Histamine H1-receptor (H1R) antagonists, or antihistamines, often induce sedative side effects when used for the treatment of allergic disorders. This study compared the sedative profiles of the second-generation antihistamines, fexofenadine and cetirizine, using 3 different criteria: subjective sleepiness evaluated by the Stanford Sleepiness Scale, objective psychomotor tests (simple and choice reaction time tests and visual discrimination tests at 4 different exposure durations), and measurement of histamine H1-receptor occupancy (H1RO) in the brain. Subjective sleepiness and psychomotor performance were measured in 20 healthy Japanese volunteers at baseline and 90 min after administration of fexofenadine 120 mg or cetirizine 20 mg in a double-blind, placebo-controlled crossover study. Hydroxyzine 30 mg was included as a positive control. H1RO was measured using positron emission tomography (PET) with (11)C-doxepin in 12 of the 20 subjects, and a further 11 volunteers were recruited to act as controls. In psychomotor tests, fexofenadine was not significantly different from placebo and significantly less impairing than cetirizine on some tasks, as well as significantly less impairing than hydroxyzine on all tasks. For subjective sleepiness, fexofenadine was not significantly different from placebo, whereas cetirizine showed a trend toward increased sleepiness compared with fexofenadine and placebo. H1RO was negligible with fexofenadine (-0.1%) but moderately high with cetirizine (26.0%). In conclusion, fexofenadine 120 mg is distinguishable from cetirizine 20 mg, as assessed by H1RO and psychomotor testing.

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The central histaminergic neuron system modulates the wakefulness, sleep-awake cycle, appetite control, learning and memory, and emotion. Previous studies have reported changes in neuronal histamine release and its metabolism under stress conditions in the mammalian brain. In this study, we examined, using positron emission tomography (PET) and [(11)C]-doxepin, whether the histaminergic neuron system is involved in human depression. Cerebral histamine H1 receptor (H(1)R) binding was measured in 10 patients with major depression and in 10 normal age-matched subjects using PET and [(11)C]-doxepin. Data were calculated by a graphical analysis on voxel-by-voxel and ROI (region of interests) basis. Binding potential (BP) values for [(11)C]-doxepin binding in the frontal and prefrontal cortices, and cingulate gyrus were significantly lower in the depressed patients than those in the normal control subjects. There was no area of the brain where [(11)C]-doxepin binding was significantly higher in the depressed patients than in the controls. ROI-based analysis also revealed that BP values for [(11)C]-doxepin binding in the frontal cortex and cingulate gyrus decreased in proportion to self-rating depressive scales scores. The results of this study demonstrate that depressed patients have decreased brain H(1)R binding and that this decrease correlates with the severity of depression symptoms. It is therefore suggested that the histaminergic neuron system plays an important role in the pathophysiology of depression and that its modulation may prove to be useful in the treatment of depression.

Keywordsfirst-generation antihistamine, histamine H1 receptor occupancy, placebo-controlled crossover study design, positron emission tomography, second-generation antihistamine ---------------------------------------------------------------------- Received WHAT THIS STUDY ADDS• This paper provides the first measurement result of cerebral H1RO of bepotastine besilate (approximately 15%) as determined by PET. • This result is in accordance with the clinical classification of bepotastine as a second-generation antihistamine.• In addition, the relationship between subjective sleepiness and cerebral H1RO of this second-generation antihistamine is demonstrated for the first time using a placebo-controlled crossover study design. AIMSAntihistamines are frequently used for treating various allergic diseases, but often induce sedation. The degree of sedation can be evaluated by measuring histamine H1 receptor occupancy (H1RO) in the brain using positron emission tomography (PET). The aim was to measure H1RO of bepotastine, a new second-generation antihistamine, and to compare it with that of diphenhydramine. METHODSEight healthy male volunteers (mean age Ϯ SD 24.4 Ϯ 3.3 years) were studied after single oral administration of bepotastine (10 mg), diphenhydramine (30 mg) or placebo, by PET imaging with 11 C-doxepin in a crossover study design. Binding potential ratio and H1ROs were calculated using placebo data and were compared between bepotastine and diphenhydramine in the anterior and posterior cingulate gyri (ACG and PCG, respectively), superior and inferior frontal cortices (SFC and IFC, respectively), orbitofrontal cortex (OFC), insular cortex (IC), lateral and medial temporal cortices (LTC and MTC, respectively), parietal cortex (PC), occipital cortex (OC) and sensorimotor cortex (SMC). Plasma concentration of each antihistamine was measured, and its correlation to H1RO was examined. RESULTSH1RO after bepotastine treatment was significantly lower than that after diphenhydramine treatment in all cortical regions (P < 0.001). Mean H1ROs of bepotastine and diphenhydramine were 14.7% and 56.4%, respectively. H1ROs of both bepotastine and diphenhydramine correlated to their respective drug plasma concentration (P < 0.001). CONCLUSIONOral bepotastine (10 mg), with its relatively low H1RO and thus minimal sedation, has the potential for use as a mildly or slightly sedative antihistamine in the treatment of various allergic disorders.

Nearly half of small hepatic nodules detected with ultrasonography were nonHCC nodules. Ultrasonographic findings may not be reliable in characterizing small hepatic nodules in cirrhosis. CT and MR imaging obtained with the various techniques are still insensitive to these hepatic nodules.

Repeated administration of methamphetamine (METH) causes reverse tolerance or behavioral sensitization in mice. However, the effects of social isolation stress on the METH-caused reverse tolerance have not been studied until now. The aim of this study was to investigate the effects of social isolation stress on METH-caused reverse tolerance by examining the prepulse inhibition of startle response (PPI). PPI was tested in socially isolated and grouped mice after repeated METH injections. Locomotor activity and PPI were also examined just after a four-week isolation rearing period as a control experiment. After completing behavioral experiments, the mice were sacrificed, and the contents of monoamines, including histamine in the brain, were measured. Social isolation stress significantly lowered the locomotion and disrupted PPI. Repeated injections of METH enhanced the effects of social isolation on PPI. The content of dopamine and histamine significantly increased in the cortex, and the turnover rate of dopamine decreased significantly. These findings demonstrate that social isolation stress significantly enhances METH-induced behavioral sensitization and that the altered histaminergic neuron system might play an important role in METH-induced behavioral sensitization in addition to dopaminergic and serotoninergic neurotransmission. Our data suggest that social isolation is involved in the development of METH-induced psychosis, schizophrenia, and other related psychiatric disorders.