Emedastine difumarate: a review of its potential ameliorating effect for tissue remodeling in allergic diseases

Background: Emedastine difumarate, a selective histamine-H1 receptor antagonist and effective antiallergic agent, inhibits various clinical symptoms of allergic rhinitis, allergic conjunctivitis, urticaria, allergic dermatitis, pruritus cutaneous, and prurigo. In addition to greater efficacy than other antihistamines, emedastine difumarate produces no adverse cardiovascular effects and exhibits minimal anticholinergic activity. Moreover, a recent study revealed that the effect of emedastine difumarate on inhibition of histamine-induced collagen synthesis in vitro was greater in dermal fibroblasts than in nasal mucosa fibroblasts. This result indicates that there are tissue-specific effects of emed-astine difumarate and that it may be more effective for treating fibrosis in skin than in nasal mucosa. However, the mechanism and role of tissue remodeling is less well established for allergic skin diseases and allergic conjunctivitis, in comparison to respiratory allergic diseases. Objective: This review outlines the involvement of histamine in the pathogenesis of tissue remodeling in a variety of organs, and presents the evidence for the effect of antihistamines on this process. Furthermore, this review also discusses antihistamines as an intervention strategy in tissue remodeling. Methods: The scientific literature, published abstracts, and selected textbooks were reviewed. Results/Conclusion: Although additional evidence is required, emerging evidence suggests that emedastine difumarate may be of value in the prevention of excess tissue remodeling in allergic skin inflammation.

[1]  I. Grzelewska-Rzymowska,et al.  [Airway remodeling in asthma]. , 2003, Pneumonologia i alergologia polska.

[2]  T. Krieg,et al.  Effect of histamine on collagen and collagen m-RNA production in human skin fibroblasts. , 1991, Journal of dermatological science.

[3]  T. Saito,et al.  Inhibitory effects of emedastine difumarate on histamine release. , 1993, Japanese journal of pharmacology.

[4]  G. Canonica,et al.  Quality of life and patients' satisfaction in chronic urticaria and respiratory allergy , 2003, Allergy.

[5]  S. Holgate,et al.  SUBEPITHELIAL FIBROSIS IN THE BRONCHI OF ASTHMATICS , 1989, The Lancet.

[6]  G. Kenyon,et al.  Matrix metalloproteinases and their inhibitors in the nasal mucosa of patients with perennial allergic rhinitis. , 2001, The Journal of allergy and clinical immunology.

[7]  E. Bröcker,et al.  Mast cell involvement in normal human skin wound healing: expression of monocyte chemoattractant protein‐1 is correlated with recruitment of mast cells which synthesize interleukin‐4 in vivo , 2000, The Journal of pathology.

[8]  P. Netland,et al.  Emedastine ophthalmic solution 0.05% versus levocabastine ophthalmic suspension 0.05% in the treatment of allergic conjunctivitis using the conjunctival allergen challenge model. , 2000, American journal of ophthalmology.

[9]  C. Noli,et al.  The mast cell in wound healing. , 2001, Veterinary dermatology.

[10]  A. Cats,et al.  HL-A 27 AND ANKYLOSING SPONDYLITIS , 1975, The Lancet.

[11]  K. Urabe,et al.  Histamine-induced IL-6 and IL-8 production are differentially modulated by IFN-gamma and IL-4 in human keratinocytes. , 2002, Journal of dermatological science.

[12]  Santa Jeremy Ono,et al.  Allergic conjunctivitis: update on pathophysiology and prospects for future treatment. , 2005, The Journal of allergy and clinical immunology.

[13]  H. Murota,et al.  Emedastine difumarate inhibits histamine-induced collagen synthesis in dermal fibroblasts. , 2008, Journal of investigational allergology & clinical immunology.

[14]  K. Takehara.  Growth regulation of skin fibroblasts. , 2000, Journal of dermatological science.

[15]  M. Abelson,et al.  An Efficacy and Tolerance Comparison of Emedastine Difumarate 0.05% and Levocabastine Hydrochloride 0.05%: Reducing Chemosis and Eyelid Swelling in Subjects with Seasonal Allergic Conjunctivitis , 2000 .

