediatric patients with atopic dermatitis and their parents. In vehicle-controlled trials, topical pimecrolimus was generally as well tolerated as vehicle. Topical pimecrolimus showed similar efficacy to topical tacrolimus 0.03% ointment in a short-term, continuous-use trial and the two agents had a generally similar tolerability profile. Although comparative data between topical pimecrolimus and topical corticosteroids are lacking in pediatric patients, and the long-term tolerability (beyond 1-2 years) of topical pimecrolimus is yet to be established, topical pimecrolimus is a useful agent in the management of pediatric patients with mild to moderate atopic dermatitis who do not achieve satisfactory treatment with other topical pharmacologic treatments, including topical corticosteroids.

Topics: Administration, Cutaneous; Child; Clinical Trials as Topic; Dermatitis, Atopic; Dermatologic Agents; Economics, Pharmaceutical; Humans; Quality of Life; Tacrolimus; Treatment Outcome

Although clinical trials for new drugs are often limited in children because of safety concerns or restrictions, new therapies or novel strategies with old drugs have recently expanded dermatologic armamentarium for pediatric patients. Oral propranolol is currently the first choice in the treatment of alarming infantile hemangiomas. In atopic dermatitis, proactive strategy with topical calcineurin inhibitors can safely prevent disease exacerbation. Tacrolimus, in particular, is also useful for the treatment of vitiligo occurring in sensitive areas such as the eyelids. Among biologic drugs, use of etanercept is safe and efficient in children and adolescents with moderate-to-severe plaque psoriasis. Engineered tissues with special antimicrobial properties (silver-coated fabrics or engineered silk) are now used to treat eczema and fungal diseases in children. In athlete's foot, the use of 5-finger socks can also be helpful.

Topics: Adolescent; Adrenal Cortex Hormones; Alopecia Areata; Autoimmune Diseases; Child; Child, Preschool; Dermatitis, Atopic; Eczema; Female; Hemangioma; Humans; Immunosuppressive Agents; Male; Propranolol; Psoriasis; Randomized Controlled Trials as Topic; Skin Diseases; Tacrolimus; Therapies, Investigational; Vitiligo

Tacrolimus 0.1% and pimecrolimus 1.0% are used for short-term and noncontinuous treatment of atopic dermatitis (AD) in patients unresponsive to conventional therapies.. To assess the cost-effectiveness of tacrolimus versus pimecrolimus in adults with AD.. Using a Markov cohort model, the authors projected clinical and economic outcomes over six weeks in adults receiving tacrolimus versus pimecrolimus. Cost-effectiveness was assessed in terms of the ratio of the expected cost of AD-related care to the expected number of days with resolved AD.. Patients receiving tacrolimus had an estimated 4.9 fewer days with active AD over six weeks (30.0 versus 34.9 for pimecrolimus). Expected costs (per patient) of AD-related care also were lower for tacrolimus patients ($501.27 versus $546.14, respectively).. While pimecrolimus is indicated for use solely in patients with mild-to-moderate AD, the trial on which this study was based included some patients with severe AD.. In adults with AD, tacrolimus 0.1% may yield better clinical outcomes and lower costs of care than pimecrolimus 1.0%.

Topics: Adult; Cost-Benefit Analysis; Dermatitis, Atopic; Humans; Ointments; Tacrolimus

Atopic dermatitis (AD) is chronically relapsing eczematous skin disorder having significant impact worldwide. Tacrolimus is the drug-of-choice which inhibits T-cell activation resulting in suppression of inflammation. However, despite being effective, most common adverse events of tacrolimus are low-and-variable bioavailability, burning sensation and pruritus at application site, which prompt for development of novel carrier that could effectively target tacrolimus to site-of-action without producing undesirable side-effects. Tacrolimus-loaded lipid-nanoparticles (T-LN) were prepared and optimized. DSC and FT-IR have been employed to study drug-excipient incompatibility and encapsulation of drug in lipid which was further confirmed by (1)H NMR. In vitro studies revealed much higher drug release, skin penetration and enhanced skin accumulation as compared to reference Protopic. In vitro and in vivo occlusion studies demonstrated similar occlusiveness for T-LN and reference however; T-LN showed significantly higher drug levels penetrating into deeper skin layers where dendritic cells responsible for immunopathogenesis of AD mainly reside. In-vivo skin retention demonstrated 3.36, 30.81 and 28.68-times higher stratum corneum, epidermal and dermal levels respectively compared to reference. Visualization of cutaneous uptake in-vivo using CLSM confirmed targeting to deeper skin layers and Draize test showed no skin irritation with PII 0.00. Thus T-LN displayed superior performance, effective skin targeting and improved safety as compared to reference.

Topics: Administration, Cutaneous; Animals; Dermatitis, Atopic; Drug Delivery Systems; Erythema; Rabbits; Rats; Skin Absorption; Swine; Tacrolimus; Treatment Outcome

Tacrolimus (FK506) and cyclosporine A (Cys A) are immunosuppressive drugs used in the treatment of inflammatory diseases and for preventing rejection of allogeneic transplants. Tacrolimus forms a complex with FK506 binding protein (FKBP), and Cys A forms a complex with cyclophilin. These tacrolimus-FKBP and Cys A-cyclophilin complexes interact with calcineurin (CaN), thereby suppressing activation of T cells. In contrast, steroidal anti-inflammatory drugs suppress the immune system mainly via inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) and the activating protein-1 (AP-1) pathway. Previously, we reported that tacrolimus, but not dexamethasone, reduced scratching behavior in a murine model of atopic dermatitis. To elucidate the mechanism involved in the inhibition of scratching behavior, we used a mouse model of allergic dermatitis to compare the characteristics of tacrolimus and Cys A treatment. We found that Cys A suppressed scratching behavior induced by application of 2,4-dinitrofluorobenzene, as did tacrolimus. In addition, both drugs attenuated increases in vascular permeability and scratching behavior induced by passive cutaneous anaphylaxis. These results indicate that inhibition of the CaN pathway plays an important role in tacrolimus- and Cys A-induced inhibition of scratching behavior in mice. Furthermore, we observed that CaN inhibitors suppressed mast cell-dependent allergic reaction.

Topics: Animals; Antipruritics; Behavior, Animal; Calcineurin Inhibitors; Capillary Permeability; Cyclosporine; Dermatitis, Atopic; Dinitrofluorobenzene; Disease Models, Animal; Immunosuppressive Agents; Male; Mice; Mice, Inbred BALB C; Passive Cutaneous Anaphylaxis; Pruritus; Tacrolimus

Topics: Administration, Topical; Adolescent; Adult; Dermatitis, Atopic; Dermoscopy; Female; Humans; Immunosuppressive Agents; Lip Diseases; Male; Melanosis; Tacrolimus

Low bone mineral density (BMD) has been reported in 30.4% of adult patients with atopic dermatitis (AD).. The aim of this study was to determine the prevalence of low BMD in children with moderate to severe AD and to investigate the relation between BMD and corticosteroid and cyclosporine therapy.. Lumbar spine BMD was measured by dual-energy X-ray absorptiometry in 60 children (age 5-16 years) with moderate to severe AD. BMD (in g/cm(2)) was expressed in Z-scores, the number of SD above or below the mean value of an age- and sex-matched reference population. In children, low BMD was defined as a Z-score less than -2. Information on lifestyle parameters and bone fractures were collected by use of a standardized questionnaire. The cumulative dose of corticosteroids and cyclosporine therapy was calculated for the previous 5-year period.. Three patients (5%) had low BMD; one patient (1.7%) had osteoporosis. The observed prevalence of low BMD in this study (6.7%; 95% confidence interval 1.8%-16.2%) does not differ from the expected prevalence of low BMD in the general population (P = .06). Overall, use of topical corticosteroids in the previous 5 years was not associated with a decrease in BMD (Z-score). When children received additional systemic treatment (oral corticosteroids and/or cyclosporine) in the previous 5 years, BMD decreased, although the decrease was not statistically significant. Correction for lifestyle parameters did not change these associations.. The number of patients studied was limited. The cumulative dose of corticosteroids and cyclosporine therapy was only registered for the previous 5 years, and relatively low amounts of topical corticosteroids were used. The definition of low BMD differs between adults (Z-score < -1) and children (Z-score < -2). Because there is no Dutch BMD reference population for children, normative BMD references were obtained from a different population (US children).. Low BMD did not occur more frequently in this population of children with moderate to severe AD compared with the general population. Use of topical corticosteroids in the previous 5 years was not associated with a decrease in BMD.

Topics: Absorptiometry, Photon; Adolescent; Adrenal Cortex Hormones; Bone Density; Child; Child, Preschool; Cyclosporine; Dermatitis, Atopic; Female; Fractures, Bone; Humans; Immunosuppressive Agents; Lumbar Vertebrae; Male; Osteoporosis; Prevalence; Risk Factors; Severity of Illness Index; Tacrolimus

Topics: Administration, Oral; Adult; Aspirin; Burns, Chemical; Dermatitis, Atopic; Drug Eruptions; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Ointments; Retrospective Studies; Tacrolimus; Young Adult

Wet-wrap treatment (WWT) with diluted topical steroids is widely used in atopic dermatitis (AD). Mice with transgenic overexpression of human apolipoprotein C1 (APOC1) in the liver and the skin are not only characterized by hyperlipidaemia and raised IgE levels, but also by pruritic dermatitis and a disturbed skin barrier function, providing a novel in vivo mouse model for AD.. We investigated an adapted WWT method in the AD model in APOC1 mice in order to establish its efficacy.. The effect of topical 0.1% and 0.03% tacrolimus ointment, tacrolimus base ointment, different dilutions of 0.05% fluticasone propionate (FP) cream and emollient on the development of dermatitis in APOC1 mice was investigated. WWT was performed with 0.03% tacrolimus ointment or 0.017% FP cream.. AD in APOC1 mice responded to topical treatment with tacrolimus or FP. In contrast to tacrolimus treatment, FP treatment was associated with loss of body weight. WWT reinforced several therapeutic aspects, notably improvements in transepidermal water loss and in epidermal thickness. WWT using tacrolimus 0.03% ointment was more effective than WWT using FP 0.017% cream.. AD in APOC1 mice responds to treatment with (diluted) tacrolimus or FP; treatment with FP cream, but not tacrolimus ointment, was associated with weight loss. In this study, the adapted WWT using tacrolimus or FP in mice had a limited improving effect as compared with open application of tacrolimus or FP.

Topics: Androstadienes; Animals; Apolipoprotein C-I; Bandages; Dermatitis, Atopic; Disease Progression; Dose-Response Relationship, Drug; Emollients; Fluticasone; Humans; Mice; Mice, Transgenic; Models, Animal; Ointments; Tacrolimus

Atopic dermatitis (AD) is a chronic inflammatory skin disease, which is accompanied by marked increases in the levels of inflammatory cells, including mast cells and eosinophils as well as T cells and macrophages. To investigate the expression pattern of chemokines in AD, a house dust mite, Dermatophagoides farinae extracts (DfE)-induced NC/Nga AD model was developed in mice, and this model was used to determine the expression levels of chemokines in atopic lesions using DNA microarrays and RT-PCR. When NC/Nga mice were repeatedly treated with DfE for 4 to 7 weeks on the back skin, the mRNA expression levels of CCL20/LARC, CCL24/eotaxin-2, CCL17/TARC, and CCL11/eotaxin-1 were markedly induced and lesser of CCL2/MCP-1, within the inflammatory lesion of the back skin. Immunohistochemical staining revealed the expression of these chemokines in the epidermis and dermis of DfE-treated NC/Nga mice. Interestingly, repeated application of tacrolimus ointment potently inhibited DfE-induced atopic dermatitis in NC/Nga mice concomitant with the inhibition of these changes in chemokine gene and protein expression levels particularly of CCL20/LARC, CCL17/TARC, and CCL11/eotaxin-1. These data indicate that severe atopic dermatitis induced by DfE accompanies elevated chemokine levels, and it was proposed that tacrolimus ointment is beneficial for the treatment of severe AD.

Topics: Allergens; Animals; Chemokines; Dermatitis, Atopic; Dermatophagoides farinae; Disease Models, Animal; Female; Immunoglobulin E; Immunosuppressive Agents; Mice; Ointments; Tacrolimus

The NC/Nga mouse spontaneously develops eczematous atopic dermatitis (AD)-like skin lesions when maintained under conventional conditions, but not when kept under specific pathogen-free (SPF) conditions. Hence, there is a need for an AD model in mice housed under SPF conditions, as this is mandatory for research animals in many countries.. We evaluated the use of the hapten FITC as an inducer of AD-like disease in NC/Nga and BALB/c mice maintained under SPF conditions. Mice were either untreated or treated with tacrolimus or betamethasone. Using the software Computer Assisted Stereological Toolbox as a stereological method, the mice were sensitized to FITC and the histological efficiency of disease induction with regard to inflammation and CD4+ and CD8+ lymphocytes, in addition to mast cells, was evaluated. The method was validated by comparison to a conventional semiquantitative observer-dependent method.. Our findings prove that FITC does indeed induce AD-like lesions in NC/Nga mice with regard to the histological appearance of the mice. However, when evaluating the immunological response in the affected areas of the mice with regard to the CD4/CD8 ratio and the effect of treatment, we found that the immune response in the NC/Nga mice differed from AD skin lesions in humans in certain aspects.. These results emphasize the importance of an assessment of not only the histological but also the immunological appearance of the skin when evaluating AD-like disease in mice as a model for AD in humans.

Topics: Animals; Anti-Inflammatory Agents; Betamethasone; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Dermatitis, Atopic; Diagnosis, Computer-Assisted; Disease Models, Animal; Female; Fluorescein-5-isothiocyanate; Fluorescent Dyes; Haptens; Immunosuppressive Agents; Mice; Mice, Inbred BALB C; Skin; Software; Tacrolimus

A potential risk of lymphoma associated with the use of topical calcineurin inhibitors is debated. We assessed the risk of lymphoma among patients treated with topical pimecrolimus, tacrolimus or corticosteroids.. We conducted a cohort study using health insurance claims data. Cohorts of initiators of topical pimecrolimus, tacrolimus and corticosteroids, along with cohorts of persons with untreated dermatitis and randomly sampled enrollees were identified from January 2002 to June 2006. Lymphomas were identified using insurance claims and adjudicated by medical records review. We adjusted for confounders by propensity score matching.. Among 92,585 pimecrolimus initiators contributing 121,289 person-years of follow-up, we identified 26 lymphomas yielding an incidence of 21/100,000 person-years. This incidence of lymphoma was similar to that among tacrolimus users (rate ratio, RR = 1.16; 95% confidence interval, CI = 0.74-1.82) as well as corticosteroid users (RR = 1.15; 95% CI = 0.49-2.72). All three topical treatments were associated with an increased risk of lymphoma compared with the general population (RR(Pim) = 2.89; RR(Tac) = 2.82; RR(Cort) = 2.10) suggesting increased detection of preexisting lymphomas.. This study did not find an increased risk of lymphoma among initiators of topical pimecrolimus relative to other topical agents during an average follow-up of 1.3 years. Longer-term studies may be needed.

Topics: Administration, Topical; Adolescent; Adult; Aged; Calcineurin Inhibitors; Child; Child, Preschool; Dermatitis, Atopic; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Infant; Lymphoma; Male; Middle Aged; Risk Factors; Tacrolimus; Young Adult

Topical calcineurin inhibitor (TCI) was reported to be an effective therapeutic agent for patients with atopic dermatitis (AD), for not only improving clinical findings but also for reducing pruritus. Recently in Japan tacrolimus ointment (0.03%) as a TCI was approved for use in children aged > or =2 years. There have been no reports, however, on the impact of TCI on quality of life (QOL) in pediatric AD in Japan. The purpose of the present study was therefore to evaluate the efficacy of tacrolimus ointment (0.03%) in the short-term and the impact on patient QOL.. A total of 30 pediatric patients with AD, whose skin problems were not sufficiently controlled by mid-high potency topical glucocorticosteroids, were enrolled. Efficacy was assessed on score of cutaneous findings, pruritus, sleeping disorder, and QOL.. Three patients discontinued because of skin burning (n = 1), generalized herpes infection (n = 1), and feeling of lack of efficacy (n = 1), leaving a final total of 27 patients who were evaluated. Significant improvements in clinical findings, pruritus, and sleeplessness were observed within 1 week of treatment and consequently each QOL category was also improved. These improvements continued for the duration of the study.. Tacrolimus ointment therapy is rapidly effective for not only clinical symptoms (cutaneous findings, pruritus and sleeplessness) but also in QOL of AD pediatric patients aged > or =2 years.

Topics: Adolescent; Child; Child, Preschool; Dermatitis, Atopic; Female; Humans; Immunosuppressive Agents; Male; Ointments; Quality of Life; Tacrolimus

An adult, male, rhesus macaque presented with pruritus and a focal, exudative, inflamed, erythematous skin lesion of approximately 2 cm in diameter on the ventral aspect of the mandible. The lesion resolved after 10 d of treatment with 1% chlorhexidine solution and triple-antibiotic ointment. However, the skin lesion subsequently recurred several times over a 2-mo period. A punch biopsy was performed, and histological changes were most consistent with a diagnosis of atopic dermatitis. Treatment with topical tacrolimus ointment, an immunosuppressive drug, proved successful in the resolution of all clinical signs after 4 mo. According to a literature review, this article is the first report of the use of tacrolimus ointment as a topical treatment of atopic dermatitis in a rhesus macaque.

Topics: Animals; Dermatitis, Atopic; Immunosuppressive Agents; Macaca mulatta; Male; Monkey Diseases; Ointments; Tacrolimus; Treatment Outcome

Topics: Administration, Topical; Contraindications; Dermatitis, Atopic; France; Humans; Neoplasms; Tacrolimus

As from 2005, the Danish Medicines Agency has recommended prescription of topical calcineurin inhibitors (TCI) to patients aged two years and older after attempting treatment with topical corticosteroids.. Via the Danish Register of Medical Product Statistics every TCI-user was identified (encrypted ID) from July 2002-2007: 18,780 tacrolimus- and 40,895 pimecrolimus users. Changes over time in first-line users are studied by 2 test and in age distributions by Mann-Whitney U-test.. 1-year prevalence and incidence have decreased since 2005. In the period 2003-2007, 21% of all tacrolimus incident users and 36% of all pimecrolimus incident users were first-line users. In the period 2003-2007, 590 tacrolimus users and 4,913 pimecrolimus users were below the age of two years. These pimecrolimus users decreased in number from 1,440 in 2003 to 480 in 2007. In four out of five first-line pimecrolimus users below the age of two years, the first prescription was issued by a general practitioner.. The decrease in the sale of TIM since 2005 coincided with the changed recommendations. On the basis of the available data, it is not possible to determine whether the percentage of first-line users are reasoned by the skin area is not suitable for corticosteroids. In 2007, the recommendation was not followed for a minor number of TIM users below the age of two years.

Topics: Administration, Topical; Adult; Child; Denmark; Dermatitis, Atopic; Drug Prescriptions; Drug Utilization; Humans; Immunosuppressive Agents; Infant; Practice Guidelines as Topic; Registries; Tacrolimus

Atopic dermatitis (AD) is characterized by highly pruritic, chronic, relapsing inflammatory skin lesions. Furthermore, therapeutic choices are limited, especially in long-standing cases, despite its increasing prevalence. This study was performed to examine the clinical efficacy and the therapeutic mechanism underlying the effects of Actinidia arguta (hardy kiwi) fruit extract in an animal model of AD. To examine the effects of A. arguta extract on AD, 2-chloro-1,3,5-trinitrobenzene-treated NC/Nga mice were orally administered A. arguta extract (100 mg/kg/day), tacrolimus (1 mg/kg/day), or dexamethasone (3 mg/kg/day) for 8 weeks. Skin severity scores, epidermal thickening, mast cell infiltration and degranulation, total serum immunoglobulin (Ig) isotypes (IgE, IgG(1)), and cytokine (interleukin [IL]-4 and interferon [IFN]-gamma) and Toll-like receptor (TLR) (TLR-2, TLR-4, and TLR-9) expressions were examined in each of the study groups. Orally administered A. arguta extract significantly reduced clinical dermatitis severity, epidermal thickness, mast cell dermal infiltration and degranulation, and total levels of serum IgE and IgG(1). Furthermore, this suppression of total serum IgE and IgG(1) levels was accompanied by a decrease in IL-4 and an increase in IFN-gamma expression in skin and splenocytes. Interestingly, TLR-9 expression was increased by oral A. arguta extract. This study confirms that A. arguta extract has potential as a dietary therapeutic agent for the treatment of AD. Furthermore, our findings suggest that its clinical efficacy and mode of action against AD are associated with the modulation of biphasic T-helper (Th) 1/Th2 cytokines, with the inhibition of Th2-mediated IgE overproduction, and possibly with the up-regulation of TLR-9.

