Topical pimecrolimus for skin disease other than atopic dermatitis

Pimecrolimus is an ascomycin macrolactam. It is a specific calcineurin inhibitor that allows topical application. The highly lipophilic nature of this compound reduces the risk of systemic absorption through normal and inflammed skin. Pimecrolimus shows activity not only against T-cell activation, but also against mast cells and pruritus. Pimecrolimus 1% cream is approved for atopic dermatitis, and also has a great potential in other inflammatory skin diseases. Clinical trials have been performed in contact- and seborrhoeic dermatitis, genital lichen sclerosus, intertriginous psoriasis and cutaneous lupus erythematosus. In other diseases, the available data are limited to small case series, or individual cases of graft-versus-host disease or Netherton's disease. Although the use of calcineurin inhibitors in the treatment of vitiligo is promising, detailed studies with pimecrolimus and ultraviolet-irradiation are necessary and there is a need for prospective randomised, double-blind controlled trials.     

Topical pimecrolimus for skin disease other than atopic dermatitis

Pimecrolimus is an ascomycin macrolactam. It is a specific calcineurin inhibitor that allows topical application. The highly lipophilic nature of this compound reduces the risk of systemic absorption through normal and inflammed skin. Pimecrolimus shows activity not only against T-cell activation, but also against mast cells and pruritus. Pimecrolimus 1% cream is approved for atopic dermatitis, and also has a great potential in other inflammatory skin diseases. Clinical trials have been performed in contact- and seborrhoeic dermatitis, genital lichen sclerosus, intertriginous psoriasis and cutaneous lupus erythematosus. In other diseases, the available data are limited to small case series, or individual cases of graft-versus-host disease or Netherton’s disease. Although the use of calcineurin inhibitors in the treatment of vitiligo is promising, detailed studies with pimecrolimus and ultraviolet-irradiation are necessary and there is a need for prospective randomised, double-blind controlled trials.     

Pimecrolimus versus topical corticosteroids in dermatology

Pimecrolimus is an ascomycin macrolactam derivative with anti-inflammatory and immunomodulatory activity that belongs to the class of calcineurin inhibitors. It was developed after the attempt to discover alternatives to corticosteroids for the treatment of inflammatory skin diseases. Although pimecrolimus has been only approved for the treatment of atopic dermatitis, many clinical reports have proved its efficacy in a variety of skin conditions. However, corticosteroids remain the treatment of choice in inflammatory skin diseases. The possibility that pimecrolimus deserves a greater role in the long-term treatment of skin diseases is discussed herein by reviewing the published clinical studies that compare pimecrolimus and corticosteroids.     

Pimecrolimus versus topical corticosteroids in dermatology

Pimecrolimus is an ascomycin macrolactam derivative with anti-inflammatory and immunomodulatory activity that belongs to the class of calcineurin inhibitors. It was developed after the attempt to discover alternatives to corticosteroids for the treatment of inflammatory skin diseases. Although pimecrolimus has been only approved for the treatment of atopic dermatitis, many clinical reports have proved its efficacy in a variety of skin conditions. However, corticosteroids remain the treatment of choice in inflammatory skin diseases. The possibility that pimecrolimus deserves a greater role in the long-term treatment of skin diseases is discussed herein by reviewing the published clinical studies that compare pimecrolimus and corticosteroids.     