[16]  A. Karalezli,et al.  Efficacy of olopatadine HCI 0.1%, ketotifen fumarate 0.025%, epinastine HCI 0.05%, emedastine 0.05% and fluorometholone acetate 0.1% ophthalmic solutions for seasonal allergic conjunctivitis: a placebo‐controlled environmental trial , 2009, Acta ophthalmologica.

[17]  E. Weeke.  Epidemiology of hay fever and perennial allergic rhinitis. , 1987, Monographs in allergy.

[18]  D. Peura,et al.  Control of gastric acid secretion in health and disease. , 2008, Gastroenterology.

[19]  D. Leung,et al.  Atopic dermatitis: the skin as a window into the pathogenesis of chronic allergic diseases. , 1995, The Journal of allergy and clinical immunology.

[20]  D. Hartmann,et al.  Contribution of 92 kDa gelatinase/type IV collagenase in bronchial inflammation during status asthmaticus. , 1999, American journal of respiratory and critical care medicine.

[21]  G. Tsukamoto,et al.  Effect of 1-(2-ethoxyethyl)-2-(4-methyl-1-homopiperazinyl)-benzimida zole difumarate (KB-2413), a new antiallergic, on chemical mediators. , 1984, Arzneimittel-Forschung.

[22]  A. Leonardi,et al.  Role of histamine in allergic conjunctivitis. , 2000, Acta ophthalmologica Scandinavica. Supplement.

[23]  H. Eichler,et al.  Pharmacokinetic and mass balance study of unlabelled and 14 C-labelled emedastine difumarate in healthy volunteers , 2002, Xenobiotica; the fate of foreign compounds in biological systems.

[24]  H. Tagami,et al.  The accelerating effect of histamine on the cutaneous wound-healing process through the action of basic fibroblast growth factor. , 2006, The Journal of investigative dermatology.

[25]  U. Herranz,et al.  Emedastine-ketoconazole: pharmacokinetic and pharmacodynamic interactions in healthy volunteers. , 2001, International journal of clinical pharmacology and therapeutics.

[26]  R. Naclerio,et al.  The histology of allergic rhinitis and its comparison to cellular changes in nasal lavage. , 1995, American journal of respiratory and critical care medicine.

[27]  L. Donnelly.  The Epithelium as a Target , 2008 .

[28]  Di Chen,et al.  Bone Morphogenetic Proteins , 2004, Growth factors.

[29]  K. Asano,et al.  Suppressive activity of fexofenadine hydrochloride on metalloproteinase production from nasal fibroblasts in vitro , 2004, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[30]  M. Taniguchi,et al.  Effect of Emedastine Difumarate on CC Chemokine-Elicited Eosinophil Migration , 2001, International Archives of Allergy and Immunology.

[31]  D. Easty,et al.  Clinical evaluation of twice-daily emedastine 0.05% eye drops (Emadine eye drops) versus levocabastine 0.05% eye drops in patients with allergic conjunctivitis. , 2001, American journal of ophthalmology.

[32]  Toshiyuki Shimizu,et al.  Suppression of Matrix Metalloproteinase Production in Nasal Fibroblasts by Tranilast, an Antiallergic Agent, In Vitro , 2005, Mediators of Inflammation.

[33]  M. Yamagiwa.  Acoustic evaluation of the efficacy of medical therapy for allergic nasal obstruction , 2006, European Archives of Oto-Rhino-Laryngology.

[34]  R. Paus,et al.  The FASEB Journal • FJ Express Full-Length Article Mast cells are required for normal healing of skin wounds in mice , 2022 .

[35]  M. Shibuya,et al.  Vascular endothelial growth factor B (VEGF-B) binds to VEGF receptor-1 and regulates plasminogen activator activity in endothelial cells. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[36]  J. Gailit,et al.  The differentiation and function of myofibroblasts is regulated by mast cell mediators. , 2001, The Journal of investigative dermatology.

[37]  P. O'Byrne,et al.  Provoked models of asthma: what have we learnt? , 2009, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[38]  J. Ramaekers,et al.  Effects of emedastine and cetirizine, alone and with alcohol, on actual driving of males and females , 2002, Journal of psychopharmacology.

