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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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 clonedGeneral History of Antihistamines
Modified from Simons FER. Antihistamines, Chapter 51, in Middleton's Allergy: Principles and Practice, Mosby, 6th Edition, 2003
Henry Dale and Patrick Laidlaw identified and described the properties of histamine (from: histos = tissue, with an amine constituent).
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.
Bernard N. Halpern introduces the 1st AH in human medicine: Phenbenzamine (Antergan). Indications: allergic rhinitis & asthma; urticaria; blood conservation.
Different classes due to different “mother” molecules
Different uses due to different properties and different development objectives
PK, lower drug-drug interactions
Receptor affinity and selectivity, efficacy
Safety, lower cardiotoxicity
No possible improvement
not even designed as an antihistamine; discovered during research of calcium channel-blocking agentsDifferent Development Objectives
Type of Improvement
Targeted Molecules for improvement
pyrilamine, antazoline, tripelennamine, diphenhydramine, clemastine, chlorpheniramine, triprolidine, promethazine, mequitazine, hydroxyzine, cyclizine, azatadine, cyproheptadine
terfenadine, astemizole, cetirizine, acrivastine, ebastine, levocabastine, loratadine, mizolastine
New or 3rd Generation:
levocetirizine, carebastine, desloratadine, fexofenadineDifferent Generation of Antihistamines
Antergan and Neo-Antergan
withdrawn from the market due to cardiotoxicityDifferent Safety Profiles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 80m and all assays performed at 72 hrs.
The diverse pharmacology, efficacy and safety characteristics will be featured in the presentations that follow mine