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The different stories: a historical perspective

Are all Antihistamines the same ?. The different stories: a historical perspective. Georges M. Halpern, MD, PhD Distinguished Professor of Pharmaceutical Sciences Hong Kong Polytechnic University. 1910 Histamine discovered. 1937 First antihistamines (AHs) synthesized.

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The different stories: a historical perspective

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  1. Are all Antihistamines the same ? The different stories:a historical perspective Georges M. Halpern, MD, PhD Distinguished Professor of Pharmaceutical Sciences Hong Kong Polytechnic University

  2. 1910 Histamine discovered 1937 First antihistamines (AHs) synthesized 1942 Antihistamines introduced for clinical use 1943 First CNS effects of AHs reported 1955 Antiallergic effects of AHs described 1981 2nd generation AHs introduced 1986 Cardiotoxic effects of AHs reported 1991 Human H2 receptor cloned 1993 Human H1 receptor cloned 1998 H1 receptor polymorphism described 1999 Human H3 receptor cloned 2000 Human H4 receptor cloned General History of Antihistamines Modified from Simons FER. Antihistamines, Chapter 51, in Middleton's Allergy: Principles and Practice, Mosby, 6th Edition, 2003

  3. 1910-1911: Discovery of Histamine Henry Dale and Patrick Laidlaw identified and described the properties of histamine (from: histos = tissue, with an amine constituent).

  4. 1937: First Animal Studies Etienne Fourneau synthesized the 1st AH (thymo-ethyl-diethylamine); Daniel Bovet, assisted by Anne-Marie Staub studied it. It was found to be too weakly active, and too toxic for clinical use.

  5. 1942: First Clinical Applications Bernard N. Halpern introduces the 1st AH in human medicine: Phenbenzamine (Antergan). Indications: allergic rhinitis & asthma; urticaria; blood conservation.

  6. Next Steps • Marked by intensive and diversified research leading to notable differences between commercially available antihistamines • different synthesis pathways, hence different classes • different chemical structures • different indications/uses in various diseases • different development objectives • different generations • different safety features • different antihistamine performance and efficacy

  7. Different Classes of Antihistamines Different classes due to different “mother” molecules

  8. Different Chemical Structures

  9. Different Applications of Antihistamines • Allergy: • 1st & 2nd generation H1-antihistamines (chlorpheniramine, diphenylhydramine, hydroxyzine, astemizole, terfenadine, cetirizine, fexofenadine, loratadine, desloratadine, levocetirizine) • Anti-Migraine: • cyproheptadine, ergotamine + diphenydramine, pizotifen • Cough, Cold and Pain relief: • diphenhydramine, doxylamine

  10. Different Applications of Antihistamines • Motion Sickness: • dimenhydrinate, hydroxyzine, promethazine theoclate • Sedatives: • doxylamine succinate, diphenhydramine, pyrilamine, promethazine hydrochloride, mepyramine maleate, trimeprazine Different uses due to different properties and different development objectives

  11. Class Active metabolite Isomer Purification PK, lower drug-drug interactions Piperidine Piperazine Piperidine Piperidine Desloratadine Cetirizine Fexofenadine Levocetirizine Receptor affinity and selectivity, efficacy Safety, lower cardiotoxicity No possible improvement not even designed as an antihistamine; discovered during research of calcium channel-blocking agents Different Development Objectives • General trend: improve tolerability and safety (less to no sedation; reduce the cholinergic effects) Type of Improvement Targeted Molecules for improvement Objective Loratadine Hydroxyzine Terfenadine Astemizole

  12. 1st Generation: pyrilamine, antazoline, tripelennamine, diphenhydramine, clemastine, chlorpheniramine, triprolidine, promethazine, mequitazine, hydroxyzine, cyclizine, azatadine, cyproheptadine 2nd Generation: terfenadine, astemizole, cetirizine, acrivastine, ebastine, levocabastine, loratadine, mizolastine New or 3rd Generation: levocetirizine, carebastine, desloratadine, fexofenadine Different Generation of Antihistamines Antergan and Neo-Antergan

  13. Still on the market withdrawn from the market due to cardiotoxicity Different Safety Profiles A set of AHs tested for toxicity (inhibition of cellular proliferation) by the MTS assay (Sussman NL et al. Cell Notes, Issue 3, 2002: 7-10). All drugs tested in quadruplicate at 80m and all assays performed at 72 hrs.

  14. Different Destinies • Some withdrawn from the market: • astemizole, terfenadine • Some failed to reach enough patients: • ebastine, levocabastine • Some quickly falling out of favour: • loratadine • Some are still going strong: • fexofenadine, cetirizine, desloratadine, levocetirizine

  15. Are all antihistamines the same ? • Apparently, they are NOT • Different synthesis pathways • Different development objectives • The uncertainty of whether a 3rd generation exists or not is also related to the different development histories and product characteristics The diverse pharmacology, efficacy and safety characteristics will be featured in the presentations that follow mine

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