1. Histamine and H1-antihistamines: Celebrating a century of progress
F. Estelle R. Simons, MD, FRCPC, Keith J. Simons, PhD 
Journal of Allergy and Clinical Immunology 
Volume 128, Issue 6, Pages e4 (December 2011)
DOI: /j.jaci
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2. Fig 1
Celebrating a century of progress: timeline featuring historical highlights related to histamine, histamine receptors, and H1-antihistamines. The physiologic and pathologic effects of histamine were described in H1-antihistamines were introduced for clinical use in the 1940s, for example, antergan (1942), diphenhydramine (1946), and chlorpheniramine (1949). In the 1980s, relatively nonsedating second (new)–generation H1-antihistamines were introduced for clinical use, and histamine-containing neurons were identified in the CNS. Cloning and characterization of human histamine receptors was reported for the H2-receptor in 1991, the H1-receptor in 1993, the H3-receptor in 1999, and the H4-receptor in
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Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

3. Fig 2
Molecular basis of action of histamine and antihistamines. A, The inactive state of the histamine H1-receptor is in equilibrium with the active state. B, The agonist, histamine, has preferential affinity for the active state, stabilizes the receptor in this conformation, and shifts the equilibrium toward the active state. C, An H1-antihistamine (inverse agonist) has preferential affinity for the inactive state, stabilizes the receptor in this conformation, and shifts the equilibrium toward the inactive state.15,18 GDP, Guanosine diphosphate; GTP, guanosine triphosphate.
Journal of Allergy and Clinical Immunology  , e4DOI: ( /j.jaci )
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4. Fig 3
Benefits and risks of H1-antihistamines. A, Beneficial effects: H1-antihistamines act directly to interfere with histamine action at H1-receptors on sensory neurons and small blood vessels, mainly post-capillary venules. They also downregulate allergic inflammation indirectly through nuclear factor-κB (NF-κB) and through calcium ion channels. B, Potential adverse effects: First (old)–generation H1-antihistamines cross the BBB and occupy CNS H1-receptors, as documented by means of PET. High H1-receptor occupancy correlates directly with impairment of CNS function, with or without accompanying sedation. These medications also potentially cause adverse effects through other mechanisms, such as their antimuscarinic and antiserotonin effects.1,7,18,31-33 DAG, 1,2-diacylglycerol; ER, endoplasma reticulum; GDP, guanosine diphosphate; GTP, guanosine triphosphate; IKr, rapid component of the delayed outward rectifying potassium channel; INa, rapid component of the inward rectifying sodium channel; IP3, inositol 1,4,5-triphosphate; PIP2, phosphatidylinositol 4,5-bisphosphate; PKCβ, protein kinase C β; PLCβ, phospholipase C β.
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5. Fig 4
Science versus reality: evidence-based use of H1-antihistamines in allergic diseases and other disorders. On the basis of well-designed randomized controlled trials and meta-analyses of such trials, the evidence base for the efficacy and safety of second (new)–generation H1-antihistamines is strong in patients with allergic rhinitis, allergic conjunctivitis, and urticaria (category of evidence I, strength of recommendation A) but not in those with atopic dermatitis and other diseases (category of evidence II-IV, strength of recommendation B, C, or D, depending on the disease). The evidence base for the efficacy and safety of first (old)–generation H1-antihistamines remains weak in patients with allergic rhinitis, allergic conjunctivitis, urticaria, atopic dermatitis, and other diseases, including CNS and vestibular disorders (category of evidence II-IV, strength of recommendation B, C, or D, depending on the disease). Their potential adverse effects remain a concern.1,18,33,42-91
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