HISTAMINE & ANTIHISTAMINE, Cheat Sheet of Pharmacology

Download HISTAMINE & ANTIHISTAMINE and more Cheat Sheet Pharmacology in PDF only on Docsity! (el MEDICAE NAISSENSIS DE DEIGRUMTER ACTA FACULTATIS DOI: 10.1515/afmnai-2015-0001 UDC: 615.218 Review article Histamine and Antihistamines Nikola Stojkovi¢!, SneZana Cekic?, Milica Ristov’, Marko Ristic, Davor Duki¢!, Masa Bini¢c!, Dragan Virijevic! ‘University of Nig, Faculty of Medicine, PhD student, Serbia “Institute of Physiology, University of Nis, Faculty of Medicine , Serbia “Doctor of Medicine SUMMARY In recent years, there has been a steady increase in the prevalence of allergic diseases. Allergic immune response represents a complex network of cellular events involving numerous immune cells and mediators. It represents the interaction of innate and acquired immune response. The key role in the immune cascade is taken by histamine, a natural component of the body, which in the allergic inflammatory response is releasesd by the mast cells and basophils. The aim of this study was to highlight the role of histamine in allergic immunological events, their effect on Th1 and Th2 subpopulation of lymphocytes and the production of the corresponding cytokines, as well as the role of histamine blockers in the treatment of these conditions. Histamine achieves its effect by binding to the four types of its receptors, which are widely distributed in the body. Histamine blockers block a numerous effects of histamine by binding to these receptors. As a highly selective second-generation antihistamine, cetirizine not only achieves its effects by binding to H1 receptors, but also attenuates numerous events during the inflammatory process. Knowledge of the effects of histamine blockers, including cetirizine, may lead to the selection of proper therapy for the treatment of allegic diseases. Key words: histamine, immune response, histamine blockers, cetirizine Corresponding author: Nikola Stojkovié phone: +381643455599 e-mail: milicar2010@hotmail.com Scientific Journal of the Faculty of Medicine in NiS 2015;32(1):7-22 Review article INTRODUCTION Over the last 30 years, the prevalence of allergic diseases (asthma, allergic rhinitis, atopic dermatitis etc.) has been rapidly growing. The goal of treatment of these conditions represents a blocking effect of histamine release from basophils and mast cells and is considered to be the key cause of all the symptoms associated with allergic inflammatory response. Antihistamines are drugs that are widely used in dealing with this type of disease. The aim of this paper was to provide the insight into the mechanism of allergic immune responses and highlight the possibility of using histamine blockers, including cetirizine, a second generation antihistamine, in solving many problems in allergy caused by intracellular communication and numerous mediators. ALLERGY An immune cascade of allergic conditions is the interactions between numerous cell types and inflammatory mediators (1). Allergic inflammatory response has three distinct phases: sensitization, early-phase responses and late-phase responses. The sensitization phase begins with the production of allergen-specific IgE-antibodies that bind to the surfaces of mast cells, basophils and antigen presentation cells (APC), causing degranulation and subsequent mediator release. Just before that occurs a differentiation and clonal expansion of allergen- specific CD4+Th2 cells, with the capability of producing IL-4 and IL-13, which are the key events in induction of IgE. Engagement of IgE on effector cells leads to sensitization of patients to specific allergen (2). At the early stage of the reaction from the mast cells and basophils are released many inflammatory mediators such as tryptase, eosinophil chemotactic factor in addition to histamine as well as newly synthesized molecules (PGD2, LCT4, bradykinin). The process of secretion of these mediators is crucial characteristic of the early stages of the response. About half of all patients who exhibit an early-phase