Some behavioral effects of histamine H1-, and H2-receptor agonists in rats.

2-Pyridylethylamine (2-PEA) and 4-methylhistamine (4-MeHI) when given intraventricularly at doses of 30 and 100 microgram had no discernible effect on spontaneous locomotor activity and did not visibly change gross behavior of rats. 4-MeHI(100 micrograms) injected to tranylcypromine-pretreated rats increased locomotor activity and induced head twitches. Locomotor activation was not antagonized by either cimetidine or metergoline but was prevented by alpha-methyl-p-tyrosine and haloperidol and reduced by phentolamine. 4-MeHI-, and histamine (HI)-induced head twitches were not antagonized by either cimetidine or metiamide but were completely abolished by metergoline and p-chlorophenylalanine. It is concluded that 4-MeHI--induced locomotor activation and both HI-, and 4-MeHI-induced head twitches are respectively catecholamine-, and serotonin-dependent phenomena. The behavioral effects of HI and HI H1-and H2-receptor agonists are discussed with regard to possible HI interactions with both catecholamine and serotonin systems in brain.     

A double-blind, placebo controlled study of the effect of the specific histamine H1-receptor antagonist, terfenadine, in chronic severe asthma.

1. The characteristic changes seen in asthma are widely regarded as being caused by local mediator release in the airways, with histamine the first putative mediator in asthma to be identified. 2. We performed a double-blind, randomised, placebo-controlled crossover trial of the effect of 4 weeks treatment with terfenadine 120 mg twice daily in chronic severe asthma. 3. Forty-two subjects (20 male and 22 female) completed the 10 week study. 4. Terfenadine had no significant treatment effect on the primary efficacy variables measured. Mean (95% CI) measurements for terfenadine vs placebo treatment periods were 1.5 vs 1.5 (-0.3, 0.3) l for FEV1, 259 vs 260 (-42, 40) l min-1 for morning PEF and 0.8 vs 0.8 (-0.3, 0.3) for global symptom scores. 5. Bronchodilator use and sleep disturbance, the secondary efficacy variables studied, showed an improvement during terfenadine treatment but this only reached statistical significance for the number of times subjects awoke from sleep (P = 0.04). 6. There was a similar frequency of minor adverse effects reported during placebo (13.6%) and terfenadine (16.7%) treatments. 7. Addition of the potent and specific histamine H1-receptor antagonist terfenadine to maintenance asthma treatment had no significant therapeutic benefit in this group of chronic severe asthmatics.     

Effects of H1-receptor blockade with terfenadine in nocturnal asthma.

1. In a single-blind placebo controlled study we have measured peak flow (PEFR) at 04.00 h and 16.00 h in eight asthmatics 6 h after placebo or terfenadine 120 mg, to determine if diurnal variation in histamine mediated effects contribute to nocturnal bronchoconstriction in asthma. 2. On placebo there was a significant diurnal variation in mean PEFR of 41 l min-1 (P less than 0.05). Terfenadine improved 04.00 h baseline mean PEFR from 242 to 278 l min-1 (P less than 0.05) but a 38 l min-1 diurnal variation in mean PEFR persisted (P less than 0.05). 3. We conclude that H1-receptor blockade with terfenadine may produce modest nocturnal bronchodilatation but does not influence the diurnal variation in PEFR in asthma suggesting that H1-receptor mediated effects are not important in the pathogenesis of nocturnal asthma.     

Pharmacology and clinical efficacy of terfenadine, a new H1-receptor antagonist

Terfenadine is the first of a new class of non-sedating H1 antihistamines. It differs from chlorpheniramine in its lower anticholinergic activity in rabbit salivation tests. In animal model distribution studies, the drug is not found in the brain. In most clinical studies sedation attributed to terfenadine was on the order of that observed with placebo. Clinical trials of efficacy show that at best terfenadine is slightly less effective than or as effective as chlorpheniramine.     

Pharmacokinetic optimisation of histamine H1-receptor antagonist therapy.

