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PubMed1983

Role of histamine and antihistamines in the nose.

The effect of an H1 antihistamine (chlorpheniramine) and an H2 antihistamine (ranitidine) nasal spray on histamine-provoked symptoms was studied in normal volunteers. Firstly it was shown that the H1 antihistamine has a marked inhibiting effect on tickling, sneezing and discharge, and secondly, that both H1 and H2 antihistamines have a weak effect on blockage. Finally, it was found that the H1 antihistamine, in the concentration used, has no demonstrable anti-cholinergic or local anaesthetic effect. It is concluded that antihistamines act locally in the nose, H1 antihistamines inhibit tickling, sneezing and hypersecretion via nervous H1 receptors, while blood vessels possess both H1 and H2 receptors.

Chlorpheniramine↗

PubMed1996

Reduction of the central nervous system adverse effects associated with antihistamines in the management of allergic disorders: strategies and progress.

To reduce the risks associated with the treatment of allergic disorders, physicians should understand the benefits and risks of drugs in the antihistamine class. The risk of central nervous system adverse effects associated with antihistamine use is significant with the use of first-generation antihistamines, which show pharmacologic activity in serotonergic, alpha-adrenergic, dopaminergic, and muscarinic-cholinergic pathways. Adverse effects reported with the use of first-generation antihistamines most often include drowsiness, fatigue, and an inability to concentrate; these effects may result in decreased compliance with therapy. The second-generation antihistamines have the property of low lipid solubility, which slows access across the blood-brain barrier. The low sedative profile of these new drugs may also be linked to a more pronounced binding to peripheral rather than brain histamine H1-receptors. The use of antihistamines with lower lipid solubility and greater specificity can provide an effective alternative for the relief of allergic symptoms, can improve compliance, and can reduce neurologic side effects. Because of the differences now recognized in the side effects of drugs of this class, an individualized approach to selection of antihistamine therapy is required.

Allergy and Immunology↗

PubMed1996

Safety of antihistamines in the treatment of allergic rhinitis in elderly patients.

Elderly patients may be more susceptible than younger persons to the sedating and anticholinergic effects of first-generation antihistamines. Second-generation antihistamines, such as loratadine, astemizole, and terfenadine, cause minimal sedation and little if any impairment in cognitive and psychomotor activity in healthy nonelderly patients. Although less extensively studied in elderly patients, it is probable that second-generation antihistamines are also less likely to induce the adverse central nervous system effects in older patients that are characteristic of the first-generation antihistamines. Toxic effects to the cardiovascular system, an issue of greater concern among elderly patients who may have subclinical heart disease, has not been observed with first-generation antihistamines. Among the second-generation antihistamines, however, astemizole and terfenadine, but not loratadine, can cause serious cardiovascular adverse effects, including death, when taken in high doses or coadministered with ketoconazole, itraconazole, or macrolide antibiotics.

Aged↗

PubMed1985

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

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.

Adult↗

PubMed1983

The biologic activity of mast cell granules. V. The effects of antihistamine treatment on rat cutaneous early- and late-phase allergic reactions.

Mast cell-dependent late-phase allergic reactions (LPR) as sequelae of immediate hypersensitivity responses (IR) occur in both human and rat skin; thus the rat has served as a useful model to investigate the pathogenesis of cutaneous LPR. To analyze the roles that histamine might play in the generation of rat LPR, the effects of H1 and/or H2 antihistamines on both LPR and antecedent blueing responses (IR) were investigated. Systemically administered diphenhydramine and cimetidine, alone or in combination, reduced blueing reactions to histamine. However, blueing responses to anti-IgE were only partially abrogated by antihistamine treatment with diphenhydramine alone or the combination of antihistamines. Diphenhydramine treatment alone partially inhibited the histologic intensity of LPR in a dose-dependent manner. Although cimetidine treatment alone had no inhibitory effect, it potentiated the diphenhydramine-induced inhibition of LPR. The inhibitory action of antihistamine treatment was apparent only in reactions elicited by anti-IgE or mast cell granules containing histamine, since LPR caused by histamine-free mast cell granules were not affected by antihistamines. This observation suggests that the inhibitory effect of antihistamines on LPR was the result of a specific blockade of histamine receptors rather than the result of a nonspecific suppressive effect. Our findings demonstrate that cutaneous inflammation generated as a result of mast cell degranulation can be significantly reduced by treatment with H1 and H2 histamine receptor antagonists.

Animals↗

PubMed1985

Skin test suppression by antihistamines and the development of subsensitivity.

