tacrolimus and Dermatitis--Allergic-Contact

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

Atopic dermatitis is today the most common chronic disease of children in Europe, the US and Japan. The 'golden standard' of therapy is topical glucocorticosteroids and emollients. The steroids have been on the market for four decades, are efficacious, but only advised for short-term treatment due to their risks of side effects.. More than 16,000 persons suffering from atopic dermatitis have been enrolled in clinical studies of tacrolimus. One third of patients with moderate to severe atopic dermatitis experience over 90% improvement in their disease over a 12-week treatment period and up to 70% of patients have over 50% improvement. A 1-year treatment leads to more than 90% improvement in 75% of patients. The most pronounced side effect is a burning sensation occurring in up to 60% of patients.. Atopic dermatitis is a chronic skin disease leading to a demand for long-term treatment control. Such treatment options have not previously been available--except for emollients which are not efficacious for controlling skin inflammation. Tacrolimus and pimecrolimus are new treatment options, free from the potential side effects of topical steroids, which are known for their efficacy in short-term treatment. The new treatment modalities prevent the eczema from relapsing and at the same time they control active eczema. The future will see a shift towards the long-term use of tacrolimus which is able to control the skin inflammation and, hopefully, shorten the course of the eczema.

Topics: Adult; Anti-Inflammatory Agents; Child; Dermatitis, Allergic Contact; Humans; Hydrocortisone; Immunosuppressive Agents; Tacrolimus; Treatment Outcome

The treatment of allergic contact dermatitis remains a major challenge. Current management strategies consist of elimination of the allergen when possible and therapy for symptoms with topical or systemic corticosteroids. With increasing exposure of the human skin to environmental antigens and haptens, more selective treatment options are needed. Advances in the elucidation of the skin immune system and of the cellular and molecular events in immunologic processes may allow targeted methods of controlling delayed hypersensitivity reactions. This review focuses on mechanisms of established therapeutic agents and new developments, such as FK 506 (tacrolimus), pentoxifylline, and vitamin D3 derivative, for suppression of any phase of allergic contact dermatitis.

Topics: Allergens; Cholecalciferol; Dermatitis, Allergic Contact; Humans; Pentoxifylline; Tacrolimus

Topics: Adolescent; Adult; Aged; Child; Child, Preschool; Dermatitis, Allergic Contact; Female; Humans; Immunosuppressive Agents; Middle Aged; Ointments; Prospective Studies; Tacrolimus; Young Adult

Although topical glucocorticoids are effective for most inflammatory skin disorders, their use is limited by local and systemic side effects. Tacrolimus and pimecrolimus are immunomodulators that provide clinicians with steroid-sparing options in the long-term topical treatment of allergic contact dermatitis.. To obtain pilot data regarding the relative efficacies of pimecrolimus 1% cream, tacrolimus 0.1% ointment, clobetasol propionate 0.05% ointment, and triamcinolone acetonide 0.1% ointment, as compared to control preparations (Vanicream and petrolatum), for treatment of experimentally induced nickel contact dermatitis.. Twenty-one volunteers with positive patch test reactions to nickel sulfate 5% at six sites (three on each arm) applied each study medication to one nickel site, respectively, twice daily for 14 days. Study medications were prepared in identical syringes, and the site of application was randomly assigned by a computer-generated randomization schedule. Assessments were performed at 3, 7, 10, and 14 days after randomization.. Most reactions were coded as resolved or as almost resolved by day 14 regardless of treatment. Although most pairwise comparisons were not statistically significant, a clear trend was observed for sites treated with active drug to do better than control sites.. Possible explanations for these results include contamination by neighboring medication sites, timing of assessments, and lack of repeated nickel applications.

Topics: Administration, Cutaneous; Adrenal Cortex Hormones; Adult; Allergens; Clobetasol; Dermatitis, Allergic Contact; Double-Blind Method; Female; Humans; Immunologic Factors; Male; Nickel; Petrolatum; Pilot Projects; Severity of Illness Index; Tacrolimus; Treatment Outcome; Triamcinolone

The low concentration of propylene glycol (PG) in pimecrolimus cream makes it unlikely that the cream will induce a PG-related irritant or allergic contact dermatitis.. To assess reactions to pimecrolimus cream in patients who are allergic to PG.. A pilot double-blind within-patient study in 20 patients, with patch testing followed by a repeated open application test (ROAT). Limitations were that patch tests and ROATs were performed on normal skin, which may be less likely to develop an allergic response than would areas of active dermatitis.. Positive PG patch-test results were confirmed in 16 patients. Patch-test scores were compatible with allergic reactions in only two patients. However, ROAT scores were negative for these two patients. Reactions with pimecrolimus or vehicle during ROAT were identified in three patients, but an allergic reaction was uncertain because none of these patients reacted with both pimecrolimus cream and vehicle. Reactions with pimecrolimus were significantly less frequent (p<.01) and less severe (p=.02) than with PG.. In patients allergic to PG, pimecrolimus cream showed a very low potential to elicit allergic skin reactions.

