Dose dependency of brain histamine H(1) receptor occupancy following oral administration of cetirizine hydrochloride measured using PET with [11C]doxepin.

AIMS: The strength of sedation due to antihistamines can be evaluated using positron emission tomography (PET). The purpose of the present study is to measure histamine H(1) receptor (H(1)R) occupancy following oral administration of cetirizine (10 and 20 mg) in order to examine dose dependency. METHODS: Fifteen healthy male volunteers (age range, 20-35 years) were divided into 3 subgroups and were studied following single oral administration of cetirizine at 10 mg (n = 5) and 20 mg (n = 5) or hydroxyzine at 30 mg (n = 5) using PET with 11C-doxepin. Each subject was scanned also following the administration of placebo. Binding potential and H(1)RO values were calculated in the prefrontal and anterior cingulate cortices. Subjective sleepiness was also measured, and the correlation to H(1)RO was examined for each antihistamine. RESULTS: The averaged H(1)ROs of cetirizine 10 mg, 20 mg, and hydroxyzine 30 mg in the prefrontal and cingulate cortices was 12.6%, 25.2%, and 67.6%, respectively. The H(1)RO of hydroxyzine 30 mg correlated well with subjective sleepiness (p < 0.001); however, those of cetirizine 10 and 20 mg showed no correlation with subjective sleepiness. CONCLUSION: It was demonstrated that the brain penetration of orally administered cetirizine was dose-dependent. Cetirizine 10 mg, with its low H(1)RO and thus minimal sedation, could be more safely used than cetirizine 20 mg for the treatment of various allergic disorders.

Comparison study of amyloid PET and voxel-based morphometry analysis in mild cognitive impairment and Alzheimer's disease.

Two techniques employed for the early diagnosis of dementia are the imaging of amyloid-beta protein using positron emission tomography (PET) and voxel-based morphometry analysis of MRI (VBM-MRI). The purpose of this study was to evaluate the clinical utility of amyloid PET and VBM-MRI for the early diagnosis and tracking of the severity of Alzheimer's disease (AD). The neuritic plaque burden and gray matter losses were evaluated using [11C]BF-227-PET and VBM-MRI in 12 healthy controls, 13 subjects with mild cognitive impairment (MCI), including 6 who converted to AD and 7 who did not convert, and 15 AD patients. The AD patients and the MCI converters exhibited a neocortical retention of BF-227 and parahippocampal gray matter loss shown by VBM-MRI. The MCI converters were more clearly distinguished from the MCI non-converters in BF-227-PET than VBM-MRI. The combined sample of the MCI converters and AD patients showed a significant correlation of MMSE scores with the global gray matter loss, but not with the BF-227 retention. These findings suggest that amyloid PET using [11C]BF-227 is better suited for the prediction of conversion from MCI to AD, while VBM-MRI appears to be better suited for tracking the severity of dementia.

Quantitative analysis of donepezil binding to acetylcholinesterase using positron emission tomography and [5-(11)C-methoxy]donepezil.

The aim of this study was to establish kinetic analysis of [5-(11)C-methoxy]donepezil ([(11)C]donepezil), which was developed for the in-vivo visualization of donepezil binding to acetylcholinesterase (AChE) using positron emission tomography (PET). Donepezil is an AChE inhibitor that is widely prescribed to ameliorate the cognitive impairment of patients with dementia. Six healthy subjects took part in a dynamic study involving a 60-min PET scan after intravenous injection of [(11)C]donepezil. The total distribution volume (tDV) of [(11)C]donepezil was quantified by compartmental kinetic analysis and Logan graphical analysis. A one-tissue compartment model (1TCM) and a two-tissue compartment model (2TCM) were applied in the kinetic analysis. Goodness of fit was assessed with chi(2) criterion and Akaike's Information Criterion (AIC). Compared with a 1TCM, goodness of fit was significantly improved by a 2TCM. The tDVs provided by Logan graphical analysis were slightly lower than those provided by a 2TCM. The rank order of the mean tDVs in 10 regions was in line with the AChE activity reported in a previous post-mortem study. Logan graphical analysis generated voxel-wise images of tDV, revealing the overall distribution pattern of AChE in individual brains. Significant correlation was observed between tDVs calculated with and without metabolite correction for plasma time-activity curves, indicating that metabolite correction could be omitted. In conclusion, this method enables quantitative analysis of AChE and direct investigation of the pharmacokinetics of donepezil in the human brain.