allergic response experience a _ late phase inflammatory reaction approximately 4-24 hours following allergen exposure. Late phase response is manifested by activation of endothelial cells and secretion of many inflammatory cytokines (TNF-a, granulocyte-macrophage colony-stimulating factor, 8 LL-3, IL-4, IL-5, IL-6, IL-8, IL-13) with strong inflows of inflammatory granulocytes (eosinophils, basophils, neutrophils and lymphocytes), except for eosinophils which have a particular role because they secrete several substances that promote the chronic late- phase inflammatory reaction During the late phase of allergic inflammatory response, which is characterized by inflammation and tissue injury, there is a return of symptoms in the early stage. Allergic diseases represent complex innate and adaptive immune responses to environmental antigens leading to inflammatory reactions with a T— helper-2 type cell and allergen-specific IgE predominance (3,4). Allergy is essentially an inflammatory disease. Our knowledge of the cells and mediators that are involved in the allergic inflammation has increased immensely during the last decade. This knowledge provides the basis of a more rational way for the development of therapeutic principles and prevention of allergic symptoms. The allergic inflammation involves a large number of cells. However, three types of cells seem to be of particular importance. These are the eosinophil granulocyte, the mast cell and the T-lymphocyte of the Th2-type. The cytokines and other molecules and the cells present in the microenvironment are the main factors which determine differentiation of naive T cells into distinct subsets such as Thl, Th2, Th9, Th17 and Th22 type memory and effector cells (5). In conditions of allergic diseases, effector Th2 cells produce not only traditional Th2 cytokines such as IL-4, IL-5, IL-9 and IL-13 (6,7), but also novel cytokines such as IL-25, IL- 31 and IL-33 which have proinflammatory functions (8-14). These cytokines induce eosinophilia, mucus production, producing of allergen-specific IgE and the recruitment of inflammatory cells to inflamed tissues. Th2 cells are the leader of the process. The main effector cells are the eosinophils and mast cells. Predominance of Th2 cells might be caused by an increased tendency to activate induced cell death of high IFN-gama producing Thi cells as it is commonly observed in patients with atopic disorders (15). Th1 cells induce apoptosis of keratinocytes in atopic dermatitis and epithelial cells and/or smooth muscle cells in asthma in the effector phase of these allergic diseases (16-20). As the major consequences of the activation of mast cells, the release of histamine and other mediators occur, which leads to acute allergic reaction. Activation of eosinophils lead to the extracellular release of a number of potent cytotoxic Scientific Journal of the Faculty of Medicine in Nis 2015;32(1):7-22 Making of H1 receptors is encoded by genes, localized on chromosome 3. The H2-receptor, in contrast, appears to suppress inflammatory and effector functions, while data regarding the role of the H4-receptor in immune response is limited. Evidence of the existence of a third histamine receptor groups (H3) was based on the activity of histamine, which could not be blocked by antagonists of H1 or H2- receptor antagonist (46). The histamine H3 receptor has been identified in the central and peripheral nervous systems as pre-synaptic receptors controlling the release of histamine and other neurotransmitters. The local predominant type of histamine receptor undergoing activation determines the type of effector response that is elicited. All four types of histamine receptor are heptahelical transmembrane molecules that transduce extracellular signals by way of G proteins to intracellular second-messenger systems. The classic model of receptor activation requires binding by a specific ligand, or agonist and binding of inverse agonist (antagonist in the older literature) leads to the inactivation, blockade of these receptors. Aspartic