Brain histamine H₁ receptor occupancy of orally administered antihistamines measured by positron emission tomography with ¹¹C‐doxepin in a placebo‐controlled crossover study design in healthy subjects: a comparison of olopatadine and ketotifen

Abstract

Brain histamine H 1 receptor occupancy of orally administered antihistamines measured by positron emission tomography with 11 C-doxepin in a placebocontrolled crossover study design in healthy subjects: a comparison of olopatadine and ketotifen AimsThe strength of sedation due to antihistamines can be evaluated by using positron emission tomography (PET). The purpose of the present study is to measure histamine H 1 receptor (H 1 R) occupancy due to olopatadine, a new second-generation antihistamine and to compare it with that of ketotifen. MethodsEight healthy males (mean age 23.5 years-old) were studied following single oral administration of olopatadine 5 mg or ketotifen 1 mg using PET with 11 C-doxepin in a placebo-controlled crossover study design. Binding potential ratio and H 1 R occupancy were calculated and were compared between olopatadine and ketotifen in the medial prefrontal (MPFC), dorsolateral prefrontal (DLPFC), anterior cingulate (ACC), insular (IC), temporal (TC), parietal (PC), occipital cortices (OC). Plasma drug concentration was measured, and correlation of AUC to H 1 R occupancy was examined.

Cerebral Histamine H1 Receptor Binding Potential Measured with PET Under a Test Dose of Olopatadine, an Antihistamine, Is Reduced After Repeated Administration of Olopatadine

“…Both methods provided similar values for BP ND . The obtained receptor occupancy value under the initial single dose of olopatadine was 15%-close to the value (14%) reported in the previous study (3) and thus supporting the validity and feasibility of the present study. In fact, the cerebellar time-activity curves showed no significant difference between the scans (Supplemental Fig.…”

“…Measurement of cerebral histamine H 1 receptor occupancy using PET with 11 Cdoxepin under a single administration of antihistamines has been effective in evaluating the sedative effect, allowing the drugs to be classified as more sedating or as less sedating (or nonsedating) (1,2). Olopatadine is a widely used antihistamine with high antiallergy efficacy and has been reported to be less sedating on the basis of PET measurements and neuropsychological tests (3). A mild sedative effect has been pointed out for olopatadine despite higher efficacy than fexofenadine, which is a nonsedating antihistamine (4).…”

Dose dependency of brain histamine H1 receptor occupancy following oral administration of cetirizine hydrochloride measured using PET with [11C]doxepin

“…It has been known that sedative antihistamines, such as hydroxyzine, ketotifen, diphenhydramine, and d-chlorpheniramine, occupy more than 50% of available H 1 Rs, resulting in high prevalence of sleepiness and cognitive decline (Yanai et al, 1995a;Okamura et al, 2000;Tagawa et al, 2001;Tashiro et al, 2006;Van Hoecke et al, 2007;Tashiro et al, 2008). Hydroxyzine is a typical sedative antihistamine that induces psychomotor impairment even at recommended doses (20-30 mg), and it has been used as a positive control in many studies Gengo and Gabos, 1987;Walsh et al, 1992;Lee and Maibach, 2001;Van Hoecke et al, 2007).…”

“…This is an efflux pump expressed in capillary endothelial cells in the BBB (Tashiro et al, 2006). Many sedative antihistamines are often lipophilic and can be absorbed in full amount in the gut, and they can freely diffuse into the brain space.…”

Olopatadine, a non‐sedating H1 antihistamine, decreases the nocturnal scratching without affecting sleep quality in atopic dermatitis

“…Half of the subjects received the oral antihistamine, olopatadine hydrochloride (OH: Allelock â 5 mg tablet, Kyowa Hakko Kirin, Tokyo, Japan), and the remaining half only placebo prepared in an identical capsule (Appendices S2 and S3). OH is a second-generation non-sedating antihistamine that is used to treat allergic disorders including urticaria, rhinitis and AD in Japan (4,5). Measurement of scratching duration and electroencephalogram recordings was performed on day À2 and À1, and then, the subjects started taking 5 mg of oral OH or placebo twice daily from day 1 to 7.…”