Blocking histamine H(1) improves learning and mnemonic dysfunction in mice with social isolation plus repeated methamphetamine injection.

The aim of this study was to investigate the effects of histamine H(1) and H(3) antagonists on learning and mnemonic dysfunction in mice. Two H(1) antagonists, pyrilamine and clozapine, and the prototypic H(3) antagonist thioperamide were used to study the role of histamine in mice with social isolation and repeated methamphetamine administration. Mice with social isolation and repeated methamphetamine administration showed significant disruption of prepulse inhibition as compared to both the socially-housed mice and isolation-housing mice. Furthermore, social isolation and repeated methamphetamine administration caused significant learning and mnemonic dysfunctions. Treatment with clozapine improved learning and mnemonic ability in all of the tasks. Pyrilamine treatment ameliorated performance in all the tests examined except for the passive avoidance test. Thioperamide, however, did not change the learning and mnemonic ability. Donepezil, an acetylcholinesterase inhibitor, reversed the learning and mnemonic dysfunction in all four tasks. The present study has shown that blockade of histamine H(1) receptor improved the learning and mnemonic ability in mice, raising the possibility that treatment with clozapine or pyrilamine may improve learning and mnemonic performance in certain patients with psychiatric diseases such as schizophrenic patients with cognitive dysfunction.

Brain histamine H1 receptor occupancy of orally administered antihistamines, bepotastine and diphenhydramine, measured by PET with 11C-doxepin.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: 'Bepotastine besilate' is a novel second-generation antihistamine developed in Japan and its antiallergic effects have already been demonstrated by various studies. However, only a few clinical studies regarding its sedative property are available. In addition, histamine H(1) receptor occupancy (H(1)RO) of this new antihistamine has never been measured by positron emission tomography (PET). WHAT THIS STUDY ADDS: This paper provides the first measurement result of cerebral H(1)RO 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 H(1)RO of this second-generation antihistamine is demonstrated for the first time using a placebo-controlled crossover study design. AIMS Antihistamines are frequently used for treating various allergic diseases, but often induce sedation. The degree of sedation can be evaluated by measuring histamine H(1) receptor occupancy (H(1)RO) in the brain using positron emission tomography (PET). The aim was to measure H(1)RO of bepotastine, a new second-generation antihistamine, and to compare it with that of diphenhydramine. METHODS: Eight healthy male volunteers (mean age +/- SD 24.4 +/- 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 H(1)ROs 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 H(1)RO was examined. RESULTS: H(1)RO after bepotastine treatment was significantly lower than that after diphenhydramine treatment in all cortical regions (P < 0.001). Mean H(1)ROs of bepotastine and diphenhydramine were 14.7% and 56.4%, respectively. H(1)ROs of both bepotastine and diphenhydramine correlated to their respective drug plasma concentration (P < 0.001). CONCLUSION: Oral bepotastine (10 mg), with its relatively low H(1)RO and thus minimal sedation, has the potential for use as a mildly or slightly sedative antihistamine in the treatment of various allergic disorders.