Second-generation, relatively nonsedating histamine H1-receptor antagonists (H1-RA) are extensively used worldwide for the symptomatic treatment of allergic rhinoconjunctivitis and chronic urticaria. Information about the pharmacokinetics and pharmacodynamics of these medications, while still incomplete, is now sufficient to permit optimisation of therapy. Published pharmacokinetic and pharmacodynamic information on these H1-RA is summarised here, and areas where more data are required are delineated. Serum concentrations of most second-generation H1-RA are relatively low, and are usually measured by radioimmunoassay. After oral administration, peak concentrations are observed within 2 or 3 h. Bioavailability has not been well studied, due to the lack of intravenous formulations. Most H1-RA are metabolised in the hepatic cytochrome P450 system: terfenadine, astemizole, loratadine, azelastine, and ebastine have 1 or more active metabolites which are present in serum in higher concentrations than the respective parent compound, and therefore can be measured by high performance liquid chromatography. Cetirizine, an active metabolite of the first generation H1-receptor antagonist hydroxyzine, is not further metabolised to any great extent in vivo, and is eliminated via renal excretion. Levocabastine is also eliminated primarily by excretion. Serum elimination half-life values differ greatly from 1 H1-RA to another, and are 24 h or less for terfenadine, astemizole, loratadine, cetirizine, azelastine and ebastine, and the active metabolites of terfenadine, loratadine and ebastine. The active metabolite of azelastine (demethylazelastine) has a serum elimination half-life value of about 2 days, while that of astemizole (demethyl-astemizole) has a value of 9.5 days. From the few published studies in which the apparent volumes of distribution of the second-generation H1-RA have been calculated, it appears that tissue distribution is extensive. In children, the half-lives of H1-RA are generally shorter than are found in adults; there is no published information on the pharmacokinetics of astemizole, loratadine, azelastine, or ebastine in children. In some elderly adults, terfenadine, loratadine and cetirizine may have longer half-lives than in young healthy adults. There is little published data on the pharmacokinetics of the second-generation H1-RA in patients with impaired hepatic function. The half-life of cetirizine is prolonged in those with impaired renal function. There is a paucity of information on the pharmacokinetics of H1-RA in neonates, in pregnancy or during lactation.(ABSTRACT TRUNCATED AT 400 WORDS)     

Chemical differentiation of histamine H1- and H2-receptor agonists.

Histamine exists predominantly as the NT-H tautomer of the monocation (IIa) at a physiological pH of 7.4 and structure-activity studies indicate that this tautomer is likely to be the pharmacologically active species for both H1 and H2 receptors. Effective H2-receptor agonists appear to require a prototropic tautomeric system whereas H1-receptor agonists do not need to be tautomeric. This identifies a chemical difference in the receptor requirements which provides the basis for obtaining selective histamine H1-receptor agonists. Thus 2-(2-aminoethyl)thiazole and 2-(2-aminoethyl)pyridine are nontautomeric and are highly selective agonists for histamine H1 receptors (H1:H2 ca. 90:1 and 30:1, respectively). In conjunction with the selective H2-receptor agonist, 4-methylhistamine, they are of great value for studying the pharmacology of histamine receptors.     

Peripheral antihistamine and central sedative effects of three H1-receptor antagonists

Summary The effects of single oral doses of three antihistamine compounds on histamine-induced itch and flare reactions were studied in 24 healthy volunteers by a double-blind balanced design. Central sedative effects were concurrently analyzed using a set of computerized neuropsychological tests and analogue ratings. Hydroxyzine 20 mg had a more pronounced inhibitory effect on the cutaneous response than 3 mg clemastine or 3 mg azatadine. Clemastine tended to cause more sedation than the other two drugs. A compound score, reflecting the balance between peripheral and CNS effects, showed hydroxyzine to have relatively more peripheral antihistamine effect and less sedative effect than the other two drugs. The independence of peripheral and CNS antihistamine effects was also suggested by correlation analysis. Subjects displayed individual sensitivity to the peripheral antihistamine effect of the three drugs; a marked antihistamine effect of one drug predicted a marked effect of the other two drugs. This was not the case for CNS sedation. The independence of peripheral and CNS effects should encourage development of new and more specific antihistamine compounds.     

Performance studies with the H1-histamine receptor antagonists, astemizole and terfenadine.

1 Effects of the antihistamines, terfenadine (60 mg) and astemizole (10 and 20 mg), on performance (visuo-motor coordination, arithmetical ability and digit symbol substitution) and on mood were studied in six healthy adult females. The study was double-blind, placebo controlled and included an antihistamine with known central effects (triprolidine 10 mg in sustained release form). 2 There were no changes in performance after terfenadine (60 mg) and astemizole (10 and 20 mg). Triprolidine (10 mg) caused a decrement in visuo-motor coordination (P less than 0.01) 0.5 h after ingestion which lasted until 3.5 h (P less than 0.001). The subject assessed their performance as impaired from 1.5-3.5 h (P less than 0.05) with triprolidine (10 mg), and their mood assessments were also altered. 3 Terfenadine (60 mg) and astemizole (10 and 20 mg) are likely to prove useful antihistamines for those involved in skilled activity.     

The H1 histamine receptor blocker, chlorpheniramine, completely prevents the increase in REM sleep induced by immobilization stress in rats

Chlorpheniramine is a selective antagonist of the H1 histaminergic receptor subtype and its effects in humans include somnolence. Chlorpheniramine affects sleep in rats, mainly by decreasing REM sleep. On the other hand, stress by immobilization induces an important increase in the percentage of REM sleep. In this study we analyzed the effects of blocking histaminergic receptors on REM sleep induced by immobilization stress. Adult male Wistar rats were chronically implanted for sleep recording. Immobilization stress was induced by placing the rat in a small cylinder for 2 h. Experimental conditions were: A. Control; B. Stress; C. Stress plus vehicle and D. Stress plus chlorpheniramine. Independent experiments were done both in the dark, as well as the light period. Results showed that the increase in REM sleep observed after immobilization stress was completely abolished by chlorpheniramine, both in the dark and in the light phase. Furthermore, the decrease in REM sleep was significant even when compared to the non-stressed control rats. REM sleep latency was also significantly longer during both light phases. The present results suggest that REM sleep is quite sensitive to histaminergic blockage. It is possible that chlorpheniramine is also blocking the cholinergic mechanisms generating REM sleep.     

