The different stories: a historical perspective

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The different storiesa historical perspective
Are all Antihistamines the same ?

• Georges M. Halpern, MD, PhD
• Distinguished Professor of Pharmaceutical
  Sciences
• Hong Kong Polytechnic University

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General History of Antihistamines
Modified from Simons FER. Antihistamines, Chapter
51, in Middleton's Allergy Principles and
Practice, Mosby, 6th Edition, 2003
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1910-1911 Discovery of Histamine

• Henry Dale and Patrick Laidlaw identified and
  described the properties of histamine (from
  histos tissue, with an amine constituent).

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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.

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1942 First Clinical Applications

• Bernard N. Halpern introduces the 1st AH 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 Methapyrilene 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 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

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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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Different Development Objectives

• General trend improve tolerability and safety
  (less to no sedation reduce the cholinergic
  effects)

Targeted Molecules for improvement
Type of Improvement
Objective
Loratadine Hydroxyzine Terfenadine Astemizole
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Different Generation of Antihistamines
Antergan and Neo-Antergan
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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.
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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

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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