In vivo visualization of donepezil binding in the brain of patients with Alzheimer's disease.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: * Deficit in central cholinergic neurotransmission is a consistent change associated with Alzheimer's disease (AD). * Donepezil hydrochloride exhibits selective inhibition of acetylcholinesterase (AChE) and is widely used for the treatment of AD. * The biodistribution of donepezil in the brain after administration is not precisely understood in vivo. * There is no method to measure the amount of binding of orally administered donepezil to AChE. WHAT THIS STUDY ADDS: * This study clearly visualizes the distribution of donepezil in human brain using [(11)C]-donepezil and positron emission tomography. * This study demonstrates prominent reduction of the donepezil binding site in the AD brain. * This study provides methodology to measure the AChE binding occupancy of orally administered donepezil and provides a new surrogate marker for evaluation and prediction of response to donepezil treatment. AIMS: The aims of this study were to visualize in vivo binding of donepezil to acetylcholinesterase (AChE) in the brain and to establish a method for measuring the amount of binding of orally administered donepezil. METHODS: [5-(11)C-methoxy]-donepezil ([(11)C]-donepezil) was radiolabelled as a positron emission tomography (PET) tracer. The biodistribution of [(11)C]-donepezil was measured by PET in 10 AD patients and six elderly normal subjects. Two AD patients underwent additional PET measurements after oral administration of donepezil for 6 months. RESULTS: [(11)C]-donepezil-PET images demonstrated high densities of tracer distribution in AChE-rich brain regions such as the striatum, thalamus, and cerebellum. Compared with elderly normal subjects, patients with mild AD exhibited about 18-20% reduction of donepezil binding in the neocortex and hippocampus, while patients with moderate AD exhibited about 24-30% reduction of donepezil binding throughout the brain. Orally administered donepezil (5 mg day(-1)) induced 61.6-63.3% reduction of donepezil binding in AD brains. The distribution volume of [(11)C]-donepezil in the hippocampus was significantly correlated with MMSE scores in AD patients. CONCLUSIONS: [(11)C]-donepezil-PET enables quantitative measurement of donepezil binding in the brain. AD patients exhibited reduction of donepezil binding in the brain, even in the early stage of disease. Longitudinal evaluation by this technique enables determination of AChE binding occupancy of orally administered donepezil.

Evaluation of the binding characteristics of [18F]fluoroproxyfan in the rat brain for in vivo visualization of histamine H3 receptor.

Histamine H3 receptors play an important role in biological functions. The aim of this research was to examine whether histamine H3 receptors can be visualized in vivo and in vitro with [18F]3-(1H-imidazol-4-yl)propyl 4-fluorobenzyl ether (fluoroproxyfan). [18F]Fluoroproxyfan was synthesized with high specific activity using [18F]benzyl bromide. The binding of [18F]fluoroproxyfan to rat brain homogenates was higher in the striatum and thalamus and was lowest in the cerebellum. The in vitro autoradiographic study successfully demonstrated the specific binding of [18F]fluoroproxyfan to the H3 receptor in the rat brain. In accordance with the in vitro bindings, the in vivo distribution of [18F]fluoroproxyfan was heterogeneous in the rat brain. In the blocking experiments, the heterogeneous distribution disappeared in the presence of large amounts of fluoroproxyfan. These data suggest that [18F]fluoroproxyfan can be potentially useful to image histamine H3 receptor noninvasively in the human brain by positron emission tomography.

Selective cognitive dysfunction in mice lacking histamine H1 and H2 receptors.

Previous pharmacological experiments provide conflicting findings that describe both facilitatory and inhibitory effects of neuronal histamine on learning and memory. Here, we examined learning and memory and synaptic plasticity in mice with a null mutation of gene coding histamine H1 or H2 receptor in order to clarify the role of these receptors in learning and memory processes. Learning and memory were evaluated by several behavioral tasks including object recognition, Barnes maze and fear conditioning. These behavioral tasks are highly dependent on the function of prefrontal cortex, hippocampus or amygdala. Object recognition and Barnes maze performance were significantly impaired in both H1 receptor gene knockout (H1KO) and H2 receptor gene knockout (H2KO) mice when compared to the respective wild-type (WT) mice. Conversely, both H1KO and H2KO mice showed better auditory and contextual freezing acquisition than their respective WT mice. Furthermore, we also examined long-term potentiation (LTP) in the CA1 area of hippocampus in H1KO and H2KO mice and their respective WT mice. LTP in the CA1 area of hippocampus was significantly reduced in both H1KO and H2KO mice when compared with their respective WT mice. In conclusion, our results demonstrate that both H1 and H2 receptors are involved in learning and memory processes for which the frontal cortex, amygdala and hippocampus interact.

Effects of histamine H(3) antagonists and donepezil on learning and mnemonic deficits induced by pentylenetetrazol kindling in weanling mice.