acid located in the third transmembrane domain of the human receptor is crucial for the affinity of histamine and histamine antagonists; this amino acid is a hallmark of G-protein-coupled receptors. All types of receptor have constitutive activity, whichis defined as the ability to trigger events even in the absence of ligand binding. It can be said that there is a balance between active and inactive states of the receptor. H1- concentratcion of histamine and Nikola Stojkovi¢, SneZana Ceki¢, Milica Ristov et al. receptor polymorphisms have been described, although it is not yet clear how they influence the clinical response to H1-antihistamines (47). Target disruption of the genes encoding the H1 receptor, is applied in mice which results in CNS function disorders, such as memory, learning, locomotion and aggressive behavior. H1 receptor deficiency also leads to numerous immunological abnormalities such as weakening of antigenic-specific response of T and B cells (48,49). The presence of leads to upregulation of H1 receptors. It was experimentally proven that antagonists cause blockade of upregulation. The concept of constitutive activity has led to a reclassification of drugs acting at the H1- receptor. For example, the H1-receptor promotes NF-kB in both a constitutive and agonist-dependent manner and all clinically available © H1-antihistamines _ inhibit constitutive H1-receptor-mediated NF-kB production (50, 51). Histamine can also be linked to one type of intracellular histamine receptor (Hic), which was described several years ago in the microsomes and nucleus. These types of receptors are comprised of the cytochrome P450 and cytochrome c (52). This type of receptor cannot yet be discussed with absolute certainty, because it is not yet clear which type of reactions are induced by histamine binding to this receptor. Localization of histamine receptors as well as the mechanism of their activation are presented in Table 1. histamine Table 1. Histamine receptors, the localization of their expression and mechanism of action (53) (source: Akdis CA, Simons FER. Histamine receptors are hot in imnumopharmacology. Eur J Pharmacol 2006; 533:69-76.) Histamine . ‘Activated intracellular G Expression : . receptors signals proteins Nerve cells, airway and vascular smooth muscles, hepatocytes, . Ca*, GMP, phospholi Hi receptors chondrocytes, endothelial cells, epithelial cells, neutrophils, p> 7 f°) PMO RM Gait eosinophils, monocytes, dendritic cells (DO), T and B cells 1 PhospnouP’ ' Nerve cells, airway and vascular smooth muscle, hepatocytes, Adenylatecyclase, cAMP, c- H2 receptors chondrocytes, endothelial cells, epithelial cells, neutrophils, <0" Seyease “Gas ae . Fos, c-Jun, PKC, p70S6K eosinophils, monocytes, dendritic cells, T and B cells HBreceptors Histaminergie neurons, eosinophils, DC, monocytes, low MAP Kinase, inhibition of expression in peripheral tissues cAMP, Ca? High expression on bone marrow and peripheral hematopoetic lls, eosinophils, neutrophils, DC, T cells, basophils, mast pcan . H4 receptors So % Sosinoph’s: néutropa® cons: pasop a's: mas” Ca®*, inhibition of CAMP —_—_Gi/os cells; low expression in nerve cells, hepatocytes and peripheral tissues SS 14. 2015;32(1):7-22 ic Journal of the Faculty of Medicine in } Review article THE ROLE OF HISTAMINE IN ALLERGIC INFLAMMATION AND IMMUNE MODULATION Histamine plays a key role in allergic inflammation, which is a complex network of cellular events that involve many cells and mediators. Histamine is released from the mast cells and basophils together with tryptase and other preformed mediators such as prostaglandins, leukotrienes, after the cross-linking of surface IgE by allergen or through mechanisms that are independent of IgE. After allergen challenge in sensitized persons, the local concentration of histamine is much higher compared to leukotrienes and other mediators. The concentration of histamine can then be measured in micrograms, whereas the concentration of leukotrienes, and other mediators may be measured in picograms. Most