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Neuroimaging of histamine $H_{1}$-receptor occupancy in human brain by positron emission tomography (PET): A comparative study of ebastine, a second-generation antihistamine, and (+)-chlorpheniramine, a classical antihistamine
| Content Provider | Scilit |
|---|---|
| Author | Tagawa, Masaaki Kano, Michiko Okamura, Nobuyuki Higuchi, Makoto Matsuda, Michiaki Mizuki, Yasuyuki Arai, Hiroyuki Iwata, Ren Fujii, Toshihiko Komemushi, Sadao Ido, Tatsuo Itoh, Masatoshi Sasaki, Hidetada Watanabe, Takehiko Yanai, Kazuhiko |
| Copyright Year | 2001 |
| Description | Journal: British journal of clinical pharmacology |
| Abstract | Aims Sedation induced by antihistamines is widely recognized to be caused by their penetration through the blood–brain‐barrier and the consequent occupation of brain histamine $H_{1}$‐receptors. We previously studied the mechanism of sedation caused by antihistamines using positron emission tomography (PET). Recently, we revealed the nonsedative characteristic of ebastine, a second‐generation antihistamine, with cognitive performance tests. In the present study, $H_{1}$‐receptor occupation by ebastine was examined in the human brain using PET. Methods Ebastine 10 mg and (+)‐chlorpheniramine 2 or 6 mg were orally given to healthy male volunteers. PET scans with $[^{11}$C]‐doxepin, a potent $H_{1}$‐receptor antagonist, were conducted near $t_{max}$ of respective drugs. Other volunteers in the control group also received PET scans. The binding potential of doxepin $(BP=Bmax/K_{d}$) for available brain $H_{1}$‐receptors was imaged on a voxel‐by‐voxel basis through graphical analysis. By setting regions of interest, the $H_{1}$‐receptor occupancy of drugs was calculated in several $H_{1}$‐receptor rich regions. Results Brain distribution of radioactivity after ebastine treatment was similar to that without any drugs. However, after the oral administration of 2 mg (+)‐chlorpheniramine, the level was lower than after ebastine and nondrug treatments. Graphical analysis followed by statistical parametric mapping (SPM96) revealed that $H_{1}$‐receptor rich regions such as cortices, cingulate gyrus and thalamus were regions where the BPs after ebastine were significantly higher than after (+)‐chlorpheniramine (2 mg). $H_{1}$‐receptor occupancies in cortex were approximately 10% by ebastine and ≥50% by either dose of (+)‐chlorpheniramine (95% confidence interval for difference in the mean receptor occupancies: 27%, 54% for 2 mg and 35%, 62% for 6 mg vs ebastine, respectively). Receptor occupancies increased with increasing plasma concentration of (+)‐chlorpheniramine, but not with concentration of carebastine, an active metabolite of ebastine. Conclusions Ebastine (10 mg orally) causes brain histamine $H_{1}$‐receptor occupation of approximately 10%, consistent with its lower incidence of sedative effect, whereas (+)‐chlorpheniramine occupied about 50% of brain $H_{1}$‐receptors even at a low but sedative dose of 2 mg; occupancy of (+)‐chlorpheniramine was correlated with plasma (+)‐chlorpheniramine concentration. |
| Related Links | http://europepmc.org/articles/pmc2014616?pdf=render https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2014616/pdf https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1046/j.1365-2125.2001.01471.x |
| Ending Page | 509 |
| Page Count | 9 |
| Starting Page | 501 |
| e-ISSN | 13652125 |
| DOI | 10.1046/j.1365-2125.2001.01471.x |
| Journal | British journal of clinical pharmacology |
| Issue Number | 5 |
| Volume Number | 52 |
| Language | English |
| Publisher | Wiley-Blackwell |
| Publisher Date | 2001-11-01 |
| Access Restriction | Open |
| Subject Keyword | Journal: British journal of clinical pharmacology (+)-chlorpheniramine Histamine H1-receptor Positron Emission Tomography (pet) Receptor Occupancy |
| Content Type | Text |
| Resource Type | Article |