Topics: Administration, Cutaneous; Adult; Allergens; Anti-Inflammatory Agents, Non-Steroidal; Dermatitis, Allergic Contact; Double-Blind Method; Female; Humans; Male; Patch Tests; Pharmaceutical Vehicles; Pilot Projects; Propylene Glycol; Skin; Tacrolimus; Treatment Outcome

Tolerability and safety of 0.1% tacrolimus ointment in treating nickel-induced allergic contact dermatitis (ACD) were evaluated.. Patients allergic to nickel applied nickel patches to each upper inner aspect of the arm for 4 to 8 hours daily. Tacrolimus was applied to patch site on one arm and vehicle to patch site on the other, twice daily. Physician's Global Assessment, signs and symptoms of ACD, pruritus scores, and adverse events were evaluated.. After 8 weeks, dermatitis in 45% of patients was clear or almost clear (Physician's Global Assessment) with tacrolimus; and 1% with vehicle (P < .001). Significant results were achieved as early as day 8. Tacrolimus was superior in ACD signs and symptoms improvement and pruritus reduction (P < .001). Adverse events were similar between treatments.. This model, involving one agent, may not be generalizable for other agents.. Tacrolimus ointment 0.1% is well tolerated and significantly more effective than vehicle in treating chronically exposed, nickel-induced ACD.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Chronic Disease; Dermatitis, Allergic Contact; Double-Blind Method; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Nickel; Ointments; Prospective Studies; Tacrolimus

Tacrolimus is a macrolactam that prevents the transcription of messenger RNA for various inflammatory cytokines in both helper T cells (types 1 and 2) (T(H)1 and T(H)2). It is currently approved for the treatment of moderate to severe atopic dermatitis, a Th2-mediated disease, in children and adults.. We sought to evaluate the safety and efficacy of tacrolimus ointment 0.1% in the treatment of nickel-induced allergic contact dermatitis, a T(H)1-mediated disease.. This was a double-blind, randomized, vehicle-controlled, bilateral paired comparison study to assess the safety and efficacy of topical tacrolimus (Protopic, Fujisawa Healthcare Inc, Deerfield, Ill) ointment 0.1% in the treatment of allergic contact dermatitis induced by nickel sulfate. Volunteers were individuals with known hypersensitivity to nickel. Reactivity to nickel was graded both as the investigator's global assessment and total signs and symptoms, which consisted of the cumulative grade from 0 to 4 for each of the following parameters: erythema, induration, vesiculation, and pruritus (range of scores: 0-16). Reactivity was assessed in the per-protocol group at 1 and 2 weeks after beginning treatment with study drug and control. Adverse events were assessed in the intent-to-treat population.. Of the 19 volunteers who completed the study (per protocol), 18 had an improvement in total signs and symptoms with tacrolimus versus 10 patients with the vehicle. Of patients, 80% had an improvement in the investigator's global assessment score on the tacrolimus-treated site versus 30% of patients on the placebo-treated site. Overall, tacrolimus was more effective than placebo in ameliorating the nickel reaction. Although the tacrolimus treated site was clear or almost clear in a greater number of individuals at week 1, this difference did not become significant until the second week of the study. Other than application site burning in 25% of volunteers, no significant adverse events were noted in the intent-to-treat population.. Topical tacrolimus (Protopic, Fujisawa Healthcare Inc) ointment 0.1% may be an option for the treatment of allergic contact dermatitis induced by nickel.