of the changes in allergic disease occur as a consequence of binding histamine to H1 receptor (38-40, 54). Hypotension, tachycardia, flushing and headache occur through both the H1 and H2 receptors (55), whereas irritation of the skin in the form of itching and nasal congestion can be caused by the activation of H1 and H3 receptors (56, 57). The role of histamine can be discussed also as a stimulatory signal for the production of cytokines and the expression of cell adhesion molecules in the late- phase of allergic reaction (55, 56, 58, 59). Histamine may have proinflammatory or antiinflammatory effects, depending on _ the predominance of the type of histamine receptor. Through the Hl-receptor, histamine has proinflammatory effect, which activation can be greatly involved in several aspects of antigen-specific immune response, including maturation of dendritic cells and the modulation of the balance of Th1 cells and Th2 cells. Histamine may induce an increase in the proliferation of Th1 cells and in the production of interferon y, which may result in blocking humoral immune responses by means of this mechanism Histamine has the capacity to influence the activity of basophils, eosinophils and fibrobalsts. The binding of histamine to histamine H1 receptor leads to many effects that are associated with symptoms of anaphylaxis and other allergic diseases (60), however, increasing evidence suggests that this process also affects a number of immune /inflammatory and effector functions (38,59). 12 Under the secretion of proinflammatory cytokines such as IL-la IL-1f, IL-6 as well as chemokines such as regulated activation (RANTES) or IL-8. This process takes place in several types of cells and tissues and leads to the progression of allergic-inflammatory responses. Histamine H1 receptor and histamine H2 receptor are found on the surface of endothelial cells. Histamine through H1 receptor leads to increased expression of adhesion molecules such as vascular cellular adhesion molecule (VCAM-1), intracellular adhesion molecule (ICAM-1) and P-selectin. Histamine regulates granulocyte accumulation in tissues in distinct ways. Allergen-induced accumulation of eosinophils in the skin, nose and airways is inhibited by histamine H1 receptor antagonists. The effect of histamine on eosinophil migration may differ according to the concentration. Whereas high concentrations inhibit eosinophil chemotaxis via histamine H1 receptor, low concentrations enhance eosinophil chemotaxis via histamine H1 receptor. One study has shown that histamine H4 receptor is the histamine receptor responsible for the selective recruitment of eosinophils. Histamine possesses all the properties of a classical leukocyte chemoattractant, including: alteration in cell shape, mobilization of intracellular calcium and up- regulation of adhesion molecule expression. influence of histamine occurs ANTIHISTAMINES More than 45 types of antihistamines are widely used around the world, thus representing the largest group of medicines used in the treatment of allergic conditions. Traditionally, this group of drugs is classified in six chemical groups: ethanolamines, ethylenediamines, alkylamines, piperazines, piperidines and phenothiazines. If antihistamines are classified according to function, then we distinguish two generations of antihistamines: first and second generation antihistamines, which are distinguished by the fact that first generation antihistamines penetrate the blood-brain barrier and have a sedative effect, while the second generation antihistamines do not possess these qualities. They are very different in terms of chemical structure, pharmacology and toxic potential. Representative of the first and second generation of antihistamines are given in Figure 2. Consequently, knowledge of their pharmacokinetic Scientific Journal of the Faculty of Medicine in Nis 2015;32(1):7-22 and pharmacodynamics characteristics is important for the correct usage of such drugs, particularly in Nikola Stojkovi¢, SneZana Ceki¢, Milica Ristov et