Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.3.16 (calcineurin)
 17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Facial and flexural psoriasis may impair the quality of life of psoriatic patients considerably. For the adequate management of psoriasis it is important to pay attention to lesions at these sensitive sites, which require an approach different to that for lesions on other sites in several respects. An extensive literature search was carried out to collect evidence-based data on facial and flexural psoriasis with respect to epidemiology, clinical aspects, pathogenetic factors and various treatments. Subsequently, a panel of experts, the Copenhagen Psoriasis Working Group (CPWG), discussed these aspects and several recommendations were formulated reconciling the evidence-based data. Facial psoriasis occurs in 17-46% of psoriatics and flexural psoriasis is experienced by 6.8-36% of patients with psoriasis. Therefore, psoriasis at these sites cannot be regarded as a rare manifestation. Facial psoriasis is a prognostic marker indicating a poor prognosis of psoriasis. Facial and flexural psoriasis cannot be regarded as distinct disease entities but rather as site variations. The clinical features of facial psoriasis suggest that there are three subtypes: hairline psoriasis, sebo-psoriasis and true facial psoriasis. Otitis externa and ocular manifestations should not be neglected. Evidence that microbiological factors may be relevant to facial and flexural psoriasis is virtually absent. For facial psoriasis the response to UV radiation is variable. At least 5% of psoriatics have photosensitive psoriasis. In these patients photosensitive diseases such as lupus erythematodes and polymorphic light eruption have to be excluded. Based on the literature assessment and working group discussions the CPWG concluded the following. (1) Low-potency topical corticosteroids, vitamin D3 analogues and calcineurin inhibitors are first choice treatments in facial and flexural psoriasis. Evidence for the efficacy of the first two modalities is at level 3 while it is at level 1 for the third one. An individualized approach is indicated; for example, in case of corticosteroid side effects in the past the other two modalities should be selected and in unstable psoriasis prone to irritation, monotherapy with vitamin D3 analogues should be avoided. (2) Antimicrobial treatments are not indicated for facial and flexural psoriasis. (3) Dithranol and tar treatment are not indicated as first-line treatment but only if the first-line options fail. (4) In case topical therapies are not effective, phototherapy and systemic treatments are indicated. (5) For future drug development the combination of vitamin D3 analogues with low strength corticosteroids is recommended.
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PMID:Psoriasis of the face and flexures. 1790 13

Ciclosporin and tacrolimus are calcineurin inhibiting immunosuppressant agents useful in the treatment of immune-mediated inflammatory dermatoses. Available data and clinical experience demonstrate ciclosporin's efficacy in treating psoriasis, atopic dermatitis, pyoderma gangrenosum, lichen planus, autoimmune bullous disease (in combination with corticosteroids), recalcitrant chronic idiopathic urticaria, and chronic dermatitis of the hands and feet. Although the role of topical tacrolimus in atopic dermatitis is well established, such experience with the oral formulation of tacrolimus has been limited. However, there are several case studies and anecdotal reports of the successful use of oral tacrolimus in various dermatoses. In this article we discuss the utility of systemic ciclosporin and tacrolimus in dermatology.
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PMID:Systemic ciclosporin and tacrolimus in dermatology. 1797 Aug 89

SDZ ASM 981 is an anti-inflammatory macrolactam which binds with high affinity to macrophilin-12. The resulting complex inhibits calcineurin, thus blocking the synthesis of inflammatory cytokines. Twice daily application of topical SDZ ASM 981 1% cream was effective in the treatment of atopic dermatitis in adults and children in clinical trials. Summarised results from 260 patients with atopic dermatitis indicate that the efficacy of SDZ ASM 981 is dose dependent. The highest concentration evaluated (1% cream) was not as effective as betamethasone valerate 1% cream in this 3-week trial. The efficacy of SDZ ASM 981 and clobetasol ointments, used under occlusion, did not differ significantly in 10 patients with chronic psoriasis. Likewise, SDZ ASM 981 0.6% and betamethasone valerate 1% creams were similarly effective in 66 patients with allergic contact dermatitis. Concentrations of SDZ ASM 981 in the blood during topical treatment were invariably below 2.1 microg/L. Oral SDZ ASM 981 20mg or 30mg twice daily were effective in a dose dependent manner in the reduction of psoriasis in adults with no evidence of adverse effects. SDZ ASM 981 was well tolerated in the available trials, exhibiting no potential for systemic adverse reactions and no atrophogenic potential, a problem commonly associated with corticosteroid treatment.
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PMID:Sdz asm 981. 1803 82