Topics: Actinidia; Administration, Oral; Animals; Dermatitis, Atopic; Dexamethasone; Epidermis; Fruit; Immunoglobulin E; Immunoglobulin G; Interferon-gamma; Interleukin-4; Male; Mast Cells; Mice; Models, Animal; Phytotherapy; Plant Extracts; Severity of Illness Index; Skin; Tacrolimus; Th1 Cells; Th2 Cells; Toll-Like Receptor 9; Trinitrobenzenes; Up-Regulation

Topics: Administration, Topical; Adult; Dermatitis, Atopic; Humans; Steroids; Tacrolimus

The Food and Drug Administration has issued a public health advisory regarding cancer risk from topical calcineurin inhibitors.. To compare the rates of cancer among patients with common dermatologic conditions who were exposed or not exposed to topical calcineurin inhibitors.. A retrospective cohort observational study used data from an integrated healthcare delivery system on 953,064 subjects with diagnoses of atopic dermatitis or eczema between 2001 and December 2004. The main endpoint was initial cancer diagnosis. Chart review was performed to confirm cancer diagnosis in the subjects exposed to topical calcineurin inhibitors when any particular cancer rate was at least 3 times higher than that in unexposed subjects. Data were analyzed using the Cox proportional hazards model.. Age- and sex-adjusted hazard ratios for all cancers were 0.93 (95% CI 0.81 to 1.07; p = 0.306) for tacrolimus-exposed versus -unexposed subjects and 1.15 (95% CI 0.99 to 1.31; p = 0.054) for pimecrolimus-exposed versus -unexposed subjects. T-cell lymphoma was the only cancer associated with a significantly increased risk among subjects exposed to tacrolimus (HR = 5.04, 95% CI 2.39 to 10.63; p < 0.001) or pimecrolimus (HR = 3.76, 95% CI 1.71 to 8.28; p = 0.010). Subsequent chart review of subjects in the exposed group with T-cell lymphoma found that 4 of 16 had skin lesions that were suspected to be the early lesions of T-cell lymphoma prior to exposure to tacrolimus or pimecrolimus. After these 4 cases were excluded, the age and sex hazard ratio for T-cell lymphoma was 5.44 (95% CI 2.51 to 11.79; p < 0.001) for tacrolimus and 2.32 (95% CI 0.89 to 6.07; p = 0.086) for pimecrolimus. There was no statistically significantly increased risk for other subgroups of cancer, including melanoma.. Exposure to topical tacrolimus or pimecrolimus was not associated with an increase in the overall cancer rate. Use of topical tacrolimus may be associated with an increased risk of T-cell lymphoma.

Topics: Administration, Cutaneous; Adolescent; Adult; Aged; Calcineurin Inhibitors; Child; Child, Preschool; Cohort Studies; Dermatitis, Atopic; Eczema; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Infant; Lymphoma, T-Cell; Male; Middle Aged; Neoplasms; Proportional Hazards Models; Retrospective Studies; Risk; Tacrolimus; Young Adult

The objective of this 4-month multicentre observational study was to evaluate safety and efficacy of intermittent long-term treatment of patients with atopic dermatitis (AD) with pimecrolimus cream 1% in the daily practice and to compare it with the preceding topical corticosteroid-based therapy in retrospective.. Overall severity of AD and individual symptoms were assessed in 3200 patients by the physician, whereas acceptance of treatment and satisfaction of patients was investigated using a patient questionnaire.. The percentage of patients clear or almost clear of symptoms increased from 12% to 82%. Seventy-four per cent of physician rated the treatment better than the preceding therapy, and 21% noted no difference. Seventy-seven per cent of the patients asserted that long-term intermittent treatment with pimecrolimus reduces the frequency of flares as opposed to less than 27% for topical corticosteroids. Patients also felt that pimecrolimus results in a higher improvement in quality of life; 84% stated that pimecrolimus stabilized the skin compared with 27% for topical steroids.. Intermittent treatment of AD patients with pimecrolimus cream 1% is effective and well tolerated, and results in higher patient satisfaction compared with topical corticosteroids in retrospective.

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Child; Dermatitis, Atopic; Dermatologic Agents; Female; Humans; Male; Middle Aged; Patient Satisfaction; Retrospective Studies; Surveys and Questionnaires; Tacrolimus

The proportion of dendritic cell subpopulations in the skin is important for the severity of atopic dermatitis because topical treatment with tacrolimus leads to rapid depletion of inflammatory dendritic epidermal cells, whereas Langerhans cells (LCs) predominate in cured sites.. The effects of tacrolimus and TGF-beta1 on LC differentiation and the idea of tacrolimus skewing the differentiation of epidermal precursors to LCs were evaluated.. The presence of LC markers, MHC, and costimulatory molecules and stimulatory capacity toward T cells of monocyte-derived LCs were analyzed. Skin samples of patients with atopic dermatitis were assessed by means of immunofluorescence microscopy before and after tacrolimus treatment. TGF-beta production of skin cells was analyzed.. Tacrolimus and TGF-beta1 act synergistically on the generation of LCs and the expression of CD40, CD80, CD86, CD83, and MHC II; stabilize TGF-beta receptor II expression; and decrease the stimulatory capacity of LCs toward T cells. In vivo the number of epidermal LCs in tacrolimus-treated skin increased.. The synergism between TGF-beta1 and tacrolimus leads to the generation of LCs, reduced expression of costimulatory and MHC II molecules, and reduced stimulatory activity. Shifting the balance of the dendritic cell population to LCs might be of major importance for the therapeutic effect of tacrolimus.

Topics: Adult; Cell Differentiation; Cytokines; Dendritic Cells; Dermatitis, Atopic; Drug Synergism; Epidermis; Female; Humans; Immunosuppressive Agents; Langerhans Cells; Male; Protein Serine-Threonine Kinases; Receptor, Transforming Growth Factor-beta Type II; Receptors, Transforming Growth Factor beta; T-Lymphocytes; Tacrolimus; Transforming Growth Factor beta1

Epigallocatechin-3-gallate (EGCG) has been shown to exert anti-inflammatory effects on the inflammatory skin conditions. However, little is known about its effect on atopic dermatitis (AD). We first attempted to assess the anti-inflammatory effect of topical application of EGCG in vivo AD model using NC/Nga mice and to determine whether EGCG exerts the anti-inflammatory effect by inhibiting macrophage migration inhibitory factor (MIF) and other cytokines that are related to immune dysregulation in the pathogenesis of AD. Murine AD-like skin lesions were made by painting Dermatophagoides pteronissinus extract (DPE). The effects of EGCG treatment were assessed by total clinical severity score and ear thickness, and by histological grading. In addition, the mRNA and protein expression of the cytokines including MIF were measured by real-time RT-PCR and immunohistochemistry. The serum levels of MIF and IgE were measured by ELISA. In the AD mouse model, EGCG significantly reduced the total clinical severity score and ear thickness (p<0.05). The histological grading was also markedly improved. The mRNA expression of MIF, TNF-alpha, IFN-gamma, IL-2 and IL-12 p40, but not of IL-4, IL-5 and IL-13 in the lesions was significantly reduced by EGCG (p<0.05). On the immunohistochemistry, EGCG also markedly diminished the expression of MIF, TNF-alpha and IFN-gamma. The serum MIF and IgE production was significantly reduced by EGCG (p<0.05). These results demonstrate that topical application of EGCG may improve the AD-like skin lesions by suppressing MIF and T helper 1 cytokines. Taken together, it is suggested that EGCG may be a potential therapeutic modality for AD.

Topics: Animals; Antigens, Dermatophagoides; Catechin; Cytokines; Dermatitis, Atopic; Ear, External; Enzyme-Linked Immunosorbent Assay; Female; Immunohistochemistry; Immunosuppressive Agents; Macrophage Migration-Inhibitory Factors; Mice; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Skin; Tacrolimus

For the treatment of a chronic disease like atopic dermatitis, sustained tolerability and efficacy of the applied medication are essential.. The present open-label, noncomparative study was conducted to obtain information on the long-term safety and efficacy of 0.1% tacrolimus ointment.. Patients aged 2 years or older with an affected body surface area of more than 5%, who previously participated in a clinical trial on tacrolimus ointment, were eligible for this study. The treatment area was defined by the investigator at study entry. Both children and adults applied continuously or intermittently 0.1% tacrolimus ointment twice daily during episodes of active disease plus an additional week after remission over a follow-up period of up to 4 years.. The intent-to-treat population comprised 782 patients, with a median age of 22 years (range 2-72). Patients remained in the study for up to 4 years. Approximately half of the patients discontinued the study prematurely; the median follow-up was 1422 days. Median tacrolimus ointment use was 31.2 g during the first week; ointment use decreased during the first year and then remained stable for the remainder of the study. The median cumulative tacrolimus use was 271.5 g at month 6, 462.5 g at month 12, 739.9 g at month 24, 1029.3 g at month 36 and 1320.8 g at month 48. Altogether 51.8% of patients discontinued the study prematurely; the main reasons were withdrawal of consent (13.3%), loss to follow-up (11.3%) and lack of efficacy (9.4%). Adverse events led to study discontinuation in 3.7% of the patients. The most frequent application site events were skin burning and pruritus. These events were most often reported in adult patients during the initial treatment period; prevalence decreased after the first week and remained at a low level throughout the study. Nonapplication site events occurred with stable incidences throughout the study period. In general, calculated daily hazard rates did not indicate an increased risk of adverse events with prolonged treatment. The total affected body surface area decreased substantially upon onset of treatment and efficacy of treatment was maintained until the end of the study with smaller but continuous improvements throughout the follow-up period. Overall, 75% of the patients and 76% of the investigators rated their satisfaction with the treatment as excellent, very good or good at the end of the study or at the time of premature discontinuation.. The safety profile of intermittent or continuous long-term application of 0.1% tacrolimus ointment for up to 4 years was consistent with that which has been established from shorter studies and gave no reason for concern. In addition, 0.1% tacrolimus ointment demonstrated sustained efficacy as reflected by the expression of high satisfaction with treatment by both patients and investigators.

Topics: Adolescent; Adult; Aged; Child; Child, Preschool; Dermatitis, Atopic; Follow-Up Studies; Humans; Immunosuppressive Agents; Middle Aged; Ointments; Statistics as Topic; Tacrolimus; Time Factors

To study corneal abnormalities in the NC/Nga mouse, which is an animal model of atopic dermatitis.. To study histopathologic changes of the eyelid, conjunctiva, and cornea, we extracted the eyeballs together with upper and lower eyelids and fixed them for examination by light and electron microscopy or snap-froze them for immunohistochemistry. Transferase mediated-dUTP digoxigenin nick-end labeling staining was performed to detect apoptotic cells. In order to assess eye scratching behavior and the effect of tacroliums hydrate ointment, we made video recordings.. Mice kept in a conventional room suffered from various grades of blepharoconjunctivitis and scratched their eyes furiously. Tacrolimus hydrate ointment reduced their eye-scratching behavior. Histopathologic study of the eyelid and conjunctiva showed that this blepharoconjunctivitis was caused by allergic inflammation. Mice with severe blepharoconjunctivitis showed thinning of the corneal epithelium, an irregular interface between the epithelium and stroma, subepithelial deposition of materials, and neovascularization of the stroma. Their corneas were cone shaped. Many transferase mediated-dUTP digoxigenin nick-end labeling-positive cells were recognized among superficial epithelial cells and keratocytes.. NC/Nga mice are a useful animal model of atopic blepharoconjunctivitis. Various corneal disorders in these mice may depend on their eye-scratching behavior.

Topics: Animals; Apoptosis; Blepharitis; CD4 Antigens; CD4-Positive T-Lymphocytes; Conjunctivitis, Allergic; Dermatitis, Atopic; Disease Models, Animal; Epithelium, Corneal; Immunoenzyme Techniques; Immunoglobulin E; Immunosuppressive Agents; In Situ Nick-End Labeling; Keratoconus; Male; Mice; Mice, Inbred Strains; Ointments; Specific Pathogen-Free Organisms; Tacrolimus

Topics: Dermatitis, Atopic; Humans; Immunosuppressive Agents; Tacrolimus

Topics: Calcineurin Inhibitors; Cyclosporine; Dermatitis, Atopic; Drug Therapy, Combination; Female; Hepatitis B, Chronic; Humans; Immunosuppressive Agents; Middle Aged; Skin; Tacrolimus

Topics: Adult; Dermatitis, Atopic; Female; Histiocytes; Humans; Immunosuppressive Agents; Neovascularization, Pathologic; Skin; Tacrolimus

Topics: Adult; Clinical Trials as Topic; Clonal Anergy; Dermatitis, Atopic; Female; Humans; Immunosuppressive Agents; Male; Ointments; Skin; T-Lymphocytes; Tacrolimus

Topics: Adult; Calcineurin Inhibitors; Child; Dermatitis, Atopic; Dermatologic Agents; Humans; Immunosuppressive Agents; Tacrolimus

Growing evidence has demonstrated the crucial role of NF-kappaB activation on disease severity in allergic disorders. In this study, we examined the clinical relevance of a novel NF-kappaB inhibitor, IMD-0354, for atopic dermatitis (AD) by its topical application. To investigate the in vivo efficacy, 1% IMD-0354 ointment was applied daily to NC/NgaTnd mice with severe dermatitis, which served as a model for human AD. During 2 weeks of treatment, scratching behavior decreased and severity of dermatitis reduced in mice treated with IMD-0354 as well as FK506 without diverse effects. Based on histological examinations, the hyperplasia of keratinocytes and infiltration of inflammatory cells were significantly reduced in the skin of IMD-0354-treated mice. The expressions of T-helper 2 cytokines and tumor necrosis factor-alpha at the affected skin sites were downregulated in IMD-0354-treated mice. Furthermore, IMD-0354 suppressed the proliferation of various immunocompetent cells, neurite outgrowth of nerve growth factor-stimulated pheochromocytoma cells, IgE production from splenic B cells, and IgE-mediated activation of mast cells in vitro. IMD-0354 effectively reduced the allergic inflammation in NC/NgaTnd mice in vivo. Thus, a drug that interferes with NF-kappaB activity may provide an alternative therapeutic strategy for the treatment of AD.

Topics: Administration, Topical; Animals; B-Lymphocytes; Benzamides; Cell Lineage; Cell Proliferation; Cells, Cultured; Dermatitis, Atopic; Down-Regulation; Immunocompetence; Immunoglobulin E; Immunosuppressive Agents; Keratinocytes; Male; Mast Cells; Mice; Mice, Inbred Strains; Neurites; NF-kappa B; Ointments; Severity of Illness Index; Skin; Spleen; Tacrolimus; Th2 Cells; Tumor Necrosis Factor-alpha

Systemic use of immunosuppressant agents increases the risk of lymphoma in transplantation. We performed a nested case-control study in the PharMetrics database to evaluate the association between topical immunosuppressants and lymphoma in a cohort of patients with atopic dermatitis. We identified cases of lymphoma and randomly selected four controls for each case, matched by length of follow-up. We used conditional logistic regression to calculate odds ratio (OR) and 95% confidence intervals (CIs) of the association between topical immunosuppressants and lymphoma. Two hundred and ninety-four cases of lymphoma occurred in 293,253 patients, 81 in patients younger than 20 years. The adjusted analysis yielded the following OR (95%CI) for: severity (OR 2.4; 95% CI 1.5-3.8), oral steroids 1.5 (1.0-2.4), "super potent" topical steroids 1.2 (0.8-1.8) , "low potency" topical steroids OR 1.1 (0.7-1.6); pimecrolimus 0.8(0.4-1.6), tacrolimus OR 0.8 (0.4-1.7), and concomitant topical steroids, pimecrolimus, and tacrolimus 1.0 (0.3-4.1). We did not find an increased risk of lymphoma in patients treated with topical calcineurin inhibitors. It is difficult to disentangle the effects of severity of disease on outcome versus the true effects of drugs. However, in the adjusted analysis, severity of AD was the main factor associated with an increased risk of lymphoma.

Topics: Administration, Topical; Adolescent; Adult; Calcineurin Inhibitors; Case-Control Studies; Child; Child, Preschool; Cohort Studies; Databases, Factual; Dermatitis, Atopic; Drug Therapy, Combination; Female; Humans; Infant; Infant, Newborn; Lymphoma; Male; Middle Aged; Risk Assessment; Severity of Illness Index; Steroids; Tacrolimus

Recent studies in murine models of allergic contact dermatitis have shown that systemic treatment with pimecrolimus in contrast to tacrolimus did not inhibit the sensitization phase, whereas both compounds equivalently suppressed the inflammatory response in sensitized animals. This finding indicated a differential sensitivity of antigen-naïve and primed T cells towards pimecrolimus and tacrolimus.. T cells obtained from healthy and allergic donors were subjected to primary and secondary stimulation by allogeneic or staphylococcal superantigen-presenting dendritic cells (DC). Human skin-derived, allergen-specific T cell clones from an atopic dermatitis patient were activated by anti-CD3 antibodies or by specific allergen-presenting DC. The inhibition of T cell proliferation and cytokine release by graded doses of calcineurin inhibitors was evaluated.. Primary stimulation of T cells was inhibited by pimecrolimus with an approximately 8-fold lower potency as compared with tacrolimus. In contrast, the secondary response of ex vivo expanded T cells activated by allogeneic or staphylococcal superantigen-presenting DC was inhibited by both compounds with equivalent potency. Likewise, both drugs showed very similar potency to inhibit the proliferation and cytokine synthesis from antigen- stimulated T cell clones and the induction of cytokines in Jurkat T cells.. These data indicate that pimecrolimus has a selectivity for antigen-primed memory T cells not seen with tacrolimus.

Topics: Cell Line; Cell Proliferation; Cytokines; Dendritic Cells; Dermatitis, Atopic; Enzyme-Linked Immunosorbent Assay; Humans; Immunosuppressive Agents; In Vitro Techniques; Jurkat Cells; Lymphocyte Activation; Lymphocyte Culture Test, Mixed; Reverse Transcriptase Polymerase Chain Reaction; T-Lymphocytes; Tacrolimus

TS-022, {4-[(1R, 2S, 3R, 5R)-5-Chloro-2-((S)-3-cyclohexyl-3-hydroxyprop-1-ynyl)-3-hydroxycyclopentyl] butylthio} acetic acid monohydrate, inhibits ADP-induced platelet aggregation, an effect significantly antagonized, as in the case of prostaglandin D(2) by the prostanoid DP(1) receptor antagonist (BW A868C). TS-022 is a prostanoid DP(1) receptor agonist, originally developed as a novel anti-pruritic drug for patients with atopic dermatitis. We examined the effects of TS-022 on experimental pruritus, cutaneous barrier disruption, and atopic dermatitis and in in vitro immune function tests. Topically applied TS-022 significantly suppressed scratching in skin-lesioned NC/Nga mice from a concentration of 2.5 nM, and this scratch-suppressive activity was significantly antagonized by BW A868C. Tacrolimus (FK-506) and dexamethasone, used as reference drugs for atopic dermatitis, also exhibited suppressive effects against scratching, but only at concentrations of 125 and 25,000 microM. TS-022 applied topically, once a day for 2 days, significantly accelerated repair of the cutaneous barrier disruption caused by mechanical scratching, from concentrations of 2.5 nM. This acceleration of repair of the disrupted cutaneous barrier by this drug was also significantly antagonized by BW A868C. FK-506 and dexamethasone showed no beneficial effects on the repair of the disrupted cutaneous barrier. Repeated topical application of 2.5 microM of TS-022 and 12.5 microM of FK-506 once a day for 6 weeks significantly improved the skin inflammation scores in the NC/Nga mice. In regard to the effects of TS-022 in vitro, the inhibitory activity of TS-022 against concanavalin A-induced cytokine production by splenocytes was marginal as compared with that of FK-506 or dexamethasone. These results suggest that the beneficial therapeutic effects of TS-022 in NC/Nga mice with atopic dermatitis are mediated by its suppressive effect on scratching and its effect of accelerating repair of the disrupted cutaneous barrier, both effects being attributable to its prostanoid DP(1) receptor agonistic activity.

Topics: Acetates; Animals; Antipruritics; Concanavalin A; Cyclohexanes; Cytokines; Dermatitis, Atopic; Dexamethasone; Humans; Hydantoins; Immunosuppressive Agents; Inflammation; Male; Mice; Platelet Aggregation; Prostaglandin D2; Pruritus; Receptors, Immunologic; Receptors, Prostaglandin; Skin; Sulfhydryl Compounds; Tacrolimus; Wound Healing

A 15-year-old male with previously documented allergic contact dermatitis from tacrolimus was allergic to pimecrolimus. This was demonstrated by double-blinded, right-versus-left provocative use testing with pimecrolimus cream 1% versus inactive vehicle applied twice daily to normal skin. The active cream but not its vehicle caused preauricular dermatitis starting after 1 week and caused isolated papules on the extensor wrist starting after 2 weeks. Patch testing on the patient's back was weakly positive (1+) with pimecrolimus cream 1% and negative with the vehicle. Higher concentrations of pimecrolimus were not available for testing. Patch tests on 30 control patients with pimecrolimus cream 1% were negative.

Topics: Adolescent; Dermatitis, Allergic Contact; Dermatitis, Atopic; Dermatologic Agents; Drug Hypersensitivity; Humans; Immunosuppressive Agents; Male; Patch Tests; Tacrolimus

Tacrolimus ointment is a topical calcineurin inhibitor for the treatment of atopic dermatitis. The primary objective of this open-label study was to assess the long-term safety of tacrolimus ointment. The primary end-point was the incidence of adverse events. Secondary end-points included the Eczema Area and Severity Index and a modified version of this index. A total of 466 children with atopic dermatitis, aged 2-15 years, applied 0.03% or 0.1% tacrolimus ointment twice daily for up to 29.5 months. Skin burning and pruritus were the most common application site events; their prevalence decreased over time. There was no increase in viral infections or other adverse events over time. Laboratory profiles were consistent with those reported in atopic populations. Substantial improvement in all efficacy end-points was observed by week 2 and maintained throughout the study. Long-term treatment with tacrolimus ointment is safe and effective in these patients with atopic dermatitis.

