Histamine H<sub>1</sub> receptor occupancy in human brains after single oral doses of histamine H<sub>1</sub> antagonists measured by positron emission tomography

Yanai, Kazuhiko; Ryu, Jong Hoon; Watanabe, Tetsu; Iwata, Ren; Ido, Tatsuo; Sawai, Yoneichi; Ito, Kazumi; Itoh, Masatoshi

doi:10.1111/j.1476-5381.1995.tb16386.x

Cited by 106 publications

(115 citation statements)

References 30 publications

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“…Position emission tomography scans have been found to be useful in the quantitative assessment of sedation caused by firstand second-generation antihistamines. It has been reported that chlorpheniramine occupied 76.8 Ϯ 4.2% of the available H1 receptors in the frontal cortex after a single oral dose of 2 mg, 31 whereas a single dose of cetirizine 20 mg occupied 20% to 50%. 32 However, these studies were done in adults.…”

Section: E118mentioning

confidence: 99%

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Central Nervous System Side Effects of First- and Second-Generation Antihistamines in School Children With Perennial Allergic Rhinitis: A Randomized, Double-Blind, Placebo-Controlled Comparative Study

Chong

Wong

et al. 2004

Pediatrics

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ABSTRACT. Objective. Allergic rhinitis is common and on the rise. Antihistamines are the mainstay of treatment and are the most commonly prescribed drugs in Singapore. Treatment-related sedation and its effect on cognition are a major concern. First-and second-generation antihistamines show varying degrees of sedation, but to date, objective studies in children are lacking. The objective of this study was to assess the sedating effect of cetirizine (second-generation antihistamine) and chlorpheniramine (first-generation antihistamine) compared with placebo using an objective neurophysiological test.Methods. This was a prospective, double-blind, placebo-controlled, randomized, single-dose, 3-way crossover study. Twenty-four children aged 7 to 14 years with allergic rhinitis completed the study. All children were randomly allocated to medication sequences and received 3 different drugs on 3 different days, at least 1 week apart. The P300 event-related potential was used as an objective test of sedation. Subjective assessment was by a visual analog scale.Results. Chlorpheniramine and cetirizine increased P300 latency when compared with baseline. No significant increase was obtained with placebo. The significant increase in P300 latency was not accompanied by significant change in subjective somnolence as measured by the visual analog scale.Conclusion. We have shown that cetirizine has sedative properties in children. The lack of correlation between P300 latency and the visual analog scale indicates that sedation induced by these drugs may not be subjectively noted. Pediatrics 2004;113:e116 -e121. URL: http: //www.pediatrics.org/cgi/content/full/113/2/e116; sedation, cetirizine, chlorpheniramine, P300 event-related potential.ABBREVIATIONS. CNS, central nervous system; ERP, event-related potential; VAS, visual analog scale; Fz , frontal location; Cz, central location; Pz, parietal location; T max , time to peak plasma drug concentration.A llergic rhinitis is on the increase worldwide as well as in Singapore. A 1994 survey showed the prevalence of rhinitis in Singapore children to be at a staggering 44%. 1 In children with allergic rhinitis, inadequate symptom control may contribute to learning impairment; school absences; poor quality of life; and emotional, social, or behavioral disturbances. 2 Oral antihistamines are the mainstay of therapy for allergic rhinitis in children 3 and have been used effectively for managing symptoms of allergic rhinitis for Ͼ50 years. They are the most commonly prescribed drugs among outpatient doctors in the public service in Singapore. 4 The major limitation of the use of first-generation antihistamines is sedation. 3 Being lipophilic molecules, they easily cross the blood-brain barrier and may exacerbate the decrease in cognitive function already experienced by the patient with allergic rhinitis. Sedating antihistamines have been shown to reduce learning performance in children. 5 In contrast, second-generation antihistamines are relatively lipophobic and therefore cross the blood-br...