The topical calcineurin inhibitors pimecrolimus (Elidel) and tacrolimus (Protopic) were initially developed for the treatment of atopic eczema (atopic dermatitis), a chronic or chronically relapsing skin condition most prevalent in infants and children. Their main advantages compared with conventional topical corticosteroid therapy are that they are more selective in their mode of action, do not induce skin atrophy and are not associated with significant systemic absorption. In addition, topical calcineurin inhibitors may represent a useful alternative to topical corticosteroids for the treatment of a number of other inflammatory skin diseases. Preferred sites for the use of topical calcineurin inhibitors are areas such as the face, neck, flexures, and genital areas, which are more susceptible to topical corticosteroid side effects. The efficacy of topical calcineurin inhibitors has been demonstrated for flexural psoriasis, seborrhoeic, contact and hand eczema. Preliminary data also support the efficacy of topical calcineurin inhibitors in lichen planus, facial lupus erythematosus, autoimmune bullous dermatosis, and vitiligo. In these latter indications, controlled studies are needed to better understand the efficacy and safety of topical calcineurin inhibitors and their role in disease management.
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PMID:Potential new indications of topical calcineurin inhibitors. 1817 92

Psoriasis comprises a broad spectrum of different clinical courses among which the chronic stable psoriasis by far occurs most frequently. The clinical presentation ranges from mild disease to more serious forms involving large areas of skin and/or joint disease. A number of modifying factors may impact on treatment choice in individual cases (eg, location of the lesions, disease phase, treatment history, response to previous treatments, comorbidity). Aside from this consideration, there are special localizations that remain some of the most difficult regions to control. Such entities are the scalp, nails, and intertriginous areas. Topical treatment of such different-to-treat areas has to be considered as a first-line intervention strategy, at least in those patients who are presenting an exclusively isolated involvement. In some situations (eg, in severe psoriasis or in patients who are refractory to topical treatment), however, a systemic treatment is indicated. Most obvious difficulties in treating these locations are due to unrealistic expectations from the patients' perspectives, time-consuming applications, side effects, cosmetic injuries, and restricted bioavailability of active compounds. Aside from hair care, initial use of keratolytics for scalp psoriasis, corticosteroids, and vitamin D3 and analogues are currently standard treatments. Recently developed new formulations of both active ingredients such as foam or gel appear to be more acceptable to patients than traditional creams or ointments. Current treatment options for nail psoriasis are very often poorly efficacious, associated with undesirable effects, or time consuming. Success has to be measured in terms of months. Topical treatments (eg, corticosteroids, vitamin D analogues, tazarotene) are mainly used, but impressive improvement rates mostly will be achieved by systemic treatment of conventional and biologic agents. Finally, the usefulness of corticosteroids, vitamin D and analogues, and calcineurin inhibitors in treating intertriginous psoriasis clearly is demonstrated. Especially the use of calcineurin inhibitors exhibits efficacy in intertriginous regions and therefore may be seen as a promising treatment option in the future. Besides the important innovations in the last years, there is a need for new effective and well-tolerated treatment modalities, especially for long-term use in the 3 difficult-to-treat locations, which encompass cosmetic acceptability.
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PMID:Psoriasis treatment in difficult locations: scalp, nails, and intertriginous areas. 1875 63

The Kv1.3 potassium channel plays an essential role in effector memory T cells and has been implicated in several important autoimmune diseases including multiple sclerosis, psoriasis and type 1 diabetes. A number of potent small molecule inhibitors of Kv1.3 channel have been reported, some of which were found to be effective in various animal models of autoimmune diseases. We report herein the identification of clofazimine, a known anti-mycobacterial drug, as a novel inhibitor of human Kv1.3. Clofazimine was initially identified as an inhibitor of intracellular T cell receptor-mediated signaling leading to the transcriptional activation of human interleukin-2 gene in T cells from a screen of the Johns Hopkins Drug Library. A systematic mechanistic deconvolution revealed that clofazimine selectively blocked the Kv1.3 channel activity, perturbing the oscillation frequency of the calcium-release activated calcium channel, which in turn led to the inhibition of the calcineurin-NFAT signaling pathway. These effects of clofazimine provide the first line of experimental evidence in support of a causal relationship between Kv1.3 and calcium oscillation in human T cells. Furthermore, clofazimine was found to be effective in blocking human T cell-mediated skin graft rejection in an animal model in vivo. Together, these results suggest that clofazimine is a promising immunomodulatory drug candidate for treating a variety of autoimmune disorders.
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PMID:Clofazimine inhibits human Kv1.3 potassium channel by perturbing calcium oscillation in T lymphocytes. 1910 61