Topics: Administration, Topical; Adolescent; Child; Child, Preschool; Dermatitis, Atopic; Female; Humans; Immunosuppressive Agents; Male; Ointments; Safety; Tacrolimus; Treatment Outcome

Atopic dermatitis (AD) affects health and quality of life (QoL) and also has great impact on both healthcare costs and costs to society.. The aim of the study was to analyse the cost-effectiveness of treatment with tacrolimus ointment vs. standard treatment in patients with moderate to severe AD.. A Markov simulation model was constructed capturing several key features of AD and its treatment: disease severity, treatment alternatives, and QoL. The model was populated with data from three sources: (i) efficacy data from a randomized controlled trial including patients with moderate to severe AD treated with either tacrolimus ointment or standard treatment (corticosteroids), (ii) resource utilization and QoL data from a patient survey including 161 Swedish patients with AD, and (iii) official price lists. Costs were calculated according to disease severity for the two treatment alternatives using the perspective of the Swedish healthcare sector. Two analyses were performed, one based on the quantity of medication used in the trial and one based on the survey data. The relationship between effectiveness of tacrolimus ointment and the amount of medication used was tested in sensitivity analyses.. In the model simulations patients with severe AD treated with tacrolimus ointment experienced on average 4.6 more AD-free weeks per year than patients given standard treatment. The corresponding figure for patients with moderate AD was 6.5 more AD-free weeks per year. The cost-effectiveness ratios [cost per Quality Adjusted Life Year (QALY) gained] for treatment with tacrolimus ointment vs. standard treatment were 2,334 British pound for moderate AD and 3,875 British pound for severe AD when treatment patterns from the survey were assumed, and 8,269 British pound for moderate AD and 12,304 British pound for severe AD when treatment patterns from the clinical trial were assumed. The results of sensitivity analyses were all well within limits to be considered cost-effective.. Estimates of the incremental cost-effectiveness ratio are far below the currently discussed threshold in Sweden, corresponding to approximately 48,700 British pound per QALY gained, and equivalent thresholds in other countries. Treatment with tacrolimus ointment in patients with moderate and severe AD can therefore be considered cost-effective.

Topics: Adult; Cost-Benefit Analysis; Dermatitis, Atopic; Female; Health Care Costs; Humans; Immunosuppressive Agents; Male; Markov Chains; Models, Economic; Ointments; Quality-Adjusted Life Years; Sweden; Tacrolimus

Female NC/Jic mice were sensitized and challenged repeatedly at 48 h intervals for 10 and 30 days by painting 1% 2,4,6-trinitrochlorobenzene (TNCB) on both ears. Mice challenged with TNCB for 30 days developed an inflammatory dermatitis with high immunoglobulin E (IgE) titer. Histological analysis with acidic Toluidine Blue staining revealed that dermal mast cells markedly differentiated and intensely degranulated, consistent with a dramatic increase in scratching behavior. A significant increase in total scratching events could be observed in mice treated with TNCB for a short period of 10 days. Extending the term of TNCB application to 30 days, the IgE titer and number of mast cells elevated significantly, and thus various drugs were evaluated pharmacologically by using the mice treated with TNCB for 30 days. Terfenadine and cyproheptadine attenuated the chronic scratching behavior. Tacrolimus and dexamethasone were less effective and cromolyn showed no effect. In addition, terfenadine and tacrolimus suppressed the degranulation of mast cells. The present chronic scratching model could be suitable to evaluate drugs effective for suppression of mast cell differentiation and degranulation by irritation, and may represent a promising tool to develop new drugs for inflammatory pruritus associated with, for example, atopic dermatitis.

Topics: Animals; Antipruritics; Cell Degranulation; Chronic Disease; Cromolyn Sodium; Cyproheptadine; Dermatitis, Atopic; Dexamethasone; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Female; Immunoglobulin E; Mast Cells; Mice; Picryl Chloride; Pruritus; Tacrolimus; Terfenadine; Time Factors

Tacrolimus is an immunosuppressive agent used in solid organ and islet transplantation. Its topical form has shown benefit in the treatment of inflammatory skin conditions. Although tacrolimus has a wide spectrum of side effects, dermatological complications related to systemic tacrolimus therapy are limited in the literature. Atopic dermatitis (AD) is a chronic pruritic cutaneous condition that usually begins in infancy and is characterized by an increased Th2 response. We report the case of a patient with type 1 diabetes mellitus (T1DM) and history of AD latent for 10 years who developed severe dermatitis and alopecia 5 months after undergoing allogeneic islet transplantation and initiating a steroid-free immunosuppressive regimen with sirolimus and tacrolimus maintenance. After exclusion of other possible causes for the progression and exacerbation of the clinical presentation of AD, discontinuation of tacrolimus and introduction of mycophenolate mofetil resulted in full remission of the symptoms. The beneficial effects of tacrolimus withdrawal suggest a cause-effect relationship between this adverse event and the utilization of the drug. Islet graft function remained stable after modification of the therapeutic regimen (stable glycemic control and unchanged C-peptide).

Topics: Adult; Alopecia Areata; Dermatitis, Atopic; Diabetes Mellitus, Type 1; Female; Humans; Immunosuppressive Agents; Islets of Langerhans Transplantation; Tacrolimus; Transplantation, Homologous; Treatment Outcome

Topics: Administration, Cutaneous; Calcineurin Inhibitors; Dermatitis, Atopic; Drug Approval; Drug Labeling; Humans; Immunosuppressive Agents; Tacrolimus; United States; United States Food and Drug Administration

Two topical calcineurin inhibitors (TCI) are available for the treatment of atopic dermatitis and there has been concern that their use could be associated with an increased risk of nonmelanoma skin cancer (NMSC).. To determine if TCI exposure is associated with an increased risk of NMSC in adults.. A case-control study using a questionnaire mailed to 5,000 adults with dermatitis.. We received responses from 70.7% of those surveyed by mail. Overall, 25.7% reported exposure to TCI. TCI exposure was 14.4% for the cases and 30.7% for the controls. Our primary analysis was a comparison between those with NMSC and those without. The unadjusted odds ratio was 0.38 (0.31-0.47) and the adjusted (age, gender, previous NMSC, history of atopic dermatitis) was 0.54 (0.41-0.69). The odds ratio of association for NMSC decreased as the number of tubes used and the potency of the agent increased.. This early study shows that TCI use is not associated with an increased risk of NMSC in adults.

Topics: Administration, Topical; Aged; Calcineurin Inhibitors; Case-Control Studies; Dermatitis, Atopic; Enzyme Inhibitors; Female; Humans; Male; Middle Aged; Skin Neoplasms; Tacrolimus

Atopic dermatitis is a chronically relapsing inflammatory skin disease. Animal models induced by relevant allergens play a very important role in the elucidation of the disease. The patients with atopic dermatitis are highly sensitized with mite allergens such as Dermatophagoides farinae (Df). Therefore, in the present study, we tried to develop a novel model for atopic dermatitis by repeated application with Df extract ointment.. Df extract ointment was repeatedly applied to the back of NC/Nga mice together with barrier disruption. Atopic dermatitis-like skin lesions were evaluated by dermatitis scores, skin histology and immunological parameters. The effect of corticosteroid and calcineurin inhibitor was also examined.. Repeated application of Df extract ointment caused rapid increase in dermatitis scores. Clinical (skin dryness, erythema, edema and erosion) and histological symptoms (dermal and epidermal thickening, hyperkeratosis, parakeratosis and inflammatory cell infiltration) in this model were very similar to those in human atopic dermatitis. Serum total and Df-specific IgE levels were elevated in this model compared with normal mice, and draining lymph node cells isolated from the mice that exhibited dermatitis produced significant amounts of interleukin-5, interleukin-13 and interferon-gamma after re-stimulation with Df. Furthermore, current first-line drugs for the treatment of human atopic dermatitis, corticosteroid and tacrolimus ointments, were effective against the clinical and histological symptoms in this model.. These results suggest that the model we have established is useful for not only elucidating the pathogenesis of atopic dermatitis but also for evaluating therapeutic agents.

Topics: Adrenal Cortex Hormones; Allergens; Animals; Betamethasone; Dermatitis, Atopic; Dermatophagoides farinae; Disease Models, Animal; Drug Evaluation, Preclinical; Female; Immunoglobulin E; Immunosuppressive Agents; Interferon-gamma; Interleukin-13; Interleukin-5; Lymph Nodes; Mice; Reproducibility of Results; Skin; Tacrolimus

In the United States, pimecrolimus cream and tacrolimus ointment are approved as second-line therapy for short-term and intermittent noncontinuous long-term treatment of atopic dermatitis (AD) in nonimmunocompromised patients aged 2 years or older who have failed to respond adequately to other topical prescription treatments (e.g., topical corticosteroids), or when those treatments are not advisable; pimecrolimus is indicated for mild to- moderate AD and tacrolimus for moderate-to-severe AD. Comparative data on the effects of pimecrolimus versus tacrolimus on AD-related health care utilization and costs among similar patients seen in typical clinical practice are currently unavailable.. To compare utilization and costs of AD-related medical care in health plan members with AD who had prior use of a topical corticosteroid and who subsequently initiate therapy with pimecrolimus cream or tacrolimus ointment.. This was an observational, retrospective study using an administrative claims database with dates of service from August 1, 2000, through October 31, 2003, and representing approximately 2.5 million members in health maintenance organizations, preferred provider organizations, and Medicare and Medicaid plans mostly located in the cities of Chicago, Kansas City, and Phoenix and in the states of Kentucky, Florida, and Texas. The study sample included all members with 1 or more pharmacy claims for a topical corticosteroid and a diagnosis of AD (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] code 691.XX (excluding 691.0X), or 692.XX (excluding 692.0X-692.8X)] who subsequently had 1 or more pharmacy claims for pimecrolimus or tacrolimus. AD-related utilization and medical care costs (plan payments plus member cost share) over 12 months of follow-up were compared between the pimecrolimus and tacrolimus groups. Because information on disease severity was not available in the administrative claims data, propensity matching was used to control for differences between groups in baseline demographic and clinical characteristics and pretreatment utilization of AD-related medical care services.. Before matching, compared with the tacrolimus group (n = 197), members in the pimecrolimus group (n = 197) were older (mean age of 38 vs. 32 years, P = 0.022), had fewer topical corticosteroid pharmacy claims (mean 2.08 vs. 3.01, P = 0.002), and had fewer grams of corticosteroids dispensed (mean 132 vs. 193, P = 0.029) in the 12 months prior to treatment. After matching, there were 157 members in each group with no statistically significant differences in pretreatment characteristics. During the 12-month follow-up period, the mean (median) number of pharmacy claims was 1.8 (1.0) for pimecrolimus versus 2.0 (1.0) for tacrolimus and the mean (median) grams of study medication were 102 (60) and 105 (60), respectively. Members in the pimecrolimus group received a lower average number of prescriptions for any topical corticosteroids (1.37 vs. 2.04, P = 0.021) and for high-potency topical corticosteroids (0.61 vs. 1.04, P = 0.023) and were less likely to initiate alternative therapy (5% vs. 17%, P <0.001) or receive antistaphylococcal antibiotics (16% vs. 27%, P = 0.014). Members in the pimecrolimus group had lower average (median) AD-related expenditures (75% to 78% attributable to AD drug cost) compared with matched tacrolimus members ($263 [$270] vs. $361 [$398], P = 0.012).. In health plan members with AD who had previously received at least 1 topical corticosteroid prescription, the customary use of pimecrolimus or tacrolimus was 1 to 2 prescriptions in 12 months of followup and only a median of 60 grams of topical medication. The difference in AD-related utilization and costs between pimecrolimus and tacrolimus was small, less than $100 per year, but favored pimecrolimus. Further research using validated measures of disease severity to control for potential confounding is needed to confirm the results of this observational study.

Topics: Administration, Topical; Adolescent; Adrenal Cortex Hormones; Adult; Child; Child, Preschool; Dermatitis, Atopic; Female; Health Expenditures; Humans; Insurance Claim Review; Male; Managed Care Programs; Pharmaceutical Services; Tacrolimus; United States

Tacrolimus applied locally is a non-steroid anti-inflammatory drug with proven efficacy in atopic dermatitis. Skin infections can occur, especially viral infections.. A 35-year-old male patient had been treated for extensive atopic dermatitis for several months with tacrolimus (Protopic). After six months of treatment, he presented a large eruption of molluscum contagiosum, in particular on the zones that had received a substantial amount of tacrolimus. The treatment was discontinued and application of a preparation containing cidofovir led to the patient's quick complete recovery, without recurrence in the ensuing months.. Viral skin infections, in particular poxvirus infections, are prompted by topical immunosuppressant treatments such as tacrolimus, usually in dose-dependent fashion. Paradoxically, they provide protection against bacterial infections by restoring the integrity of the cutaneous barrier. Application of cidofovir successfully treated a severe form of molluscum contagiosum rapidly without any noticeable adverse effects. This confirms several observations about the efficacy and the good safety of this drug in the treatment of infections by DNA viruses. It provides an additional therapeutic prospect for immunodepressed patients who often present extensive and resistant forms of infections that are usually common.

Topics: Adult; Dermatitis, Atopic; Face; Humans; Immunosuppressive Agents; Male; Molluscum Contagiosum; Tacrolimus

A previous study had identified 45 items assessing the impact of atopic dermatitis (AD) on the whole family. From these it was intended to develop two separate scales, one assessing impact on carers and the other determining the effect on the child.. The 45 items were included in three clinical trials designed to test the efficacy of a new topical treatment (pimecrolimus, Elidel cream 1%) in the treatment of AD in infants and children and in validation studies in the UK, US, Germany, France and the Netherlands. Rasch analyses were undertaken to determine whether an internationally valid, unidimensional scale could be developed that would inform on the direct impact of AD on the child.. Rasch analyses applied to the data from the trials indicated that the draft measure consisted of two scales, one assessing the QoL of the carer and the other (consisting of 12 items) measuring the impact of AD on the child. Three of the 12 potential items failed to fit the measurement model in Europe and five in the US. In addition, four items exhibiting differential item functioning (DIF) by country were identified. After removing the misfitting items and controlling for DIF it was possible to derive a scale; The Childhood Impact of Atopic Dermatitis (CIAD) with good item fit for each trial analysis. Analysis of the validation data from each of the different countries confirmed that the CIAD had adequate internal consistency, reproducibility and construct validity. The CIAD demonstrated the benefits of treatment with Elidel over placebo in the European trial. A similar (non-significant) trend was found for the US trials.. The study represents a novel method of dealing with the problem of DIF associated with different cultures. Such problems are likely to arise in any multinational study involving patient-reported outcome measures, as items in the scales are likely to be valued differently in different cultures. However, where all items in a scale fit both a single theoretical construct and the Rasch measurement model, it is feasible to conceive of outcome measures with a different set of items in each language.

Topics: Child; Child, Preschool; Cross-Cultural Comparison; Dermatitis, Atopic; Europe; Humans; Infant; Models, Statistical; Psychometrics; Quality of Life; Randomized Controlled Trials as Topic; Reproducibility of Results; Severity of Illness Index; Tacrolimus; Treatment Outcome; United States

Kaposi's varicelliform eruption is the most important problem in treating patients with atopic dermatitis (AD) with tacrolimus ointment. It has been considered that Kaposi's varicelliform eruption occurs due to decreased levels of interleukin (IL)-18. The aim of this study was to examine the relationship between Kaposi's varicelliform eruption and genetic polymorphisms in the IL-18 gene. IL-18 gene promoter polymorphisms were analyzed in 21 AD patients treated with tacrolimus ointment and in 100 healthy volunteers. Six AD patients with Kaposi's varicelliform eruption during the treatment with tacrolimus ointment showed significantly higher frequency in G-to-C mutations at the IL-18 gene promoter region -137 compared with 15 AD patients without Kaposi's varicelliform eruption. The 15 AD patients without Kaposi's varicelliform eruption as well as 100 healthy volunteers did not have mutations of G-to-C at the IL-18 gene promoter region -137. These results suggest that the onset of Kaposi's varicelliform eruption following the treatment with tacrolimus ointment is associated with the mutation of G-to-C in the IL-18 gene promoter region -137, and that caution is required when using tacrolimus ointment for treating AD patients with this mutation.

Topics: Adult; Dermatitis, Atopic; DNA Mutational Analysis; Female; Genetic Markers; Humans; Immunoglobulin E; Immunosuppressive Agents; Interleukin-18; Japan; Kaposi Varicelliform Eruption; Male; Point Mutation; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Risk Factors; Simplexvirus; Statistics, Nonparametric; Tacrolimus

Atopic dermatitis is the most common chronic inflammatory skin disease of childhood and is increasing in prevalence throughout the world. Morbidity and resource use for atopic dermatitis are comparable to other chronic diseases. Topical corticosteroids are first-line therapeutic agents for atopic dermatitis; topical calcineurin inhibitors are considered second-line agents for patients who are older than 2 years. The aims of this study were to examine trends in visits for atopic dermatitis in children in the United States between 1997 and 2004, identify factors that were associated with a pediatric visit for atopic dermatitis, and assess changes in the treatment of atopic dermatitis over time.. Visits for atopic dermatitis by children (0-18 years) to office-based physicians and hospital outpatient departments using 1997-2004 National Ambulatory Medical Care Survey and National Hospital Ambulatory Care Survey databases were analyzed. Medication prescribing rates during 2 time periods (1997-2000 and 2001-2004) were also analyzed.. There were an estimated 7.4 million visits for atopic dermatitis. Statistically significant differences in patients with atopic dermatitis included age 2 to 5 years, black race, Asian race, and specialist or hospital outpatient clinic evaluation. The increase in atopic dermatitis visits per year was statistically significant. No statistical differences in prescribing rates were identified between the 2 time periods. Between 1997 and 2000, topical corticosteroids were prescribed in 34% of visits, decreasing to 25% between 2001 and 2004. Between 2001 and 2004, topical calcineurin inhibitors were prescribed in 23% of visits. In the same period, topical corticosteroids were prescribed in 24% of visits by children who were younger than 2 years; topical calcineurin inhibitors were prescribed in 22% of visits.. Visits for atopic dermatitis in children are increasing. A recommended first-line treatment was prescribed in a minority of the visits.

Topics: Administration, Topical; Adolescent; Adrenal Cortex Hormones; Age Distribution; Calcineurin Inhibitors; Child; Child, Preschool; Cross-Sectional Studies; Databases as Topic; Dermatitis, Atopic; Drug Utilization; Female; Health Care Surveys; Histamine H1 Antagonists; Humans; Immunosuppressive Agents; Infant; Infant, Newborn; Male; Medicine; Office Visits; Outpatient Clinics, Hospital; Racial Groups; Retrospective Studies; Sex Distribution; Specialization; Tacrolimus; United States

Pimecrolimus cream 1% has proven to be well-tolerated and effective in controlled clinical studies in patients with atopic dermatitis (AD). In a 15-week patient self-observation study, safety and efficacy was investigated in the daily practice.. 3502 patients with AD (mean age 26.2 +/- 18 years, 62% female) received pimecrolimus cream 1% from 810 physicians in the German Federal Republic. The severity of the disease was assessed at baseline, two times during the 15-week observation period and at the end of treatment. Patients recorded daily the degree of erythema and pruritus. At the end of treatment, safety and efficacy were assessed by the physician based on patient's daily records and by the patient.. The percentage of patients with severe or massive AD decreased from 25% to 7%, whereas the percentage of patients without or with mild symptoms increased from 9% to 55%.The efficacy of treatment was rated by physicians as good or very good in 83.5% of cases and by 79% of patients. At baseline 35% of the patients were free of flares as compared to 75% at the end of therapy. Disease control was better in patients who followed the recommended treatment algorithm for pimecrolimus cream. Tolerability was mostly rated as good or very good.. Treatment with pimecrolimus cream 1% for patients with AD is well-tolerated and effective in daily practice.

Topics: Adult; Dermatitis, Atopic; Dermatologic Agents; Drug Administration Schedule; Female; Germany; Humans; Male; Self-Examination; Tacrolimus; Treatment Outcome

Topics: Administration, Topical; Adolescent; Adult; Animals; Asthma; Bronchial Hyperreactivity; Dermatitis, Atopic; Follow-Up Studies; Humans; Immunosuppressive Agents; Middle Aged; Prospective Studies; Tacrolimus

Topics: Adult; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Male; Ointments; Recurrence; Schizophrenia; Schizophrenic Psychology; Tacrolimus

(1) In clinical trials of topical tacrolimus (an immunosuppressant), transient skin irritation, usually at the site of application, occurred in about 0.5% to 1.3% of adult patients who had also ingested ethyl alcohol. This adverse effect has also been observed with topical pimecrolimus, a related drug. (2) Three paediatric cases have also been published. The alcohol they ingested was one of the excipients of an oral drug. (3) If skin irritation occurs at the application site for topical tacrolimus, the role of ethyl alcohol, which may have been used as an excipient for a co-administered oral drug, should be borne in mind.

Topics: Adult; Child; Dermatitis, Atopic; Ethanol; Exanthema; Humans; Immunosuppressive Agents; Skin Diseases; Tacrolimus

Topics: Administration, Topical; Calcineurin Inhibitors; Dermatitis, Atopic; Dermatologic Agents; Humans; Immunosuppressive Agents; Ointments; Practice Guidelines as Topic; Tacrolimus

To report on quality of life (QoL) and health-related quality of life (HRQL) impacts of pimecrolimus (Elidel, Novartis A.G., Basel, Switzerland, SDZ ASM 981) 1% cream in the long-term treatment of paediatric atopic dermatitis.. QoL and HRQL data are presented from two 12-month international clinical trials evaluating the efficacy and safety of pimecrolimus 1% cream. Both trials were randomized and double blinded and compared two treatment strategies, one involving the use of emollients, pimecrolimus and topical corticosteroids, the other is 'usual care' (emollients plus topical corticosteroids) with a vehicle cream to maintain study blinding. The first trial (the infant trial) involved patients between ages 3 months and 2 years, whereas the children trial included patients aged 2-17 years. In both trials, QoL of the affected child's parent was evaluated with the parent's index of quality of life in atopic dermatitis (PIQoL-AD). HRQL was assessed in the children trial only with the children's dermatology life quality index (CDLQI). QoL and HRQL assessments were conducted at baseline, 6 weeks, 6 months and 12 months.. Generalized linear modelling of PIQoL-AD scores at each post-baseline visit showed a greater impact on parent's QoL for pimecrolimus compared with control at all time-points in both trials. HRQL scores showed a greater improvement from baseline for children in the pimecrolimus group compared with those in the control group at all time-points.. The results show a beneficial impact of pimecrolimus on parents' QoL in paediatric atopic dermatitis, confirming findings from earlier shorter term trials. There was also a clear benefit to the HRQL of the children treated.