Childhood epilepsy is one of the main risk factors for a variety of problems involving cognition and behavior. Pentylenetetrazol (PTZ) kindling is currently an acceptable model for epilepsy research. The objectives of this study are to clarify the learning and mnemonic characteristics of PTZ kindling in developing mice, and to examine the effects of thioperamide and JNJ-5207852, two histamine H(3) receptor antagonists and donepezil, an acetylcholinesterase (AChE) inhibitor, on learning and memory deficits induced by PTZ kindling in the brains of developing mice. PTZ kindling led to learning and mnemonic deficits as assessed by social discrimination, acoustic fear conditioning, water maze and passive avoidance tests. Thioperamide and JNJ-5207852, ameliorated PTZ kindling-induced learning and mnemonic deficits in all tests except for the water maze test. In addition, the learning and mnemonic impairments induced by PTZ kindling were significantly improved by donepezil in all tests. These findings suggest that histamine and acetylcholine are involved in the different processes of learning and memory in the brain and that histamine H(3) receptor antagonists might be useful in the treatment of cognitive impairment in epilepsy.

Enhanced antinociception by intracerebroventricularly administered orexin A in histamine H1 or H2 receptor gene knockout mice.

Orexins are neuropeptides that are mostly expressed in the posterior and lateral hypothalamus, and related to the central control of appetite, arousal, and antinociception. Orexin neurons projected to the tuberomammillary nucleus and orexins may release histamine from the histamine neurons in this nucleus. Histamine is known to cause hypernociception. The roles of histamine H1 and H2 receptors in the orexin A-induced antinociception, however, have not been clarified yet. Here we studied the effects of histamine H1 and H2 receptors on orexin A-produced antinociception using histamine receptor knockout mice in four assays of nociception; the hot-plate, the tail-flick, the tail-pressure and the capsaicin tests. Furthermore we studied effects of histamine H1 and H2 receptor antagonists on orexin A-produced antinociception in C57BL/6 mice. The antinociceptive effects of i.c.v. orexin A were greater in histamine H1 receptor or H2 receptor knockout mice than in the wild-type mice in all four assays of pain. Furthermore, treatment of C57BL/6 mice with a combination of i.c.v. orexin A and d-chlorpheniramine (a histamine H1 receptor antagonist) or cimetidine (a histamine H2 receptor antagonist) showed a greater antinociception than i.c.v. orexin A alone in all four assays. These findings suggest the possibility that orexin A may activate H1 and H2 receptors in the supraspinal levels through the release of histamine from neurons, which might attenuate the antinociceptive effects of orexin A. Thus, the blocking of the histamine H1 or H2 receptor may produce antinociception and enhance the orexin A-induced antinociception.

Blockage of histamine H1 receptor attenuates social isolation-induced disruption of prepulse inhibition: a study in H1 receptor gene knockout mice.

RATIONALE: Histaminergic neurotransmission has been implicated in the pathophysiology of stress-related psychiatric diseases. Although several atypical antipsychotics are potent H1 antagonists, the clinical significance of interaction between atypical antipsychotics and H1 receptors is still unknown. OBJECTIVE: In this study, we investigated the effects of H1 receptors blockage on social isolation-induced behavioral changes in H1 receptor gene knockout (H1KO) mice and their wild-type (WT) mice. METHODS: Both H1KO and their WT mice were subjected to 4-week social isolation rearing after weaning (21 postnatal days). After the 4-week isolation period, mice behavioral changes were evaluated using behavioral tests. RESULTS: Locomotor activity in home cages was significantly lower in isolation-reared WT mice than in socially reared WT mice. However, no change in locomotor activity was observed between socially and isolation-reared H1KO mice. Social isolation significantly impaired prepulse inhibition (PPI) of startle response in WT mice but not in H1KO mice. In addition, social isolation significantly impaired spatial learning and memory in WT mice but not in H1KO mice. Furthermore, H1KO mice treated with methamphetamine (METH) showed no enhancement in isolation-induced disruption of PPI. A neurochemical study revealed that isolation-reared WT mice had significantly lower dopamine (DA) levels and slightly increased DA turnover in the cortex than socially reared WT mice. Conversely, isolation-reared H1KO mice showed significantly higher DA contents as compared with socially reared H1KO mice. CONCLUSION: The results of our study indicate that blockage of H1 receptor-mediated neurotransmission attenuates social isolation-induced behavioral changes and that the therapeutic effects of atypical antipsychotics are mediated, at least in part, by interaction with H1 receptors in the brain.