Topics: Administration, Topical; Adult; Cross-Over Studies; Dermatitis, Allergic Contact; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Middle Aged; Nickel; Ointments; Patch Tests; Reference Values; Risk Assessment; Severity of Illness Index; Tacrolimus; Treatment Outcome

Contact dermatitis is a common clinical problem, with prevalent sensitizers being cosmetics, metals, medicines, and plants. Plants of the Toxicodendron species cause allergic contact dermatitis (ACD) in 50% to 70% of the population. Pimecrolimus is an ascomycin macrolactam developed for the treatment of inflammatory skin diseases and approved by the US Food and Drug Administration for atopic dermatitis. There are studies supporting the effectiveness of macrolactams when administered before antigen challenge, but there are no studies describing the effectiveness of these drugs in the treatment of established human ACD.. To investigate the effect of topical pimecrolimus in the treatment of Toxicodendron-induced ACD once rash is evident.. Poison ivy tincture was applied to the bilateral anterior forearms of 12 subjects with Finn Chambers (Allerderm Diagnostic Products, Petaluma, CA). After dermatitis was evident, volunteers treated each arm twice daily with either 1% topical pimecrolimus cream or placebo in a blinded fashion. Outcomes measured were a dermatitis grading score and time to rash and itch resolution.. The median +/- SEM time for rash resolution was 16.55 +/- 1.59 days in the treatment group and 16.27 +/- 1.82 days in the placebo group (P = 0.601). The median time for itch resolution was 4.73 +/- 1.56 days in the treatment group and 4.91 +/- 1.59 days in the placebo group (P = 0.167). The average dermatitis score was 2.26 +/- 0.17 in the treatment group and 2.32 +/- 0.15 in the placebo group (P = 0.62).. The application of topical pimecrolimus is ineffective in the treatment of ongoing Toxicodendron-induced ACD.

Topics: Administration, Topical; Adolescent; Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; Dermatitis, Allergic Contact; Dermatitis, Toxicodendron; Dermatologic Agents; Exanthema; Female; Humans; Male; Middle Aged; Pruritus; Severity of Illness Index; Tacrolimus; Time Factors; Treatment Outcome

The aim of this study was to evaluate the ability of topical tacrolimus 0.1% under occlusion for 48 h to suppress nickel-elicited allergic contact dermatitis in a randomized, petrolatum- and mometasone furoate 0.1% ointment-controlled double-blind, intra-individual study which included 28 women volunteers. 3 closed patch tests (Finn Chambers on Scanpor, Epitest Ltd Oy, Tuusula, Finland) containing 0.1 ml of 5% nickel sulfate in petrolatum were applied on day 0. After removal on day 2, the study compounds were applied under occlusion for 48 h. The eczema reaction and the degree of erythema were evaluated clinically and by reflectance spectrophotometry at days 4 and 7, respectively. Mean visual scores corresponding to petrolatum-treated sites were significantly higher than those corresponding to both mometasone furoate and tacrolimus at days 4 (P < 0.001) and 7 (P < 0.001). In both tacrolimus- and mometasone furoate-treated sites, there was a significant decrease in visual scores with time (P < 0.001) from day 2 to day 7, and the corresponding mean decreases in scores were 0.73 and 1.04, respectively. The difference between both was 0.30 in favour of tacrolimus (95% confidence intervals, -0.04 and 0.65), although this did not reach statistical significance (P = 0.084). Mean erythema index values were similar at day 2. Significant differences among treatment sites were seen at days 4 (P < 0.001) and 7 (P < 0.001). The decrease was significantly more pronounced on day 7 in patches where tacrolimus had been supplied (P < 0.5). This method might provide useful means to compare different concentrations and/or presentations of tacrolimus or other calcineurin inhibitors and topical anti-inflammatory agents.

Topics: Administration, Topical; Adult; Anti-Allergic Agents; Dermatitis, Allergic Contact; Dose-Response Relationship, Drug; Double-Blind Method; Emollients; Erythema; Female; Humans; Immunosuppressive Agents; Irritants; Middle Aged; Mometasone Furoate; Nickel; Ointments; Patch Tests; Petrolatum; Pregnadienediols; Spectrophotometry; Tacrolimus; Time Factors

Topics: Adult; Dermatitis, Allergic Contact; Dermatologic Agents; Dose-Response Relationship, Drug; Eczema; Female; Humans; Tacrolimus

Topics: Adult; Anti-Bacterial Agents; Dermatitis, Allergic Contact; Dermatologic Agents; Facial Dermatoses; Female; Humans; Lip Diseases; Mupirocin; Patch Tests; Tacrolimus