Topics: Administration, Cutaneous; Adolescent; Adult; Calcineurin Inhibitors; Child; Child Welfare; Child, Preschool; Dermatitis, Atopic; Dermatologic Agents; Female; Humans; Infant; Male; Peptidylprolyl Isomerase; Quality of Life; Randomized Controlled Trials as Topic; Severity of Illness Index; Surveys and Questionnaires; Tacrolimus; Treatment Outcome

Topics: Administration, Topical; Dermatitis, Atopic; Drug Combinations; Female; Gelatin; Glycerol; Humans; Immunosuppressive Agents; Middle Aged; Occlusive Dressings; Ointments; Tacrolimus; Zinc Compounds

Topics: Animals; Dermatitis, Atopic; Dexamethasone; Disease Models, Animal; Drug Evaluation; Haptens; Humans; Mice; Pruritus; Tacrolimus

Atopic dermatitis (AD) has the potential to cause a long-term economic impact on patients, their families, and the healthcare system.. To determine if 1% pimecrolimus cream is cost-effective in treating mild-to-moderate AD in patients 2-17 years of age.. Data on the efficacy of AD management with 1% pimecrolimus cream (Elidel, Novartis Pharma GmbH, Wehr, Germany) were obtained from a 12-month, randomized, double-blind, multinational, controlled clinical trial comparing pimecrolimus and conventional therapy. Markov modeling was used for the economic model, based on: (i) Investigator's Global Assessment scores assessed at each visit during the clinical trial; (ii) estimated costs for medication and physician visits for each level of disease severity; and (iii) utility values for each level of disease severity. The perspective was that of a third-party payer.. In 2004 US dollars, the incremental cost-effectiveness of 1% pimecrolimus cream was 38,231 US dollars per quality-adjusted life year (QALY) gained compared with conventional therapy. Sensitivity analyses showed a range of 27,299 US dollarsto 63,457 US dollars per QALY gained.. With an incremental cost-effectiveness ratio of <50,000 US dollars per QALY gained, 1% pimecrolimus cream offers a cost-effective therapeutic option in the management of AD.

Topics: Administration, Topical; Adolescent; Child; Child, Preschool; Cost-Benefit Analysis; Dermatitis, Atopic; Dermatologic Agents; Double-Blind Method; Female; Humans; Male; Quality-Adjusted Life Years; Randomized Controlled Trials as Topic; Tacrolimus

Keratinocyte apoptosis mediated by Fas/Fas ligand molecular interactions and subsequent caspase activation is believed to play an important role in the pathogenesis of atopic dermatitis (AD), in particular for the formation of spongiosis. To estimate epidermal caspase activation in normal and AD skin under in vivo conditions, we analysed caspase-3 cleavage by immunohistology. In normal skin as well as non-lesional AD skin, we detected caspase-3 cleavage in single cells of the basal layer. In contrast, in acute lesional AD skin, we not only obtained evidence for increased expression of cleaved caspase-3 in keratinocytes of the basal layer but also observed caspase-3 cleavage in one or more layers of the spinous cell layer, in particular in spongiotic areas. Short-term topical treatment of the skin lesions with tacrolimus or pimecrolimus abolished the expression of cleaved caspase-3 in the spinous layer. Moreover, epidermal caspase-3 cleavage correlated with the numbers of dermal interferon-gamma (IFN-gamma)-expressing CD4+ and CD8+ lymphocytes in skin lesions of AD patients, supporting the view that IFN-gamma is important for the activation of proapoptotic pathways in keratinocytes. This is also confirmed by the observation of increased Fas expression on keratinocytes in acute AD lesions that was markedly reduced following topical calcineurin inhibitor treatment. These data suggest that caspase-3 cleavage in the spinous layer of the epidermis is a pathologic event contributing to spongiosis formation in AD, whereas cleavage of caspase-3 in basal cells might represent a physiologic mechanism within the process of epidermal renewal.

Topics: Adolescent; Adult; Apoptosis; Caspase 3; Caspases; Dermatitis, Atopic; Dermatologic Agents; fas Receptor; Female; Humans; Immunosuppressive Agents; Interferon-gamma; Keratinocytes; Lymphocytes; Male; Middle Aged; Skin; Tacrolimus

Topics: Adrenal Cortex Hormones; Dendritic Cells; Dermatitis, Atopic; Dermatologic Agents; Humans; Tacrolimus

Topics: Administration, Cutaneous; Calcineurin Inhibitors; Dermatitis, Atopic; Dermatologic Agents; Drug Approval; Humans; Tacrolimus; United States

Conventional treatments for atopic eczema include topical corticosteroids (TCS) and emollients. Pimecrolimus, an immunosuppressant, was licensed in the U.K. in 2003 as an alternative treatment of mild to moderate atopic eczema.. To assess the cost-utility of pimecrolimus as a treatment for mild and moderate atopic eczema when compared with conventional treatments which use TCS and emollients.. A Markov state-transition model was developed to represent the cyclical nature of atopic eczema and provide an economic analysis of cost-utility for treatment alternatives from the perspective of a third party payer (U.K. National Health Service). A range of methods was used to obtain data for transition probabilities, costs and quality of life. These included a systematic review of published effectiveness data, expert opinion, and a utility study conducted by the authors. Separate cohort analyses were modelled to distinguish between children and adult populations and between differing treatment patterns for facial and body eczema. One-way sensitivity analyses and probabilistic sensitivity analysis (using Monte-Carlo simulation) were performed.. Baseline cost-utility outputs from the model show that, in all tested scenarios, TCS dominate pimecrolimus (i.e. TCS are both cheaper and more effective). However, the differences in benefits between treatments output by the model are very small. Sensitivity analyses highlight the importance of cost variations in pimecrolimus. Where pimecrolimus is compared with emollient only it is probably cost effective at a willingness-to-pay threshold of 30 000 UK pounds per quality-adjusted life year.. There are likely to be few situations in which the use of pimecrolimus for the treatment of atopic eczema can be justified on economic grounds. Exceptions are likely to be in cases where TCS have been shown to be ineffective, unacceptable due to adverse events, or where a patient is unwilling to accept TCS treatment despite appropriate education and support and emollient alone is the alternative clinical option.

Topics: Adult; Child; Costs and Cost Analysis; Dermatitis, Atopic; Drug Costs; Drug Therapy, Combination; Emollients; England; Glucocorticoids; Humans; Immunosuppressive Agents; Markov Chains; Quality of Life; Sensitivity and Specificity; Severity of Illness Index; Tacrolimus; Treatment Failure; Treatment Outcome

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Aged; Dermatitis, Atopic; Dermatologic Agents; Female; Herpes Simplex; Humans; Immunocompromised Host; Immunosuppressive Agents; Male; Middle Aged; Opportunistic Infections; Retrospective Studies; Tacrolimus

Atopic dermatitis (AD), a significant problem in Japan, has a major impact on health-related quality of life (QOL). The development of steroid phobia in patients with AD may restrict the therapeutic options available to these patients. Tacrolimus ointment is a safe and effective nonsteroid treatment for AD. It may be an appropriate alternative for patients with AD and steroid phobia. The aim of this study was to determine the impact of AD on QOL and to investigate the effect of tacrolimus ointment on QOL in patients with steroid phobia.. Firstly, QOL scores were investigated in patients with AD and steroid phobia using the World Health Organization Quality of Life instrument, WHOQOL-26, and were compared with QOL scores from a previous study in volunteers from Tokyo, Japan. Secondly, patients with steroid phobia received tacrolimus ointment treatment for 12 weeks. Quality of life scores were assessed using WHOQOL-26 at baseline and study end.. The overall mean QOL score of 106 patients with AD was significantly lower than that of 708 volunteers (3.1 +/- 0.5 vs. 3.3 +/- 0.5, P < 0.001). The overall QOL score improved from 2.9 +/- 0.4 at baseline to 3.3 +/- 0.4 following 12 weeks' tacrolimus ointment treatment in 35 patients with AD and steroid phobia (P < 0.001).. Atopic dermatitis significantly lowers QOL. Tacrolimus ointment is associated with a significant improvement in QOL in patients with steroid phobia, indicating that it is an effective alternative to topical corticosteroids in these patients.

Topics: Attitude to Health; Dermatitis, Atopic; Health Status; Humans; Immunosuppressive Agents; Ointments; Quality of Life; Safety; Social Behavior; Surveys and Questionnaires; Tacrolimus; Tokyo; World Health Organization

Atopic eczema is one of the most common diseases in dermatology. Patients suffer from both the chronic relapsing skin disease and the associated emotional stress. Itching and visible lesions on the face and hands are the most unpleasant features for many often young patients, seriously reducing their quality of life. New therapeutic approaches have changed the management of atopic eczema in recent years. Relatively potent new drugs with fewer side effects than corticosteroids help to control the disease. This review focuses on the basic principles of modern atopic eczema treatment, emphasizing basic emollient therapy and topical therapy with calcineurin inhibitors.

Topics: Adolescent; Adult; Anti-Inflammatory Agents; Calcineurin Inhibitors; Child; Combined Modality Therapy; Dermatitis, Atopic; Dose-Response Relationship, Drug; Emollients; Humans; Immunoglobulin E; Immunosuppressive Agents; Infant; Pruritus; Quality of Life; Tacrolimus; Urea

Topics: Administration, Topical; Animals; Calcineurin Inhibitors; Dermatitis, Atopic; Dermatologic Agents; Enzyme Inhibitors; Humans; Immunosuppressive Agents; Tacrolimus

Topics: Administration, Topical; Calcineurin Inhibitors; Dermatitis, Atopic; Dermatologic Agents; Enzyme Inhibitors; Humans; Immunosuppressive Agents; Tacrolimus

JTE-907, N-(benzo[1,3]dioxol-5-ylmethyl)-7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxamide, is a selective cannabinoid CB2 receptor antagonist/inverse agonist. The anti-pruritic activity of JTE-907 was studied in NC mice with chronic dermatitis, a model of atopic dermatitis. The oral dose of JTE-907 (1 and 10 mg/kg/day), an immunosuppressant agent tacrolimus (1 mg/kg/day) and a glucocorticoid betamethasone 17-valerate (1 mg/kg/day) for 20 days suppressed the spontaneous scratching and cutaneous nerve activity of NC mice. JTE-907 (10, but not 1, mg/kg) and tacrolimus, but not betamethasone, tended to alleviate the dermatitis. Betamethasone inhibited the body weight gain. These results suggest that JTE-907 suppresses spontaneous itch-associated responses of NC mice without adverse effects such as weight loss.

Topics: Administration, Oral; Animals; Behavior, Animal; Betamethasone Valerate; Body Weight; Dermatitis, Atopic; Dioxoles; Disease Models, Animal; Dose-Response Relationship, Drug; Glucocorticoids; Immunosuppressive Agents; Male; Mice; Mice, Inbred Strains; Pruritus; Quinolones; Receptor, Cannabinoid, CB2; Severity of Illness Index; Skin; Tacrolimus

To investigate the role of Toll-like receptor(TLR) 2 and TLR4 in pathogenesis of atopic dermatitis(AD) and the effect of topical tacrolimus ointment on expression of TLR2 and TLR4 in lesional AD skin.. Immunohistochemistry was employed to study the expression of TLR2 and TLR4 in normal skin and lesional AD skin before and after using topical tacrolimus ointment.. The basal keratinocytes in normal skin constitutively expressed TLR2 and TLR4. In contrast, lesional epidermis from 9 patients with acute AD overexpressed TLR2 and TLR4 on the whole epidermis keratinocytes with membranous and cytoplasmic staining pattern. After using topical tacrolimus ointment for three weeks, TLR2 and TLR4 were expressed on basal and suprabasal keratinocytes with membranous and cytoplasmic staining pattern.. These data suggest that TLR2 and TLR4 expressed by epidermal keratinocytes constitute part of the innate immune system of the skin, and increased TLR2 and TLR4 expression may be related to the skin innate immuno-inflammatory response in atopic dermatitis. Topical tacrolimus may directly or indirectly inhibit or down-regulate TLR2 and TLR4 expression in KC and inhibit skin innate immuno-inflammatory response related to TLR-NFkappaB signal transduction and regulation in atopic dermatitis.

Topics: Administration, Cutaneous; Adolescent; Adult; Child; Child, Preschool; Dermatitis, Atopic; Female; Humans; Immunohistochemistry; Immunosuppressive Agents; Keratinocytes; Male; Middle Aged; Ointments; Tacrolimus; Toll-Like Receptor 2; Toll-Like Receptor 4

Itching is the most important problem in many allergic and inflammatory skin diseases especially in atopic dermatitis. However, animal models for allergic dermatitis useful for the study of itching have rarely been established. We established a mouse allergic dermatitis model involving frequent scratching behavior by repeated painting with 2,4-dinitrofluorobenzene (DNFB) acetone solution onto the mouse skin, and comparatively examined the effects of tacrolimus and dexamethasone on the dermatitis and associated scratching behavior. Repeated DNFB painting caused typical dermatitis accompanied by elevated serum immunoglobulin E (IgE) and frequent scratching behavior. An apparent thickening of the epidermis and dermis, and the significant accumulation of inflammatory cells were observed. Increased interferon (IFN)-gamma mRNA expression and the induction of interleukin (IL)-4 and IL-5 mRNA expression were also observed in the skin lesion. The scratching behavior was inhibited by dibucaine and naloxone. Although tacrolimus reduced the increased expression of IFN-gamma and IL-4 mRNA, dexamethasone potently depressed that of IFN-gamma, IL-4 and IL-5 mRNA. Dexamethasone inhibited the accumulation of lymphocytes and eosinophils, although tacrolimus did not. Both drugs failed to inhibit the elevation of serum IgE levels. Tacrolimus significantly inhibited the scratching behavior that was associated with the inhibition of nerve fiber extension into the epidermis, whereas dexamethasone failed to have any effect. The mouse dermatitis model seems to be beneficial for the study of itching associated with allergic dermatitis, such as atopic dermatitis, and tacrolimus seems to exhibit an anti-itch effect through the inhibition of nerve fiber extension at least in part.

Topics: Allergens; Anesthetics, Local; Animals; Antipruritics; Behavior, Animal; Dermatitis, Allergic Contact; Dermatitis, Atopic; Dexamethasone; Dibucaine; Dinitrofluorobenzene; Disease Models, Animal; Glucocorticoids; Immunoglobulin E; Interferon-gamma; Interleukin-4; Interleukin-5; Male; Mice; Mice, Inbred BALB C; Naloxone; Narcotic Antagonists; Pruritus; RNA, Messenger; Skin; Tacrolimus

Staphylococcus aureus-producing superantigens (SAgs), such as staphylococcal enterotoxin B (SEB) or toxic shock syndrome toxin-1 (TSST-1), are frequently observed in atopic dermatitis (AD). However, little has been done to establish the association of immune responses to SAgs and the therapeutic response to immunosuppressive drugs in AD. Therefore, we investigated the prevalence and role of SAgs in the pathophysiology and immunosuppressive drug sensitivity in AD patients.. We classified 29 patients into two groups on the basis of their clinical AD scores: a low-score group (n = 14) corresponding to mild to moderate patients and a high-score group (n = 15) corresponding to severe patients. We estimated the plasma anti-SEB or TSST-1 IgE of these patients and healthy subjects by ELISA. We also estimated individual drug sensitivity by determining drug concentrations that would give 50% inhibition (IC(50)) of peripheral-blood mononuclear cell (PBMC) proliferation in vitro.. The levels of plasma anti-SEB or TSST-1 IgE in the severe patients were significantly higher than those in the mild to moderate patients (p < 0.05 and p < 0.01, respectively). When stimulated with concanavalin A in vitro, PBMCs in the severe patients exhibited low sensitivity to the suppressive efficacy of tacrolimus (FK506) as compared to the mild to moderate patients (p < 0.01). Furthermore, there was a significant correlation between the IC(50)s of FK506 and plasma anti-TSST-1 IgE levels (p < 0.01).. We showed that PBMCs in severe AD patients exhibited lower sensitivity to FK506, and had higher plasma levels of anti-TSST-1 IgE as compared to the mild AD patients. SAgs appear to be one of the causes of decreased PBMC sensitivity to FK506, and therefore an alternative treatment would be useful based on the individual drug sensitivity data and anti-TSST-1 IgE levels.

Topics: Adult; Bacterial Toxins; Cells, Cultured; Dermatitis, Atopic; Drug Resistance; Enterotoxins; Female; Humans; Immunoglobulin E; Immunosuppressive Agents; Leukocytes, Mononuclear; Male; Severity of Illness Index; Staphylococcus aureus; Superantigens; Tacrolimus; Up-Regulation

Topics: Administration, Cutaneous; Calcineurin Inhibitors; Dermatitis, Atopic; Drug Approval; Drug Labeling; Humans; Immunosuppressive Agents; Tacrolimus; United States; United States Food and Drug Administration

Atopic dermatitis (AD) is a recurrent inflammatory skin disease characterized by high serum levels of IgE and Th2-type cytokines such as IL-4, IL-5 or IL-13. Chemokines attract leukocytes in inflamed tissues. We have previously found that thymus and activation regulated chemokine (TARC)/CCL17 and macrophage-derived chemokine (MDC)/CCL22 are highly secreted in the plasma levels of AD patients. Dendritic cells (DCs) are antigen-presenting cells that are divided into two subgroups including monocyte derived DCs (MoDCs) and plasmacytoid DCs (pDCs).. The aim of the study was to elucidate CCL17 and CCL22 production by MoDCs in AD patients, psoriasis vulgaris (PsV) patients and healthy controls (HC).. MoDCs were obtained from AD patients, PsV patients or HC and were cultured. In addition, the chemokine levels were measured in the supernatants.. We found that the CCL22 levels produced by MoDCs in AD patients to be significantly higher than those of PsV patients and HC. There was a significant correlation between the CCL22 levels produced by MoDCs and the SCORAD index. No significant difference in the CCL17 levels produced by MoDCs was detected among AD patients, PsV patients or HC. Immunosuppressive drugs such as dexamethasone (Dex), tacrolimus and cyclosporine (Cys) inhibited the CCL22 production by MoDCs in the AD patients.. These data suggest that the CCL22 level produced by MoDCs thus reflects the disease activity of AD and it may also play an important role regarding the production of CCL22 in the pathogenesis of AD.

Topics: Adolescent; Adult; Anti-Inflammatory Agents; Chemokine CCL17; Chemokine CCL22; Chemokines, CC; Cyclosporine; Dendritic Cells; Dermatitis, Atopic; Dermatologic Agents; Dexamethasone; Female; Gene Expression Regulation; Humans; Immunosuppressive Agents; Interleukin-12; Interleukin-18; Male; Middle Aged; Monocytes; Psoriasis; Severity of Illness Index; Tacrolimus

Three children with severe atopic dermatitis were noted at routine follow-up to have developed multiple small pigmented macules during long-term therapy with topical tacrolimus 0.1% (Protopic, Fujisawa). Representative lesions in two of the three cases were confirmed histologically as simple lentigines. The focal distribution of lentigines to sites of tacrolimus use, and the temporal association between use of tacrolimus and development of lesions, suggest that topical tacrolimus is of direct aetiological relevance to their development. Careful long-term follow-up will be required to assess the clinical implications of these findings and whether they represent an increase in risk for melanocytic neoplasia.

Topics: Administration, Cutaneous; Child; Child, Preschool; Dermatitis, Atopic; Drug Eruptions; Female; Humans; Immunosuppressive Agents; Lentigo; Male; Tacrolimus

Topics: Adult; Aged; Anal Canal; Calcineurin Inhibitors; Dermatitis, Atopic; Dermatologic Agents; Female; Humans; Male; Middle Aged; Tacrolimus

Topics: Administration, Topical; Adult; Child; Dermatitis, Atopic; Dermatologic Agents; Humans; Patient Compliance; Tacrolimus; Treatment Outcome

Topics: Dermatitis, Atopic; Drug Eruptions; Ethanol; Humans; Immunosuppressive Agents; Infant; Male; Ointments; Pharmaceutical Vehicles; Tacrolimus

Pimecrolimus (SDZ ASM 981), an ascomycin derivative, as one of the new classes of immunomodulating macrolactams, is specifically effective in the treatment of inflammatory skin diseases. The interest in pimecrolimus is highly important for its significant anti-inflammatory activity, cell-selective inhibition of inflammatory cytokines, immunomodulatory capabilities, and low systemic immunosuppressive potential. The mechanism of action of pimecrolimus is the blockage of T cell activation, blocking signal transduction pathways in T cells, and inhibition of the synthesis of inflammatory cytokines, specifically Th1- and Th2-type cytokines. Several studies have evaluated the effectiveness of pimecrolimus as the treatment of choice for inflammatory skin diseases.