Pimecrolimus for the treatment of inflammatory skin disease

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

Pimecrolimus for the treatment of inflammatory skin disease

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

Targeting mast cells: Uncovering prolific therapeutic role in myriad diseases

The mast cells are integral part of immune system and they have pleiotropic physiological functions in our body. Any type of abnormal stimuli causes the mast cells receptors to spur the otherwise innocuous mast cells to degranulate and release inflammatory mediators like histamine, cytokines, chemokines and prostaglandins. These mediators are involved in various diseases like allergy, asthma, mastocytosis, cardiovascular disorders, etc. Herein, we describe the receptors involved in degranulation of mast cells and are broadly divided into four categories: G-protein coupled receptors, ligand gated ion channels, immunoreceptors and pattern recognition receptors. Although, activation of pattern recognition receptors do not cause mast cell degranulation, but result in cytokines production. Degranulation itself is a complex process involving cascade of events like membrane fusion events and various proteins like VAMP, Syntaxins, DOCK5, SNAP-23, MARCKS. Furthermore, we described these mast cell receptors antagonists or agonists useful in treatment of myriad diseases. Like, omalizumab anti-IgE antibody is highly effective in asthma, allergic disorders treatment and recently mechanistic insight of IgE uncovered; matrix mettaloprotease inhibitor marimistat is under phase III trial for inflammation, muscular dystrophy diseases; ZPL-389 (H4 receptor antagonist) is in Phase 2a Clinical Trial for atopic dermatitis and psoriasis; JNJ3851868 an oral H4 receptor antagonist is in phase II clinical development for asthma, rheumatoid arthritis. Therefore, research is still in inchoate stage to uncover mast cell biology, mast cell receptors, their therapeutic role in myriad diseases.     

Targeting c-kit in the therapy of mast cell disorders: Current update

Classically, mast cells have been widely associated with allergic reactions and parasite infections, but recent studies have elucidated the important role of these cells in innate and acquired immunity, wound healing, fibrosis, and chronic inflammatory diseases. Mast cells release an impressive array of proinflammatory and immunoregulatory mediators after activation induced by either immunoglobulin-E (IgE)-dependent or IgE-independent mechanisms. Proliferation, differentiation, survival and activation of mast cells are regulated by stem cell factor (SCF), the ligand for the c-kit tyrosine kinase receptor which is expressed on the mast cell surface. Inappropriate c-kit activation causes accumulation of mast cells in tissues resulting in mastocytosis. A number of activating mutations in c-kit have recently been identified and these mutations results in aberrant mast cell growth. Thus, c-kit inhibitors may have potential application in multiple conditions associated with mast cell disorders including systemic mastocytosis, anaphylaxis, and asthma. The present perspective aims to summarize recent findings in mast cell biology and the role of c-kit tyrosine kinase inhibitors in the treatment of different mast cell associated disorders.     

Pharmacological targeting of the KIT growth factor receptor: a therapeutic consideration for mast cell disorders

KIT is a member of the tyrosine kinase family of growth factor receptors which is expressed on a variety of haematopoietic cells including mast cells. Stem cell factor (SCF)-dependent activation of KIT is critical for mast cell homeostasis and function. However, when KIT is inappropriately activated, accumulation of mast cells in tissues results in mastocytosis. Such dysregulated KIT activation is a manifestation of specific activating point mutations within KIT, with the human D816V mutation considered as a hallmark of human systemic mastocytosis. A number of other activating mutations in KIT have recently been identified and these mutations may also contribute to aberrant mast cell growth. In addition to its role in mast cell growth, differentiation and survival, localized concentration gradients of SCF may control the targeting of mast cells to specific tissues and, once resident within these tissues, mast cell activation by antigen may also be amplified by SCF. Thus, KIT inhibitors may have potential application in multiple conditions linked to mast cells including systemic mastocytosis, anaphylaxis, and asthma. In this review, we discuss the role of KIT in the context of mast cells in these disease states and how recent advances in the development of inhibitors of KIT activity and function may offer novel therapies for the treatment of these disorders.     

The role of mast cells in the structural alterations of the airways as a potential mechanism in the pathogenesis of severe asthma

Mast cells, traditionally regarded as effector cells of the immune system, have more recently been demonstrated to be key figures in initiating, developing and sustaining complex pathophysiological processes underlying asthma and other allergic diseases. Asthma is characterised by airway inflammation alongside a disturbance to airway physiology manifesting as variable airflow obstruction and airway hyper-responsiveness (AHR). Evidence has emerged that mast cells influence airway function by forming close intercellular relationships with different structural components of the airway wall. In asthma, mast cells are seen to localise to the airway epithelium, to mucous glands and to the airway smooth muscle (ASM). It is mast cell-ASM interaction that is most fundamental to the asthma phenotype and many mast cell mediators have been demonstrated to have important effects on ASM function. In asthma, alongside the inflammatory and physiological changes, structural changes occur to the airway wall in the form of denudation of the epithelium, goblet cell and mucous gland hyperplasia, subepithelial fibrosis, abnormal extracellular matrix (ECM) deposition, vascular proliferation and increased ASM mass. There are many ways in which mast cells can contribute to these structural changes through direct cell to cell communication and more indirectly through mediator release. Mast cells exhibit an array of diverse functions and roles and are fundamental to our current understanding of asthma pathogenesis including severe asthma. Novel targeting of mast cells and their mediators therefore should offer significant therapeutic potential in the treatment of asthma.     