The suppression of skin test reactivity by single doses of six antihistamines was measured before and after a period of daily antihistamine ingestion in 18 subjects. Single doses of hydroxyzine, 50 mg; chlorpheniramine, 16 mg; and promethazine, 50 mg; induced significant suppression of skin test reactivity at 2 hr, whereas the suppression produced by tripelennamine, 100 mg; diphenhydramine, 50 mg; and cyproheptadine, 16 mg; did not differ significantly from that produced by placebo. After 3 wk of treatment with hydroxyzine, 75 mg per day, the suppressive effect of hydroxyzine as well as the five clinically unrelated antihistamines was significantly reduced. Although the response to chlorpheniramine was also reduced after chronic treatment with chlorpheniramine, 24 mg per day, the difference was not statistically significant. We conclude that antihistamines in the doses used differ greatly in their suppressive effect on skin test reactivity. The antihistamine producing the most skin test suppression, hydroxyzine, when it was taken daily for 3 wk, caused the development of partial tolerance not only to its own effect but to those of clinically unrelated antihistamines.

Adolescent↗

PubMed2006

Optimization by factorial design of a capillary zone electrophoresis method for the simultaneous separation of antihistamines.

A 3(2) full factorial design was used to optimize the experimental conditions of a capillary zone electrophoresis method aimed at achieving simultaneous separation and quantification of the antihistamines brompheniramine, chlorpheniramine, cyproheptadine, diphenhydramine, doxylamine, hydroxyzine, and loratadine according to their therapeutic group. A statistical program, SPSS, was used to calculate the mathematical model with which to obtain the response surface. Critical parameters such as pH and applied voltage were studied to evaluate their effect on resolution and on efficiency. Optimum separation conditions were phosphate buffer pH 2.0, 5kV, and 2psis(-1) at 214nm. The analysis time was below 9min and the theoretical plates were between 6000 and 63,000N. Calibration curves were prepared for the antihistamines. The limits of detection were 4-14ngmL(-1), which allow their quantification in pharmaceuticals. The RSD% of each antihistamine was fairly good. Up to seven antihistamines belonging to the antihistaminic H(1)-receptor group were separated in the same electropherogram. The proposed method was then applied to the determination of antihistamines in pharmaceutical, urine, and serum samples with recoveries in agreement with the stated contents.

Algorithms↗

PubMed2006

Selective inhibition of Kir currents by antihistamines.

In the present study, the effects of antihistamines on inwardly rectifying potassium (Kir) channels expressed in Xenopus oocyte were investigated using two-electrode voltage clamp technique. Firstly, effects of antihistamines on two members of Kir2.0 sub-family, Kir2.1 and Kir2.3 were compared. For antihistamines that selectively block histamine H(1) receptor, the first-generation antihistamines mepyramine and diphenhydramine inhibited Kir2.3 current by 25.0+/-2.9% and 17.3+/-0.7% at concentrations of 100 microM, respectively. In contrast, the second- and third-generation antihistamines astemizole and desloratadine were completely devoid of any inhibitory effect on Kir2.3 current. Histamine H(2) receptor antagonist cimetidine, at 100 microM, failed to inhibit Kir2.3 current. On the other hand, Kir2.1 current was not sensitive to any of these drugs. The mepyramine-induced inhibition of Kir2.3 current was significantly reduced by a single point mutation in Kir2.3 (Kir2.3(I213L)), which enhances Kir2.3-PIP(2) interaction. Secondly, the effect of mepyramine was also tested on Kir3.4*, another member of Kir family. 100 microM mepyramine produced a 30.3+/-4.6% inhibition on Kir3.4* current. These results suggest that the first-generation histamine H(1) receptor antagonists selectively inhibit Kir currents. The inhibitory effect of antihistamines on Kir currents may be involved in their neuronal and cardiac toxic effects caused by drug overdosing.

Animals↗

PubMed1989

Benzo- and pyrido-1,4-oxazepin-5-ones and -thiones: synthesis and structure-activity relationships of a new series of H1 antihistamines.

A series of novel benzo- and pyrido-1,4-oxazepinones and -thiones which represents a new structural class of compounds possessing H1 antihistaminic activity was synthesized, and the SARs were evaluated. The antihistaminic activity was determined by blockade of histamine-induced lethality in guinea pigs. The sedative potential was determined by comparison of the EEG profiles of the compounds with those of known sedating and nonsedating antihistamines. Several of the compounds were shown to possess potent H1 antihistaminic activity and to be free of the cortical slowing with synchronized waves and spindling activity found in the EEG of sedative antihistamines. One compound, 2-[2-(dimethylamino)ethyl]-3,4-dihydro-4-methylpyrido[3,2-f]-1,4- oxazepine-5(2H)-thione (rocastine) is currently undergoing clinical evaluation as a nonsedating H1 antihistamine.