Effects of fexofenadine and hydroxyzine on brake reaction time during car-driving with cellular phone use.

Antihistamines are a mainstay treatment for allergic rhinitis; however, many older agents cause adverse events, including sedation and central nervous system (CNS) impairment. Research has shown sedating effects of antihistamines on driving; currently, no known study has examined whether cellular phone usage while driving further compounds impairment in individuals administered antihistamines. The aim of this study was to examine this endpoint. In a randomized, double-blind, placebo-controlled, three-way crossover study, healthy volunteers received fexofenadine HCl 120 mg, hydroxyzine HCl 30 mg and placebo. Brake reaction time (BRT) was used to examine driving performance across four conditions: driving only; driving while completing simple calculations; complex calculations; and conversing on a cellular phone. Subjective sedation assessments were also conducted. Brake reaction time with and without cellular phone usage in fexofenadine-treated subjects did not differ significantly from placebo in any condition. In contrast, hydroxyzine-treated subjects were significantly more sedated and had slower BRTs, suggesting slower hazard recognition and brake application, compared with the fexofenadine and placebo groups in all conditions. Importantly, cellular phone operation was an additive factor, increasing BRTs in hydroxyzine-treated volunteers. Fexofenadine did not impair CNS function in subjects involved in a divided attention task of driving and cellular phone operation.

Enhanced antinociception by intracerebroventricularly and intrathecally-administered orexin A and B (hypocretin-1 and -2) in mice.

Orexins are neuropeptides located exclusively in neurons of the lateral hypothalamic area, which send projections to most monoaminergic nuclei, such as noradrenergic locus coeruleus, dopaminergic ventral tegmental areas, and histaminergic tuberomammillary nuclei. The present work was carried out to examine the role of orexins in nociception in mice. C57BL/6 mice were administered with orexin A and B intracerebroventricularly (i.c.v.), intrathecally (i.t.) and subcutaneously (s.c.) to reveal the sites of action of these peptides and to examine the pain thresholds using four kinds of nociceptive tasks. Orexins showed antinociceptive effects in all four types of assays for thermal (hot-plate, tail-flick, paw-withdrawal), mechanical (tail-pressure), chemical (formalin, capsaicin and abdominal stretch) nociceptions and nociceptin-induced behavioral responses, when administered i.c.v. or i.t., whereas the s.c. administration was ineffective. The antinociceptive effects of orexin A were more remarkable than those of orexin B. The i.c.v. administration of orexin A was as effective as, or more potent than the i.t. administration. The effects of orexin A were completely blocked by adenosine type 1 receptor antagonists, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) and theophylline, but not by naloxone, suggesting a possible involvement of the adenosine-containing neurons and/or the adenosine pathway in these orexin actions. The i.c.v. administration of nociceptin had no significant effects on orexin expression in the brain and spinal cord. The present findings suggest that orexins have an antinociceptive role in at least four different types of pains, probably acting on both the brain and spinal cord.

Histamine H1 receptors in schizophrenic patients measured by positron emission tomography.

Increasing evidence has shown that the histaminergic neuron system is implicated in the pathophysiology of schizophrenia. The aim of this study was to compare the distribution of histamine H1 receptors between schizophrenics and normal human subjects in vivo using positron emission tomography (PET). H1 receptor binding was measured in 10 normal subjects and 10 medicated schizophrenic patients by PET and [11C] doxepin, a radioligand for the H1 receptor. The binding potential (BP=Bmax/K(D)) of [11C] doxepin for available brain H1 receptors was calculated by a graphical analysis on voxel-by-voxel basis and compared between schizophrenics and normal subjects using the regions of interest (ROIs) and the statistical parametrical mapping (SPM99). BP values for H1 receptors in the frontal and prefrontal cortices and the cingulate gyrus were significantly lower among the schizophrenic patients than among the control subjects. On the contrary, there were no areas of the brain where H1 receptors were significantly higher among the schizophrenic patients than the control subjects. The results of our study suggest that the central histaminergic neuron system could be involved in the pathophysiology of schizophrenia, although further studies are needed to confirm this hypothesis.