al. patients belonging to extreme age groups, pregnant women, or subjects with concomitant diseases. First-Generation H,-Receptor Antagonists GO . O ic a pion, on, if Hoc oH NC 1 « © CH, CHOC, CH On Hydronyzine cr ‘Second-Generation Hy-Receptor Antagonists Ox tar EO ncn Oppon Tartanadine p ont holt, cit, ocr, on YW er Cotirizine cH Ketotfen © i FR ©. QP Opa Qhn Astemizole q h-C-o—cn, cH, pronen Activastine Cy Loratadine SOY oa ; Figure 2: Drugs of the first and second generation of antihistamines (61) (source: Simons FER, Simons KJ. The pharmacology and use of H1-receptor antagonist drugs. N Engl J Med 1994; 330: 1663-1670) After oral application, most antihistamines show a good degree of absorption. The effective concentration of antihistamines is achieved three hours after application, which confirms the above thesis. These molecules have the characteristic of liposolubility, which enables them to pass through cell membranes with extreme ease. Concomitant administration with food can change the plasma concentrations of these drugs, explained by the presence of P glycoprotein across cell membranes and the organic anion transporter polypeptides. These proteins function as active transport systems for other molecules, showing affinity for them. Antihistamine shows a good degree of binding to plasma proteins (78% to 99%). The group of enzymes belonging to the P450 which can be Scientific Journal of the Faculty of Medicine in } cytohrome system performs metabolization and detoxification of most antihistamines. Only acrivastine, levocetirizine, desloratadine and fexofenadine (62) avoid this metabolic passage through the liver to an important degree, which makes them more predictable in terms of their desirable and undesirable effects. Fexofenadine is eliminated in stool, while cetirizine and levocetirizine are eliminated in urine. Fexofenadine is eliminated without metabolic changes while cetirizine and levocetirizine are eliminated in unaltered form Other antihistamines undergo the transformation in the liver, thereby resulting in metabolites which may be active or inactive. Their concentrations in plasma depend on the activity of the P450 enzyme system. Metabolism of antihistamines and drug interaction are given in Table 2. 13 2015;32(1):7-22 Review article 10. 41. 12. 16 . Akdis . Akdis CA. Allergy and hypersensitivity: mechanisms of allergic disease. Curr Opin Immunol 2006; 18(6):718-26. http: //dx. doi.org/10.1016/j.coi.2006.09.016 . Akdis M, Akdis CA. Mechanisms of allergen specific immunotherapy. J Allergy ClinImmunol 2007; 119(4):780-91. http: //dx. doi.org/10.1016/j.jaci.2007.01.022 . Akdis M,Burgler S, Crameri R et al. Interleukins, from 1 to 37, and interferon-gamma: Receptors, functions, and roles in diseases. J Allergy ClinImmunol 2011; 127(3):701-21, e70. . Akkoc T, Akdis M, Akdis CA: Update in the mechanisms of allergen-specific immunotheraphy. Allergy Asthma Immunol Res 2011; 3(1):11-20. http: //dx. doi.org/10.1016/j.coi.2006.06.003 M: Healthy response to allergens.T regulatory cells and more.Curr Opin Immunol 2006; 18(6):738-44. http: //dx. doi.org/10.1016/j.coi.2006.06.003 immune . Iwakura Y,Ishigame H, Saijo S, Nakae S. Functional specialization of interleukin-17 family members. Immunity 2011; 34(2):149-62. http://dx.doi.org/10.1016/j.immuni.2011.02.012 . Wang YH, Angkasekwinai P, Lu N et al. IL-25 augments type 2 immune responses by enhancing the expansion and functions of TSLP-DC- activated Th2 memory cells. J Exp Med 2007; 204(8):1837-47. http://dx.doi.org/10.1084/jem.20070406 Goswami S,Angkasekwinai P, Shan M et al. Divergent functions for airway epithelial matrix metalloproteinase 7 and retinoic acid in experimental asthma. Nat Immunol 2009; 10(5):496-503. http://dx.doi.org/10.1038/ni.1719 Bilsborough J, Leung DY, Maurer M et al. IL-31 is associated with cutaneous lymphocyte antigen- positive skin homing T cells in patients with atopic dermatitis. J Allergy ClinImmunol 2006; 117(2):418-25. http://dx.doi.org/10.1016/.jaci-2005.10.046 Dillon SR, Sprecher C, Hammond A et al. Interleukin 31, a cytokine produced by activated T cells, induces dermatitis in mice Nat Immunol 2004; 5(7):752-60. http://dx.doi.org/10.1038/ni1084 13. 