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8/11/2019 Antihistamines 101 Munich 06-05
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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 ?
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1910-1911: Discovery of Histamine
Henry Dale and Patrick
Laidlaw identified
and described theproperties of
histamine (from:
histos= tissue, withan amine
constituent).
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1937: First Animal Studies
Etienne Fourneau
synthesized the 1st
AH (thymo-ethyl-
diethylamine); DanielBovet, assisted by
Anne-Marie Staub
studied it.
It was found to be too
weakly active, and
too toxic for clinical
use.
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1942: First Clinical Applications
Bernard N. Halpern
introduces the 1stAH
in human medicine:
Phenbenzamine
(Antergan).
Indications: allergic
rhinitis & asthma;urticaria; blood
conservation.
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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
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Different Classes of Antihistamines
Ethylenediamines:
Pyrilamine
(mepyramine)
Antazoline
Methapyri lene
Tripelennamine
Ethanolamines
Diphenhydramine
Clemastine
Diphenylpyraline
Doxylamine
Phenyltoxamine
Alkylamines:
Desbrompheniramine
Dexchlorpherniramine
Chlorpheniramine
Dimethindene
Pheniramine
Phenothiazines:
Promethazine
Methdilazine
Trimeprazine
Piperazines:
Cyclizine
Buclizine
Hydroxyzine
Meclizine
Piperidines:
Cyproheptadine
Azatadine
Loratadine
Different classes due to different mother molecules
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Different Chemical Structures
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Different Applications of Antihistamines
Allergy:1st& 2ndgeneration 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
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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
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PK, lower drug-drug
interactions
Receptor affinity and
selectivity, efficacy
Safety, lowercardiotoxicity
Different Development Objectives
General trend: improve tolerability and safety (less tono sedation; reduce the cholinergic effects)
Targeted Molecules
for improvementType 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; discoveredduring research of calcium channel-blocking agents
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Different Generation of Antihistamines
Antergan and Neo-Antergan
1stGeneration:
pyrilamine, antazoline, tripelennamine, diphenhydramine,
clemastine, chlorpheniramine, triprolidine, promethazine,mequitazine, hydroxyzine, cyclizine, azatadine, cyproheptadine
2ndGeneration:
terfenadine, astemizole, cetirizine, acrivastine, ebastine,levocabastine, loratadine, mizolastine
New or 3rdGeneration:
levocetirizine, carebastine, desloratadine, fexofenadine
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Different Safety Profiles
0
0.2
0.4
0.6
0.8
1
1.2
1.4
Numberofviablec
ells(absorbance)
cetiriz
ineco
ntrol
fexofe
nadine
diphen
hydram
ine
chlor
pheni
ramine
hydro
xyzine
lorata
dine
terfen
adine
astem
izole
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. CellNotes, Issue 3, 2002: 7-10). All drugs tested in quadruplicate at 80m and all assays performed at 72 hrs.
Still on the market
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Are all antihistamines the same ?
Apparently, they are NOT
Different synthesis pathways
Different development objectives
The uncertainty of whether a 3rdgeneration 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