Topics: Chronic Disease; Dermatitis, Atopic; Eczema; Immunologic Factors; Immunosuppressive Agents; Inflammation; Psoriasis; Skin Diseases; Tacrolimus

Topics: Adolescent; Adult; Dermatitis, Atopic; Female; Humans; Hyperpigmentation; Immunosuppressive Agents; Male; Neck; Ointments; Tacrolimus

Topics: Adult; Animals; Child; Child, Preschool; Dermatitis, Atopic; Dermatologic Agents; Eczema; Humans; Immunosuppressive Agents; Lymphoma; Skin Neoplasms; Tacrolimus

Topics: Animals; Child; Dermatitis, Atopic; Dermatologic Agents; Eczema; Haplorhini; Humans; Leukemia; Lymphoma; Mice; Skin Neoplasms; Tacrolimus

Topics: Administration, Oral; Administration, Topical; Adrenal Cortex Hormones; Dermatitis, Atopic; Family Practice; Female; Humans; Immunosuppressive Agents; Male; Prognosis; Risk Assessment; Sensitivity and Specificity; Tacrolimus; Treatment Outcome

Topics: Dermatitis, Atopic; Dermatologic Agents; Dermatology; Germany; Humans; Immunosuppressive Agents; Ointments; Societies, Medical; Tacrolimus; United States; United States Food and Drug Administration

Topics: Calcineurin Inhibitors; Child; Dermatitis, Atopic; Dermatologic Agents; Humans; Tacrolimus; United States; United States Food and Drug Administration

In several clinical trials the topical application of pimecrolimus was shown to be effective in the treatment of atopic dermatitis (AD). By targeting calcineurin-dependent signaling pathways, pimecrolimus controls cytokine gene expression. The purpose of this study was to investigate the effect of pimecrolimus on the inflammatory infiltrate and cytokine expression pattern in AD upon topical therapy.. From 10 patients with acute AD, skin biopsies as well as immunophenotype and cytokine production of peripheral blood mononuclear cells (PBMC) were examined before and 3 weeks after therapy.. The clinical improvement was associated with a marked regression of histopathological features. In particular, the density of the inflammatory infiltrate mostly containing lymphocytes and eosinophils declined. By double immunofluorescent staining, a reduced expression of the T helper (Th) 2 cytokines interleukin (IL)-5, IL-10, and IL-13 in both CD4+ and CD8+ T cells was demonstrated after therapy. Pimecrolimus therapy was also associated with a reduced expression of the Th1 cytokine interferon (IFN)-gamma. Interestingly, the numbers of epidermal CD1a+ dendritic cells increased following treatment. In the peripheral blood, a decrease of lymphocytes and eosinophils was noticed, but the distribution of lymphocyte subpopulations and their capacity of cytokine production did not change.. Topical pimecrolimus exhibits anti-inflammatory effects in AD by reducing the inflammatory cell infiltrate and cytokine expression in the dermis.

Topics: Administration, Topical; Adolescent; Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; Cell Count; Cytokines; Dermatitis, Atopic; Female; Humans; Leukocytes, Mononuclear; Male; Middle Aged; Tacrolimus

Topics: Administration, Topical; Adolescent; Adult; Age Factors; Animals; Calcineurin Inhibitors; Child; Dermatitis, Atopic; Dose-Response Relationship, Drug; Humans; Immunosuppressive Agents; Lymphoma; Mice; Neoplasms; Neoplasms, Experimental; Product Surveillance, Postmarketing; Tacrolimus

There is a lack of studies on the effect of tacrolimus on eosinophils and related molecules including eotaxin, CCR3, RANTES and interleukin (IL)-5.. To investigate the effects of tacrolimus on in vivo eosinophil counts and on the related molecules eotaxin, CCR3, RANTES and IL-5 in patients with atopic dermatitis (AD).. Lesional skin specimens and sera were obtained from 15 patients with AD and from 15 normal controls. For 8 weeks, the patients with AD applied 0.03% tacrolimus ointment to all affected areas twice daily. Blood sampling and skin biopsies were then repeated. We evaluated serum eotaxin and IL-5 levels, and tissue eotaxin, CCR3, RANTES and IL-5 levels. Additionally, tissue levels of eotaxin and CCR3 mRNA were measured.. After treatment with topical tacrolimus twice daily for 8 weeks, significant decreases were found in serum IL-5 levels, immunoreactive cell counts of eotaxin, IL-5, CCR3 and RANTES in AD skin, and tissue eosinophil counts. However, the change in the serum eosinophil count was not statistically significant, and mRNA levels of eotaxin and CCR3 were not decreased significantly after treatment.. Topical tacrolimus reduces the number of eosinophils in tissue and suppresses the expression of eotaxin, CCR3, RANTES and IL-5 related to proliferation, recruitment, activation and survival of eosinophils.

Topics: Adolescent; Adult; Biomarkers; Case-Control Studies; Chemokine CCL11; Chemokine CCL5; Chemokines, CC; Child; Child, Preschool; Dermatitis, Atopic; Eosinophilia; Female; Humans; Immunohistochemistry; Immunosuppressive Agents; Interleukin-5; Korea; Leukocyte Count; Male; Ointments; Receptors, CCR3; Receptors, Chemokine; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Skin; Tacrolimus

Topics: Administration, Topical; Adult; Androstadienes; Calcineurin Inhibitors; Child; Child, Preschool; Clinical Trials as Topic; Critical Pathways; Cross-Sectional Studies; Dermatitis, Atopic; Early Diagnosis; Fluticasone; Follow-Up Studies; Glucocorticoids; Humans; Immunosuppressive Agents; Incidence; Infant; Long-Term Care; Recurrence; Tacrolimus; Treatment Outcome

Tacrolimus ointment is approved for the treatment of moderate to severe atopic dermatitis (AD). We sought to evaluate the efficacy and safety of tacrolimus ointment 0.03% compared with vehicle in the treatment of patients with mild to moderate AD.. Two identically designed, independent, randomized, double-blind, 6-week studies--one pediatric and one adult--in patients with mild to moderate AD were conducted. Combined data from 617 patients were used in the analysis. The primary efficacy end point was percentage of patients with treatment success (defined as "clear" or "almost clear" on the Investigator's Global AD Assessment) at end of study.. As early as day 4, treatment success occurred in 17.7% of patients treated with tacrolimus compared with 9.8% of patients treated with vehicle ( P = .003), and by study end had increased to 49.7% for tacrolimus versus 29.0% for vehicle (P < .0001). Tacrolimus was associated with significantly less application site pruritus than vehicle (29.0% vs 37.5%; P = .03). There was no difference between tacrolimus and vehicle in the incidence of application site skin burning and stinging.. Tacrolimus ointment 0.03% is effective and safe for the management of mild to moderate AD in both adult and pediatric patients, and has a rapid onset of action.

Topics: Adolescent; Adult; Aged; Child; Child, Preschool; Dermatitis, Atopic; Female; Humans; Immunosuppressive Agents; Infant; Male; Middle Aged; Ointments; Randomized Controlled Trials as Topic; Tacrolimus; Treatment Outcome

We sought to evaluate the safety and efficacy of tacrolimus ointment in a large cohort of adult and pediatric patients with atopic dermatitis (AD).. A cohort of 3964 adult and 3959 pediatric patients with AD were enrolled in this open-label noncomparative study. Patients applied tacrolimus 0.03% or 0.1% ointment twice daily to the affected areas. Efficacy and safety assessments included percentage of body surface area affected and incidence of adverse events, respectively.. A total of 7923 patients were evaluated; 95.5% had severe or moderate AD at baseline. There was a 52% decrease from baseline in the mean percentage of body surface area affected at month 1 and a 91% decrease at month 18. Two of the most common adverse events, skin burning and pruritus, were generally mild, transient in nature, and decreased in prevalence as AD improved. Severity and frequency of other common adverse events were consistent with expected rates in the general population.. Tacrolimus ointment monotherapy in almost 8000 pediatric and adult patients led to continuous improvement in AD and revealed no change in the safety profile reported in previous clinical trials.

Topics: Adult; Child; Cohort Studies; Dermatitis, Atopic; Female; Humans; Immunosuppressive Agents; Male; Ointments; Tacrolimus; Treatment Outcome

We sought to determine the effect of treatment with topical tacrolimus on B- and T-cell immunity including the primary antibody response to pneumococcal polysaccharide vaccine in children with atopic dermatitis.. In this open-label, noncomparative study, 23 children aged 2 to 12 years with moderate to severe atopic dermatitis were treated with tacrolimus 0.03% ointment twice daily for 7 weeks, immunized with a 23-valent pneumococcal polysaccharide vaccine after 3 weeks of treatment, and had their antibody response measured (for 12 pneumococcal serotype antigens present in the vaccine) before and 4 weeks after vaccination. None had received pneumococcal vaccine before the study. Patient antibody and cellular immune responses were assessed at each study visit (baseline, week 3, and week 7).. No significant changes in complete blood cell count, lymphocyte subsets, CD4/CD8 ratio, immunoglobulin levels, antibody titers to tetanus and Haemophilus influenzae , or lymphoproliferative responses were noted during the tacrolimus ointment treatment period. Tacrolimus blood levels were 1 ng/mL or less in all 23 children. Protective pneumococcal titers to all 12 serotypes were observed in 2 of 23 (9%) children prevaccination and in 16 of 23 (70%) children postvaccination. All 6 children who had protective titers to 0 to 5 of the 12 serotypes developed protective titers to an additional 5 to 11 serotypes. Of the patients, 91% had a greater than 4-fold increase in titer for at least 4 of 12 pneumococcal serotypes.. Topical application of tacrolimus ointment does not affect the serologic response to pneumococcal vaccine or interfere with preexisting T- and B-cell immune responses.

Topics: Antibodies, Bacterial; Antibody Formation; Child; Child, Preschool; Dermatitis, Atopic; Female; Humans; Immunity, Cellular; Immunosuppressive Agents; Male; Pneumococcal Vaccines; Streptococcus pneumoniae; Tacrolimus; Vaccination

Roughly one third of children with atopic dermatitis (AD) have IgE-mediated food allergy. Most parents and pediatricians assume foods also cause the eczema, a focus that diverts proper skin therapy and has negative outcomes including nutritional deficiency, costly referrals, and unnecessary testing. This project investigates the relationship between food allergy and AD, both before and after treatment in an established AD population. During an open trial of topical tacrolimus we observed a decrease in parental food allergy concern during good control of their child's eczema. We tested this observation by follow-up interviews and a questionnaire study to compare parental estimates of food allergy concerns after therapy with concerns before beginning the trial. Study subjects were children 11 years old and younger with AD and suspicion of food allergy. AD and food allergy parameters, pre- and post-treatment, were retrospectively assessed by a questionnaire given to the parents.. Twenty-three patients were enrolled: 16 had positive food allergy tests (7 RAST and/or 10 skin prick tests) and 30% had a definite history of immediate IgE reactions to foods. Ninety-five percent of parents felt that food allergy exacerbated their child's AD. Treatment durations were 3 to 45 months. Parental concern of food allergy decreased significantly from 7.7 to 4.0 on a 10 point scale (P < .001). Additionally, estimated food reactions decreased by approximately 80% during 1- and 6-month periods (P = .001).. In this selected university-based childhood AD population, nearly all parents were convinced their child had food allergy and further that the food contributed to the AD. The level of concern about food reactions was significantly decreased and the number of food reactions declined during effective topical therapy. This preliminary assessment of parental perceptions suggests that successful, stable therapy of AD reduces perceived food reactions and allays parental concerns about food allergy. Such therapy may encourage parents to refocus on direct skin care as the primary effort in AD therapy. We conclude that the effect of successful AD treatment on food allergy and food allergy concern are of interest and worthy of further study.

Topics: Child; Child, Preschool; Dermatitis, Atopic; Female; Food Hypersensitivity; Humans; Immunosuppressive Agents; Male; Retrospective Studies; Tacrolimus

Topics: Administration, Topical; Calcineurin Inhibitors; Child; Child, Preschool; Clinical Trials as Topic; Dermatitis, Atopic; Drug-Related Side Effects and Adverse Reactions; Humans; Risk Assessment; Tacrolimus; United States; United States Food and Drug Administration

Topics: Dermatitis, Atopic; Dermatologic Agents; Humans; Immunosuppressive Agents; Neoplasms; Tacrolimus

Topics: Child; Dermatitis, Atopic; Dermatologic Agents; Humans; Immunosuppressive Agents; Tacrolimus

Since their approval, topical calcineurin inhibitors have proven to be effective medications in the treatment of atopic eczema. On March 10, 2005, the Food and Drug Administration (FDA) followed the advice of the Pediatric Advisory Council and issued a "black box warning" for the use of Protopic (Tacrolimus) und Elidel (Pimecrolimus). This FDA alert has caused worldwide uncertainty among parents and patients. Several dermatological societies have issued critical position statements. This report reviews the existing information underlying the warning and places it into the context of current knowledge.

Topics: Administration, Topical; Calcineurin Inhibitors; Child; Child, Preschool; Dermatitis, Atopic; Dermatologic Agents; Drug Labeling; Germany; Humans; Infant; Infant, Newborn; Informed Consent; Practice Guidelines as Topic; Practice Patterns, Physicians'; Tacrolimus; United States; United States Food and Drug Administration

It has been established recently that CD4+CD25+ regulatory T cells (Tregs) play an important role in controlling various immune responses. Immunosuppressive drugs are often used to treat immune dysregulation but are frequently associated with undesirable side-effects.. We examined the suppressive capacity of circulating Tregs in patients with atopic dermatitis (AD). Combined effects of Tregs and tacrolimus on the inhibition of T-cell proliferation in vitro were also assessed.. CD4+CD25+ and CD4+CD25- T cells were isolated from peripheral blood mononuclear cells using immunomagnetic beads. CD4+CD25- T cells were stimulated with purified protein derivative (PPD) or house dust mite allergen (Der p1) for 6 or 7 days, respectively. A dose range of tacrolimus and CD4+CD25+ T cells were added separately, or together. Proliferation was measured by (3)H-thymidine incorporation.. CD4+CD25+ T cells from normal controls and patients with AD are anergic and inhibit the proliferation of CD4+CD25- T cells in response to PPD and Der p1 in vitro in a dose-dependent manner. Addition of tacrolimus and Tregs together showed significantly stronger inhibition of proliferation than either on their own. This was true for both antigens and both in normal controls and in patients with AD.. CD4+CD25+ T cells in patients with AD have normal suppressive activity compared with healthy controls. Tregs and tacrolimus have additive effects on the inhibition of proliferation in response to PPD and Der p1.

Topics: Antigens, Dermatophagoides; Arthropod Proteins; Cell Proliferation; Cells, Cultured; Cysteine Endopeptidases; Dermatitis, Atopic; Humans; Immune Tolerance; Immunosuppressive Agents; Lymphocyte Activation; Receptors, Interleukin-2; T-Lymphocytes, Regulatory; Tacrolimus; Th1 Cells; Th2 Cells; Tuberculin

Topics: Administration, Cutaneous; Child; Dermatitis, Atopic; Female; Food Hypersensitivity; Humans; Immunosuppressive Agents; Tacrolimus

Topical treatment with tacrolimus may be complicated by ingestion-related flushing caused by consuming small amounts of alcohol, a reaction that can be mistaken for food allergy.. To increase awareness of a drug interaction with alcohol that can mimic food allergy.. We describe 3 patients who used topical tacrolimus, 2 with an atopic history and 1 without, who presented with a flushing reaction after ingesting alcohol.. Cessation of topical tacrolimus use resolves the alcohol-related skin reaction.. A careful history, including consideration of alcohol use, should be obtained in patients who use topical tacrolimus and present with new skin complaints, because these factors may be evidence of an avoidable drug interaction and not worsening of atopic disease or a food allergy.

Topics: Adult; Dermatitis, Atopic; Ethanol; Exanthema; Female; Food Hypersensitivity; Humans; Immunosuppressive Agents; Male; Tacrolimus

Nerve growth factor (NGF) is an important substance in the skin, where it can modulate nerve maintenance and repair. However, the direct link between NGF and pruritic disease such as atopic dermatitis is not yet fully understood. To determine whether NGF plays a major role in atopic dermatitis and in the development or maintenance of skin lesions, we performed a study using NC/Nga mice and compared mice with and without skin lesions. Our examinations of the NC/Nga mice sought to detect nerve fibers in the epidermis, measured serum and skin NGF content, and observed skin NGF by immunohistochemistry staining. We also examined the effects of anti-NGF antibody on dermatitis symptoms in NC/Nga mice. In these mice, nerve fibers were significantly increased in the epidermis of lesioned skin, and the NGF content of the serum and skin was significantly elevated. Anti-NGF antibodies significantly inhibited the development and proliferation of skin lesions and epidermal innervation and significantly inhibited any growth in scratching but did not ameliorate scratching already developed. Our findings suggest that NGF plays important roles in the pathogenesis of atopic dermatitis-like skin lesions and that inhibiting the physiological effects of NGF or suppressing increased NGF production may prevent or even moderate the symptoms of atopic dermatitis.

Topics: Animals; Antibodies; Dermatitis, Atopic; Disease Models, Animal; Immunohistochemistry; Male; Mice; Nerve Fibers; Nerve Growth Factor; Skin; Tacrolimus

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Algorithms; Calcineurin Inhibitors; Child; Child, Preschool; Controlled Clinical Trials as Topic; Dermatitis, Atopic; Dermatologic Agents; Double-Blind Method; Eczema; Humans; Immunosuppressive Agents; Infant; Ointments; Practice Guidelines as Topic; Tacrolimus; Time Factors

Topics: Administration, Topical; Adult; Dermatitis, Atopic; Humans; Immunocompromised Host; Immunosuppressive Agents; Kaposi Varicelliform Eruption; Male; Ointments; Tacrolimus

FK506 ointment (tacrolimus ointment, protopic) is a new drug therapeutically effective for patients with atopic dermatitis (AD). However, the mechanism of action of FK506 ointment on AD is not fully understood.. We examined the effect of FK506 ointment on mite antigen-induced dermatitis in NC/Nga mice. Clinical symptoms and ear thickness were recorded, and histopathological studies and in vitro analyses were performed.. Topical application of FK506 ointment (0.03-0.3%) suppressed the development of dermatitis. In the lesional skin, both interleukin (IL)-4 and interferon (IFN)-gamma were detected, even though the IL-4+/IFN-gamma- T helper 2 (Th2) population was predominant in the regional lymph nodes (LNs). Topical application of FK506 treatment reduced the elevated level of both IL-4 and IFN-gamma in the skin, but did not decrease the expansion of the Th2 population in the LNs.. Topical application of FK506 ointment suppresses dermatitis by inhibiting the activation of inflammatory cells locally, without systemic immune suppression, in this AD model.

Topics: Administration, Topical; Animals; Antigens, Dermatophagoides; CD4 Antigens; Dermatitis, Atopic; Disease Models, Animal; Female; Flow Cytometry; Immunohistochemistry; Immunosuppressive Agents; Intercellular Adhesion Molecule-1; Interferon-gamma; Interleukin-1; Interleukin-4; Lymph Nodes; Mice; Mice, Inbred Strains; Specific Pathogen-Free Organisms; Tacrolimus; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1

Topics: Adjuvants, Immunologic; Dermatitis, Atopic; Female; Humans; Immunosuppressive Agents; Infant; Tacrolimus; Treatment Outcome

Tacrolimus ointment is increasingly used for anti-inflammatory treatment of sensitive areas such as the face, and recent observations indicate that the treatment is effective in steroid-aggravated rosacea and perioral dermatitis. We report on rosaceiform dermatitis as a complication of treatment with tacrolimus ointment.. Six adult patients with inflammatory facial dermatoses were treated with tacrolimus ointment because of the ineffectiveness of standard treatments. Within 2 to 3 weeks of initially effective and well-tolerated treatment, 3 patients with a history of rosacea and 1 with a history of acne experienced sudden worsening with pustular rosaceiform lesions. Biopsy revealed an abundance of Demodex mites in 2 of these patients. In 1 patient with eyelid eczema, rosaceiform periocular dermatitis gradually appeared after 3 weeks of treatment. In 1 patient with atopic dermatitis, telangiectatic and papular rosacea insidiously appeared after 5 months of treatment.. Our observations suggest that the spectrum of rosaceiform dermatitis as a complication of treatment with tacrolimus ointment is heterogeneous. A variety of factors, such as vasoactive properties of tacrolimus, proliferation of Demodex due to local immunosuppression, and the occlusive properties of the ointment, may be involved in the observed phenomena. Future studies are needed to identify individual risk factors.

Topics: Acne Vulgaris; Administration, Topical; Adult; Dermatitis, Atopic; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Male; Middle Aged; Ointments; Risk Assessment; Rosacea; Sampling Studies; Severity of Illness Index; Tacrolimus

Since 1999, combination therapy with tacrolimus and topical steroids has been widely used for the treatment of adolescent/adult-type atopic dermatitis. In order to determine the clinical doses of topical tacrolimus and steroids for daily treatment of atopic dermatitis and to elucidate their beneficial and adverse effects, we analyzed the clinical data from 215 patients with atopic dermatitis who were more than 16 years old. Less than 70 g of tacrolimus and less than 15 g of steroids were applied to 90% of the patients on the face and neck, and less than 75.8 g of tacrolimus and less than 322 g of steroids were applied to 90% of the patients on the trunk and extremities during the six-month treatment period. Topical tacrolimus is much more frequently used on face and neck lesions (99.1%); in only 39.5% of cases was it used on the trunk and extremities. The majority of patients improved after six months of the combination topical therapy; however, atopic dermatitis was not controlled in 6% of the patients. The combination therapy did not seem to increase the risk of cutaneous infections; however, the incidence of herpes simplex infection on the face and neck was 2.8% at pre-treatment and slightly increased to 4.7% during the therapy. The incidence of all steroid-induced adverse effects was reduced both in frequency and intensity with a decrease in the dose of topical steroids through simultaneous tacrolimus application. Combination therapy with topical tacrolimus and steroids is useful for treating atopic dermatitis, but a small percentage of the patients still cannot be satisfactorily treated. For such patients, adjustments of the dose and rank of topical steroids and tacrolimus and other therapeutic adjuncts are necessary.