The immunosuppressant cyclosporine A (CsA) is a specific pharmacological inhibitor of calcineurin, the Ca2+-calmodulin activated phospho-Ser/Thr-specific protein phosphatase. Although calcineurin-inhibiting compounds are applied for local treatment of psoriasis or atopic dermatitis in dermatological practice, little is known about the functions of calcineurin in epidermis-derived malignancies. We investigated the effects of CsA on two human melanoma cell lines, the metastasis forming HT168 and WM35 established from an RGP primary lesion. CsA of 2 microM lowered the enzyme activity by 50% and caused elevation in both mRNA and protein expression of calcineurin. Cell proliferation was diminished, as well as the cellular morphology and the actin organization were altered in both cell lines. CsA increased cell death moderately in both cell lines and reduced the metabolic activity of HT168 cells, but not that of WM35 cells. CsA also elevated the expressions of both Bcl-2 and ERK1/2. Fibronectin guided migration of HT168 cells was stimulated under the effect of CsA, while that of WM35 cells was reduced, moreover, HT168 cells switched from the expression of beta3 to beta1 integrin, but WM35 cells continued to express beta3. Based on our results we propose a multiple, partly malignancy-dependent role of calcineurin in these melanoma cell lines.
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PMID:Inhibition of calcineurin by cyclosporine A exerts multiple effects on human melanoma cell lines HT168 and WM35. 1928 56

Topical therapy continues to be one of the pillars of psoriasis management. Topical corticosteroids and vitamin D analogs are the drugs of choice during the induction phase, and vitamin D analogs continue to be drugs of choice for maintenance therapy. Tazarotene and dithranol are suitable options in patients with certain, specific characteristics. The calcineurin inhibitors can be considered to be second-line treatment for psoriasis of the face and flexures. The efficacy and safety of the fixed-dose combination of betamethasone and calcipotriol in the induction phase is greater than that of either drug alone. The combination of corticosteroids with salicylic acid achieves better results than corticosteroids in monotherapy. None of the drugs evaluated stands out over the others in all clinical situations, and their use must therefore be individualized in each patient and adjusted according to the course of the disease.
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PMID:[Update of the topical treatment of psoriasis]. 1945 4

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.
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PMID:Pimecrolimus in dermatology. 1952 13

Ciclosporin A (CsA) is widely utilized for the treatment of inflammatory skin diseases such as psoriasis. The therapeutic effects of CsA are thought to be mediated via its immunosuppressive action on infiltrating lymphocytes in skin lesions. CsA and tacrolimus block T cell activation by inhibiting the phosphatase calcineurin and preventing translocation from the cytoplasm to the nucleus of the transcription factor Nuclear Factor of Activated T cells (NFAT). As calcineurin and NFAT 1 have been shown to be functionally active in cultured human keratocytes, expression of other NFAT family members such as NFAT-2 and possible functional activation was investigated in human keratocytes. RT-PCR and Western Analysis were used to investigate the presence of NFAT-2 mRNA and protein in human keratocytes. Tissue culture of human keratocytes and immunostaining of cells on coverslips and confocal microscopy were used to assess the degree of nuclear localisation of NFAT-2 in cultured cells. Keratome biopsies were taken from patients with psoriasis (lesional and non-lesional skin) and normal skin and immunohistochemistry was used to assess the NFAT-2 localisation in these biopsies using a well characterized anti-NFAT-2 antibody. The NFAT-2 mRNA and protein expression was demonstrated using RT-PCR and Western blotting. Moreover, the expression of NFAT-2 in normal skin, non-lesional and lesional psoriasis showed a striking basal staining suggesting a role for NFAT-2 in keratocytes proliferation. A range of cell types in the skin express NFAT-2. The expression of NFAT-2 in human keratocytes and response to different agonists provides perhaps a unique opportunity to examine the regulation, subcellular localization and kinetics of translocation of different NFATs in primary cultured human cells. In these experiments the author assessed the expression, localization of NFAT-2 in cultured human keratocytes and measured the degree of nuclear localisaion of NFAT-2 using immunofluorescence and confocal microscopy and whether CsA and tacrolimus inhibit NFAT-2 nuclear translocation. As with NFAT 1, differentiation-promoting agents that increase intracellular calcium concentration induced nuclear translocation of NFAT-2 in cultured keratocytes but with different kinetics. These data provide the first evidence of that NFAT-2 is expressed in normal skin, psoriasis and that NFAT-2 functionally active in human keratocytes and that nuclear translocation of NFAT-2 in human skin cells has different kinetics than NFAT 1 suggesting that NFAT-2 may play an important role in regulation of keratocytes proliferation and differentiation at a different stage. Inhibition of this pathway in human epidermal keratocytes many account, in part for the therapeutic effects of CsA and tacrolimus in skin disorders such as psoriasis. Thus, supporting our previous work data that calcineurin/NFAT is functionally active not only in T cells, but in skin cells.
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PMID:Expression, localisation and functional activation of NFAT-2 in normal human skin, psoriasis, and cultured keratocytes. 1968 89


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