Animals↗

PubMed2002

H1-antihistamines: inverse agonism, anti-inflammatory actions and cardiac effects.

This review addresses novel concepts of histamine H1-receptor function and attempts to relate them to the anti-inflammatory effects of H1-antihistamines. Furthermore, the molecular mechanisms underlying the cardiotoxic effects of H1-antihistamines are discussed. H1-receptors are G-protein-coupled-receptors (GPCRs), the inactive and active conformations of which coexist in equilibrium. The degree receptor activation in the absence of histamine is its 'constitutive activity'. In this two-state model, histamine acts as an agonist by combining with and stabilizing the activated conformation of the H1-receptor to shift the equilibrium towards the activated state. Drugs classified previously as antagonists act as either inverse agonists or neutral antagonists. Inverse agonists combine with and stabilize the inactive conformation of the receptor to shift the equilibrium towards the inactive state. Thus, they may down-regulate constitutive receptor activity, even in the absence of histamine. Neutral antagonists combine equally with both conformations of the receptor, do not affect basal receptor activity but do interfere with agonist binding. All H1-antihistamines examined to date are inverse agonists. As the term 'H1-receptor antagonists' is obviously erroneous, we suggest that it be replaced by 'H1-antihistamines'. The observations that H1-receptors modulate NF-kappaB activation and that there are complex interactions between GPCRs, has allowed us to postulate receptor dependent-mechanisms for some anti-inflammatory effects of H1-antihistamines, e.g. inhibition of ICAM-1 expression and the effects of bradykinin. Finally, the finding that blockade of HERG1 K+ channels is the mechanism by which some H1-antihistamines may cause cardiac arrhythmias has allowed the development of preclinical tests to predict such activity.

Animals↗

PubMed2002

Non-sedating antihistamine drugs and cardiac arrhythmias -- biased risk estimates from spontaneous reporting systems?

AIMS: This study used spontaneous reports of adverse events to estimate the risk for developing cardiac arrhythmias due to the systemic use of non-sedating antihistamine drugs and compared the risk estimate before and after the regulatory action to recall the over-the-counter status of some of these drugs. METHODS: All suspected adverse drug reactions (ADRs) reported until July 1999 to the Netherlands Pharmacovigilance Foundation Lareb were used to calculate the ADR reporting odds ratio, defined as the ratio of exposure odds among reported arrhythmia cases, to the exposure odds of other ADRs (non-cases), adjusted for gender, age, reporter, year of reporting and comedication, stratified for the periods before and after the governmental decision in the Netherlands. RESULTS: Seven-hundred and thirty-seven cases of arrhythmia were reported, out of which there were 43 instances where the patients were using non-sedating antihistamines. In general non-sedating antihistamines are associated with cardiac arrhythmia to a higher extent in comparison with other drugs (ADR reporting odds ratio 2.05 [95% CI: 1.45, 2.89]). The association between arrhythmias and non-sedating antihistamine drugs calculated before 1998 was not significantly higher than 1 (OR 1.37 [95% CI: 0.85, 2.23]), whereas the risk estimate calculated after the governmental decision did significantly differ from 1 (OR 4.19 [95% CI: 2.49, 7.05]). CONCLUSIONS: Our data suggest that non-sedating antihistamines might have an increased risk for inducing arrhythmias. Our findings, however, strongly suggest that the increased risk identified can at least partly be explained by reporting bias as a result of publications about and mass media attention for antihistamine induced arrhythmias.

Adolescent↗

PubMed2003

Comparative in vivo bioactivity of modern H1-antihistamines on AMP challenge in atopic asthma.

