Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033774 (pruritus)
 14,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Nonclinical and early clinical development of tacrolimus ointment for the treatment of atopic dermatitis. 1114 92

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.
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PMID:Topical noncorticosteroid immunomodulation in the treatment of atopic dermatitis. 1211 47

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.
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PMID:Tacrolimus ointment: a new therapy for atopic dermatitis--review of the literature. 1213 28

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.
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PMID:[Antipruritic effects of pimecrolimus and tacrolimus]. 1271 60

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.
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PMID:[The treatment of atopic dermatitis in adults with topical calcineurin inhibitors]. 1271 62

The ichthyoses are a heterogeneous group of inherited scaling skin disorders that can also affect other organs. Management should be directed at both the skin and other sites. Skin therapy is not specific at this time, although new products may offer more directed therapy in the future. Moisturizers and keratolytics are the mainstay of topical therapy. Calcipotriene, retinoids, and for select types, anti-inflammatories such as topical steroids and calcineurin inhibitors have also been used. Systemic therapy is limited to the retinoids. Superinfection of the skin should be anticipated and treated. Pruritus can be disabling. Failure to sweat normally may result in heat intolerance. Eye care should seek to prevent corneal changes resulting from ectropion and more specific changes associated with specific disorders. Haring can be impaired by the accumulation of material in the external auditory canal. Severely affected children may require caloric supplementation to avoid growth retardation. Affected individuals and their family should be counseled about the long term outlook and the genetic nature of their disorder, and informed of FIRST, the Foundation for Ichthyosis and Related Skin Types, the lay foundation that offers support and information.
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PMID:Management of the ichthyoses. 1461 Jun 14

Sustained calcium signaling induces a state of anergy or antigen unresponsiveness in T cells, mediated through calcineurin and the transcription factor NFAT. We show here that Ca(2+)-induced anergy is a multistep program that is implemented at least partly through proteolytic degradation of specific signaling proteins. Calcineurin increased mRNA and protein of the E3 ubiquitin ligases Itch, Cbl-b and GRAIL and induced expression of Tsg101, the ubiquitin-binding component of the ESCRT-1 endosomal sorting complex. Subsequent stimulation or homotypic cell adhesion promoted membrane translocation of Itch and the related protein Nedd4, resulting in degradation of two key signaling proteins, PKC-theta and PLC-gamma1. T cells from Itch- and Cbl-b-deficient mice were resistant to anergy induction. Anergic T cells showed impaired calcium mobilization after TCR triggering and were unable to maintain a mature immunological synapse, instead showing late disorganization of the outer ring containing lymphocyte function-associated antigen 1. Our results define a complex molecular program that links gene transcription induced by calcium and calcineurin to a paradoxical impairment of signal transduction in anergic T cells.
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PMID:Calcineurin imposes T cell unresponsiveness through targeted proteolysis of signaling proteins. 1498 8

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.
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PMID:Tacrolimus ointment (Protopic) for atopic dermatitis. 1555 Sep 92

Treatment modalities of patients with atopic dermatitis (AD) are dependent on patient age, on the intensity of both skin symptoms and subjective signs of the disease i.e. itch and sleep disturbances, on the body surface involved with lesions, as well as on the type of sensitizing allergens. The characteristic of these allergens is crucial to start prophylaxis and to make decision about specific immunotherapy. In asymptomatic period of the disease the most important factor is to prevent dryness of the skin using emollients, which reconstruct integrity and continuity of stratum corneum. This procedure prevents penetration of air-borne allergens across damaged skin barrier into the skin. In mild AD cases, pimecrolimus (mainly in children) and corticosteroids of the lowest potency alternatively with their basis should be recommended. In moderate intensity AD either topical treatment with calcineurin inhibitors i.e. tacrolimus and pimecrolimus or topical corticosteroids from 4-5 group of American classification should be applied. In addition, PUVA/UVB phototherapy may be beneficial, as well as immunotherapy with specific airborne allergen/s. Coexisting bacterial skin infections should be treated with systemic antibiotics (macrolides, quinolones, and cephalosporins), viral herpes infection systemically using acyclovir for 5-7 days, and fungal infections applying ketoconazole orally, accompanied by topical treatment with miconazole or other antimycotics. Severe AD is an indication for the systemic use of cyclosporin A (rather than corticosteroids), and antibiotics as mentioned above. Prolonged 3-5 year specific immunotherapy is significant concern for selected cases. Sensitive skin areas such as face, orbicular skin, flexures should be treated with pimecrolimus and tacrolimus rather than with corticosteroids, however, topical corticosteroids are recommended on involved skin of the trunk and the extremities besides of flexures. While the improvement of severe AD is reached, the treatment modalities for benign and mild AD should be observed. In all AD patients with active skin lesions antihistaminic drugs of 2nd generation reactive with H1 receptor are a gold standard (or short treatment with these drugs of 1st generation to achieve a sedative effect, followed by the 2nd generation drug), as well as tranquilizers as the combined treatment. There is no reason for the use of anti-leukotriene drugs.
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PMID:[Diagnostic, prophylactic and therapeutic guidelines in patients with atopic dermatitis. Position paper by the task force of the National Specialists on Dermatology, Venereology and Allergology]. 1568 65

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 experience with use of topical calcineurin inhibitors over longer periods, regular use of these agents, particularly in children, should be undertaken only after careful consideration of individual cases. Sun protection should also be advised.
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PMID:Safety and efficacy of topical calcineurin inhibitors in the treatment of childhood atopic dermatitis. 1579 78


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