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Section: E118mentioning

confidence: 99%

“…Central H1-receptor occupancy increased significantly with increasing plasma concentration of chlorpheniramine but not with increasing concentration of the active metabolite of ebastine 39 or terfenadine. 31 We know of no such studies with cetirizine.…”

Section: E118mentioning

confidence: 99%

Central Nervous System Side Effects of First- and Second-Generation Antihistamines in School Children With Perennial Allergic Rhinitis: A Randomized, Double-Blind, Placebo-Controlled Comparative Study

Chong

Wong

et al. 2004

Pediatrics

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“…The averaged arterial blood concentration was used to calculate the values of the binding potential (BP=Bmax/K d ) of doxepin for available brain H 1 -receptors in each subject as reported previously [4,20]. Parametric neuroimages which present the volume of distribution (V d ) for [ 11 C]-doxepin were generated by graphical analysis [4,21].…”

Section: Image Analysismentioning

confidence: 99%

Neuroimaging of histamine H₁‐receptor occupancy in human brain by positron emission tomography (PET): A comparative study of ebastine, a second‐generation antihistamine, and (+)‐chlorpheniramine, a classical antihistamine

Tagawa¹,

Kano²,

Okamura

et al. 2001

Brit J Clinical Pharma

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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 signi®cantly higher than after (+)-chlorpheniramine (2 mg). H 1 -receptor occupancies in cortex were approximately 10% by ebastine and i50% by either dose of (+)-chlorpheniramine (95% con®dence 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.

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“…Furthermore, this technology has been applied to a direct in vivo measurement of drug effectiveness in humans, highlighting the essential information needed in the fields of drug development including pharmacology, toxicology, gene targeting, and pharmaceuticals. [2][3][4][5][6][7][8] In recent years, by exploiting new detection technologies, several high-resolution PET and SPECT systems have been developed for imaging the biodistribution of a radiolabeled molecule in small laboratory animals. [5][6][7][8][9] These devices permit noninvasive and repetitive imaging of both the temporal and the spatial biodistribution in a single living animal.…”

Section: Introductionmentioning

confidence: 99%

In vivo Imaging of Brain Dopaminergic Neurotransmission System in Small Animals with High-resolution Single Photon Emission Computed Tomography

et al. 2003

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Histamine H₁ receptor occupancy in human brains after single oral doses of histamine H₁ antagonists measured by positron emission tomography

Cited by 106 publications

References 30 publications

Central Nervous System Side Effects of First- and Second-Generation Antihistamines in School Children With Perennial Allergic Rhinitis: A Randomized, Double-Blind, Placebo-Controlled Comparative Study

Central Nervous System Side Effects of First- and Second-Generation Antihistamines in School Children With Perennial Allergic Rhinitis: A Randomized, Double-Blind, Placebo-Controlled Comparative Study

Neuroimaging of histamine H₁‐receptor occupancy in human brain by positron emission tomography (PET): A comparative study of ebastine, a second‐generation antihistamine, and (+)‐chlorpheniramine, a classical antihistamine

In vivo Imaging of Brain Dopaminergic Neurotransmission System in Small Animals with High-resolution Single Photon Emission Computed Tomography

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Histamine H1 receptor occupancy in human brains after single oral doses of histamine H1 antagonists measured by positron emission tomography

Cited by 106 publications

References 30 publications

Central Nervous System Side Effects of First- and Second-Generation Antihistamines in School Children With Perennial Allergic Rhinitis: A Randomized, Double-Blind, Placebo-Controlled Comparative Study

Central Nervous System Side Effects of First- and Second-Generation Antihistamines in School Children With Perennial Allergic Rhinitis: A Randomized, Double-Blind, Placebo-Controlled Comparative Study

Neuroimaging of histamine H1‐receptor occupancy in human brain by positron emission tomography (PET): A comparative study of ebastine, a second‐generation antihistamine, and (+)‐chlorpheniramine, a classical antihistamine

In vivo Imaging of Brain Dopaminergic Neurotransmission System in Small Animals with High-resolution Single Photon Emission Computed Tomography

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Histamine H₁ receptor occupancy in human brains after single oral doses of histamine H₁ antagonists measured by positron emission tomography

Neuroimaging of histamine H₁‐receptor occupancy in human brain by positron emission tomography (PET): A comparative study of ebastine, a second‐generation antihistamine, and (+)‐chlorpheniramine, a classical antihistamine