Histamine H1 Receptor Occupancy Research Articles

Quantitative prediction of histamine H1 receptor occupancy by the sedative and non-sedative antagonists in the human central nervous system based on systemic exposure and preclinical data

Significant histamine H1 receptor occupation in the central nervous system (CNS) is associated with sedation. Here we examined the time profiles of the H1 receptor occupancy (RO) in the CNS using sedative (diphenhydramine and ketotifen) and non-sedative (bepotastine and olopatadine) antagonists at their therapeutic doses by integrating in vitro and animal data. A pharmacokinetic model was constructed to associate plasma concentrations and receptor binding in the brain. Dissociation and association rate constants with the H1 receptor and plasma and brain unbound fractions were determined in vitro. Passive and active clearances across the blood–brain barrier (BBB) were estimated based on physicochemical properties and microdialysis studies in mice and monkeys. The estimated RO values were comparable with the reported values determined at time to maximum concentration (Tmax) of plasma by positron-emission tomography in humans. The simulation suggested that the predicted maximum ROs by bepotastine and olopatadine were greater than the reported values. Sensitivity analysis showed that active transport across BBB had a significant impact on the RO duration of the H1 antagonists examined. The present study demonstrated that modeling and simulation permits a reasonable RO estimation in the human CNS. Our findings will facilitate the development of CNS-acting drugs.

Histamine H1 receptor occupancy by the new-generation antipsychotics olanzapine and quetiapine: a positron emission tomography study in healthy volunteers.

Histamine H1 antagonists have hypnotic, appetite-promoting, and sedative side effects. Most second-generation antipsychotics have potent antagonistic effects on histamine H1 receptor (H1R). Positron emission tomography (PET) can measure the H1R occupancy (H1RO) in vivo, although there are no reports regarding antipsychotics. We studied the H1RO of olanzapine and quetiapine in vivo with respect to their plasma concentrations and subjective drowsiness by performing human PET imaging studies with [(11)C]doxepin, a potent PET ligand of H1R. Six healthy Japanese male volunteers were enrolled. Cross-randomized PET imaging was performed after a single oral administration of olanzapine (2.5 mg), quetiapine (25 mg), or placebo. PET data were analyzed by region of interest and voxel-by-voxel analysis. We concurrently measured plasma drug concentrations by liquid chromatography/tandem mass spectrometry and evaluated subjective sleepiness. The binding potential ratios of olanzapine and quetiapine in the cerebral cortex were significantly lower than that of the placebo. The H1RO values of olanzapine and quetiapine in the cortex were approximately 61-80 and 56-81%, respectively. The binding potential ratios of the drugs were significantly lower than that of the placebo in the dorsolateral prefrontal and lateral temporal cortices, and anterior and posterior cingulate gyri. The H1RO values in the cortex were significantly correlated with subjective sleepiness but not plasma drug concentrations. Olanzapine and quetiapine have high H1RO values in the human brain under their clinical minimum doses. This study provides a foundation of the properties by which new-generation antipsychotics block the central histaminergic system in humans.

Brain histamine H1 receptor occupancy measured by PET after oral administration of levocetirizine, a non-sedating antihistamine

Objective: Histamine H1 receptor (H1R) antagonists often have sedative side effects, which are caused by the blockade of the neural transmission of the histaminergic neurons. We examined the brain H1R occupancy (H1RO) and the subjective sleepiness of levocetirizine, a new second-generation antihistamine, comparing fexofenadine, another non-sedating antihistamine, as a negative active control.Methods: Eight healthy volunteers underwent positron emission tomography (PET) imaging with [11C]doxepin, a PET tracer that specifically binds to H1Rs, after a single oral administration of levocetirizine (5 mg), fexofenadine (60 mg) or placebo in a double-blind crossover study. Binding potential ratios and H1ROs in the cerebral cortices regions were calculated using placebo. Subjective sleepiness was assessed with the Line Analogue Rating Scale and the Stanford Sleepiness Scale.Results: There was no significant difference between the mean brain H1RO after levocetirizine administration (8.1%; 95% CI: −9.8 to 26.0%) and fexofenadine administration (−8.0%; 95% CI: −26.7 to 10.6%). Similarly, subjective sleepiness was not significantly different between the two antihistamines and placebo. Neither subjective sleepiness nor plasma concentrations was significantly correlated with the brain H1RO of the two antihistamines.Conclusion: At therapeutic dose, levocetirizine does not bind significantly to the brain H1Rs and does not induce significant sedation.

