Positron emission tomography evaluation of sedative properties of antihistamines

Abstract

The use of PET to examine antihistamine penetration in the human brain in relation to psychometric and other functional measures of CNS effects is a major breakthrough and provides a new standard by which the functional CNS effects of antihistamines can be related directly to H(1) receptor occupancy. Therapy with antihistamines can be better guided by considering histamine H(1) receptor occupancy from the view of their sedative properties.

Molecular Determinants Responsible for Sedative and Non-sedative Properties of Histamine H1–Receptor Antagonists

“…Actually, the rank order of sedative and nonsedative properties of antihistamines, which was evaluated by positron emission tomography (PET) by use of [ 11 C]doxepin in vivo (26), was not entirely identical but mostly compatible with our results: some discrepancies observed might be explained, at least in part, by the fact that the receptor occupancy by antihistamines in the brain varied according to their doses administrated (27), which resulted in changes in the rank order of their sedative and non-sedative properties in vivo (26). Thus, the assertion that sedative and non-sedative properties of antihistamines can be predominantly determined by their membrane-penetrating ability rather than their extrusion from the brain via P-glycoproteins is strengthened by the results that the QSAR model constructed on the basis of their membrane penetrating ability alone discriminated almost perfectly between sedative and non-sedative antihistamines.…”

International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors

“…Although the newer antihistamines generally display high H 1 receptor affinity and higher selectivity versus nontargets than that of the older ones, side effects can still be observed (notably antimuscarinic effects and sedation when taken with alcohol or other depressant drugs Yanai et al, 2011). With the patent expiry of many second-generation drugs and their widespread availability over the counter at low costs, the medicine agencies are looking for genuine innovation and novelty: one of the outcomes of this is the development of combination therapies, e.g., antiinflammatory properties such as inhibition of neuropeptide or leukotriene signaling (Scannell et al, 2004;Beaton and Moree, 2010).…”

Histamine and H1-antihistamines: Celebrating a century of progress

“…High H 1 -receptor occupancy is associated with decreased histaminergic neurotransmission and impaired CNS function on objective tests. [31][32][33][96][97][98] Penetration of the BBB is related to lipophilicity, relatively low molecular weight, and lack of substrate recognition by the P-glycoprotein efflux pump expressed on the luminal surfaces of nonfenestrated endothelial cells in the CNS vasculature.…”

“…Second-generation H 1 -antihistamines do not exacerbate the CNS effects of concurrently used ethanol, benzodiazepines, and other CNS-active substances. 1,18,31,33,[96][97][98]123 About 15 years ago, regulatory agencies rescinded their approval for astemizole and terfenadine, the second-generation H 1 -antihistamines initially introduced, because they potentially cause QT interval prolongation and torsade de pointes. Subsequently, regulatory agencies have scrutinized all secondgeneration H 1 -antihistamines for their proarrhythmic potential and required studies of their cardiac safety at standard doses and high off-label doses, as well as drug interaction studies and studies in the elderly and other vulnerable patients.…”