14. 15. 16. 17. 18. 19. 20. 21. Kakkar R, Lee RT. The IL-33/ST2 pathway. therapeutic target and novel biomarker. Nat Rev Drug Discov 2008; 7(10):827-40. http://dx.doi.org/10.1038/nrd2660 Liew FY, Pitman NI, McInnes IB. Disease associated functions of IL-33: the new kid in the IL-1 family. Nat Rev Immunol 2010; 10(2):103-10. http://dx.doi.org/10.1038/nri2692 Akkoc T, de Koning PJ, Ruckert B et al. Increased activation-induced cell death of high IFN-gamma- producing T(H)1 cells as a mechanism of T(H)2 predominance in atopic diseases. J Allergy Clin Immunol 2008; 121(3):652-8, el. Meyer N, Zimmermann M, Burgler S et al. IL-32 is expressed by human primary keratinocytes and modulates keratinocyte apoptosis in atopic dermatitis. J Allergy ClinImmunol 2010; 125(4):858- 65, e10. Solarewicz-Madejek K,Basinski TM Crameri R et al. T cells and eosinophils in bronchial smooth muscle cell death in asthma. ClinExp Allergy 2009; 39(6):845-55. http://dx.doi.org/10.1111/j.1365-2222.2009.03244.x Trautmann A, Akdis M, Kleemann D et al. T cell- mediated Fas-induced keratinocyte apoptosis plays a key pathogenetic role in eczematous dermatitis. J Clin Invest 2000; 106(1):25-35. http: //dx.doi.org/10.1172/JCI9199 Trautmann A, Schmid-Grendelmeier P, Kruger K et al. T cells and eosinophils cooperate in the induction of bronchial epithelial cell apoptosis in asthma. J Allergy ClinImmunol 2002; 109(2):329- 37. http: //dx.doi.org/10.1067/mai.2002.121460 Zimmermann M, Koreck A, Basinski T et al. TNF- like weak inducer of apoptosis (TWEAK) and TNF-alpha cooperate in the induction of keratinocyte apoptosis. J Allergy ClinImmunol 2011; 127(1):200-7, 207 e1-10. Canonica GW, Blaiss M. Antihistaminic, anti- inflammatory, and antiallergic properties of the nonsedating second-generation _ antihistamine desloratadine: a review of the evidence. World Allergy Organ J. 2011;4(2):47-53. http://dx.doi.org/10.1097/WOX.0b013e3182093e19 Scientific Journal of the Faculty of Medicine in Nis 2015;32(1):7-22 22. 23. 24. 25. 26. 27. 28. 29. Haas H, Panula P. The role of histamine and the tuberomamillary nucleus in the nervoussystem. Nat Rev Neurosci 2003;4:121-30. http://dx.doi.org/10.1038/nrn1034 Yokoyama H. The role of central histaminergic neuron system as an anticonvulsive mechanism in developing brain. Brain Dev 2001; 23:542-7. http://dx. doi.org/10.1016/S0387-7604(01)00261-3 Broid DH, Gleich GJ, Cuomo AJ et al. Evidence of ongoing mast cell and eosinophil degranulation in symptomatic asthma airway. J Allergy Clin Immunol 1991; 88: 637— 48. http://dx.doi.org/10.1016/0091-6749(91)90158-K Casale TB, Wood D, Richerson HB et al. Elevated bronchoalveolar lavage fluid histamine levels in allergic asthmatics are associated —_ with methacholine bronchial hyperresponsiveness. J Clin Invest. 1987; 79:1197-203. http://dx.doi.org/10.1172/JCI112937 Jarjour NN, Calhoun WJ, Schwartz LB, Busse WW. Elevated bronchoalveolar lavage fluid histamine levels in allergic asthmatics are associated with increased airway obstruction. Am. Rev.Respir. Dis.1991; 144: 83-7. http://dx.doi.org/10.1164/ajrecm/144.1.83 Liu MC, Bleecker ER, Lichtenstein LM et al. Evidence for elevated levels of histamine, prostaglandin D2, and other bronchoconstricting prostaglandins in the airways of subjects with mild asthma. Am. Rev.Resp. Dis.1990; 142:126-32. http://dx.doi.org/10.1164/ajrccm/142.1.126 Wardlaw AJ, Dunnette S, Gleich GJ et al. Eosinophils and mast cells in bronchoalveolar lavage in subjects with mild asthma. Relationship to bronchial hyperreactivity.Am. Rev.Respir. Dis. 1988; 137: 62-9. http://dx.doi.org/10.1164/ajrecm/137.1.62 SE, Fowler AA 3rd, Schwartz LB. Activation of pulmonary mast cells by bronchoalveolar allergen challenge. In vivo release of histamine and tryptase in atopic subjects with and without asthmaAm Rev. Respir. Dis.1988; 137:1002- 8. http://dx.doi.org/10.1164/ajrecm/137.5. 