Contact hypersensitivity (CHS) is thought to be associated mainly with the activation of T helper (Th) type 1 cells. However, evidence also suggests that Th type 2 cells (Th2) and cytokines play roles in the development of CHS in humans. The present study examines the Th2 response during the development of CHS in response to 2,4,6-trinitrochlorobenzene (TNCB) in GATA-3-transgenic (GATA-3 Tg) mice. GATA-3 Tg mice were immunized with 7% TNCB applied to abdominal shaved skin. Seven days later, the mice were challenged with 1% TNCB applied to the left ear. Ear swelling, cytokine production in the skin of the ear, and the levels of IgE, IgG1 and IgG2a were measured. Furthermore, we examined the effects of medical treatment on TNCB-induced contact dermatitis using this model. The ear-swelling responses of TNCB-sensitized/challenged GATA-3 Tg mice were significantly greater than those of similarly treated wild-type (WT) mice. The expression of both IL-5 and IL-13 in TNCB sensitized/challenged skin tissues and the IgE response after challenge were obviously increased in the GATA-3 Tg mice, whereas the expression of IFN-γ was identical in the challenged skin tissues of GATA-3-Tg and WT mice. When TNCB-sensitized GATA-3 Tg mice were treated with a high dose of tacrolimus, ear swelling was not significantly decreased, compared with the results in WT mice. These results suggest that GATA-3-induced Th2-dominant responses play a critical role in the pathogenesis of allergic types of dermatitis, such as atopic dermatitis, and may lead to useful new drug development in the future.

Topics: Animals; Cell Separation; Cells, Cultured; Dermatitis, Allergic Contact; Disease Models, Animal; Flow Cytometry; GATA3 Transcription Factor; Gene Expression Regulation; Humans; Immunization; Immunoglobulin E; Interleukin-13; Interleukin-5; Mice; Mice, Inbred C57BL; Mice, Transgenic; Picryl Chloride; Skin; Tacrolimus; Th2 Cells

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

Knowledge of the effect of topically applied calcineurin antagonists such as tacrolimus on the sensitization phase of allergic contact dermatitis is currently limited.. To investigate tacrolimus-dependent immunomodulation on gene expression alterations in human antigen-presenting cells which are stimulated with small-molecular-weight contact allergens.. Monocyte-derived dendritic cells (moDC) and THP-1 cells were stimulated with the contact sensitizer cinnamic aldehyde (CAld) and compared with the very strong experimental sensitizer 2,4,6-trinitrobenzene sulfonic acid (TNBS) in vitro. Quantitative PCR analysis was used to detect gene expression changes, particularly of interleukin (IL) 8, as an indicator of differential dendritic cell (DC) gene expression after sensitizer stimulation in the absence or presence of tacrolimus and betamethasone at two different concentrations.. DC activation was clearly demonstrated by a significant IL-8 upregulation after 24 h, whereas tacrolimus or betamethasone alone did not affect IL-8 baseline expression. Betamethasone and, to a lesser extent, tacrolimus led to a marked reduction of chemical-induced IL-8 expression by TNBS and CAld.. The results of the present study support the hypothesis that the calcineurin inhibitor tacrolimus has modulatory effects on human antigen-presenting cells during the sensitization phase of allergic contact dermatitis. In addition, moDC as well as THP-1 cells may serve as a system to study immune-modulating effects of drugs such as glucocorticoids or calcineurin antagonists.

Topics: Acrolein; Antigen-Presenting Cells; Betamethasone; Cell Line, Tumor; Dendritic Cells; Dermatitis, Allergic Contact; Gene Expression Regulation; Humans; Immunosuppressive Agents; Interleukin-8; Monocytes; Polymerase Chain Reaction; Tacrolimus; Trinitrobenzenesulfonic Acid

Topics: Adrenal Cortex Hormones; Dermatitis, Allergic Contact; Female; Humans; Middle Aged; Papaveraceae; Tacrolimus

Topics: Child; Dermatitis, Allergic Contact; Dermatologic Agents; Eczema; Female; Humans; Ointments; Patch Tests; Tacrolimus

The contact with a jellyfish is usually followed by acute inflammatory lesions, characterized by erythema, swelling, vesicles, and bullae, accompanied by burning and pain sensation. The pathogenesis is due to the direct toxic effect of the fluid contained in jellyfish tentacles. Sometimes, jellyfish may induce delayed cutaneous lesions. Delayed cutaneous reaction to jellyfish represents a clinical entity where eczematous lesions develop after days or months after contact with the invertebrate. We report the case of a patient with a delayed and persistent skin reaction due to jellyfish envenomation successfully treated with pimecrolimus.

