Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.3.16 (calcineurin)
17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Immunosuppressants dampen the immune response or restore balance among immune system components. They are primarily used to prevent allograft rejection after organ transplantation and to prevent or treat disease flares in autoimmune diseases. Immunosuppressants available at present include the calcineurin inhibitors (cyclosporin, tacrolimus), antimetabolites (azathioprine, leflunomide, methotrexate, mycophenolate mofetil), antiproliferatives (sirolimus), monoclonal antibodies to T lymphocyte (basiliximab, daclizumab, muromonab-CD3) and anticytokines (anakinra, etanercept, infliximab). The immunosuppressive market grows at a rate of > 10% yearly, with total sales in 2001 of US$2.7 billion. Immunotherapy in transplantation and autoimmune diseases is tending towards the use of multi-drug regimens tailored for the individual patient. At least 23 new immunosuppressants are currently in advanced clinical testing or preregistration, and can be divided into three groups. First, emerging drugs targeting intracellular ligands in immune cells are primarily analogues of currently-marketed agents, which attempt to provide improved pharmaceutical or safety profiles compared with the prototype compound. They are largely being developed in organ transplantation. Second, emerging drugs targeting cell surface ligands on immune cells attempt to antagonise novel molecular sites to interfere with immune cell activation via costimulatory signals, immune cell adhesion to tissues or the vasculature and immune cell trafficking. These agents are being primarily developed in rheumatoid arthritis, psoriasis and/or multiple sclerosis. Finally, emerging drugs acting as anticytokines, which largely follow on from the success of those on the market, by antagonising the function of tumour necrosis factor or a narrow selection of interleukins. All are being assessed in rheumatoid arthritis. Drug development of immunosuppressants is increasingly attempting to intervene in disease progression over the long term. These efforts bring with them trial design and regulatory issues, such as what markers can be used as trial outcome measures, over what duration do trials need to be conducted and what labelling claims are allowed. With the intensive activity in this field, it is likely that several new drugs will reach the market in the coming decade. One caveat, however, is that emerging immunosuppressants that are likely to capture a reasonable share of this increasingly-fragmented market must demonstrate the ability to achieve disease remission or long-term slowing of disease progression.
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PMID:Immunosuppressants in advanced clinical development for organ transplantation and selected autoimmune diseases. 1461 Sep 11

The calcineurin inhibitors cyclosporin A (CsA), tacrolimus (FK506) and pimecrolimus (ASM981) are on the market for the oral treatment of psoriasis and atopic dermatitis and topical treatment of atopic dermatitis, respectively. The effect of these treatments on the immune response was investigated in this study after immunisation of rats with keyhole limpet hemocyanin (KLH). Male rats (10 per group) were orally administered pimecrolimus at 10 or 30 mg/kg/day), tacrolimus at 3 mg/kg/day or CsA at 20 mg/kg/day for 4 weeks. Control animals similarly received the vehicle only. The last five animals per group were immunised and challenged with KLH on days 16 and 24, respectively. Eight days after the last injection, the immune function was investigated by detecting KLH-specific antibodies in the serum and by examination of cell infiltration at the site of the KLH-challenge. In addition, a correlation between functional and structural changes was established by quantification of lymphocyte sub-populations in the blood or residing in lymphatic tissue. In KLH-immunised rats, CsA caused complete suppression of the KLH-specific IgM and IgG production, whereas only IgG production was affected by pimecrolimus at 30 mg/kg/day and more so by tacrolimus at 3 mg/kg/day. Immunophenotyping of lymphocyte sub-populations in spleen and lymph node indicated a decrease in T lymphocytes with pimecrolimus at 30 mg/kg/day, tacrolimus and CsA, whereas these changes were marginal for pimecrolimus at 10 mg/kg/day. Immunophenotyping of peripheral white blood cells (WBC) revealed a decrease in the absolute number of T lymphocytes with all three test items. In comparison with non-immunised animals, a slight increase in absolute numbers of T lymphocytes was observed in KLH-immunised animals treated with pimecrolimus at 10 or 30 mg/kg/day. In conclusion, the ability of the immune system to respond to KLH was not affected by pimecrolimus at 10 mg/kg/day whereas a decrease in immune function was noted in the other groups as follows: pimecrolimus (30 mg/kg/day) < tacrolimus (3 mg/kg/day) < CsA (20 mg/kg/day).
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PMID:Determination of the effect of calcineurin inhibitors on the rat's immune system after KLH immunisation. 1509 58

Tacrolimus ointment and pimecrolimus cream are approved in the United States for treatment of atopic dermatitis. Tacrolimus and pimecrolimus are both calcineurin inhibitors and function as immunosuppressants. Their mechanisms have been discussed elsewhere. This article will discuss their utility in treating psoriasis.
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PMID:The use of topical tacrolimus and pimecrolimus to treat psoriasis: a review. 1534 85

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.
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PMID:Tacrolimus ointment: the treatment of atopic dermatitis and other inflammatory cutaneous disease. 1546 48