Social isolation stress significantly enhanced the disruption of prepulse inhibition in mice repeatedly treated with methamphetamine.

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.

Pharmacological effects of carcinine on histaminergic neurons in the brain.

1 Carcinine (beta-alanyl histamine) is an imidazole dipeptide. The present study was designed to characterize the pharmacological effects of carcinine on histaminergic activity in the brain and on certain neurobehavior. 2 Carcinine was highly selective for the histamine H3 receptor over H1 or H2 receptor (Ki (microM)=0.2939+/-0.2188 vs 3621.2+/-583.9 or 365.3+/-232.8 microM, respectively). 3 Carcinine at a dose of 20 mg kg(-1) slightly increased histidine decarboxylase (HDC) activity in the cortex (from 0.186+/-0.069 to 0.227+/-0.009 pmol mg protein(-1) min(-1)). In addition, carcinine (10, 20, and 50 mg kg(-1)) significantly decreased histamine levels in mice brain. 4 Like thioperamide, a histamine H3 receptor antagonist, carcinine (20, 50 microM) significantly increased 5-HT release from mice cortex slices, but had no apparent effect on dopamine release. 5 Carcinine (20 mg kg(-1)) significantly inhibited pentylenetetrazole-induced kindling. This inhibition was completely reversed by (R)-alpha-methylhistamine, a representative H3 receptor agonist, and alpha-fluromethylhistidine, a selective HDC inhibitor. 6 Carcinine (20 mg kg(-1)) ameliorated the learning deficit induced by scopolamine. This amelioration was reversed by (R)-alpha-methylhistamine as evaluated by the passive avoidance test in mice. 7 Like thioperamide, carcinine dose-dependently increased mice locomotor activity in the open-field test. 8 The results of this study provide first and direct evidence that carcinine, as a novel histamine H3 receptor antagonist, plays an important role in histaminergic neurons activation and might be useful in the treatment of certain diseases, such as epilepsy, and locomotor or cognitive deficit.

Central effects of fexofenadine and cetirizine: measurement of psychomotor performance, subjective sleepiness, and brain histamine H1-receptor occupancy using 11C-doxepin positron emission tomography.

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.

Decreased histamine H1 receptor binding in the brain of depressed patients.

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.

Evaluation of the binding characteristics of [5-(11)C-methoxy]Donepezil in the rat brain for in vivo visualization of acetylcholinesterase.

Donepezil, an acetylcholinesterase (AChE) inhibitor, has not been evaluated for its binding characteristics using a radioactive tracer, although its inhibitory action on AChE has been studied. The aim of this research is to examine whether AChE can be visualized in vivo and in vitro with [(11)C]donepezil. [5-(11)C-methoxy]Donepezil was synthesized by O-methylation using [(11)C]methyl triflate. The binding of [(11)C]donepezil to brain homogenates was higher in the brain stem and striatum, and it was lowest in the cerebellum. The in vitro autoradiographic study successfully demonstrated the specific binding of [(11)C]donepezil to AChE in the rat brain. The IC(50) value of binding was approximately 10 nM, which is comparable to the reported value for inhibiting enzyme activity (6 nM). Saturation experiments revealed that the B(max) and K(d) of [(11)C]donepezil binding in vitro are 65 fmol/mg tissue and 39.8 nM, respectively. In accordance with the in vitro bindings, the in vivo distribution of [(11)C]donepezil was heterogeneous in the rat brain. In the blocking experiments, the heterogeneous distribution disappeared in the presence of a large amount of unlabeled donepezil. These data suggest that [5-(11)C-methoxy]donepezil can be potentially useful to image AChE non-invasively in the human brain by positron emission tomography.