Topics: Administration, Topical; Adolescent; Animals; Bites and Stings; Dermatitis, Allergic Contact; Female; Follow-Up Studies; Humans; Hypersensitivity, Delayed; Leg Dermatoses; Risk Assessment; Scyphozoa; Severity of Illness Index; Skin Tests; Tacrolimus; Time Factors; Treatment Outcome

Topics: Adolescent; Dermatitis, Allergic Contact; Humans; Immunosuppressive Agents; Male; Patch Tests; Tacrolimus

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

Pimecrolimus suppresses the proinflammatory cytokine production of cutaneous T and mast cells (1). It is used to treat atopic dermatitis and is the active ingredient in the topical formulation pimecrolimus 1.0% cream (Elidel, Novartis Pharma AG, Basel, Switzerland).

Topics: Aged; Dermatitis, Allergic Contact; Dermatologic Agents; Female; Humans; Tacrolimus

Topics: Dermatitis, Allergic Contact; Humans; Immunosuppressive Agents; Occupational Diseases; Ointments; Tacrolimus

Topics: Administration, Topical; Calcineurin Inhibitors; Dermatitis, Allergic Contact; Drug Hypersensitivity; Humans; Immunosuppressive Agents; Propolis; Tacrolimus; Waxes

Topics: Adult; Allergens; Dermatitis, Allergic Contact; Female; Humans; Immunosuppressive Agents; Kaposi Varicelliform Eruption; Potassium Dichromate; Tacrolimus

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

We report an atopic dermatitis patient with recurrent hand dermatitis who developed a severe allergic contact dermatitis from the use of Elidel cream. Diagnostic patch tests showed an isolated contact allergy to the emulsifier oleyl alcohol present in the product. Pimecrolimus appeared to have had an aggravating effect on the dermatitis in spite of its immunosuppressive effects. The initial clinical appearance of the patient's widespread dermatitis was atypical with resemblance to subacute cutaneous lupus erythematosus. Even though emulsifiers are widely used in topical products, contact allergic reactions to these are relatively uncommon.

Topics: Adult; Allergens; Calcineurin Inhibitors; Dermatitis, Allergic Contact; Dermatologic Agents; Diagnosis, Differential; Exanthema; Fatty Alcohols; Female; Humans; Patch Tests; Tacrolimus

Nanocrystalline silver has both antimicrobial and anti-inflammatory properties. However, the exact mechanisms underlying these activities are not known.. The objectives of this study were to assess the anti-inflammatory effects of nanocrystalline silver using a murine model of allergic contact dermatitis, compare the effects with those of tacrolimus and a high potency steroid, and to relate the effects to modulation of pro-inflammatory cytokines and apoptosis of inflammatory cells.. Dermatitis was induced on the ears of BALB/c mice using dinitrofluorobenzene. Topical treatment, including vehicles, 1% nanocrystalline silver cream, tacrolimus ointment and a high potency steroid, was applied once a day for 4 days. Ear swelling was measured and the erythema was evaluated daily. After 4 days of treatment the mice were killed and samples from the ears were collected for histological and immunohistochemical examination, terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick end labelling (TUNEL) staining and extraction of total RNA for reverse transcriptase polymerase chain reaction (RT-PCR).. Significant reductions of ear swelling, erythema and histopathological inflammation in mice ears were observed after 4 days of treatment with 1% nanocrystalline silver cream, tacrolimus ointment or a high potency steroid with no significant difference among them. Both RT-PCR and immunohistochemical staining of sections from ear biopsies demonstrated that nanocrystalline silver, tacrolimus and steroid significantly suppressed the expression of tumour necrosis factor (TNF)-alpha and interleukin (IL)-12. TUNEL staining demonstrated a significant increase in the numbers of apoptotic cells in material from the group treated with nanocrystalline silver when compared with that from groups treated with vehicle, tacrolimus or steroid.. This study demonstrates that nanocrystalline silver inhibits allergic contact dermatitis in mice, similar to steroid and tacrolimus. Nanocrystalline silver suppresses the expression of TNF-alpha and IL-12 and induces apoptosis of inflammatory cells; mechanisms by which nanocrystalline silver may exert its anti-inflammatory effects.

Topics: Animals; Anti-Inflammatory Agents; Apoptosis; Crystallization; Dermatitis, Allergic Contact; Dinitrofluorobenzene; Female; Glucocorticoids; Immunohistochemistry; Immunosuppressive Agents; In Situ Nick-End Labeling; Interleukin-12; Mice; Mice, Inbred BALB C; Models, Animal; Nanostructures; Ointments; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Silver; Staining and Labeling; Tacrolimus; Tumor Necrosis Factor-alpha