Sirolimus, a macrocyclic lactone with a novel mechanism of action, augments acute rejection prophylaxis when administered in combination with cyclosporine (CsA) and steroids and seems to reduce the occurrence and progression of chronic vascular obliterative processes. Although clinical studies in psoriasis patients suggest that sirolimus is not nephrotoxic, the drug does show a range of toxic side effects, including altered lipid metabolism, myelosuppression, arthropathy, and impaired wound healing. Our experience with 1008 renal transplant patients who were administered sirolimus demonstrates that through careful therapeutic drug monitoring, it is possible to maximize the benefits and minimize the hazards of chronic immunosuppression with a sirolimus-based regimen. While sirolimus was initially introduced as an adjunctive agent to calcineurin inhibitors, it now serves as the base for therapies that spare the exposure to these nephrotoxic drugs. However, to optimize the use of sirolimus as base therapy, further work is necessary to determine appropriate target concentrations over time, the requirement for concomitant steroids and/or nucleoside synthesis blockers, and the best countermeasure strategies to overcome the drug's adverse effects.
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PMID:Sirolimus-based immunosuppression: present state of the art. 1559 84

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.
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PMID:Mechanism of action and emerging role of immune response modifier therapy in dermatologic conditions. 1564 61

The advent of new topical agents such as topical calcineurin inhibitors, as well as the reformulations of older agents in new vehicles, has broadened the treatment approaches to psoriasis and atopic dermatitis. The clinician must now consider additional novel physiologic pathways and mechanisms of action as well as expanding options for combination therapy. Combination therapy is especially beneficial when the selected agents possess differing mechanisms of action that provide additive or synergistic efficacy, reducing the required doses of the individual agents compared with monotherapy and potentially limiting side effects. Therapeutic approaches also can be rotated or used in various sequences for maintenance therapy. In psoriasis, a number of trials have demonstrated the effectiveness of combination therapy. Although combination therapy has not been extensively studied in atopic dermatitis, many practitioners combine topical corticosteroids and topical calcineurin inhibitors in their clinical practice because the two drug classes have different and possibly complementary mechanisms of action. For both diseases, the decision as to what agents are combined must also be tempered by patient type, disease presentation or severity, and patient preferences.
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PMID:Mechanisms of action of topical therapies and the rationale for combination therapy. 1596 60

A variety of therapeutic options are available to treat psoriasis and atopic dermatitis (AD). Local agents typically are used to treat localized and milder forms of disease, whereas phototherapy and systemic agents are used for more generalized and severe disease. Various combinations and sequences of topical or systemic therapies, or both, have been utilized in the treatment of psoriasis and, less frequently, of AD. Conventional systemic therapies for psoriasis, such as corticosteroids, oral calcineurin inhibitors, antimetabolites, and retinoids, are limited by their propensity to cause serious side effects. More recently, a number of immunobiologic agents, such as monoclonal antibodies, recombinant cytokines, and fusion proteins, have been approved by the Food and Drug Administration or are undergoing development as systemic antipsoriatic treatments. In many of these categories, a number of exciting new therapies are in development that may augment the existing armamentarium available to clinicians for the treatment of inflammatory skin diseases.
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PMID:Therapeutic options in the treatment of psoriasis and atopic dermatitis. 1596 62

Topical corticosteroids remain the most commonly used topical treatments for inflammatory dermatoses, including psoriasis and atopic dermatitis. Topical corticosteroids are available in a variety of vehicles-creams, ointments, lotions, gels, and, more recently, foam. The vehicle used can substantially affect the individual agent's clinical action, potency, and acceptability to the patient. Moreover, some vehicles are better suited for specific body areas. Selection of the appropriate product should be determined by area of usage, physician experience, cost, and patient preference, particularly regarding vehicle. Although topical corticosteroids are associated with several side effects, including skin atrophy, telangiectases, purpura, and striae formation, appropriate usage can minimize these occurrences. Judicious use includes short-term, appropriate application as initial monotherapy or in combination strategies with other therapeutic agents that ideally possess complementing mechanisms of action. Examples include pulsing with high-potency topical corticosteroids and combination regimens with other topical agents such as topical calcineurin inhibitors, calcipotriene, or tazarotene. Appropriate education of patients and caregivers alike will facilitate the optimal use of these medications.
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PMID:Corticosteroids: options in the era of steroid-sparing therapy. 1596 64

Bullous pemphigoid (BP) is a cutaneous autoimmune disease predominantly affecting older patients which can cause death either due to severe clinical manifestations or due to the side effects of systemic immunosuppressive treatment. Topical treatment with corticosteroids is an established alternative to systemic treatment. However, prolonged application is accompanied by side effects such as skin atrophy. Recently, the immunomodulatory calcineurin antagonists tacrolimus and pimecrolimus have been introduced for topical treatment of skin diseases. Tacrolimus has been reported to be effective in several inflammatory skin disorders such as atopic dermatitis, psoriasis, lichen planus, lupus erythematosus and pyoderma gangraenosum. Efficacy has also been described in the topical treatment of BP in some cases. Here we present the case of a 89 year old patient with BP. He was treated with 0.1% tacrolimus ointment, which was able to control the disease. We briefly review the literature and discuss the potential role of tacrolimus as a novel option for the topical treatment of BP.
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PMID:[Topical treatment of bullous pemphigoid with tacrolimus. Case report with brief literature review]. 1637 15


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