Bilastine vs. hydroxyzine: occupation of brain histamine H1‐receptors evaluated by positron emission tomography in healthy volunteers

AimA close correlation exists between positron emission tomography (PET)-determined histamine H1-receptor occupancy (H1RO) and the incidence of sedation. Antihistamines with H1RO <20% are classified as non-sedating. The objective was to compare the H1RO of bilastine, a second generation antihistamine, with that of hydroxyzine.MethodsThis randomized, double-blind, crossover study used PET imaging with [11C]-doxepin to evaluate H1RO in 12 healthy males (mean age 26.2 years), after single oral administration of bilastine (20 mg), hydroxyzine (25 mg) or placebo. Binding potentials and H1ROs were calculated in five cerebral cortex regions of interest: frontal, occipital, parietal, temporal, insula. Plasma bilastine concentrations, subjective sedation (visual analogue scale), objective psychomotor performance (digital symbol substitution test), physiological variables and safety (adverse events, AEs), were also evaluated.ResultsThe mean binding potential of all five regions of interest (total binding potential) was significantly greater with bilastine than hydroxyzine (mean value 0.26 vs. 0.13, P < 0.01; mean difference and 95% CI −0.130 [−0.155, 0.105]). There was no significant difference between bilastine and placebo. Overall H1RO by bilastine was significantly lower than that by hydroxyzine (mean value −3.92% vs. 53.95%, P < 0.01; mean difference and 95% CI 57.870% [42.664%, 73.075%]). There was no significant linear relationship between individual bilastine plasma concentrations and total binding potential values. No significant between-treatment differences were observed for sedation and psychomotor performance. Twenty-six non-serious AEs were reported. Sleepiness or sedation was not reported with bilastine but appeared in some subjects with hydroxyzine.ConclusionsA single oral dose of bilastine 20 mg had minimal H1RO, was not associated with subjective sedation or objective impairment of psychomotor performance and was devoid of treatment-related sedative AEs, thus satisfying relevant subjective, objective and PET criteria as a non-sedating antihistamine.

Histamine H1 receptor occupancy by the new-generation antidepressants fluvoxamine and mirtazapine: a positron emission tomography study in healthy volunteers

Histamine H₁ antagonists have hypnotic, appetite-promoting, and sedative effects. The affinities of various antidepressants for histamine receptors have only been partially determined in vitro and animal study. Positron emission tomography (PET) can clarify the in vivo dynamics of antidepressants at histamine receptors. We performed human PET imaging with [¹¹C]doxepin, a selective PET ligand of the histamine H₁ receptor (H₁R), to study the in vivo affinities of fluvoxamine and mirtazapine for the H₁R. The subjects were five male healthy Japanese volunteers. We performed cross-randomized PET imaging after single oral administration of fluvoxamine (25mg), mirtazapine (15 mg), or placebo. PET data were analyzed by region-of-interest and voxel-by-voxel analysis. We concurrently measured plasma drug concentrations, using liquid chromatography/tandem mass spectrometry and subjective sleepiness. The binding potential ratio of mirtazapine in brain cortex was significantly lower than that of fluvoxamine or placebo. Fluvoxamine did not occupy the H₁R, whereas H₁R occupancy (H₁RO) of mirtazapine reached 80-90 % in the cerebral neocortex. In the voxel-by-voxel analysis, the binding potential of mirtazapine was significantly lower than placebo in the dorsolateral prefrontal cortex, lateral temporal cortex, anterior cingulate gyrus, and posterior cingulate gyrus. The H₁RO of mirtazapine depended on the plasma drug concentration (AUC(0-180 min)) and was related to subjective sleepiness. Our results demonstrate a low affinity of fluvoxamine and a very high affinity of mirtazapine for the human brain H₁R in vivo. This study provides a basis for investigating the efficacy of new-generation antidepressants in central histamine systems.

Positron emission tomography evaluation of sedative properties of antihistamines

Introduction: H1 antihistamines are often used in the medication for allergic diseases, coughs and colds, and insomnia, with or without prescription, even though their sedative properties are a potentially dangerous unwanted side effect that is not properly recognized. These sedative properties have been evaluated using the incidence of subjective sleepiness, objective cognitive and psychomotor functions, and positron emission tomography (PET) measurement of H1 receptor occupancy.Areas covered: This article reviews the current updated literature on the sedative properties of antihistamines examined by PET measurement of H1 receptor occupancy.Expert opinion: The use of PET to examine antihistamine penetration in the human brain in relation to psychometric and other functional measures of CNS effects is a major breakthrough and provides a new standard by which the functional CNS effects of antihistamines can be related directly to H1 receptor occupancy. Therapy with antihistamines can be better guided by considering histamine H1 receptor occupancy from the view of their sedative properties.