Cilomilast and tacrolimus as well as rapamycin are potential drugs for the treatment of allergic skin diseases like atopic dermatitis and allergic contact dermatitis.. To compare the in vitro and in vivo immunomodulatory effects of the phosphodiesterase 4 inhibitor cilomilast with those of tacrolimus and rapamycin.. The in vitro action of cilomilast, tacrolimus and rapamycin were tested in a mixed leucocyte reaction (MLR). In vivo, the inhibitory action of the immunomodulatory drugs was compared in the toluene-2,4-diisocyanate (TDI)-induced allergic inflammatory response with particular focus on dendritic cell (DC) function.. Cilomilast, tacrolimus and rapamycin were all able to inhibit DC-mediated T-cell activation in a MLR. But it was demonstrated for cilomilast that the target cells are T cells rather than DC. In vivo, a combination of systemic and topical administration of each of these three substances significantly inhibited swelling in the murine ear 16 h after TDI challenge. There was also a reduction in the weight of the draining auricular lymph node, in lymphocyte cell count, and in the number of emigrated DC. The density of Langerhans cells in the epidermis was correspondingly higher in mice treated with cilomilast, tacrolimus and rapamycin than in those treated with vehicle. All three substances were found to inhibit DC migration ex vivo in a skin DC migration assay performed on ear tissue after TDI challenge.. DC migration into the draining lymph node also takes place in the elicitation phase of allergic contact dermatitis and this migration can be influenced by tacrolimus and rapamycin, and, to a lesser extent, by cilomilast.

Topics: Animals; Carboxylic Acids; CD11c Antigen; Cells, Cultured; Cyclohexanecarboxylic Acids; Cytokines; Dendritic Cells; Dermatitis, Allergic Contact; Female; Histocompatibility Antigens Class II; Immunosuppressive Agents; Langerhans Cells; Leukocyte Count; Lipopolysaccharides; Lymph Nodes; Lymphocyte Culture Test, Mixed; Matrix Metalloproteinase 9; Mice; Mice, Inbred BALB C; Nitriles; Organ Size; Sirolimus; Skin; Tacrolimus

A 35-year-old man developed well-demarcated, oedematous and erosive erythematous lesions on the nasal bridge and retroauricular regions bilaterally. His eyeglass frame was repaired by an optician 2 weeks prior to symptom onset. Patch testing revealed a positive reaction to scrapings of nose pads and temples of the frame in petrolatum. Because the patient did not take our exhortation to change eyeglass frames, we advised him to cover their nose pads and temples with vinyl tape to prevent direct skin contact. Although topical corticosteroid therapy produced clinical resolution temporally, recurrences were not prevented. After starting tacrolimus ointment therapy, recurrence has not occurred for 9 months. Tacrolimus may be effective for allergic contact dermatitis patients who cannot avoid repeated allergen exposure, as it may not only reduce inflammation but inhibit recurrences.

Topics: Adult; Coloring Agents; Dermatitis, Allergic Contact; Eyeglasses; Humans; Immunosuppressive Agents; Male; Ointments; Patch Tests; Phenylenediamines; Secondary Prevention; Tacrolimus

Topics: Administration, Topical; Adult; Dermatitis, Allergic Contact; Dermatitis, Occupational; Female; Food Handling; Humans; Immunosuppressive Agents; Proteins; Tacrolimus

The anti-inflammatory activity of topical nanocrystalline silver cream was assessed and compared with the effects of topical steroids and currently available immunosuppressants using a guinea pig model of allergic contact dermatitis. Dermatitis was induced with dinitrochlorobenzene and treated with different concentrations of nanocrystalline silver, medium and high potency steroids, tacrolimus and pimecrolimus, or appropriate vehicles once daily for 5 days. Erythema was evaluated daily (on a score of 0 to 4, from absent to very severe) and histopathology of the skin biopsies was evaluated after 5 days of treatment. Prior to treatment, the average scores of erythema in all the groups were in the range of 3(+) to 4(+). In the no treatment and vehicles groups these scores remained at about this level for the subsequent 5 days of the study. Nanocrystalline silver reduced erythema within 1 day of treatment in a concentration-dependent manner with significant reduction at silver concentrations of 0.5% and 1% (P < 0.05) and this reduction progressed throughout the study period. Steroids and immunosuppressants produced similar decreases in erythema, with no significant differences compared to 0.5% and 1% nanocrystalline silver. In skin biopsies scored for degree of inflammatory response, effects of treatments mirrored erythema results. This study suggests that nanocrystalline silver cream may have therapeutic potential for topical treatment of inflammatory skin diseases.