Topics: Administration, Cutaneous; Adult; Dermatitis, Atopic; Drug Administration Schedule; Drug Therapy, Combination; Extremities; Facial Dermatoses; Female; Humans; Immunosuppressive Agents; Male; Severity of Illness Index; Steroids; Tacrolimus; Treatment Outcome

The action of tacrolimus ointment on pruritus in atopic dermatitis is still unclear. In this open study we investigated both the relationship between the severity of eruptions and the degree of itch and scratching in patients with atopic dermatitis and the effects of topical tacrolimus on these symptoms. Seventy adults with moderate to severe atopic dermatitis with facial eruptions that were recalcitrant to topical steroids applied a 0.1% tacrolimus ointment twice per day after discontinuation of topical steroid. The eruption scores and an assessment of the itch and scratching were recorded for 12 weeks. Oral antihistamine was prescribed at least one month before the study and continued unchanged during the study in each patient. The percentage reduction in the score of itch and scratching after two weeks (n=59) was significantly higher than in the score of eruption. Although there was no significant relationship between the severity of the eruptions and the degree of itch and scratching during steroid application, a relationship became significant after four weeks (n=59) of tacrolimus use by a one-factor ANOVA analysis. This suggests that tacrolimus ointment is effective for the itch and scratching in cases where degrees might be discrepant from the severity of eruptions in patients with recalcitrant facial eruptions of AD.

Topics: Administration, Topical; Analysis of Variance; Dermatitis, Atopic; Facial Dermatoses; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Ointments; Probability; Prospective Studies; Pruritus; Severity of Illness Index; Tacrolimus; Treatment Outcome

Thymus and activation regulated chemokine (TARC) is a CC chemokine that attracts CCR4+ T cells. We reported previously that TARC is an important chemokine that defines Th2 imbalance in the pathogenesis of atopic dermatitis (AD).. This study was undertaken to clarify TARC producing cells in peripheral blood mononuclear cells (PBMCs), the regulation of dust mite-allergen clude extract (DME) and different immunosuppressive drugs (Tacrolimus (FK506), cyclosporine (CsA), dexamethasone (Dex)) on TARC production by peripheral PBMCs from AD patients in vitro.. Monocyte derived dendritic cells (MoDCs) were generated from and TARC mRNA levels were examined and comapared with those from T cells in PBMCs from AD patients. PBMCs were cultured with or without DME and/or immunosuppressive drugs (Tacrolimus, CsA, Dex) for 7 days and TARC levels were measured.. PBMCs from AD patients which were cultured with DME stimulation for 7 days showed significantly higher levels of TARC production than those from healthy controls. RT-PCR demonstrated that TARC mRNA was expressed in CD4+ T cells, CD8+ T cells and MoDCs. Tacrolimus, CsA and Dex individually suppressed TARC production by PBMCs from AD patients which were co-cultured with DME for 7 days. Gel shift analysis revealed differential inhibitory effects of these immunosuppressive drugs on NFkappaB activity in PBMCs from AD patients.. Our data demonstrate that TARC producing cells are MoDCs, T cells as well as epidermal keratinocytes in AD. We suggest that MoDCs might regulate the immune responses by attracting T cells and CD25+ T cells in the pathogenesis of AD. We also showed the important role of DME on TARC production and the inhibitory effect of the immunosuppressive drugs on TARC production by PBMCs from AD patients, that can regulate ongoing immune responses in the pathogenesis of AD.

Topics: Adult; Case-Control Studies; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Chemokine CCL17; Chemokines, CC; Cyclosporine; Dendritic Cells; Dermatitis, Atopic; Dexamethasone; Dust; Female; Humans; Immunosuppressive Agents; Leukocytes, Mononuclear; Male; NF-kappa B; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tacrolimus; Up-Regulation

To study the clinical efficacy of a noninvasive suction device that measures eyelid skin elasticity in the treatment of eyelid atopic dermatitis using tacrolimus (FK-506) ointment.. Ten patients with eyelid atopic dermatitis treated with tacrolimus ointment and 10 normal volunteers participated in this study. The cutometer SEM575 was used to quantitatively evaluate eyelid skin elasticity. Severity of the eyelid atopic dermatitis was scored, and comparisons were made before and after treatment.. Skin elasticity of patients with eyelid atopic dermatitis was significantly lower than that of normal volunteers (31.3 +/- 5.2% vs 40.2 +/- 7.8%, respectively). Skin elasticity of patients with eyelid atopic dermatitis improved significantly to 37.5 +/- 6.3% after treatment with tacrolimus ointment. The total severity score for eyelid atopic dermatitis also improved from 2.77 +/- 1.11 to 1.77 +/- 1.15.. Measurement of skin elasticity using the cutometer SEM575 is a useful and reliable method for objective and quantitative evaluation of eyelid skin condition in patients with eyelid atopic dermatitis. The efficacy of short-term tacrolimus ointment treatment in patients with eyelid atopic dermatitis was confirmed quantitatively using this apparatus.

Topics: Adult; Dermatitis, Atopic; Diagnostic Techniques, Ophthalmological; Elasticity; Eyelid Diseases; Female; Humans; Immunosuppressive Agents; Male; Ointments; Skin; Skin Physiological Phenomena; Tacrolimus

(1) Drug therapy for exacerbations of atopic dermatitis (atopic eczema) should only be considered when simple measures and emollients are inadequate. The first-line option is a topical corticosteroid with a level of potency appropriate for the affected site and the patient's age. (2) Tacrolimus, an immunosuppressant used orally or parenterally to prevent graft rejection, is now marketed in France as an ointment, in two dose strengths, for the treatment of atopic dermatitis. It is approved for use when topical corticosteroids fail, in patients aged at least two years. (3) According to a comparative trial in adults, tacrolimus, when used as a first-line treatment, is no more effective than a class II (strong) topical corticosteroid. Several clinical trials show that it is better than the excipient in both adults and children. The 0.1% strength seems to be slightly more active than the 0.03% strength in adults. (4) It is not known whether tacrolimus is effective after topical corticosteroid failure. (5) In comparative trials the main systemic adverse events in patients using tacrolimus ointment were flu-like syndromes and headache. Local adverse events included burning or pruritus at the site of application in about 50% of patients. These local effects are due to both the excipient and tacrolimus. (6) Severe skin infections and skin cancer cannot be ruled out as serious side effects. (7) Tacrolimus uptake through the skin exposes patients to systemic adverse effects and drug interactions. (8) In practice, patients with atopic dermatitis, however severe, have no reason to use tacrolimus, at least pending studies showing it is effective after topical corticosteroid failure.

Topics: Administration, Oral; Administration, Topical; Adrenal Cortex Hormones; Adult; Child; Clinical Trials as Topic; Contraindications; Dermatitis, Atopic; Drug Approval; Drug Interactions; France; Humans; Immunosuppressive Agents; Ointments; Pruritus; Quality of Life; Randomized Controlled Trials as Topic; Tacrolimus

The topical immunomodulators tacrolimus and pimecrolimus are novel therapeutic options for atopic dermatitis (AD). The inhibition of nuclear factor of activated T cell-dependent proinflammatory cytokine production in cutaneous lymphocytes is an established effect of topical immunomodulators, which additionally influence mast cells, eosinophils, and dendritic cells (DCs). The latter include a reduced expression of the high-affinity IgE receptor FcepsilonRI, a reduced stimulatory capacity of lesional DCs, and a selective depletion of the inflammatory dendritic epidermal cells (IDECs) but not of Langerhans cells (LCs) from the lesional skin.. Because induction of apoptosis in lymphocytes is a reported tacrolimus effect, we asked whether tacrolimus ointment induces apoptosis of LCs or IDECs in AD lesions.. Epidermal single-cell suspensions were prepared from AD lesions of 9 tacrolimus-treated and 5 hydrocortisone butyrate-treated patients with AD before and after 1 week of treatment. Cell numbers, apoptosis rate, and immunophenotype were assessed by using the standardized FACS technique with terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling, Annexin V, and 3-color immunophenotyping. Freshly isolated LCs and monocyte-derived DCs served as in vitro controls.. Tacrolimus and steroid ointment induced a selective depletion of IDECs from the epidermis and reduced the expression of the costimulatory molecules CD80 and CD86. Tacrolimus ointment did not increase the rate of apoptotic DCs, whereas steroid ointment did so. The isolation-induced high apoptosis rate of freshly isolated LCs was unaffected by both drugs.. Tacrolimus ointment selectively depletes IDECs and alters the immunophenotype of epidermal DCs in AD lesions, but there is no evidence for tacrolimus-induced DC apoptosis in this phenomenon.

Topics: Administration, Topical; Apoptosis; Cell Culture Techniques; Dendritic Cells; Dermatitis, Atopic; Epidermis; Glucocorticoids; Humans; Immunosuppressive Agents; In Situ Nick-End Labeling; Langerhans Cells; Ointments; Tacrolimus

We investigated the effects of several agents on the established itching model in NC/Nga mice, model of atopic dermatitis-like disease, to elucidate related characteristics. The number of spontaneous scratching behaviors (the duration time is over 1.5 s) by NC/Nga mice with severe skin lesions was measured before and after administration of agents for 24 h. The scratching behavior by NC/Nga mice was significantly suppressed by administration of dexamethasone or tacrolimus, but not by chlorpheniramine maleate or cyproheptadine hydrochloride. These results suggest that this method shows a good correlation with the effectiveness of drugs prescribed for itching in humans with atopic dermatitis, and histamine and serotonin do not play an important role in causing the scratching behavior seen by NC/Nga mice. The scratching behavior was also significantly suppressed by naloxone hydrochloride, dibucaine or capsaicin. These results suggest that the scratching behavior seen in this model is caused by itching signal transmission through neural system. Furthermore, we found that theophylline, pinacidil or limaprost had scratching suppression effects in this model.

Topics: Alprostadil; Animals; Antipruritics; Behavior, Animal; Capsaicin; Chlorpheniramine; Cyproheptadine; Dermatitis, Atopic; Dexamethasone; Dibucaine; Male; Mice; Mice, Inbred Strains; Naloxone; Pinacidil; Pruritus; Tacrolimus; Theophylline; Time Factors

A case of molluscum contagiosum arising on the face and neck of a woman using topical tacrolimus over a period of 6 weeks for the treatment of atopic dermatitis is presented. Of particular note, these lesions remained confined to areas treated with tacrolimus and did not extend to adjacent regions treated with topical corticosteroids.

Topics: Administration, Topical; Adult; Betamethasone Valerate; Dermatitis, Atopic; Female; Humans; Immunosuppressive Agents; Molluscum Contagiosum; Ointments; Tacrolimus; Treatment Outcome; Tretinoin

Topics: Cost-Benefit Analysis; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Tacrolimus

In several clinical studies, topical calcineurin inhibitors have been shown to be effective in the treatment of atopic dermatitis (AD). They target signaling pathways that control gene expression, particularly the expression of cytokines.. We examined the cellular infiltrate in skin lesions of 10 patients with AD and characterized the cytokine pattern expressed by the infiltrating cells before and after short-term topical therapy with tacrolimus 1% ointment.. Skin biopsies were examined for histologic alterations (hematoxylin and eosin staining), composition of the cellular inflammatory infiltrate (immunofluorescence), and cytokine expression (ribonuclease protection assay, ELISA, immunofluorescence) before as well as 1 and 3 weeks after initiation of tacrolimus therapy. For comparison, biopsies from nonlesional AD and normal skin were analyzed. Systemic immunologic effects were assessed by analyzing peripheral blood leukocytes (immunofluorescence) as well as in vitro stimulated pan-T-cell cytokine production (ELISA).. All patients showed a significant improvement of their skin lesions associated with a marked regression of spongiosis, acanthosis, and density of the cellular infiltrate in the dermis. The last was a result of reduced infiltration of T cells, B cells, and eosinophils. In contrast, the numbers of mast cells did not change. Moreover, the expression of the T H 2 cytokines IL-5, IL-10, and IL-13 in CD4 + T cells was reduced after therapy. Interestingly, tacrolimus therapy was also associated with a reduction of CD8 + T cells expressing the T H 1 cytokine IFN-gamma. Furthermore, the numbers of epidermal CD1a + dendritic cells increased after treatment. In the peripheral blood, a decrease of granulocytes (eosinophils and neutrophils) but no changes in the distribution of lymphocyte subpopulations were noticed.. Topical tacrolimus treatment has anti-inflammatory effects on AD skin as indicated by reduced infiltration of cytokine expressing inflammatory cells. No evidence for drug-induced systemic immunosuppression was obtained.

Topics: Administration, Topical; Adolescent; Adult; Chemotaxis, Leukocyte; Cytokines; Dermatitis, Atopic; Dermis; Female; Humans; Immunosuppressive Agents; Leukocytes; Male; Middle Aged; Tacrolimus

To report a case of atopic eyelid disease treatment using topical tacrolimus in a patient with open-angle glaucoma following corticosteroid discontinuation.. Interventional case report.. A 59-year-old white man with a history of treated open-angle glaucoma (latanoprost 0.005%) was referred to our department for atopic eyelid disease. The patient had received previous treatment with topical corticosteroid ointments (hydrocortisone acetate 1%/dexamethasone 0.1% ointments) that, even though they were effective in controlling atopic eyelid disease, were complicated by markedly elevated intraocular pressure (IOP) (steroid responder). Topical steroids were discontinued while other treatment modalities (such as eyelid hygiene, artificial tears, topical antihistamine drugs, topical mast cell stabilizers, or topical/oral antibiotics) were proven ineffective.. Topical tacrolimus 0.03% ointment (Protopic; Fujisawa, Dublin, Ireland) was applied to the eyelid skin twice daily. An improvement of eyelid inflammation was observed while eczematous skin lesions and erosions were resolved within 15 days. After 6 months of continued topical tacrolimus treatment, there was no evidence of atopic dermatitis recurrence. During this period IOP remained controlled without any evidence of deregulation.. Treatment of atopic eyelid disease with topical tacrolimus, following corticosteroid discontinuation in a steroid responder patient with open-angle glaucoma, seems to be an effective alternative treatment to corticosteroids without the risk of IOP increase.

Topics: Administration, Topical; Dermatitis, Atopic; Eyelid Diseases; Glaucoma, Open-Angle; Glucocorticoids; Humans; Immunosuppressive Agents; Intraocular Pressure; Male; Middle Aged; Tacrolimus

Tacrolimus ointment (Protopic, Fujisawa) is an effective agent in a class of topical immunomodulators. Its mechanism of action is based on calcineurin inhibition, which results in decreased T-cell activation and inflammatory cytokine release. Tacrolimus ointment is safe and effective for short- and long-term treatment of atopic dermatitis (AD) in pediatric and adult patients. The most common adverse events associated with its use are a transient burning sensation and pruritus at the site of application. Unlike topical corticosteroid agents, tacrolimus ointment does not cause a reduction in collagen synthesis or skin thickness. Because tacrolimus ointment does not cause skin atrophy, it may be safely used for months or years on all skin areas, including the face and intertriginous areas.

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Age Factors; Calcineurin Inhibitors; Child; Child, Preschool; Dermatitis, Atopic; Dermatologic Agents; Double-Blind Method; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Multicenter Studies as Topic; Ointments; Peptidylprolyl Isomerase; Randomized Controlled Trials as Topic; Safety; Tacrolimus; Time Factors

Topics: Anti-Inflammatory Agents; Dermatitis, Atopic; Humans; Hydrocortisone; Immunosuppressive Agents; Research Design; Tacrolimus

Topics: Administration, Topical; Adult; Alcohol Drinking; Dermatitis, Atopic; Dose-Response Relationship, Drug; Drug Interactions; Ethanol; Female; Flushing; Humans; Male; Middle Aged; Rosacea; Tacrolimus

Topics: Administration, Topical; Adrenal Cortex Hormones; Biopsy, Needle; Dermatitis, Atopic; Facial Dermatoses; Female; Follow-Up Studies; Humans; Immunohistochemistry; Immunosuppressive Agents; Middle Aged; Ointments; Risk Assessment; Rosacea; Severity of Illness Index; Tacrolimus; Treatment Outcome

To describe the effects of topical tacrolimus treatment of severe atopic eyelid disease.. Interventional consecutive case series.. A description of clinical findings and therapeutic response for five consecutive adult patients (mean age, 56.2 years; range 44-62) treated with topical tacrolimus for severe atopic eyelid disease at one institution.. Five patients with bilateral atopic eyelid disease that was refractory to treatment with topical corticosteroids were treated with tacrolimus 0.03% ointment, applied to the affected eyelid skin of both eyes twice daily. Eyelid induration, erythema, and eczematous changes were substantially improved within 1 to 3 weeks after initiation of topical tacrolimus treatment in all patients. There was an associated decrease in ocular surface irritation and inflammatory signs in each of four patients who also had atopic keratoconjunctivitis. No adverse effect associated with tacrolimus treatment was noted during continued treatment for 5 to 14 months. All patients were able to discontinue longstanding use of topical corticosteroid drugs.. Application of topical tacrolimus on eyelid skin may be effective for treatment of severe atopic dermatitis of the eyelids, and may have secondary benefits for atopic keratoconjunctivitis. Topical tacrolimus may be used for at least 1 year without apparent adverse reaction in some patients, although the rate of adverse reaction cannot be determined from this small series.

Topics: Administration, Topical; Adult; Conjunctivitis, Allergic; Dermatitis, Atopic; Eyelid Diseases; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Ointments; Tacrolimus

Few cost-effectiveness analyses have been conducted on topical therapies for atopic dermatitis.. We sought to compare cost-effectiveness of high-potency topical corticosteroids (HPTCs) and tacrolimus ointment for the treatment of moderate to severe atopic dermatitis for patients who are not responsive to or not well controlled with mid-potency topical corticosteroids.. A Markov model represented the cyclic nature of atopic dermatitis. Clinical outcomes were derived from published literature. "Efficacy" was defined as disease-controlled days on which patients experienced a greater than 75% improvement in their disease. Resource use and changes in management were on the basis of opinions of a physician panel; secondary treatment was an oral antibiotic with topical corticosteroids. Sensitivity analyses were conducted for all variables.. The model was sensitive to duration of continuous treatment with HPTCs. HPTCs, when limited to 2-week treatment cycles, were associated with the highest total costs ($1682 per year) and the least efficacy (185 disease-controlled days). HPTCs in 4-week treatment intervals and tacrolimus ointment were similar in total costs and efficacy ($1317 vs $1323 for 194 vs 190 disease-controlled days, respectively). Although primary drug costs were higher for patients treated with tacrolimus ointment, patients treated with regimens of HPTCs incurred higher secondary drug costs.. In the base case analyses, tacrolimus ointment was more cost-effective than HPTCs administered in 2-week treatment cycles, and similar in cost-effectiveness to 4-week cycles of HPTCs.

Topics: Administration, Topical; Adult; Anti-Inflammatory Agents; Cost-Benefit Analysis; Dermatitis, Atopic; Glucocorticoids; Health Care Costs; Humans; Immunosuppressive Agents; Markov Chains; Ointments; Recurrence; Retreatment; Tacrolimus; Treatment Outcome

The calcineurin inhibitors pimecrolimus and tacrolimus are important tools for long-term management of atopic dermatitis in childhood. These drugs are approved in Germany for the intermittent long-term treatment of moderate to severe (tacrolimus ointment) or mild to moderate (pimecrolimus cream) atopic dermatitis in children older than 2 years. Recent study results show that these agents are also effective in infants (aged 3-23 months) with atopic dermatitis. During the long-term treatment of children and infants with calcineurin inhibitors, the therapeutic success can be maintained and there is a continuous increase in the response rate. Long-term use of calcineurin inhibitors in atopic dermatitis is well tolerated locally and systemically, leads to reduction of disease flares and has a corticosteroid sparing effect.

Topics: Administration, Topical; Adolescent; Calcineurin Inhibitors; Child; Child, Preschool; Dermatitis, Atopic; Female; Humans; Immunosuppressive Agents; Long-Term Care; Male; Randomized Controlled Trials as Topic; Tacrolimus

In about 60% of cases, atopic eczema can persist in adulthood with distinctive clinical features and disease course. The introduction of the topical calcineurin inhibitors pimecrolimus 1% cream and tacrolimus 0.03 and 0.1% ointment clearly improves the long-term management of atopic eczema in adult patients; this has been shown in several large clinical studies and is confirmed by the growing practical experience with these substances. Topical calcineurin inhibitors are, even when applied for weeks and months, safe, well tolerated and efficient; they have a rapid and positive effect on pruritus and the potential--as shown in clinical studies with pimecrolimus 1% cream--to reduce the number of eczema flares, to significantly prolong the time to a first flare and to reduce or even eliminate the need for topical corticosteroids.

Topics: Administration, Topical; Adolescent; Adult; Aged; Calcineurin Inhibitors; Clinical Trials as Topic; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Long-Term Care; Middle Aged; Tacrolimus

Topics: Dermatitis, Atopic; Humans; Tacrolimus; Treatment Outcome

Topics: Adult; Contraindications; Dermatitis, Atopic; Herpes Simplex; Humans; Immunosuppressive Agents; Kaposi Varicelliform Eruption; Tacrolimus

Topics: Dermatitis, Atopic; Humans; Immunosuppressive Agents; Tacrolimus

Topics: Administration, Oral; Adult; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Male; Tacrolimus

Topics: Dermatitis, Atopic; Dermatologic Agents; Humans; Immunosuppressive Agents; Ointments; Skin; Tacrolimus; Treatment Outcome

Atopic dermatitis (AD) is a pruritic recurring inflammatory skin disease. Recently, topical tacrolimus has been developed to treat AD. This report presents the first clinical experience with topical tacrolimus in Taiwan. This open-label, single-arm study was conducted at three centers from February to May 2002. The duration of each individual treatment was 4 weeks. Two groups were defined: pediatric and adult. Efficacy was evaluated on the basis of the physician's global evaluation at the end of treatment. Success was defined as at least 50% improvement. Other evaluations included the Eczema Area and Severity Index (EASI), the percentage of body surface area (BSA) involved, the patient's assessment of pruritus, and the patient's assessment of overall response. Safety profile was established by monitoring changes in hematology and biochemistry profiles and tacrolimus concentration in blood. All adverse events were recorded. Twenty-six pediatric patients and 42 adult patients were enrolled. Overall success rates were 80.8% and 82.1% in the pediatric and adult groups, respectively. The declines in EASI, percentage of BSA affected, and patient's assessment of pruritus were significant (p < 0.001); 88% and 100% of pediatric and adult patients, respectively, reported a favorable response to treatment. Changes in blood samples were unremarkable. Of pediatric and adult patients, 61.5% and 76.2%, respectively, reported adverse events. The most common adverse event reported was skin burning, which did not result in discontinuation of therapy. This report reveals that tacrolimus ointment is effective and safe for the treatment of AD in Taiwanese patients.