BACKGROUND: Modern H(1)-antihistamines differ in their in vitro binding affinity, but their comparative in vivo bioactivity in asthmatic airways is unknown. OBJECTIVES: We compared clinically recommended doses of 3 H(1)-antihistamines on airway hyperresponsiveness to AMP challenge (the primary outcome variable). METHODS: Sixteen atopic patients with mild-to-moderate asthma of whom 10 were receiving inhaled corticosteroid therapy (all had positive results to house dust mite on skin prick testing) were randomized in a double-blind, placebo-controlled, cross-over fashion to receive single doses of 5 mg of desloratadine, 180 mg of fexofenadine hydrochloride (FEX), 5 mg of levocetirizine dihydrochloride (LEV), or placebo, with AMP challenge performed 12 hours after dosing. RESULTS: All H(1)-antihistamines demonstrated significantly greater (P <.05) geometric mean +/- SEM AMP PC(20) values compared with that of placebo (86 +/- 29 mg/mL): desloratadine, 189 +/- 54 mg/mL; FEX, 176 +/- 57 mg/mL; and LEV, 163 +/- 48 mg/mL. Prechallenge forced expiratory flow at 25% to 75% of maximal lung volume (percent predicted) but not FEV(1) was significantly higher (P <.05) for all H(1)-antihistamines compared with that of placebo (53% +/- 4%): desloratadine, 62% +/- 4%; FEX, 62% +/- 4%; and LEV, 59% +/- 3%. There were no significant differences in either AMP PC(20) or lung function values among the H(1)-antihistamines. CONCLUSION: Single doses of H(1)-antihistamines improved airway hyperresponsiveness and small-airways caliber to a similar degree. Data for in vitro binding affinity do not therefore translate into commensurate differences in in vivo bioactivity at clinically recommended doses.

Acetates↗

PubMed2002

Use of antihistamine drugs in early pregnancy and delivery outcome.

OBJECTIVE: To study the impact of antihistamine use in early pregnancy on delivery outcome. METHODS: Using prospectively collected information on drug use in early pregnancy, delivery outcome was studied among 17 266 women with 17 776 deliveries and 18 197 infants. The analysis was performed according to the main reason for antihistamine use: nausea and vomiting in pregnancy and allergy. RESULTS: In the nausea and vomiting in pregnancy group, we found a significant increase in twin births and a significant reduction in preterm births, low birth weight and being small-for-gestational age among singletons. The perinatal death rate was reduced and the rate of congenital malformations was normal. A reduction was seen in the occurrence of congenital cardiovascular defects after the use of antihistamines. The odds ratio for specified cardiac defects, with the exception of ventricular and atrium septal defects, after the use of antihistamines for nausea and vomiting in pregnancy (0.54) was significantly lower than that for non-cardiovascular congenital malformations (0.95). No statistically significant effects on delivery outcome were seen after the use of antihistamine drugs for allergy. However, there was a non-significant tendency for a reduced risk for cardiovascular defects (odds ratio 0.71). CONCLUSIONS: The beneficial effects on delivery outcome observed are most probably related to the underlying nausea and vomiting in pregnancy. There is no clear teratogenic effect of the antihistamines studied.

Adult↗

PubMed1998

"Conventional" antihistamines slow cardiac repolarization in isolated perfused (Langendorff) feline hearts.

We examined the effects of "conventional" antihistamines on cardiac repolarization by using the isolated perfused feline heart model. Representative drugs from the major classes of antihistamines were tested. Each of the antihistamines evaluated in this study elicited a dose-dependent slowing of cardiac repolarization, as indicated by the QT prolongations observed from electrocardiogram (ECG) tracings recorded during these experiments. The concentrations of drugs tested ranged from 1 to 30 microM. Of the drugs analyzed, clemastine and hydroxyzine appeared to be the most potent (relative EC50 values, 5.2 and 6.6 microM, respectively), causing the QT to lengthen by as much as 40-50% at a concentration of 10 microM. Brompheniramine, chlorpheniramine, and diphenhydramine displayed intermediate potencies with respect to QT prolongation (relative EC50 values, 11-13 microM), whereas cyproheptadine, chlorcyclizine, and promethazine were the least potent of the antihistamines tested (relative EC50 values, 16-20 microM). It is concluded that the antihistamines evaluated in this study act directly on the heart to slow cardiac repolarization. These findings could have important clinical relevance for patients taking excessive dosages of conventional antihistamines and those at risk of developing cardiac arrhythmias.

Animals↗

PubMed2001

Preclinical comparison of ebastine and other second generation H1-antihistamines.

The present study was performed to compare the properties of ebastine--the long duration of antiallergic effect and less penetration to the CNS--with those of other H1-antihistamines. Passive cutaneous anaphylactic reaction was induced and the dye leakage from the skin measured after oral administration of the various H1-antihistamines in guinea pigs. The H1-antihistamines examined inhibited passive cutaneous anaphylactic reactions, with ED50 values of 1.55-5.77 mg/kg administered orally. Evaluation at doses close to the ED50 values determined that the rank order of the various H1-antihistamines for the duration of antiallergic effects, calculated from the AUC, was as follows: ebastine>cetirizine> or =oxatomide=loratadine=epinastine. The inhibition of [3H]-mepyramine binding to the cortical membrane was examined ex vivo after oral administration of the drugs in rats. Ketotifen as a positive control of sedative antihistamine, oxatomide, cetirizine, ebastine and epinastine dose-dependently inhibited the [3H]-mepyramine binding to rat cortical membranes. However, ebastine and epinastine did not show 50% [3H]-mepyramine binding inhibition even at 100 mg/kg orally In conclusion, ebastine was shown to be a potent and long-lasting H1-antihistamine with less effect to the CNS. Consequently, in conjunction the two experimental models used in this study--passive cutaneous anaphylactic reaction in guinea pigs and ex vivo [3H]-mepyramine binding to rat cortical membrane--may be important to estimate the duration of antiallergic effects of drugs and to detect their sedative effects, which are important indicators in the development of new antiallergic drugs.