Role of inflammatory mediators in asthma.

Release of inflammatory mediators such as histamine and products of arachidonic acid metabolism has been demonstrated in bronchoalveolar lavage fluid of patients with asthma. Their precise cellular source is not clear but many cells types such as eosinophils, macrophages and mast cells may contribute to the generation of a wide variety of chemical mediators. These can mimic many of the features associated with asthma including bronchoconstriction, bronchial hyperresponsiveness and airway microvascular leakage. Development of specific mediator receptor antagonists or inhibitors of mediator synthesis may clarify the role of particular inflammatory mediators such as the sulphidopeptide leukotrienes or platelet-activating factor in asthma. It seems unlikely that only one particular mediator is responsible for all the manifestations of asthma.     

Suppression of mast cell-mediated allergic reaction by Amomum xanthiodes.

The mast cell-mediated immediate-type allergic reaction is involved in many allergic diseases such as asthma, allergic rhinitis and sinusitis. Stimulation of mast cells starts the process of degranulation resulting in release of mediators such as histamine and an array of inflammatory cytokines. In this report, we investigated the effect of aqueous extract of Amomum xanthiodes (Zingiberaceae) (AXE) on the mast cell-mediated allergy model and studied its possible mechanisms of action. AXE inhibited compound 48/80-induced systemic reactions and serum histamine release in mice. AXE decreased immunoglobulin E (IgE)-mediated passive cutaneous anaphylaxis reaction. AXE reduced histamine release and intracellular calcium from rat peritoneal mast cells activated by compound 48/80. Furthermore, AXE decreased the activation of p38 mitogen-activated protein kinase (MAPK) but not extracellular signal-regulated kinase and c-jun N-terminal kinase, and downstream tumor necrosis factor (TNF)-alpha production in phorbol 12-myristate 13-acetate and calcium ionophore A23187-stimulated human mast cells. Our findings provide evidence that AXE inhibits mast cell-derived allergic reactions, and that intracellular calcium, TNF-alpha, and p38 MAPK are involved in these effects.     

Anti-allergic effects of Teucrium japonicum on mast cell-mediated allergy model

The mast cell-mediated immediate-type allergic reaction is involved in many allergic diseases such as asthma, allergic rhinitis, and sinusitis. Stimulation of mast cells starts the process of degranulation resulting in release of mediators such as histamine and an array of inflammatory cytokines. In this report, we investigated the effect of aqueous extract of Teucrium japonicum Houttuyn (Labiatae) (AXTJ) on the mast cell-mediated allergy model and studied its possible mechanisms of action. AXTJ inhibited compound 48/80-induced systemic reactions and serum histamine release in mice. AXTJ decreased immunoglobulin E-mediated passive cutaneous anaphylaxis reaction. AXTJ reduced histamine release and intracellular calcium from rat peritoneal mast cells activated by compound 48/80. In addition, AXTJ attenuated activation of nuclear factor (NF)-κB, and downstream tumor necrosis factor (TNF)-α expression in phorbol 12-myristate 13-acetate and calcium ionophore A23187-stimulated human mast cells. Our findings provide evidence that AXTJ inhibits mast cell-derived allergic reactions and involvement of intracellular calcium, TNF-α, and NF-κB in these effects.     

Pimecrolimus: absorption, distribution, metabolism, and excretion in healthy volunteers after a single oral dose and supplementary investigations in vitro.