Topics: Adolescent; Adult; Child; Child, Preschool; Dermatitis, Atopic; Drug Evaluation; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Ointments; Tacrolimus

Immunomodulators include both immunostimulatory and immunosuppressive agents. Obligate contact sensitizers such as diphencyprone or dinitrochlorobenzene have been used against viral and autoimmune diseases. Newer agents such as the toll-like receptor agonists imiquimod and resiquimod have been clinically used to treat viral infections and skin cancers in immunocompetent and immunosuppressed patients. On the other hand, the topical immunosuppressive agents tacrolimus and pimecrolimus have been used with great success in the treatment of chronic inflammatory diseases in children and adults. The introduction of this new class of drugs (i.e. Calcineurin inhibitors) marked the beginning of the post-cortisone era in clinical dermatology. Toll-like receptor agonists and calcineurin antagonists will supplement corticosteroids to improve specific dermatological therapy. Topical immunotherapy with both immunostimulatory and immunosuppressive agents show potential for effective and patient-friendly treatment of inflammatory, infectious and neoplastic skin diseases. Long-term evaluation will define the tolerability and the safety profile.

Topics: Adjuvants, Immunologic; Administration, Topical; Adult; Aged; Aged, 80 and over; Aminoquinolines; Asthma; Autoimmune Diseases; Bowen's Disease; Child; Cyclopropanes; Dermatitis, Atopic; Dinitrochlorobenzene; Female; Follow-Up Studies; Herpes Simplex; Humans; Imidazoles; Imiquimod; Immunity, Cellular; Immunocompromised Host; Immunoglobulin A; Immunosuppressive Agents; Lichen Sclerosus et Atrophicus; Male; Molluscum Contagiosum; Papillomavirus Infections; Precancerous Conditions; Skin Diseases; Skin Diseases, Viral; Skin Neoplasms; Tacrolimus; Time Factors; Warts

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Calcineurin Inhibitors; Dermatitis, Atopic; Doxycycline; Facial Dermatoses; Female; Humans; Mite Infestations; Rosacea; Tacrolimus

Interleukin (IL)-16 serves as a natural ligand of CD4 molecules and induces chemotaxis in CD4-expressing cells such as T cells, eosinophils, dendritic cells and monocytes. We examined the serum levels of IL-16 in patients with adult atopic dermatitis when their eruptions were aggravated and in non-atopic healthy controls, and then analysed the possible correlation between these values and the levels of several clinical markers. The serum levels of IL-16 were significantly higher in patients with atopic dermatitis than in the controls--both in exacerbation status and after conventional treatment. Multiple regression analyses showed that serum IL-16 was a predictor of the eosinophil count. Circulating IL-16 levels decreased significantly in patients with atopic dermatitis after topical treatment with corticosteroids or tacrolimus. These findings provide evidence that IL-16 plays a role in the exacerbation of chronic adult atopic dermatitis.

Topics: Administration, Cutaneous; Adolescent; Adrenal Cortex Hormones; Adult; Case-Control Studies; Dermatitis, Atopic; Enzyme-Linked Immunosorbent Assay; Female; Humans; Interleukin-16; Male; Middle Aged; Tacrolimus

Topics: Administration, Cutaneous; Adult; Dermatitis, Atopic; Diagnosis, Differential; Facial Dermatoses; Humans; Immunosuppressive Agents; Male; Ointments; Skin Neoplasms; Tacrolimus

Atopic dermatitis (AD) is a chronic, relapsing, highly pruritic inflammatory skin disease that is particularly prevalent in the paediatric population. Emollients and topical corticosteroids have represented the standard of treatment for patients with AD, despite their numerous adverse effects and patients' tendency towards steroid resistance. Topical tacrolimus marks the introduction of an entirely new class of medications, the non-corticosteroid topical immunomodulators. Numerous short- and long-term and ongoing paediatric and adult studies have demonstrated the excellent efficacy and superb safety profile of this anti-inflammatory agent. The authors review many of these landmark studies and discuss the mechanism of action and safety profile of tacrolimus, in the context of the pathophysiology of AD.

Topics: Administration, Cutaneous; Child; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Dermatitis, Atopic; Drug Administration Schedule; Health Care Costs; Humans; Immunosuppressive Agents; Ointments; Tacrolimus

Topics: Administration, Topical; Adult; Anti-Inflammatory Agents; Calcineurin Inhibitors; Child; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Infant; Secondary Prevention; T-Lymphocytes; Tacrolimus

Atopic dermatitis (AD) is a common inflammatory skin disease that affects adults and children. Tacrolimus (FK 506) ointment is a recently developed topical immunomodulator that has been approved for use in patients with AD who are older than 2 years. Concern regarding potential systemic toxic effects has limited treatment options for children younger than 2 years. We wanted to determine whether topical tacrolimus therapy is safe and effective in patients with AD who are younger than 2 years.. Twelve patients fitting our criteria who were treated with tacrolimus ointment were identified by retrospective chart review. Data collected included severity of AD, response to therapy, concentration and blood levels of tacrolimus, any adverse effects, and results of laboratory tests, including complete blood cell count, liver function tests, and serum chemistry profiles. As the review was retrospective, baseline laboratory studies were not performed. All the patients experienced improvement in their symptoms, and no significant adverse effects were noted. Nine patients used 0.03% tacrolimus ointment; 3 used 0.1%. All patients had blood levels of tacrolimus that were less than 1.5 ng/mL. There was no apparent difference in tacrolimus levels in patients whether they were treated with 0.03% or 0.1% ointment. Four patients had elevated platelet counts.. Tacrolimus ointment appears to be effective and safe in the treatment of AD in children younger than 2 years.

Topics: Administration, Topical; Age Factors; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Infant; Ointments; Retrospective Studies; Severity of Illness Index; Tacrolimus; Treatment Outcome

Tacrolimus is a T-cell-selective cytokine inhibitor. The topical formulation was specifically developed for treating inflammatory skin diseases, including atopic dermatitis (AD). The purpose of this study was to evaluate the efficacy and safety of topically applied tacrolimus ointment (Protopic) in treating Taiwanese patients with moderate to severe AD.. This was an open-labeled, non-comparative, single-center study. Enrolled patients applied Protopic twice daily for up to 4 weeks. Efficacy was evaluated on the basis of the physician's global evaluation of clinical response (PG). Other evaluations included the Eczema Area and Severity Index and the percentage of body surface area; the total score for clinical signs was used for evaluating the efficacy. A safety assessment was based on adverse events reported by patients or observed by the physician. Blood was sampled for the evaluation of tacrolimus levels.. In total, 30 patients (16 pediatric and 14 adult patients) with moderate to severe AD were enrolled in this study. At the end of treatment, the PG was 92.3% for the pediatric group and 100% for the adult group. Other efficacy evaluations also showed significant improvement. Two patients had detectable blood tacrolimus concentrations. Skin itching and burning on the application site was a common but temporary side effect. No significant adverse events related to Protopic were observed.. The results of the study suggest that Protopic ointment may be a safe and effective therapy for treating patients at least 2 years of age with moderate to severe AD.

Topics: Administration, Topical; Adolescent; Adult; Child; Child, Preschool; Dermatitis, Atopic; Female; Humans; Immunosuppressive Agents; Male; Ointments; Safety; Tacrolimus

Topics: Administration, Topical; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Ointments; Tacrolimus

The physical and chemical compatibility of desoximetasone ointment 0.25% and tacrolimus ointment 0.1%, both widely used to treat atopic dermatitis, were determined. A 1:1 (w/w) mixture of desoximetasone ointment 0.25% (Topicort, Taro Pharmaceuticals USA, Inc.) and tacrolimus ointment 0.1% (Protopic, Fujisawa Healthcare, Inc.) were prepared and stored under three different temperature/relative humidity conditions: 25 degrees C/60% RH; 30 degrees C/60% RH; and 40 degrees C/75% RH. Unmixed ointments stored under the same temperature and humidity conditions as the mixture served as controls. Samples were evaluated at days 1, 2, 7, 14, and 28 for color, degree of physical separation, and chemical stability via reverse-phase high performance liquid chromatography. Ranges of relative recovery for each active ingredient for all storage conditions ((% Mixture/% Control) x 100) were 89.6-109.3% for tacrolimus and 99.0-103.4% for desoximetasone. No significant difference in physical appearance or chromatographic profile between the mixture and controls was observed. Therefore, we conclude that desoximetasone ointment 0.25% (Topicort) and tacrolimus ointment 0.1% (Protopic) are physically and chemically compatible up to four weeks when mixed in a ratio of 1:1 (w/w).

Topics: Administration, Cutaneous; Anti-Inflammatory Agents; Chemistry, Pharmaceutical; Dermatitis, Atopic; Desoximetasone; Drug Stability; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Ointments; Tacrolimus

The purpose of this study was to evaluate the risk of cutaneous infection in patients with atopic dermatitis treated with tacrolimus ointment.. Data for 1554 patients with atopic dermatitis, treated with tacrolimus ointment in 5 clinical trials, were analyzed.. In 3 controlled studies, the 12-week adjusted incidence of all cutaneous infections in patients treated with the vehicle, 0.03%, and 0.1% tacrolimus ointment, respectively, was 18.0%, 24.8%, and 17.7% for adult patients, and 20.9%, 19.6%, and 23.6% for pediatric patients. The incidence of any individual cutaneous infection was not significantly higher in the tacrolimus group than in the vehicle group, with the exception of folliculitis in adults. In two open-label studies, there was no evidence of an increased risk of cutaneous infections with long-term use of 0.1% tacrolimus ointment (up to 1 year), based on the incidence of adverse events, incidence by cumulative length of exposure, or hazard rates.. Treatment with tacrolimus ointment (0.03% or 0.1%) does not increase the risk of cutaneous bacterial, viral, or fungal infections in patients with atopic dermatitis.

Topics: Adolescent; Adult; Child; Child, Preschool; Clinical Trials as Topic; Dermatitis, Atopic; Double-Blind Method; Female; Folliculitis; Humans; Immunosuppressive Agents; Male; Opportunistic Infections; Skin Diseases, Infectious; Tacrolimus

Topics: Acyclovir; Adult; Antiviral Agents; Dermatitis, Atopic; Face; Female; Humans; Immunosuppressive Agents; Kaposi Varicelliform Eruption; Ointments; Recurrence; Simplexvirus; Tacrolimus; Virus Activation

Topics: Dermatitis, Atopic; Humans; Immunosuppressive Agents; Risk Assessment; Tacrolimus

Topics: Administration, Cutaneous; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Male; Middle Aged; Tacrolimus; Vitiligo

Topics: Dermatitis, Atopic; Humans; Immunosuppressive Agents; Tacrolimus

Topics: Administration, Topical; Adolescent; Adult; Child; Child, Preschool; Clinical Trials as Topic; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Ointments; Tacrolimus

The factors controlling infiltration of inflammatory cells into atopic dermatitis (AD) lesions remain to be fully explored. Recently, epidermal cells in lesional AD were reported to contain increased messenger (m)RNA levels of IL-16, a cytokine that induces chemotactic responses in CD4(+)T cells, monocytes, and eosinophils.. We sought to determine the expression of IL-16 in epidermal cells in normal skin and skin from AD lesions and to investigate whether Langerhans cell (LC)-derived IL-16 may contribute to the initiation of atopic eczema.. The cutaneous expression of IL-16 was investigated by in situ hybridization and immunohistochemistry. Expression of IL-16 was also investigated in freshly isolated LCs and in keratinocytes by intracellular cytokine staining, quantitative real-time RT-PCR, and ELISA.. Low levels of IL-16 mRNA, but no stored IL-16 protein, were detected in keratinocytes and LCs isolated from normal skin. Synthesis, storage, and secretion of IL-16 could be induced in LCs, but not keratinocytes, by activation with phorbol ester and ionomycin. In normal skin (n = 10) neither keratinocytes nor LCs expressed IL-16. In contrast, IL-16 was contained in approximately 40% of CD1a(+)LCs in patients with active AD (n = 16). IL-16 expression in LCs in patients with AD correlated with the number of infiltrating CD4(+)cells (r =.72, P =.0017) and was completely downregulated parallel to the clinical response of AD lesions to topical treatment with FK506.. LC-derived IL-16 may participate in the recruitment and activation of inflammatory cells in AD.

Topics: Antibodies, Monoclonal; Dermatitis, Atopic; Humans; Interleukin-16; Langerhans Cells; Skin; Tacrolimus

Topics: Adult; Child; Child, Preschool; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Infant; Randomized Controlled Trials as Topic; Tacrolimus

Topics: Dermatitis, Atopic; Dermatologic Agents; Evidence-Based Medicine; Humans; Immunosuppressive Agents; Tacrolimus

Pimecrolimus is an immunomodulating medication that inhibits production of inflammatory cytokines in the skin and this compound was specifically developed for the treatment of inflammatory skin diseases. Phase II and III clinical trials with the topical formulation of pimecrolimus (Elidel cream, Novartis) have shown that it is safe and effective for use in patients with atopic dermatitis (AD). The US FDA recently approved Elidel for use in patients >or=2 years of age and older with mild to moderate atopic dermatitis (AD).

Topics: Anti-Inflammatory Agents, Non-Steroidal; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Randomized Controlled Trials as Topic; Tacrolimus

Topics: Adjuvants, Immunologic; Administration, Topical; Adult; Child; Costs and Cost Analysis; Dermatitis, Atopic; Humans; Tacrolimus

Topics: Dermatitis, Atopic; Female; Humans; Male; Ointments; Staphylococcus; Tacrolimus

There have been several reports about Th1/Th2 imbalances in atopic dermatitis (AD), but there have been few precise investigations about the differences between Th1 and Th2 cytokine secretion patterns of peripheral blood mononuclear cells (PBMCs) in such patients. We cultured PBMCs, taken from AD patients and healthy subjects, with dust mite extract (DME) and measured subsequent immunoreactive interferon (IFN)-gamma (Th1 cytokine), interleukin (IL)-4, IL-5, and IL-13 (Th2 cytokines) levels in the supernatants by ELISA assays. There is a difference between IL-4 and IL-13 secretion patterns by DME-stimulated PBMCs in AD subjects; immunoreactive IL-4 levels were detectable maximally within 24-h cultures, while IL-13 levels increased time-dependently within 7-day cultures. IL-13 levels were significantly elevated in AD subjects compared to healthy subjects, while IFN-gamma levels did not significantly differ between the two groups. IL-13 levels were significantly higher in AD patients who had high levels (>100 U/ml) of Dermatophagoides pteronyssinus-specific IgE (Dp-IgE) than in those AD patients who had low levels (<10 U/ml) of Dp-IgE. Tacrolimus (FK-506), at a concentration of 10(-8) M, significantly inhibited DME-induced IL-13 production from PBMCs. These findings suggest that IL-13 produced by Th2 cells are involved in IgE overproduction in AD subjects.

Topics: Adult; Antigens, Dermatophagoides; Cells, Cultured; Cytokines; Dermatitis, Atopic; Female; Glycoproteins; Humans; Immunoglobulin E; Immunosuppressive Agents; Interferon-gamma; Interleukin-13; Interleukin-4; Interleukin-5; Male; Monocytes; Reference Values; Tacrolimus; Th1 Cells; Th2 Cells; Time Factors

The immunosuppressive macrolide tacrolimus (FK506) has been shown to inhibit allergic contact dermatitis in animal models as well as in human beings. More recently, successful treatment of atopic dermatitis with an ointment containing tacrolimus has been reported.. We explored the effects of this compound on epidermal Langerhans' cells (LCs), which are known to play an important pathophysiologic role in inflammatory skin diseases.. The expression of the intracellular FK506 binding protein (FKBP12) was monitored on freshly isolated and cultured epidermal LCs. Phenotyping and functional exploration of LCs treated with different concentrations of tacrolimus and beta-methasone valerate (betaMv) were performed.. FKBP12 is expressed in freshly isolated LCs but is lost while they are maturating into mature dendritic cells. Tacrolimus inhibited the expression of IL-2R (CD25) and of the costimulatory molecules CD80 (B7.1) and CD40. Expression of MHC class I and II was also affected, whereas CD86 (B7.2) expression was not altered. In contrast, betaMv strongly increased the expression of CD25. Paradoxically, while decreasing CD40 and MHC class I expression, betaMv significantly increased the expression of MHC class II, CD80, and CD86 on cultured LCs but impaired their allostimulatory activity. Tacrolimus was about 100 times more potent than betaMv at inhibiting LC stimulatory function.. Tacrolimus can exert immunopharmacologic alterations on LCs, which may account, at least in part, for the therapeutic effect of this compound in eczematous skin diseases.

Topics: Administration, Topical; Anti-Inflammatory Agents; Antigens, CD; B7-1 Antigen; B7-2 Antigen; Betamethasone Valerate; Dermatitis, Atopic; Down-Regulation; Glucocorticoids; Histocompatibility Antigens Class I; Histocompatibility Antigens Class II; Humans; Immunosuppressive Agents; Langerhans Cells; Membrane Glycoproteins; Receptors, IgE; Skin; Tacrolimus; Tacrolimus Binding Protein 1A

Topics: Dermatitis, Atopic; Humans; Immunosuppressive Agents; Staphylococcus aureus; Superantigens; Tacrolimus

Topics: Angina, Unstable; Angioplasty, Balloon, Coronary; Anticoagulants; Botulinum Toxins; Botulinum Toxins, Type A; Dermatitis, Atopic; Dermatologic Agents; Eczema; Hirudin Therapy; Hirudins; Humans; Immunosuppressive Agents; Neuromuscular Agents; Peptide Fragments; Recombinant Proteins; Tacrolimus; Torticollis; United States; United States Food and Drug Administration

Topics: Administration, Topical; Adult; Colony Count, Microbial; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Skin Diseases, Bacterial; Staphylococcal Infections; Staphylococcus aureus; Tacrolimus

Topics: Adjuvants, Immunologic; Administration, Topical; Dermatitis, Atopic; Humans; Immunotherapy; Tacrolimus

Topics: Animals; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Mice; Tacrolimus

Topics: Administration, Topical; Adult; Antibody Formation; Child; Dermatitis, Atopic; Dose-Response Relationship, Drug; Erythema; Humans; Immunity, Cellular; Pruritus; Randomized Controlled Trials as Topic; Tacrolimus

Topics: Adult; Child; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Ointments; Tacrolimus

Topics: Administration, Topical; Adult; Anti-Inflammatory Agents; Child; Cyclosporine; Dermatitis, Atopic; Glucocorticoids; Humans; Immunosuppressive Agents; Tacrolimus

Tacrolimus (FK506) ointment showed remarkable efficacy against atopic dermatitis in animal models and clinical trials. The suppressive effect of tacrolimus on the production of the cytokines involved in atopic dermatitis (IL-2, IL-3, IL-4, IL-5, IFN-gamma and GM-CSF) from human peripheral blood mononuclear cells (PBMC) was investigated. We constructed a new cytokine production system in which T cells are activated by direct stimulation in vitro with anti-CD3/CD2 or anti-CD3/CD28 antibody combination. Tacrolimus inhibited the production of these cytokines by both stimulations. In a comparative study with steroids (alclometasone dipropionate and betamethason valerate) in anti-CD3/CD2 system, tacrolimus and both steroids inhibited Th1 cytokines (IL-2, IFN-gamma), Th2 cytokines (IL-4, IL-5) and IL-3, GM-CSF (produced by both Th1 and Th2). The suppressive effect of tacrolimus on cytokine production was stronger than that of alclometasone dipropionate and equal to or stronger than that of betamethason valerate. The effective dose of tacrolimus (IC50, 0.02-0.11 ng/ml) is almost the same as for Th1 and Th2 cytokines, and 1 ng/ml of tacrolimus suppressed all cytokines completely. These results suggest that tacrolimus suppresses the allergic cytokines from T cells, and that tacrolimus ointment is effective against atopic dermatitis through the inhibition of cytokine production.

Topics: Betamethasone; CD28 Antigens; CD3 Complex; CD4 Antigens; Cell Separation; Cells, Cultured; Cytokines; Depression, Chemical; Dermatitis, Atopic; Enzyme-Linked Immunosorbent Assay; Humans; Immunosuppressive Agents; Indicators and Reagents; Methylprednisolone; Monocytes; Steroids; Tacrolimus

Because interferon-gamma, interleukin-4, and interleukin-5 have been identified at the mRNA and protein levels in the lesional skin of patients with atopic dermatitis, we investigated the roles played by granulocytes as effector cells in allergic inflammation by using two unique murine skin models. In vitro generated Th1 and Th2 cells from naïve splenocytes of antiovalbumin T cell receptor transgenic BALB/C mice were adoptively transferred with ovalbumin into the ear pinnae or air-pouches produced in the back skin of naïve, nontransgenic BALB/C mice. The injection of Th1 cells with ovalbumin induced delayed type ear swelling that peaked at 48 h, whereas that of Th2 resulted in ear swelling that peaked at a much earlier time, 24 h. Histologic study of the swollen ear skin and granulocytes recruited into the air-pouch demonstrated that, although the Th1-induced inflammation caused a neutrophil-predominant infiltrate with few eosinophils, larger numbers of eosinophils accumulated in the Th2-induced inflammation. Using these murine models, we further evaluated the effects of drugs used for the treatment of atopic diseases. The results showed that FK506 administration could effectively reduce skin inflammation induced by either Th cells. Interestingly, the neutrophil elastase inhibitor ONO-6818 efficiently inhibited Th1-induced inflammation. In contrast, a leukotriene receptor antagonist, ONO-1078, specifically suppressed Th2-induced inflammation. We also found that each ONO drug exerted direct influence on specified granulocytes, as neither affected in vitro production of relevant Th cytokines. Thus, we succeeded in developing animal skin inflammation models in which we can evaluate the contribution of protein antigen-specific Th1 or Th2 cells through the action of granulocytic effector cells.