Topics: Administration, Cutaneous; Animals; Anti-Inflammatory Agents, Non-Steroidal; Dermatitis, Allergic Contact; Dermatologic Agents; Dinitrochlorobenzene; Disease Models, Animal; Female; Glucocorticoids; Guinea Pigs; Immunosuppressive Agents; Nanotechnology; Silver; Tacrolimus

A 9-year-old boy developed allergic contact dermatitis from tacrolimus ointment. Tacrolimus was proven to be the allergen by right-versus-left double-blinded provocative use testing of tacrolimus ointment 0.1% versus inactive vehicle applied twice daily to normal preauricular and antecubital skin. Facial dermatitis appeared after 1 week and antecubital dermatitis after 7 weeks. Furthermore, patch testing of each individual ingredient was positive only with tacrolimus; a concentration of 2.5% in ethanol was required. Forty control patients had negative patch tests with tacrolimus 5% in ethanol. We hypothesize that the unusually long time required to elicit a positive use test on the arm and the high patch test concentration required on the back are caused by low percutaneous absorption through normal extrafacial skin. This is likely to be caused in part by the high molecular weight of tacrolimus. A similar phenomenon may occur when patch testing with neomycin sulfate.

Topics: Child; Dermatitis, Allergic Contact; Humans; Immunosuppressive Agents; Male; Ointments; Patch Tests; Tacrolimus

Topics: Case-Control Studies; Catechols; Dermatitis, Allergic Contact; Dermatitis, Contact; Dermatitis, Irritant; Dermatitis, Toxicodendron; Humans; Immunosuppressive Agents; Ointments; Pilot Projects; Single-Blind Method; Sodium Dodecyl Sulfate; Surface-Active Agents; Tacrolimus; Toxicodendron

Pimecrolimus (SDZ ASM 981), an ascomycin derivative, inhibits the phosphatase calcineurin and blocks the production of inflammatory cytokines in T cells. In contrast to corticosteroids, pimecrolimus has a cell selective mode of action, exerting e.g. no effect on dendritic cells, which have a central function in the skin-associated immune system. Pimecrolimus shows less permeation through skin than corticosteroids and tacrolimus which indicates a lower potential for systemic side effects after topical application. In animal models pimecrolimus has a marked dose-dependent anti-inflammatory activity. However, treatment with pimecrolimus does not induce skin atrophy in contrast to corticosteroids. In contrast to tacrolimus, pimecrolimus does not impair the primary immune reaction in the sensitization phase of allergic contact dermatitis and has generally less effect on systemic immune reactions. In summary, the pharmacological profile of pimecrolimus suggests high clinical efficacy together with excellent safety.

Topics: Administration, Topical; Animals; Betamethasone Valerate; Calcineurin Inhibitors; Cytokines; Dermatitis, Allergic Contact; Disease Models, Animal; Drug Evaluation, Preclinical; Humans; Immunosuppressive Agents; Langerhans Cells; Mice; Rats; Swine; T-Lymphocytes; Tacrolimus

The development of topical calcineurin inhibitors resulted in a significant improvement in the treatment of inflammatory skin diseases such as atopic dermatitis. In addition, an excellent amelioration of pruritus could be observed. Other itchy dermatoses such as chronic irritative hand dermatitis, rosacea, graft-versus-host-disease, renal pruritus, lichen sclerosus, prurigo simplex, prurigo nodularis, scrotal eczema, and inverse psoriasis also have been treated successfully with pimecrolimus and tacrolimus. The antipruritic effect currently is believed to be related to the inhibition of inflammatory cytokines. Furthermore, recent investigations indicate a release of neuropeptides from sensory nerve fibers and degranulation of mast cells mediated by pimecrolimus and tacrolimus. Similar effects have been observed during capsaicin treatment. These findings may provide a possible explanation for initially observed calcineurin inhibitors related side-effects such as burning and pruritus. Moreover, the antipruritic potency may be related to a direct effect on nerve fibers leading to suppression of itch mediated by unknown mechanisms.

