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

2. General History of Antihistamines 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 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 1 st 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 1 st 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 Ethylenediamines: Pyrilamine (mepyramine) Antazoline Methapyrilene TripelennamineEthanolamines Diphenhydramine Clemastine Diphenylpyraline Doxylamine Phenyltoxamine Alkylamines: Alkylamines: Desbrompheniramine Dexchlorpherniramine Chlorpheniramine Dimethindene PheniraminePhenothiazines: Promethazine Methdilazine Trimeprazine Piperazines: Cyclizine Buclizine Hydroxyzine Meclizine Piperidines: Cyproheptadine Azatadine Loratadine Different classes due to different “mother” molecules

8. Different Chemical Structures

9. Different Applications of Antihistamines Allergy: – –1 st & 2 nd 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. PK, lower drug-drug interactions Receptor affinity and selectivity, efficacy Safety, lower cardiotoxicity Different Development Objectives General trend: improve tolerability and safety (less to no sedation; reduce the cholinergic effects) Targeted Molecules for improvement Type of Improvement Loratadine Hydroxyzine Terfenadine Astemizole ObjectiveClass Piperidine Piperazine Piperidine Piperidine Isomer Purification Levocetirizine Active metabolite Desloratadine Cetirizine Fexofenadine No possible improvement not even designed as an antihistamine; discovered during research of calcium channel-blocking agents

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

13. Different Safety Profiles withdrawn from the market due to cardiotoxicity 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. Still on the market

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 Different Destinies Some withdrawn from the market: Some withdrawn from the market: –astemizole, terfenadine Some failed to reach enough patients: Some failed to reach enough patients: –ebastine, levocabastine Some quickly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

15. Are all antihistamines the same ? Apparently, they are NOT Apparently, they are NOT –Different synthesis pathways –Different development objectives –The uncertainty of whether a 3 rd 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