Brain histamine H1 receptor occupancy of loratadine measured by positron emission topography: comparison of H1 receptor occupancy and proportional impairment ratio

We have evaluated the sedative properties of H1-antihistamines by using positron emission tomography (PET) and ¹¹C-doxepin. The purpose of the present study was to measure histamine H1 receptor occupancy (H1RO) of loratadine 10 mg in patients with allergic rhinitis and to compare this occupancy with that of d-chlorpheniramine 2 mg, a first-generation antihistamine. We also compared our PET findings with the proportional impairment ratio reported by McDonald et al. The H1RO of loratadine 10 mg and d-chlorpheniramine 2 mg were evaluated in human brains in a double-blind and crossover design using ¹¹C-doxepin PET. Eleven young male patients with allergic rhinitis were examined by PET following oral single administration of loratadine 10 mg and d-chlorpheniramine 2 mg. Loratadine 10 mg occupied 11.7 ± 19.5% of histamine H1 receptors in the cortex, whereas d-chlorpheniramine 2 mg occupied 53.0 ± 33.2% in the same area, suggesting a non-sedating property of loratadine at a dose of 10 mg. The H1RO values of loratadine and d-chlorpheniramine as well as those of previous studies were found to be significantly proportional to the proportional impairment ratio (r = 0.899). Measurement of H1RO is a sensitive and absolute method to characterize the non-sedating property of drugs with H1 antagonistic activity.

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

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. 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. 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. 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.

P-glycoprotein Limits the Brain Penetration of Olopatadine Hydrochloride, H1-Receptor Antagonist

Olopatadine, a new second-generation antihistamine, is widely used in the treatment of allergic disorders. The low levels of histamine H1 receptor occupancy in human brain by olopatadine, which is related to its minimal sedation, suggest its low penetration into the brain. The present study evaluates the impact of P-glycoprotein (P-gp) on brain penetration and plasma concentration of olopatadine. The uptake amount of olopatadine in human P-gp transfected LLC-PK1 cells (LLC-GA5-COL150) was lower than that in LLC-PK1. The uptake of olopatadine in LLC-GA5-COL150 was increased in the same level as that in LLC-PK1 in the presence of cyclosporine A, a P-gp inhibitor. After intravenous or oral administration of olopatadine to wild type (WT) and mdr1a/1b knockout (KO) mice at a dose of 1 mg/kg, the brain concentration in KO mice was higher than that in WT mice. On the other hand, the plasma concentration of olopatadine after either route of administration was not different between WT and KO mice. These results suggest that olopatadine is a substrate of P-gp, and that P-gp limits the brain penetration but dose not affect the plasma concentration of olopatadine.

Relationship between histamine H1 receptor occupancy (RO) and reduction of symptoms of seasonal allergic rhinitis (SAR) by levocetirizine (L) in subjects exposed to pollen in an environmental exposure unit (EEU)

Relationship between histamine H1 receptor occupancy (RO) and reduction of symptoms of seasonal allergic rhinitis (SAR) by levocetirizine (L) in subjects exposed to pollen in an environmental exposure unit (EEU)

Histamine H1 receptor occupancy and pharmacodynamics of second generation H1-antihistamines

The predictive efficacy of drugs in humans is frequently estimated from both a high affinity for their receptor as measured in vitro and a long plasmatic half-life. This is grossly misleading since one key parameter is missing: drug concentration at the receptor site in vivo. As a case study we compared the efficacies of three H(1) antihistamines in inhibiting histamine-induced wheal and flare in humans at two different time points with the above mentioned parameters. It is concluded that estimating in vivo receptor occupancy, which takes into account both the affinity of the drug for the receptor and its free plasma concentration, is a far better predictor for human pharmacodynamics and hence antihistamine potency, than considering in vitro affinity and plasmatic half-life only.

Sedative profiles of antihistamine drugs evaluated by subjective sleepiness, cognitive tests, and PET for measurement of cerebral histamine H1 receptor occupancy