1002 Wenzel Scientific Journal of the Faculty of Medicine in N 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. Nikola Stojkovi¢, SneZana Ceki¢, Milica Ristov et al. Johnson HH Jr, DeOreo GA, Lascheid WP, Mitchell F. Skin histamine levels in chronic atopic dermatitis. J. Invest.Dermatol. 1960; 34:237-8 (1960). Juhlin L. Localization and content of histamine in normal and diseased skin. ActaDerm.Venereal. 1967; 47: 383-91. Greaves MW, Soendergaard J. Urticariapigmentosa and factitious urticaria. Arch Dermatol. 1970;101: 418-25. http://dx.doi.org/10.1001/archderm.1970.04000040 040009 Kaplan AP, Horakova Z, Katz SI. Assessment of tissue fluid histamine levels in patients with urticaria. J. Allergy Clin. Immunol. 1978; 61:350-4. http://dx.doi.org/10.1016/0091-6749(78)90113-6 Tuomisto L, Kilpelainen H, Riekkinen P. Histamine and histamine-N-methyltransferase in the CSF of patients with multiple sclerosis. Agents Actions 1983; 13:255-7. http://dx.doi.org/10.1007/BF01967346 Petersen LJ, Hansen U, Kristensen JK et al. Studies on mast cells and histamine release in psoriasis: the effect of ranitidine. ActaDerm.Venereol. 1998; 78:190-3. http://dx.doi.org/10.1080/000155598441503 Frewin DB, Cleland LG, Jonsson, JR, Robertson PW. Histamine levels in human synovial fluid. J.Rheumatol.1986; 13:13-4. Crisp AJ. Studies of histamine in the rheumatoid joint.Rheumatol. Int. 1984; 4:125-8 (1984). Akdis CA, Blaser K. Histamine in the immune regulation of allergic inflammation. J Allergy ClinImmunol 2003; 112:15-22. http://dx.doi.org/10.1067/mai.2003.1585 MacGlashan D Jr. Histamine a mediator of inflammation. J Allergy ClinImmunol 2003; 112:Suppl 4:53-9. http://dx.doi.org/10.1016/S0091-6749(03)01877-3 Schneider E, Rolli-Derkinderen M, Arock M, Dy M. Trends in histamine research: new functions during immune responses and hematopoiesis. Trends Immunol 2002;23:255-63. http://dx.doi.org/10.1016/S1471-4906(02)02215-9 17 2015;32(1):7-22 Review article 41. 42. 43. 4a. 45. 46. 47. Le Coniat M, Traiffort E, Ruat M et al. Chromosomal localization of the human histamine H1-receptor Hum_ Genet 1994;94: 186-8. http://dx.doi.org/10.1007/BF00202867 Gantz I, Schaffer M, DelValle J, et al. Molecular cloning of a gene encoding the histamine H2 receptor. ProcNatlAcadSci U S A 1991;88:429-33. (Erratum, ProcNatlAcadSci U S A 1991;88:5937.] http://dx.doi.org/10.1073/pnas.88.13.5937a Oda T, Morikawa N, Saito Y et al. Molecular cloning and characterization of a novel type of histamine receptor preferentially expressed in leukocytes. J Biol Chem 2000;275:36781-6. http://dx. doi.org/10.1074/jbe.M006480200 Lovenberg TW, Roland BL, Wilson SJ et al. Cloning and functional expression of the human histamine H3_ receptor. Mol Pharmacol 1999;55:1101-7. Bakker RA, Schoonus SB, Smit MJ et al. Histamine H1-receptor activation of nuclear factor-kappa B: roles for G beta gamma- and G _alpha(q/11)- subunits in constitutive and agonist-mediated signaling. MolPharmacol 2001;60:1133-42. Arrang JM, Garbarg M, Schwartz JC et al. Autoinhibition of brain histamine release mediated by a novel class (H3) of histamine receptor. Nature 1983; 302:832-7. http://dx.doi.org/10.1038/302832a0 Hall IP. Pharmacogenetics of asthma.EurRespir J 2000;15:449-51. http://dx.doi.org/10.1034/j.1399-3003.2000.15.04.x gene. 48.Banu Y, Watanabe T. Augmentation of antigen 49. 50. 18 receptor-mediated responses by histamine H1 receptor signaling. J Exp Med 1999;189:673-82. http://dx.doi.org/10.1084/jem.189.4.673 Yanai K, Son LZ, Endou M et al. Targeting disruption of histamine H1 receptors in mice: behavioral and neurochemical characterization. Life Sci 1998;62:1607-10. http://dx.doi.org/10.1016/S0024-3205(98)00115-5 Leurs R, Church MK, Taglialatela M HI- antihistamines: inverse agonism, anti-inflammatory actions and cardiac effects. ClinExp Allergy. 2002;32:489- 98. http://dx.doi.org/10.1046/j.0954-7894.2002.01314.x 51. 52. 53. 54. 55. 56. 57. 58. 59. Bakker RA, Wieland K, Timmerman H, Leurs R. Constitutive activity of the histamine H(1) receptor reveals inverse agonism of histamine H1 receptor antagonists. Eur J Pharmacol. 