Topics: Administration, Topical; Animals; Antipruritics; Calcineurin Inhibitors; Dermatitis, Allergic Contact; Humans; Immunosuppressive Agents; Mast Cells; Microscopy, Fluorescence; Neuropeptides; Pruritus; Skin; Substance P; Tacrolimus; Treatment Outcome

Pimecrolimus (SDZ ASM 981, Elidel) is a nonsteroid inflammatory cytokine inhibitor specifically developed for the treatment of inflammatory skin diseases. Its effect on the elicitation and sensitization phases of oxazolone-induced contact hypersensitivity was compared with tacrolimus and cyclosporine A (CyA) in BALB/c mice using the ear swelling assay. The compounds were administered orally. Elicitation was dose-dependently inhibited by all three compounds. The minimal effective doses were 30 mg per kg (pimecrolimus, tacrolimus) and 90 mg per kg (CyA), respectively. There was no impairment of sensitization by pimecrolimus up to the highest dose tested (120 mg per kg), in contrast to CyA (60% inhibition at 60 mg per kg) and tacrolimus (71% inhibition at 30 mg per kg). Weight and cellularity of the draining lymph nodes in mice treated with tacrolimus or CyA during sensitization were reduced. In addition, proliferation of T cells after secondary stimulation was inhibited in cell cultures from lymph nodes of mice treated with tacrolimus or CyA. Thus, in contrast to tacrolimus and CyA, pimecrolimus exerts a more selective immunomodulatory effect. It does not impair the primary immune response (sensitization phase) but effectively inhibits the secondary phase, the elicitation phase that is the clinical manifestation of contact hypersensitivity.

Topics: Animals; Cell Division; Cells, Cultured; Cyclosporine; Dermatitis, Allergic Contact; Dermatologic Agents; Female; Immunosuppressive Agents; Lymph Nodes; Male; Mice; Mice, Inbred BALB C; T-Lymphocytes; Tacrolimus

Chronic allergic contact dermatitis was induced in rat ear by repeated application of oxazolone. This dermatitis was accompanied by sustained ear swelling and marked epidermal hyperplasia. In the induced ear, there was marked inflammatory cell infiltration into the dermis site and the interferon-gamma amount increased in both protein and mRNA, while the interleukin-4 amount changed minimally. Topical administration of FK506 (tacrolimus hydrate) dramatically suppressed ear swelling and epidermal hyperplasia as well as the increase in interferon-gamma expression. Betamethasone valerate also showed suppressive effects, but 1,25-dihydroxyvitamin D(3) (calcitriol) had no effect. These results suggest that interferon-gamma plays an important role in dermatitis and this model could be a useful pharmacological model for chronic dermatitis featuring epidermal hyperplasia in which interferon-gamma plays a crucial role, such as psoriasis. FK506 demonstrating suppressive effects as potent as those of betamethasone valerate shows potential as a topically usable drug for such skin disorders.

Topics: Animals; Betamethasone; Calcitriol; Dermatitis, Allergic Contact; Ear; Enzyme-Linked Immunosorbent Assay; Glucocorticoids; Immunosuppressive Agents; Interferon-gamma; Interleukin-4; Oxazolone; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Skin; Tacrolimus

Soft tissue augmentation with bovine collagen is a common and safe aesthetic procedure. Despite adequate pretreatment testing, allergic reactions can develop. The medical literature provides little guidance to the clinician in the management of bovine collagen hypersensitivity.. We describe a case of bovine collagen allergy treated with 0.1% topical tacrolimus and corticosteroids.. Clinical evaluation and management of a patient with bovine collagen hypersensitivity.. Our patient responded to combined therapy with oral corticosteroids and topical tacrolimus.. Topical tacrolimus may be a useful first-line or adjuvant therapy in the management of bovine collagen allergic reactions. Further clinical experience with its use for bovine collagen hypersensitivity is required to determine its true efficacy in this condition.

Topics: Administration, Oral; Administration, Topical; Animals; Cattle; Collagen; Cosmetic Techniques; Dermatitis, Allergic Contact; Drug Therapy, Combination; Humans; Hypersensitivity, Delayed; Injections; Intradermal Tests; Prednisone; Retreatment; 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: Administration, Topical; Allergens; Anti-Inflammatory Agents, Non-Steroidal; Dermatitis, Allergic Contact; Dermatologic Agents; Humans; Nickel; Ointments; Patch Tests; Skin; Tacrolimus

Topical FK506 has recently been shown to have an anti-inflammatory effect in vivo in humans. In this study its effects in contact dermatitis were studied in the guinea pig model. Topical FK506 suppressed both irritant and allergic patch-test reactions. The most prominent suppressive effect was seen when skin sites were pretreated with FK506. Topical FK506 did not impair the induction of contact allergy as assessed by challenges, although it suppressed local lymph node cell accumulation during contact allergy induction. Topical FK506 may hold promise as a treatment for skin disorders that respond to oral FK506 or cyclosporin A.

Topics: Administration, Topical; Animals; Cell Division; Cyclosporine; Dermatitis, Allergic Contact; Dermatitis, Irritant; Guinea Pigs; Lymph Nodes; Tacrolimus