[39]  S. Holgate,et al.  Airway remodeling in asthma: new insights. , 2003, The Journal of allergy and clinical immunology.

[40]  T. Tsuchida,et al.  Effects of cimetidine and omeprazole on angiogenesis in granulation tissue of acetic acid-induced gastric ulcers in rats. , 1990, Digestion.

[41]  T. Saito,et al.  General pharmacology of 1-(2-ethoxyethyl)-2-(4-methyl-1-homopiperazinyl)benzimidazole difumarate. 1st communication: effects on the central nervous system. , 1988, Arzneimittel-Forschung.

[42]  C. Akdis,et al.  Connective tissue growth factor expression is regulated by histamine in lung fibroblasts: potential role of histamine in airway remodeling. , 2007, The Journal of allergy and clinical immunology.

[43]  K. Nékám,et al.  Emedastine difumarate versus loratadine in chronic idiopathic urticaria: a randomized, double-blind, controlled European multicentre clinical trial. , 2006, European journal of dermatology : EJD.

[44]  R. Shikiar,et al.  The effect of fexofenadine hydrochloride on productivity and quality of life in patients with chronic idiopathic urticaria. , 2007, Cutis.

[45]  S. Xu,et al.  Olopatadine (AL-4943A): ligand binding and functional studies on a novel, long acting H1-selective histamine antagonist and anti-allergic agent for use in allergic conjunctivitis. , 1996, Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics.

[46]  A. Assandri,et al.  Clinical Study of the Therapeutic Efficacy and Safety of Emedastine Difumarate versus Terfenadine in the Treatment of Seasonal Allergic Rhinitis , 2004, Arzneimittelforschung.

[47]  D. Tschumperlin,et al.  Mechanical stimuli to airway remodeling. , 2001, American journal of respiratory and critical care medicine.

[48]  K. Nishioka,et al.  Substance P augments fibrogenic cytokine-induced fibroblast proliferation: possible involvement of neuropeptide in tissue fibrosis. , 1997, Journal of dermatological science.

[49]  M. Abelson,et al.  A randomized, double-blind, placebo-controlled comparison of emedastine 0.05% ophthalmic solution with loratadine 10 mg and their combination in the human conjunctival allergen challenge model. , 2002, Clinical therapeutics.

[50]  K. Yokota,et al.  General pharmacology of 1-(2-ethoxyethyl)-2-(4-methyl-1-homopiperazinyl)benzimidazole difumarate. 2nd communication: Effects on the circulation and the other systems. , 1988, Arzneimittel-Forschung.

[51]  M. Radice,et al.  Histamine effects on conjunctival fibroblasts from patients with vernal conjunctivitis. , 1999, Experimental eye research.

[52]  H. Nagata,et al.  Extensive interstitial collagen deposition on the basement membrane zone in allergic nasal mucosa. , 1999, Acta oto-laryngologica.

[53]  Y. Ishihara,et al.  Effects of antiulcer agents on healing of mepirizole-induced duodenal ulcers in rats. , 1983, Digestion.

[54]  M. Abelson,et al.  An efficacy and tolerance comparison of emedastine difumarate 0.05% and levocabastine hydrochloride 0.05%: reducing chemosis and eyelid swelling in subjects with seasonal allergic conjunctivitis. Emadine Study Group. , 2000, Acta ophthalmologica Scandinavica. Supplement.

[55]  R. Gerth van Wijk,et al.  Allergen‐induced matrix metalloproteinase‐9 in nasal lavage fluid , 1999, Allergy.

[56]  M. Artuc,et al.  Mast cells and their mediators in cutaneous wound healing – active participants or innocent bystanders? , 1999, Experimental dermatology.

[57]  Judy Pearsall,et al.  The Concise Oxford Dictionary , 1999 .

[58]  A. James,et al.  The structure of large and small airways in nonfatal and fatal asthma. , 1993, The American review of respiratory disease.

[59]  A. Gressner,et al.  Fibroblast growth factor 16 and 18 are expressed in human cardiovascular tissues and induce on endothelial cells migration but not proliferation. , 2006, Biochemical and biophysical research communications.