2000;387:R5-R7. http://dx.doi.org/10.1016/S0014-2999(99)00803-1 Labella FS, Brandes LJ. Interaction of histamine and other bio-amines with cytochromes P450: implications for cell growth modulation and chemopotentiation by drugs. Semin. Cancer Biol2000; 10:47-53. http://dx.doi.org/10.1006/scbi.2000.0307 Akdis CA, Simons FER. Histamine receptors are hot in immunopharmacology. Eur J Pharmacol. 2006; 533:69-76. http://dx.doi.org/10.1016/j.ejphar.2005.12.044 Schmelz M, Schmidt R, Bickel A et al. Specific C- receptors for itch in human skin. Neurosci 1997; 17:8003-8. Spitaler MM, Hammer A, Malli R, Graier WF. Functional analysis of histamine receptor subtypes involved in endotheliummediated relaxation of the human _ uterine artery. ClinExpPharmacolPhysiol 2002;29: 711-6. http://dx.doi.org/10.1046/j.1440-1681.2002.03704.x Sugimoto Y, Iba Y, Nakamura Y et al. Pruritus- associated response mediated by cutaneous H3 receptors. ClinExp Allergy 2004;34:456-9. http://dx.doi.org/10.1111/j.1365-2222.2004.01876.x McLeod RL, Mingo GG, Herczku C, et al. Combined histamine H1 and H3_ receptor blockade produces nasal decongestion in an experimental model of nasal congestion Am J Rhinol 1999;13:391-9. http: //dx.doi.org/10.2500/105065899781367483 Fujikura T, Shimosawa T, Yakuo I Regulatory effect of histamine H1 receptor antagonist on the expression of messenger RNA encoding CC chemokines in the human nasal mucosa. J Allergy ClinImmunol 2001; 107:123-8. http: //dx.doi.org/10.1067/mai.2001.111236 Jutel M, Watanabe T, Akdis M et al.Immune regulation by histamine.Curr.Opin.Immunol.2002; 14, 735-740. http://dx. doi.org/10.1016/S0952-7915(02)00395-3 Scientific Journal of the Faculty of Medicine in Nis 2015;32(1):7-22 97. 98. Namazi MR. Cetirizine and allopurinol as novel weapons against autoimmune disorders. J IntImmunopharmacol 2004: 4 (3): 349-53. Pestelli E, Caproni M, Giomi B et al. Cetirizine reduces the number of tryptase-positive mast cells in psoriatic patients: a double-blind controlled study. Int J Tissue React 2001: 23(3): 97-103. Scientific Journal of the Faculty of Medicine in N Nikola Stojkovi¢, SneZana Ceki¢, Milica Ristov et al. 99. Hemmati AA, Mikaili P, Khodayar MJ et al. The protective effect of Cetirizine against Bleomycine induced pulmonary fibrosis in rats. Pak J Med Sci 2008: 24 (6): 813-20. 21 2015;32(1):7-2. Review article Histamin i antihistamini Nikola Stojkovic!, SneZana Ceki@, Milica Ristov3, Marko Risti¢!, Davor Duki¢!, MaSa Bini¢!, Dragan Virijevic! 1Univerzitet u Nisu, Medicinski fakultet, Student postdiplomskih studija, Srbija “Institut za patofiziologiju, Univerzitet u NiSu, Medicinski fakultet, Srbija 3Doktor medicine SAZETAK Poslednjih godina beleZi se kontinuirani rast prevalencije alergijskih oboljenja. Alergijski imunski odgovor predstavlja jednu kompleksnu mreZu ¢elijskih dogadaja u kojoj uéestvuju mnogobrojne imunske celije i medijatori. On predstavlja interakciju urodenog i stecenog imunskog odgovora. Kljucnu ulogu u imunoloskoj kaskadi zauzima histamin, prirodni sastojak tela, koga u alergijskom inflamatornom odgovoru oslobadaju mastociti i bazofili. Cilj ovog rada bio je naglasiti ulogu histamina u alergijskim imunoloskim dogadajima, njegov efekat na Thi i Th2 subpopulaciju limfocita i produkciju odgovarajucih citokina, kao i ulogu blokatora histamina u tretmanu ovih stanja. Histamin ostvaruje svoj efekat vezivanjem za ¢etiri tipa svojih receptora koji su Siroko distribuirani u organizmu. Blokatori histamina blokiraju mnogobrojne efekte histamina vezivanjem za ove receptore. Cetirizin, visoko selektivni antihistaminik druge generacije, ne ostvaruje svoje efekte samo vezivanjem za H1 receptore vec dovodi do atenuisanja mnogobrojnih zbivanja tokom inflamacijskog procesa. Dobro poznavanje efekata histaminskih blokatora, medu njima i cetirizina, moze dovesti do pravog odabira terapije u tretmanu alergijskih oboljenja. Kijucne reci: histamin, imunski odgovor, blokatori histamina, cetirizin 22 Scientific Journal of the Faculty of Medicine in Nis 2015;32(1):7-22