Animals↗

PubMed1996

Antihistamines: topical vs oral administration.

The pathogenesis of allergic rhinitis is complex, involving not only histamine and mast cell-derived tryptase, but also eosinophil- and neutrophil-derived mediators, cytokines, and intercellular cell adhesion molecules (ICAM-1). It is surprising that antihistamines, which block only one component of the process, have proved so effective in the management of allergic rhinitis. Research has therefore focused on whether antihistamines have additional pharmacological activities. In vitro studies have shown that high concentrations of second generation antihistamines can block inflammatory mediator release from basophils and mast cells, and reduce ICAM-1 expression in epithelial cell lines. In vivo studies have also shown an effect on the allergen-induced inflammatory reaction; both oral and intranasal antihistamines cause a reduction in nasal symptoms and inflammatory cell influx. Oral terfenadine and cetirizine and intranasal levocabastine and azelastine have also demonstrated a lowering of ICAM-1 expression on epithelial cells. With regard to clinical efficacy, topical levocabastine (0.5 mg/mL eye drop solution and 0.5 mg/mL nasal spray) was shown to be more effective than oral terfenadine (60 mg twice daily) in relieving ocular itch (P = 0.02) and reducing nasal symptoms in allergic rhinoconjunctivitis. In a further study, levocabastine eye drops were as effective and well tolerated as sodium cromoglycate in seasonal allergic rhinitis. Intranasal azelastine (0.28 mg twice daily) showed a trend for superior relief of rhinorrhoea and nasal obstruction compared with oral terfenadine (60 mg twice daily). In addition, intranasal azelastine (0.28 mg twice daily) resulted in significant reductions in sneezing, nasal obstruction, rhinorrhoea and itching in perennial rhinitis, compared with the lower efficacy of beclomethasone dipropionate (0.1 mg twice daily). As well as benefits in efficacy, topical administration is associated with improved safety. Some antihistamines, particularly those metabolized in the liver, are associated with occasional reports of severe side-effects. It is therefore logical to administer antihistamines directly to the target organ.

Administration, Oral↗

PubMed1980

Prevention and treatment of serous otitis media with an oral antihistamine. A double-blind study in pediatric practice.

Serous otitis media (SOM) is a common and troublesome disease in childhood. Although antihistamines are commonly prescribed to prevent or treat SOM, there have been no controlled clinical trials to determine the efficacy of such interventions. This study was designed to determine if antihistamines are of value in the prevention or treatment of SOM. Using a randomized double-blind method, 206 children with acute otitis media were treated with antibiotics and either brompheniramine maleate or placebo. The children were evaluated two weeks later by tympanometry and, independently, by combined pneumatoscopy and otoscopy. There were no significant differences overall between the treatment and control groups in terms of preventing SOM: 44% of those on antihistamine and 41% of those on placebo had SOM after two weeks of therapy. However, children with a history of serous otitis media did significantly better on placebo than did those on antihistamine, and children without a history of serous otitis media did significantly better on antihistamine than did those on placebo. One hundred children continued to use antihistamine or placebo for four more weeks. There were no significant differences between the treatment and control groups in terms of resolution of SOM (64% versus 68%).

Adolescent↗

PubMed1996

Special considerations in the treatment of seasonal allergic rhinitis in adolescents: the role of antihistamine therapy.

The symptoms of seasonal allergic rhinitis often develop during adolescence. Teen-age students with seasonal allergic rhinitis may experience decreased academic performance and productivity from the disease or because of the sedative effects of some antihistamines. The pharmacologic effects of nonsedating second-generation antihistamines are compared with those of classical antihistamines. The effects of antihistamines on sedation and motor and cognitive function are discussed. The role of antiinflammatory agents, decongestants, and combination products is reviewed. Potential drug interactions must be considered along with factors such as drug-induced weight gain and the use of antihistamines in potentially pregnant patients in selecting appropriate antihistamine therapy for adolescent patients.

Adolescent↗