The absorption and disposition of pimecrolimus, a calcineurin inhibitor developed for the treatment of inflammatory skin diseases, was investigated in four healthy volunteers after a single oral dose of 15 mg of [(3)H]pimecrolimus. Supplementary information was obtained from in vitro experiments. Pimecrolimus was rapidly absorbed. After t(max) (1-3 h), its blood concentrations fell quickly to 3% of C(max) at 24 h, followed by a slow terminal elimination phase (average t(1/2) 62 h). Radioactivity in blood decreased more slowly (8% of C(max) at 24 h). The tissue and blood cell distribution of pimecrolimus was high. The metabolism of pimecrolimus in vivo, which could be well reproduced in vitro (human liver microsomes), was highly complex and involved multiple oxidative O-demethylations and hydroxylations. In blood, pimecrolimus was the major radiolabeled component up to 24 h (49% of radioactivity area under the concentration-time curve(0-24) h), accompanied by a large number of minor metabolites. The average fecal excretion of radioactivity between 0 and 240 h amounted to 78% of dose and represented predominantly a complex mixture of metabolites. In urine, 0 to 240 h, only about 2.5% of the dose and no parent drug was excreted. Hence, pimecrolimus was eliminated almost exclusively by oxidative metabolism. The biotransformation of pimecrolimus was largely catalyzed by CYP3A4/5. Metabolite pools generated in vitro showed low activity in a calcineurin-dependent T-cell activation assay. Hence, metabolites do not seem to contribute significantly to the pharmacological activity of pimecrolimus.     

Antibacterial agent triclosan suppresses RBL-2H3 mast cell function

Triclosan is a broad-spectrum antibacterial agent, which has been shown previously to alleviate human allergic skin disease. The purpose of this study was to investigate the hypothesis that the mechanism of this action of triclosan is, in part, due to effects on mast cell function. Mast cells play important roles in allergy, asthma, parasite defense, and carcinogenesis. In response to various stimuli, mast cells degranulate, releasing allergic mediators such as histamine. In order to investigate the potential anti-inflammatory effect of triclosan on mast cells, we monitored the level of degranulation in a mast cell model, rat basophilic leukemia cells, clone 2H3. Having functional homology to human mast cells, as well as a very well defined signaling pathway leading to degranulation, this cell line has been widely used to gain insight into mast-cell driven allergic disorders in humans. Using a fluorescent microplate assay, we determined that triclosan strongly dampened the release of granules from activated rat mast cells starting at 2 μM treatment, with dose-responsive suppression through 30 μM. These concentrations were found to be non-cytotoxic. The inhibition was found to persist when early signaling events (such as IgE receptor aggregation and tyrosine phosphorylation) were bypassed by using calcium ionophore stimulation, indicating that the target for triclosan in this pathway is likely downstream of the calcium signaling event. Triclosan also strongly suppressed F-actin remodeling and cell membrane ruffling, a physiological process that accompanies degranulation. Our finding that triclosan inhibits mast cell function may explain the clinical data mentioned above and supports the use of triclosan or a mechanistically similar compound as a topical treatment for allergic skin disease, such as eczema.     

Formulary review of therapeutic alternatives for atopic dermatitis: focus on pimecrolimus

OBJECTIVE: Atopic dermatitis (AD), often called eczema, is characterized by intense pruritus, erythema, dry skin, and inflammation. The condition is chronic and relapsing, and often occurs in patients with a family history of the atopic triad (asthma, allergic rhinitis, and AD). Use of topical steroids has been the mainstay of medical treatment for AD. Steroid-free treatments for AD, with a more favorable safety profile, have become available within the past 2 years. Tacrolimus ointment, a topical immunomodulator, became available in early 2001 and is indicated for moderate-to-severe AD. A similar but highly skinselective cytokine inhibitor, pimecrolimus cream 1%, became available in March 2002. Pimecrolimus is indicated for mild-to-moderate AD. The objective of this article is to review the key characteristics that differentiate pimecrolimus from steroids and tacrolimus in the treatment of AD. METHODS: Using secondary resources, the clinical aspects and conventional treatment strategies for AD are reviewed as are the pivotal clinical studies with pimecrolimus and literature on quality of life and economic burden of disease for AD patients and families. SUMMARY: Pimecrolimus is an effective, steroid-sparing therapy for mild-tomoderate AD. Early treatment prevents flares, the agent works quickly to reduce signs and symptoms of more advanced AD, and it is safe and appropriate for intermittent long-term therapy. Pimecrolimus has fewer side effects than topical steroids and a better side-effect profile than tacrolimus. It can also be used as a first-line therapy. In studies with patients aged 2 to 17 years, it has been shown to be particularly effective in improving eczema of the face and neck, and its use may improve quality of life for many patients, especially children. A single-strength dose (1%) is safe and medically beneficial for pediatric, adolescent, and adult patients. The direct drug cost of pimecrolimus compares favorably with tacrolimus, but it is significantly more expensive than generic topical steroid creams.     