Histamine H1 receptor antagonists (antihistamines), used for the treatment of allergic disorders, often induce sedative side effects in patients. Such sedative side effects are potentially dangerous because they sometimes result in serious accidents among people who drive cars, operate aircrafts or heavy machinery. Recent drug development has produced various new generation antihistamines with potent anti-allergic effects but with limited sedation. It has become important to evaluate sedative properties of different antihistamines. In general, the limited sedative property results from limited permeability of blood-brain barrier. To measure the sedative property, various methods have been introduced such as measurement of subjective sleepiness, objective computer cognitive tests, actual car driving tests, measurement of cerebral histamine H1 receptor blockade with positron emission tomography (PET), etc. The present study compared sedative properties of a classical antihistamine (hydroxyzine), and of two different second-generation antihistamines, fexofenadine and cetirizine, in healthy Japanese volunteers, using the following measurements: (1) subjective sleepiness; (2) computer-based psychomotor tests; (3) brake reaction time (BRT) during actual car driving, with and without talking on a cellular phone; and (4) brain histamine H1R occupancy (H1RO) using PET with [11C]doxepin, a potent radioligand for histamine H1 receptors. Subjects were administered a single dose of fexofenadine 120 mg or cetirizine 20 mg in a double-blind, placebo-controlled, crossover design. Hydroxyzine 30 mg was included as a positive control. Subjective sleepiness, psychomotor performance (n=20) and H1RO with PET (n=12) were measured at baseline and 90 min post-dose. The car driving test (n=18) was conducted at baseline, and at 90 and 240 min post-dose. In results, fexofenadine was not significantly different from placebo for subjective sleepiness and computer-based psychomotor tests, and was significantly less impairing than cetirizine on some measurements (p 50%). In summary, the assessments had the following sensitivity to differentiate between the sedative profiles of antihistamines: H1RO with PET > psychomotor test > BRT with phone = sleepiness > BRT without phone. Fexofenadine 120 mg demonstrated a non-sedative profile and could be differentiated from cetirizine 20 mg. Drivers administered hydroxyzine were slower at recognizing hazards ahead and applying the brake compared with subjects given fexofenadine or placebo. Importantly, cellular phone operation was an additive factor, increasing BRTs in subjects given hydroxyzine. In contrast, fexofenadine did not impair CNS function in subjects involved in a divided attention task of driving and cellular phone operation.

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.

New findings in pharmacological effects induced by antihistamines: from PET studies to knock‐out mice

Antihistamines are efficacious drugs to be used for the symptomatic relief of allergic diseases. The safety issue of antihistamines is of central importance because of their widespread use in current medical practice. To better understand the pharmacological effects of antihistamines on the central nervous system (CNS), we used two kinds of new methods, positron emission tomography (PET) and gene targeting regarding on histamine H1 receptors. The histamine H1 receptor occupancy was examined in young male volunteers with[11C]-doxepin (a potent H1 antagonist) after the oral or intravenous administration of antihistamines. In other studies, the cognitive performance was also measured tachistoscopically before and after taking antihistamines. The mutant mice lacking H1 receptors were used in the behavioural and neurochemical experiments to re-evaluate the role of H1 receptors. The H1-receptor occupancy in the human frontal cortex caused by antihistamines is significantly correlated with the reported values of incidence of sleepiness in clinical trials, and the occupancy is well proportional to the impaired cognitive performance. The behavioural studies of the H1-receptor knock-out mice confirmed the role of H1 receptors in arousal, the sleep-wake cycle, locomotion, nociception and aggressive behaviour. The pharmacological effects induced by H1 antagonism were re-evaluated by the PET and gene-targetting. Although any serious effects could not be observed in mice by the destruction of the H1-receptor gene, the cognitive performance was impaired in humans after taking first generation antihistamines in recommended doses.

S11-5 - Histamine H1 receptor occupancy in the human brain after single oral doses of antihistamines measured by PET.

S11-5 - Histamine H1 receptor occupancy in the human brain after single oral doses of antihistamines measured by PET.

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

1. Histamine H1 receptor occupancy in the human brain was measured in 20 healthy young men by positron emission tomography (PET) using [11C]-doxepin. 2. (+)-Chlorpheniramine, a selective and classical antihistamine, occupied 76.8 +/- 4.2% of the averaged values of available histamine H1 receptors in the frontal cortex after its administration in a single oral dose of 2 mg. Intravenous administration of 5 mg (+)-chlorpheniramine almost completely abolished the binding of [11C]-doxepin to H1 receptors (H1 receptor occupancy: 98.2 +/- 1.2%). 3. Terfenadine, a nonsedative antihistamine, occupied 17.2 +/- 14.2% of the available H1 receptors in the human frontal cortex after its administration in a single oral dose of 60 mg. 4. There was no correlation between H1 receptor occupancy by terfenadine and the plasma concentration of the active acid metabolite of terfenadine in each subject. 5. PET data on human brain were essentially compatible with those on H1 receptor occupancy in guinea-pig brain determined by in vivo binding techniques, although for the same H1 receptor occupancy the dose was less in human subjects than in guinea-pigs. 6. The PET studies demonstrated the usefulness of measuring H1 receptor occupancy with classical and second-generation antihistamines in human brain to estimate their unwanted side effects such as sedation and drowsiness quantitatively.

P-551 - Histamine H1 receptor occupancy in the brain under living conditions after single oral doses of antihistamines: basic animal experiments and human PET studies.

P-551 - Histamine H1 receptor occupancy in the brain under living conditions after single oral doses of antihistamines: basic animal experiments and human PET studies.