The action of histamine, histamine H1-and H2-receptor agonists on noradrenaline level in rat brain.

Intraventricularly administered histamine (HI) (20--1000 micrograms) decreased noradrenaline (NA) .level in rat hypothalamus. 4-Methyl-HI (4-MeHI), but not 2-pyridylethylamine (2-PEA), reproduced the action of HI. Neither HI, nor 4-MeHI induced depression of hypothalamic NA content was antagonized by HI H2-receptor antagonists, cimetidine or metiamide. Chloropyramine reversed the NA-depleting action of HI.     

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.     

Hyperlipemic responses induced by centrally administered histamine H1- and H2-receptor agonists in rats

The H1-receptor agonist 2-pyridylethylamine (PEA), and the H2-receptor agonists dimaprit and impromidine administered intracerebroventricularly (i.c.v.) to conscious rats considerably increased the concentration of free fatty acids (FFA) in the blood serum. The hyperlipemic effect of PEA was abolished by mepyramine, a H1-receptor antagonist. Responses to dimaprit and impromidine were not antagonized by cimetidine. These results suggest that central H1-receptor stimulation elicits the hyperlipemic responses in rats. The role of central H2-receptors in this reaction is not clear.     

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.

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 H1-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, H1-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 [11C]-doxepin, a potent H1-receptor antagonist, were conducted near tmax of respective drugs. Other volunteers in the control group also received PET scans. The binding potential of doxepin (BP = Bmax/Kd) for available brain H1-receptors was imaged on a voxel-by-voxel basis through graphical analysis. By setting regions of interest, the H1-receptor occupancy of drugs was calculated in several H1-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 H1-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). H1-receptor occupancies in cortex were approximately 10% by ebastine and > or = 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 H1-receptor occupation of approximately 10%, consistent with its lower incidence of sedative effect, whereas (+)-chlorpheniramine occupied about 50% of brain H1-receptors even at a low but sedative dose of 2 mg; occupancy of (+)-chlorpheniramine was correlated with plasma (+)-chlorpheniramine concentration.     

Electrophysiological actions of histamine and H1-, H2-receptor antagonists in cardiac tissue

Electrophysiological investigations of histamine in different cardiac tissues have led to the following results: Histamine and the H2-agonists dimaprit and impromidine show similar actions on electrophysiological parameters of ventricular myocardium (especially a decrease in action potential duration), which are completely blocked by cimetidine and enhanced by the phosphodiesterase inhibitor 1-methyl,3-isobutylxanthine (IBMX). These effects may be explained by an increase in cellular cAMP leading to an increase in slow inward current and outward currents as shown by voltage clamp experiments. Histamine in contrast to IBMX increases action potential duration at 90% repolarization (APD90) in atria. Histamine effects in atrial myocardium are completely reversed by the H1-antagonist dimetindene. Stimulation of atrial H1-receptors is suggested to directly cause an increase in Ca-channel conductance independent of intracellular cAMP content. Histamine reduces AH-interval, increases V max of NH-cells and may induce AV-node arrhythmias (at concentrations greater than or equal to 3 mumol/l). These effects remain unchanged by dimetindene, but are reversed by cimetidine. The results indicate that histamine increases AV-nodal conduction via H2-receptors. Unspecific membrane actions of cimetidine are not observed up to 100 mumol/l. Dimetindene increases action potential duration (APD) in left atria and decreases Vmax at concentrations greater than or equal to 10 mumol/l. However, H1-antagonistic actions of dimetindene are already observed at concentrations 1,000 to 10,000 times lower (pA2-values 8.39-9.12) so that unspecific membrane actions are suggested not to occur on a therapeutic dose level.     

Synthesis and pharmacological identification of neutral histamine H1-receptor antagonists

In the present study we searched for neutral antagonists for the human histamine H(1)-receptor (H(1)R) by screening newly synthesized ligands that are structurally related to H(1)R agonists for their affinity using radioligand displacement studies and by assessing their functional activity via performing a NF-kappaB driven reporter-gene assay that allows for the detection of both agonistic and inverse agonistic responses. Starting from the endogenous agonist for the H(1)R, histamine, we synthesized and tested various analogues and ultimately identified several compounds with partial inverse agonistic properties and two neutral H(1)-receptor antagonists, namely 2-[2-(4,4-diphenylbutyl)-1H-imidazol-4-yl]ethylamine (histabudifen, 18d) (pK(i) = 5.8, alpha = 0.02) and 2-[2-(5,5-diphenylpentyl)-1H-imidazol-4-yl]ethylamine (histapendifen, 18e) (pK(i) = 5.9, alpha = -0.09).