Anti-IgE monoclonal antibody (omalizumab) in the treatment of atopic asthma and allergic respiratory diseases

Since the discovery of immunoglobulin E (IgE) antibodies thirty-six years ago, our understanding of the mechanisms of allergy has improved to such an extent that we can now better differentiate allergy from non-allergic hypersensitivity, and allergic/atopic from intrinsic/non-atopic bronchial asthma. IgE antibodies are crucial immune mediators of airway inflammation in allergic atopic asthma and IgE-mediated hypersensitivity reactions are the likely mechanisms of allergen-induced airway obstruction. In addition, IgE may cause chronic airway inflammation in asthma through effector cells activated via high-affinity (Fcepsilon RI) or low-affinity (Fcepsilon RII) IgE receptors. Therapeutic anti-IgE antibodies able to reduce free IgE levels and to block the binding of IgE to Fcepsilon RI without cross-linking IgE and triggering degranulation of IgE-sensitised cells have been developed. This non-anaphylactogenic anti-IgE monoclonal antibody (rhuMAb-E25; omalizumab) binds IgE at the same site as these antibodies bind Fcepsilon RI and Fcepsilon RII. As a consequence, omalizumab inhibits IgE effector functions by blocking IgE binding to high-affinity receptors on IgE effector cells and does not cause mast cell or basophil activation because it cannot bind to IgE on cell surfaces where the Fcepsilon R1 receptor already masks the anti-IgE epitope. Studies in patients with atopic asthma demonstrated that omalizumab decreases serum IgE levels and allergen-induced bronchoconstriction during both the early and late-phase responses to inhaled allergen. In several clinical controlled trials omalizumab resulted to be able to reduce asthma-related symptoms, to decrease corticosteroid use and to improve quality of life of asthmatic patients.The anti-IgE approach to asthma treatment has several advantages, including concomitant treatment of other IgE-mediated diseases (allergic rhinitis, allergic conjunctivitis, atopic dermatitis and food allergies), a favourable side-effect profile and a twice-monthly dosing frequency.     

Mastocytosis: advances in molecular diagnosis and therapeutics

Systemic mastocytosis is a rare myeloproliferative-like disease, characterized by an abnormal proliferation of mast cells in various organs. Two types of clinical manifestations can be distinguished: those related to release of mast cell mediators release and those related to tumor proliferation involving different organs, these later defining systemic mastocytosis. Until recently, treatment was mainly symptomatic, without anti tumor effect. These last years, advances have been made in the understanding of the disease with the discovery of the presence, in a number of patients, of mutations of the c-kit oncogene, coding for the receptor of the major growth factor for mast cells. These mutations induce autophosphorylation of the c-kit receptor in the absence of its ligand, the Stem Cell Factor. Based on experiences acquired in the treatment of myeloproliferative disorders, evaluation of new therapeutics, such as cladribine or interferon-alpha, is in progress. Finally, it would be possible to design, in the very next future, new tyrosine kinase inhibitors targeting specifically the mutant forms of c-Kit found in patients suffering from systemic mastocytosis.     

Tachykinins and neuro-immune interactions in asthma

Excitatory non-adrenergic-non-cholinergic neuropeptides, such as the tachykinins substance P and neurokinin A, and its receptors are present in human and animal airways. Tachykinins are biologically active at extremely low concentrations. These peptides can cause potent inflammatory effects and can affect airway function in a way that resembles features of asthma. Local release of tachykinins affects blood vessels (vasodilatation and increased vascular permeability) and bronchial smooth muscle (bronchoconstrition and hyperresponsiveness). Neuropeptide research has revealed that tachykinins also play an important modulatory role in immune reactions. Tachykinins stimulate immune cells, such as mast cells, lymphocytes, and macrophages and are chemotactic for neutrophils and eosinophils. Vice versa, a range of immune cell mediators can also induce the release of tachykinins from excitatory NANC nerve endings in the airways. In the last 20 years, significant advances have been made in investigations of the interaction between immune cells and nervous systems in chronic inflammatory diseases such as asthma.