Topics: Animals; Cells, Cultured; Chromones; Dermatitis, Atopic; Disease Models, Animal; Ear; Edema; Enzyme Inhibitors; Eosinophils; Hypersensitivity; Immunosuppressive Agents; Leukotriene Antagonists; Male; Mice; Mice, Inbred BALB C; Neutrophils; Ovalbumin; Oxadiazoles; Pyrimidinones; Skin; Tacrolimus; Th1 Cells; Th2 Cells

Topics: Dermatitis, Atopic; Humans; Immunosuppressive Agents; Tacrolimus

Topical corticosteroids are commonly applied in atopic dermatitis (AD) treatment. However, their chronic use may be associated with significant side effects at the application site. Skin atrophy and other undesirable effects are frequently seen after long-term corticosteroid treatment. In addition, when application of corticosteroids is discontinued, a rebound phenomenon in the facial lesions can occur within several days. Topical tacrolimus, an immunosuppressant currently used to prevent rejection after solid-organ transplantation, presents a potential alternative therapeutic agent for AD.. The present study is the first trial designed to evaluate the efficacy and safety of topically applied tacrolimus ointment after corticosteroid discontinuation without a washout phase in severe, long-term facial AD.. Forty-seven patients with facial refractory AD were recruited, of whom 38 had undergone topical corticosteroid treatment for at least 4 weeks before enrollment (group 1) and the other 9 had not received steroid treatment (group 2). All 47 patients received 0.1% tacrolimus ointment, and the severity index and pruritus score were assessed as an AD clinical activity index every week and compared with baseline data.. Both the severity index and pruritus score improved significantly in group 1 after 1 and 2 weeks of application (p < 0.01, respectively). Group 2 showed the greatest improvement at 4 weeks (p < 0.05). In this trial, none of the patients experienced a rebound phenomenon associated with tacrolimus treatment. A transient sensation of burning at the application site was the only adverse event in 31 of the 47 (66%) enrolled patients, but this condition improved after several days. Spectrophotometric assessment of the facial lesion following treatment revealed significant improvement in group 1 (p < 0.05).. The present results indicate that topical tacrolimus treatment following corticosteroid discontinuation is safe and effective in refractory facial AD.

Topics: Administration, Topical; Adolescent; Adult; Dermatitis, Atopic; Dermatologic Agents; Facial Dermatoses; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Male; Middle Aged; Ointments; Tacrolimus

Systemic and topical administration routes of tacrolimus and cyclosporin A (CsA) were compared in effects on early and late phases of elicited T-cell-mediated contact sensitivity (CS), and effects on early and late phases of cutaneous immunoglobulin E (IgE) antibody-mediated hypersensitivity responses in mice. Thus, both CS and IgE responses in the skin have an early mast-cell-dependent phase, and also a late inflammatory phase. We measured the effects of both immunosuppressants on both phases of the respective T cell versus IgE responses. Systemic administration of both agents completely suppressed CS and IgE late-phase responses, but failed to affect either early phase. In contrast, when topical CsA was used, low doses abolished the early phase of IgE responses, but even high doses did not inhibit the early phase of CS. Conversely, topical tacrolimus inhibited the early phase of CS more potently than the early phase of cutaneous IgE hypersensitivity responses. Thus, topical treatment was needed to inhibit the early phases and the two agents acted differentially, suggesting differing susceptibility of the early phases, that are probably due to different signalling mechanisms. These studies underscore the potential value of topical administration of these powerful immunosuppressive agents in the treatment of allergic diseases that exhibit features of early-phase mast-cell-dependent inflammation, and late inflammation due to mast cells or to T cells, such as atopic dermatitis or asthma, since the early phase is predominantly susceptible to topical application, while the last phase of both IgE and T-cell inflammation responds to systemic treatment with both agents.

Topics: Administration, Cutaneous; Animals; Cyclosporine; Dermatitis, Allergic Contact; Dermatitis, Atopic; Female; Immunoglobulin E; Immunosuppressive Agents; Male; Mice; Mice, Inbred BALB C; Mice, Inbred CBA; Picryl Chloride; T-Lymphocytes; Tacrolimus

Activation and skin-selective homing of T cells and effector functions in the skin represent sequential events in the pathogenesis of atopic dermatitis and allergic contact dermatitis.. T cell-mediated keratinocyte apoptosis plays a key pathogenetic role in the formation of eczematous dermatitis. IFN-gamma released from activated T cells upregulates Fas on ke-ratinocytes, which renders them susceptible to apoptosis. The lethal hit is given to keratinocytes by means of Fas ligand expressed on the T-cell surface or released to the inflammatory microenvironment. We sought to investigate whether drugs used for the treatment of eczematous disorders interfere with this pathogenic pathway.. T cell-mediated, Fas-induced keratinocyte apoptosis in a keratinocyte-T cell coculture system serves as an in vitro model of eczematous dermatitis. We tested, in this model, whether immunomodulatory agents (dexamethasone, cyclosporine A, rapamycine, tacrolimus/FK506, intravenous immunoglobulin [IVIG], and theophylline) are able to inhibit apoptosis of keratinocytes. Additionally, skin biopsy specimens from patients with untreated and successfully treated eczematous dermatitis were evaluated for keratinocyte apoptosis.. Dexamethasone, cyclosporine A, FK506, rapamycine, and IVIG are inhibitors of keratinocyte apoptosis induced by activated T cells. This effect is mediated by 2 major mechanisms directed on T cells or keratinocytes. T-cell activation was mainly inhibited by dexamethasone, FK506, cyclosporine A, and rapamycine. Interestingly, high-dose dexamethasone and IVIG directly inhibited Fas-mediated keratinocyte apoptosis. In vivo keratinocyte apoptosis was significantly reduced after successful topical treatment of eczematous lesions.. These results demonstrate mechanisms of action of current treatment approaches and provide a future for more focused therapeutic applications.

Topics: Acute Disease; Apoptosis; Cells, Cultured; Cyclosporine; Dermatitis, Allergic Contact; Dermatitis, Atopic; Dexamethasone; fas Receptor; Humans; Immunoglobulins, Intravenous; Immunosuppressive Agents; Interleukin-12; Keratinocytes; Sirolimus; T-Lymphocytes; Tacrolimus; Th1 Cells; Theophylline

Topics: Dermatitis, Atopic; Humans; Immunosuppressive Agents; Tacrolimus; Treatment Outcome

(1) Atopic dermatitis (AD) is a chronic dermatological condition characterized by pruritus (itchiness) and rash. Topical corticosteroids are the mainstay of pharmacotherapy. (2) Tacrolimus ointment is a new topical anti-inflammatory agent available in Canada through the Special Access Program. (3) It is approved as a second line agent for short or long term intermittent treatment of moderate to severe AD. (4) Clinical trials suggest it is both effective and safe, but comparative studies with corticosteroids and long-term information are limited.

Topics: Canada; Clinical Trials as Topic; Dermatitis, Atopic; Drug Approval; Drug Costs; Humans; Immunosuppressive Agents; Japan; Tacrolimus; Technology Assessment, Biomedical; United States; United States Food and Drug Administration

Topics: Administration, Topical; Contraindications; Dermatitis, Atopic; Drug Interactions; Humans; Immunosuppressive Agents; Tacrolimus

Topics: Administration, Topical; Adolescent; Adult; Aged; Child; Child, Preschool; Clinical Trials as Topic; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Infant; Middle Aged; Ointments; Tacrolimus

Topics: Administration, Topical; Adult; Adverse Drug Reaction Reporting Systems; Animals; Autoimmune Diseases; Child; Clinical Trials as Topic; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Skin Diseases; Tacrolimus; Treatment Outcome

Topics: Adrenal Cortex Hormones; Animals; Cytokines; Dermatitis, Atopic; Disease Models, Animal; Humans; Immunoglobulin E; Mice; Skin; Species Specificity; Tacrolimus

Magnesium deficiency in hairless rats results in a transient erythematous rash within several days, the pathogenetic mechanisms of which are not yet well defined. However, the extremely pruritic rash closely mimics the acute clinical features of atopic dermatitis. Owing to the similarity of clinical signs between hypomagnesaemic rats and patients with atopic dermatitis, this rodent skin condition holds promise as a model for the in vivo evaluation of new treatment modalities against pruritic inflammatory skin conditions. The efficacy of the new ascomycin macrolactam derivative SDZ ASM 981 was tested in hypomagnesaemic rats by systemic or topical administration using prophylactic or therapeutic treatment regimens. Oral treatment of diseased rats with SDZ ASM 981 (12.5 mg kg-1 daily) inhibited the erythematous pruritic rash within 1 day after the start of treatment. This was associated with a clear reduction in histaminaemia, leucocytosis, eosinophilia and serum nitric oxide levels. The same daily oral dose of SDZ ASM 981 administered before the onset of the rash proved to be an efficacious prophylactic treatment regimen to prevent signs. Topical treatment of the ears with 0.4% SDZ ASM 981 locally inhibited and prevented inflammatory changes in a therapeutic and prophylactic treatment regimen, respectively. The histo- and immunopathological skin changes, as well as the numbers of degranulated mast cells in the dermis, were reversed towards normal after oral and topical administration. The pharmacological activity of SDZ ASM 981 reported here corresponds well to its anti-inflammatory and antipruritic activity observed in atopic dermatitis patients, confirming the usefulness of this rat model in drug evaluations.

Topics: Administration, Oral; Administration, Topical; Animals; Dermatitis, Atopic; Dermatologic Agents; Magnesium Deficiency; Male; Rats; Rats, Nude; Tacrolimus

Topics: Administration, Topical; Adolescent; Adult; Anti-Inflammatory Agents; Dermatitis, Atopic; Drug Resistance; Erythema; Facial Dermatoses; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Male; Ointments; Tacrolimus; Time Factors; Treatment Outcome

The immunosuppressive macrolides are a novel class of antiinflammatory substances, which could supplant glucocorticosteroids for the topical treatment of some chronic inflammatory skin diseases. Cyclosporine A (CyA), well known from transplantation medicine for years, is licensed in Germany for oral treatment of psoriasis and atopic dermatitis but is not suitable for topical therapy. Tacrolimus (FK506) penetrates the inflamed epidermis and is regarded as the key immunosuppressive macrolide. Clinical trials have demonstrated the efficacy of FK506 ointment for atopic dermatitis, many case reports have been published regarding other inflammatory skin diseases. The ascomycin derivative ASM 981 has many of the properties of FK506 but less data is available at present. Sirolimus (Rapamycin) is structurally related to FK506 but has other biological effects since its molecular actions involve different biochemical pathways. A review of the biochemical and cellular properties, mode of action, therapeutic efficacy and unwanted side effects, as well as data from clinical trials and status of licensing, is given for the respective drugs.

Topics: Administration, Topical; Clinical Trials as Topic; Cyclosporine; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Psoriasis; Sirolimus; Tacrolimus

Recent evidence suggests that 0.1% tacrolimus ointment is an effective treatment of atopic dermatitis. Tacrolimus is an immunosuppressive agent that interferes with cell-mediated immunity. We have observed 2 cases of eczema herpeticum among 36 patients with atopic dermatitis treated with a topical preparation containing 0.1% tacrolimus. A 29-year-old male patient developed generalized herpetic lesions on his face on the 4th day of treatment. His SCORAD was then 73, and the tacrolimus blood level was 7.5 ng/ml. A 23-year-old woman developed disseminated herpetic lesions on her neck, face, shoulders and legs during the 9th week of treatment. Her SCORAD was then 41, tacrolimus blood levels were <3 ng/ml 2 weeks before the infection. Herpes simplex virus type 1 antigens were identified in several lesions by direct immunofluorescence in both patients. Neither patient recalled previous episodes of cold sores. The lesions resolved quickly under intravenous acyclovir treatment but resulted in important facial scarring in the male patient.. Eczema herpeticum is a well-known complication of atopic dermatitis. Available data do not allow to link topical tacrolimus with an increased risk for eczema herpeticum, but they are insufficient to exclude an association. Future studies and careful documentation of cases are needed in order to better characterize patients at risk.

Topics: Adult; Dermatitis, Atopic; Facial Dermatoses; Female; Humans; Immunosuppressive Agents; Kaposi Varicelliform Eruption; Male; Ointments; Tacrolimus

Topics: Adult; Child; Dermatitis, Atopic; Drug Approval; Humans; Immunosuppressive Agents; Ointments; Tacrolimus; United States; United States Food and Drug Administration

The effects of FK506 (tacrolimus hydrate) ointment on cutaneous allergic reactions in mice and rats were investigated. FK506 ointment showed significant suppressive effects on delayed allergic reactions in both species, and especially in rats, its inhibitory action was much stronger than that of alclometasone dipropionate, a so-called medium class steroid ointment. On the other hand, FK506 ointment did not inhibit the immediate allergic reaction in rats. FK506 ointment suppressed the delayed allergic reactions in locally passively sensitized mice to the same degree as that in actively sensitized mice. Accordingly, it is speculated that FK506 ointment inhibits the activation of sensitized T lymphocytes (Th1 cells) already accumulated in the dermis.

Topics: Animals; Dermatitis, Atopic; Drug Evaluation, Preclinical; Female; Immunosuppressive Agents; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Inbred C57BL; Rats; Rats, Inbred BN; Rats, Inbred Lew; Tacrolimus; Tuberculin; Vasculitis, Leukocytoclastic, Cutaneous

The effects of the anticytokine interleukin 10 (IL-10) are mediated by specific receptors. In this study we examined the role of the IL-10 receptor (IL-10R) in the pathophysiology of atopic eczema.. For this purpose we analyzed the expression of IL-10R in the skin of patients with acute and chronic atopic eczema in comparison to the expression in healthy individuals using in situ binding experiments with fluorescently labeled IL-10 and semiquantitative reverse transcriptase-PCR specific for IL-10R1. In addition, we studied the influence of the Th2-associated cytokine interleukin-4 (IL-4), the Th1-associated gamma-interferon (IFN-gamma), the immunosuppressive drug FK506, the H1-antagonist loratadine and UVA irradiation on the expression of IL-10R1 in cultured normal human keratinocytes.. We found that IL-10 receptor mRNA and protein are strongly downregulated in acute phase atopic lesions. Furthermore we could show that IL-4, IFN-gamma, FK506, loratadine and UVA enhance the mRNA levels of the IL-10R1 in vitro in normal cultured keratinocytes. We could also demonstrate restored IL-10R1 mRNA levels in lesional atopic skin of a patient after UVA1 therapy.. Our results demonstrate for the first time that IL-10 receptors may have a role in the pathogenesis of atopic eczema and its upregulation by FK506 and UVA could explain the therapeutic efficacy of these agents.

Topics: Acute Disease; Adult; Aged; Cells, Cultured; Chronic Disease; Cytokines; Dermatitis, Atopic; Gene Expression Regulation; Humans; Immunosuppressive Agents; Keratinocytes; Middle Aged; Receptors, Interleukin; Receptors, Interleukin-10; RNA, Messenger; Tacrolimus; Ultraviolet Therapy

The effect of tacrolimus hydrate (FK506) ointment on spontaneous dermatitis in NC/Nga (NC) mice was examined. FK506 ointment (0.1-1%) suppressed the development of dermatitis and was also therapeutically effective against established dermatitis. Increases in CD4-positive T cells (helper T cells), mast cells, eosinophils and immunostaining of interleukin (IL)-4, IL-5 and IgE were confirmed in the skin of the NC mice, and FK506 ointment suppressed all of these changes. Increased plasma IgE was also confirmed in the NC mice, and treatment with FK506 ointment reduced the plasma IgE level. These results suggested that FK506 suppressed the dermatitis by inhibiting the activation of inflammatory cells and by blocking the cytokine network in the skin of the NC mice. The commercially available steroid ointments showed only marginal effect on the development of dermatitis and showed some signs of side effects such as alopecia or atrophy of the skin. The effect of the steroids might have been masked by these side effects because the steroids showed similar inhibitory effects on the skin histopathological changes and the increase of plasma IgE. From these results, FK506 ointment can be expected to be a useful drug for atopic dermatitis.

Topics: Animals; Dermatitis, Atopic; Disease Models, Animal; Female; Immunoglobulin E; Immunoglobulin G; Male; Mice; Ointments; Tacrolimus

Interleukin 13 (IL-13) shares several functional properties with IL-4 and has been shown to be capable of inducing IgE synthesis.. To determine whether the production of IL-13 by peripheral blood mononuclear cells (PBMC) from patients with atopic dermatitis (AD) is connected with the development of AD.. We examined PBMC from 52 patients with AD and 23 healthy volunteers as controls. PBMC were cultured with or without antigen extracted either from Dermatophagoides farinae or house dust for 48 h, and then the supernatants were measured for IL-13 by competitive enzyme immunoassay. We also examined the effect of the immunosuppressant FK506 on the production of IL-13 by antigen-stimulated PBMC from AD patients.. The levels of IL-13 produced by non-stimulated PBMC in AD were significantly higher than those in controls. The IL-13 levels in AD were increased after antigen stimulation and were higher than those in controls. Moreover, the enhanced production of IL-13 in AD was suppressed by FK506.. We suggest that IL-13 may play some role in the development of AD.

Topics: Adolescent; Adult; Allergens; Dermatitis, Atopic; Female; Humans; Immunosuppressive Agents; Interleukin-13; Leukocytes, Mononuclear; Male; Tacrolimus

The effects of tacrolimus ointment on immediate, late and delayed-type cutaneous allergic reactions and normal skin thickness were investigated in mice and compared with those of steroid ointments. Tacrolimus ointment had no effect on ear edema in the immediate phase of the biphasic reaction and did not inhibit passive cutaneous anaphylaxis, but in the late phase of the biphasic reaction, it inhibited the ear edema. It also showed a clear inhibitory effect on the delayed-type reaction. These evidence suggest that the clinical effect of tacrolimus ointment against atopic dermatitis (AD) may be mainly due to its inhibitory action on late and delayed-type reactions. The steroid ointments inhibited all the reactions mentioned above, and the effects were more potent than those of tacrolimus. Moreover, they also decreased the normal ear thickness, suggesting that the inhibitory effect of the steroid ointments was partially due to skin atrophic action. The same ointments applied to the ears during the induction phase showed an enhancement of delayed-type reaction at the effector phase. Tacrolimus ointment did not show such a rebound effect or skin atrophy. Thus, tacrolimus ointment was expected to be more useful than the steroids for the treatment of AD.

Topics: Animals; Dermatitis, Atopic; Female; Hypersensitivity, Delayed; Hypersensitivity, Immediate; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Inbred Strains; Ointments; Passive Cutaneous Anaphylaxis; Skin; Tacrolimus

Topics: Anti-Inflammatory Agents; Dermatitis, Atopic; Down-Regulation; Humans; Immunosuppressive Agents; Lymphocyte Activation; Receptors, IgE; T-Lymphocytes; Tacrolimus

Topics: Administration, Cutaneous; Dermatitis, Atopic; Humans; Ointments; Patient Dropouts; Tacrolimus

An HPLC/MS/MS assay for tacrolimus in whole blood using FR900520 as an internal standard was validated over the standard curve range of 0.100-10.040 ng ml-1. The calibration curve for tacrolimus in human blood gave a slope of 0.2481, an intercept of 0.007, and a correlation coefficient (r) of 0.9996, with no interference noted from human blood, analyte, or internal standard stock solutions. Use of EDTA or heparin as the preservative in blood resulted in no significant differences. Samples were stable for at least the time required to assay the maximum number of samples that could be placed in the automated system. The limit of sensitivity of the assay was set at the concentration of the lowest nonzero standard tested, i.e., 0.100 ng ml-1. However, validation of the assay to a limit of 0.010 ng ml-1 is currently underway. The within-run and between-run precision and accuracy of the method were determined for four quality control samples. The highest CV was seen at 0.1 ng ml-1 (17.6% within-run and 15.9% between-run), with other CV < 5%. The recovery ranged 79.6-81.3% for tacrolimus over the range 0.3-8.0 ng ml-1 and was 63.10 +/- 1.37% for FR900520. There was a linear correlation (r2 = 0.963) between assay results by HPLC/MS/MS and ELISA in whole blood from atopic dermatitis patients treated with topical tacrolimus ointment. The difference between the means +/- S.D. determined by HPLC/MS/MS (1.22 +/- 1.46 ng ml-1) and ELISA (1.12 +/- 1.29 ng ml-1) was significant by a paired t-test (P < 0.001) Similarly, there was a linear correlation (r2 = 0.841) between assay results by HPLC/MS/MS and IMx in whole blood from solid organ transplant patients treated with tacrolimus. The difference between the means was significantly higher (P < 0.001) for the IMx (15.80 +/- 8.37 ng ml-1) than the HPLC/MS/MS (13.42 +/- 6.87 ng ml-1).

Topics: Calibration; Chromatography, High Pressure Liquid; Dermatitis, Atopic; Edetic Acid; Enzyme-Linked Immunosorbent Assay; Heparin; Humans; Immunosuppressive Agents; Mass Spectrometry; Ointments; Reference Standards; Reproducibility of Results; Tacrolimus

Topics: Administration, Topical; Adolescent; Adult; Dermatitis, Atopic; Facial Dermatoses; Female; Humans; Immunosuppressive Agents; Male; Tacrolimus