[60]  A. Thompson,et al.  Effect of 60 mg twice-daily fexofenadine HCl on quality of life, work and classroom productivity, and regular activity in patients with chronic idiopathic urticaria. , 2000, Journal of the American Academy of Dermatology.

[61]  P. Hebda,et al.  Mast cell and myofibroblast in wound healing. , 1993, Dermatologic clinics.

[62]  F. Horak,et al.  Clinical Study of the Therapeutic Efficacy and Safety of Emedastine Difumarate versus Cetirizine in the Treatment of Seasonal Allergic Rhinitis , 2004, Arzneimittelforschung.

[63]  T. Tango,et al.  Review of fexofenadine in the treatment of chronic idiopathic urticaria , 2002, International journal of dermatology.

[64]  C. Akdis,et al.  T cells and eosinophils cooperate in the induction of bronchial epithelial cell apoptosis in asthma. , 2002, The Journal of allergy and clinical immunology.

[65]  O. Ishikawa,et al.  Effect of activated human mast cells and mast cell-derived mediators on proliferation, type I collagen production and glycosaminoglycans synthesis by human dermal fibroblasts. , 2002, European journal of dermatology : EJD.

[66]  Pascal Schneider,et al.  Generation of the primary hair follicle pattern. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[67]  J. Bousquet,et al.  Allergic rhinitis: a disease remodeling the upper airways? , 2004, The Journal of allergy and clinical immunology.

[68]  M. Abelson,et al.  Comparison of the topical ocular antiallergic efficacy of emedastine 0.05% ophthalmic solution to ketorolac 0.5% ophthalmic solution in a clinical model of allergic conjunctivitis. , 1999, Acta ophthalmologica Scandinavica. Supplement.

[69]  S. Isogai,et al.  Bronchial subepithelial fibrosis and expression of matrix metalloproteinase-9 in asthmatic airway inflammation. , 1998, The Journal of allergy and clinical immunology.

[70]  F. Simons,et al.  Histamine receptors are hot in immunopharmacology. , 2006, European journal of pharmacology.

[71]  Sabine Werner,et al.  Roles of activin in tissue repair, fibrosis, and inflammatory disease. , 2006, Cytokine & growth factor reviews.

[72]  R. de Marco,et al.  Comparison of Emedastine 0.05% or Nedocromil Sodium 2% Eye Drops and Placebo in Controlling Local Reactions in Subjects with Allergic Conjunctivitis , 2002, European journal of ophthalmology.

[73]  K. Shirato,et al.  Eosinophils as a source of matrix metalloproteinase-9 in asthmatic airway inflammation. , 1997, American journal of respiratory cell and molecular biology.

[74]  Weeke Er.  Epidemiology of hay fever and perennial allergic rhinitis , 1987 .

[75]  G. Ciprandi,et al.  Safety and Efficacy Comparison of Emedastine 0.05% Ophthalmic Solution Compared to Levocabastine 0.05% Ophthalmic Suspension in Pediatric Subjects with Allergic Conjunctivitis , 2000 .

[76]  R. Paus,et al.  The mast cell products histamine and serotonin stimulate and TNF-alpha inhibits the proliferation of murine epidermal keratinocytes in situ. , 1997, Journal of dermatological science.

[77]  P. Howarth,et al.  Remodelling of the upper airways in allergic rhinitis: is it a feature of the disease? , 2003, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[78]  T. Casale,et al.  Once-daily fexofenadine HCl improves quality of life and reduces work and activity impairment in patients with seasonal allergic rhinitis. , 1999, Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology.

[79]  K. Nishioka,et al.  Mast-cell-derived mediators induce epidermal cell proliferation: clue for lichenified skin lesion formation in atopic dermatitis. , 1992, International archives of allergy and immunology.

[80]  A. Leonardi,et al.  Randomized, double-masked, placebo-controlled comparison of the efficacy of emedastine difumarate 0.05% ophthalmic solution and ketotifen fumarate 0.025% ophthalmic solution in the human conjunctival allergen challenge model. , 2002, Clinical therapeutics.