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PubMed1996

Model for outcomes assessment of antihistamine use for seasonal allergic rhinitis.

BACKGROUND: Drug selection for optimal treatment of common medical conditions may be difficult and involve many diverse factors. OBJECTIVE: The efficacy, safety, quality of life, and cost of treatment of seasonal allergic rhinitis with cetirizine, chlorpheniramine, or terfenadine were compared in a prospective, two-phase, randomized, single-blind clinical trial conducted in a managed care setting. METHODS: In phase I, which lasted 2 weeks, patients were randomized to receive one of the study drugs. In phase II, which lasted 4 weeks, the initial treatment was continued unless patients were dissatisfied, in which case they could be randomly assigned to receive another study drug. In both phases pseudoephedrine could be taken as needed. Patients kept daily diaries of symptoms and costs, and study drugs were evaluated at the end of each phase for efficacy, safety, and effect on quality of life by means of a validated questionnaire. A multiattribute outcomes assessment model for formulary decision making was used to rank the antihistamines. RESULTS: Physicians' and patients' assessments in phases I and II indicated that cetirizine and chlorpheniramine were significantly more effective than terfenadine (p < 0.05). Incidence of sedation in phase I and phase II was 40.5% and 16.7% for chlorpheniramine, 11.6% and 9.8% for cetirizine, and 6.7% and 5.1% for terfenadine, respectively. At the end of phase I, 28.9% of the patients treated with chlorpheniramine, 50% of the patients treated with terfenadine, and 69.4% of the patients treated with cetirizine were satisfied with their therapy and chose not to switch their medication. Quality of life scores improved most after treatment with cetirizine and least after treatment with terfenadine. CONCLUSION: The result of this trial indicate that antihistamine selection is best made with the use of a multiattribute evaluation that includes quality of life. In this study cetirizine was favored by patients and physicians most often, followed by chlorpheniramine and then terfenadine.

Adolescent↗

PubMed1997

Efficacy of antihistamine pretreatment in the prevention of adverse reactions to Hymenoptera immunotherapy: a prospective, randomized, placebo-controlled trial.

BACKGROUND: Some clinical studies suggest that a combination of an H1- and H2-antagonist may be effective in the prophylaxis of allergic reactions. OBJECTIVE: The efficacy of pretreatment with an H1/H2-antagonist combination, H1-antagonist alone, or placebo in the prophylaxis of local and systemic adverse reactions to specific immunotherapy with Hymenoptera venom was compared. METHODS: In a prospective, randomized, double-blind, placebo-controlled study, 121 patients with Hymenoptera venom allergy were treated with rush immunotherapy and pretreatment with one of the following: 120 mg of terfenadine plus 300 mg of ranitidine, 120 mg of terfenadine alone, or placebo. The incidence of unwanted systemic adverse and local reactions was recorded for up to 50 weeks. RESULTS: In seven patients (6%), six in the placebo group and one in the terfenadine group, systemic side effects required cessation of therapy (p = 0.005). Subjective symptoms occurred in four patients (10%) in the terfenadine plus ranitidine group and in three patients (7%) in the terfenadine group. Regarding local reactions, significantly fewer patients treated with a combination of terfenadine and ranitidine and with terfenadine alone as compared with placebo had severe local symptoms of erythema (29%, 29%, and 49%), edema (24%, 18%, and 41%), and pruritus (13%, 11%, and 31%) at week 1 (p < 0.05). This therapeutic benefit was limited to the first 4 weeks of treatment. Treatment with a combination of terfenadine and ranitidine was not superior to treatment with terfenadine alone. CONCLUSIONS: Pretreatment with H1-antihistamines with or without H2-antihistamines significantly reduced local and systemic adverse reactions to immunotherapy with Hymenoptera venom and may therefore be helpful in the management of immunotherapy.

Administration, Oral↗

PubMed2003

Middle ear fluid histamine and leukotriene B4 in acute otitis media: effect of antihistamine or corticosteroid treatment.

OBJECTIVE: Two potent mediators of acute inflammation, histamine and leukotriene B4 (LTB4), have been shown to play important roles in the pathogenesis and clinical course of acute otitis media (AOM) in children. The purpose of this study was to evaluate the ability of adjuvant drugs, antihistamine and corticosteroid, in reduction of the levels of histamine and LTB4 in the middle ear and their ability to improve outcomes of AOM. METHODS: Eighty children with AOM (aged 3 months to 6 years) were enrolled in a prospective, randomized, double-blind, placebo controlled study. All children received one dose of intramuscular ceftriaxone and were randomly assigned to receive either chlorpheniramine maleate (0.35 mg/kg per day) and/or prednisolone (2 mg/kg per day) or placebos three times a day for 5 days. Tympanocentesis was performed at enrollment and after 5 days of adjuvant drug treatment. MEFs were collected for bacterial and viral studies and histamine and LTB4 levels. The subjects were followed for the duration of middle ear effusion or up to 3 months. RESULTS: Histamine or LTB4 levels in the MEF after 5 days of treatment were not significantly reduced by adjuvant drug treatment. However, subjects receiving corticosteroid had a lower rate of treatment failure during the first 2 weeks and shorter duration of middle ear effusion. CONCLUSIONS: Five day of antihistamine or corticosteroid treatment does not reduce the levels of histamine or leukotriene B4 in the MEF of children with AOM. Positive clinical outcomes of AOM cases associated with corticosteroid treatment needs to be confirmed in a larger clinical trial of children with intact tympanic membranes, who do not receive tympanocentesis.

Acute Disease↗

PubMed1983

Acute otitis media in children: are decongestants or antihistamines necessary?

This study was designed to investigate the efficacy of a decongestant-antihistamine preparation in combination with antibiotic treatment of acute otitis media. The effectiveness of a new Dimetapp (DIM) preparation was assessed in comparison with each of its components (brompheniramine maleate [BPM] and phenylephrine hydrochloride [PEH] as well as a placebo (PL) vehicle in the treatment of acute otitis media. In a randomized double blind study, 98 children were treated in the emergency department or outpatient medical clinics at Children's Hospital of Michigan with amoxicillin and either DIM, BPM, PEH, or PL. They were evaluated at two weeks by clinical examination, pneumatoscopy, and tympanometry. Fifty-eight patients (59%) continued to have evidence of fluid in the middle ear. These patients were continued on the test medications for another two weeks and then reevaluated. There were significant differences between the treatment groups (DIM, BPM, and PEH) and the control PL group; the patients receiving Dimetapp or placebo fared better than those receiving BPM or PEH. However, there was no difference in the overall response between Dimetapp and placebo. Antihistamine-decongestant therapy does not appear to be necessary in the treatment of acute otitis media in children.

Acute Disease↗

PubMed2002

Cardiotoxicity of new antihistamines and cisapride.

Although the new second-generation nonsedative antihistamines terfenadine and astemizole were launched as highly selective and specific H(1)-receptor antagonists, they were later found to cause prolongation of the QT-interval and severe cardiac arrhythmias. The prolongation of the QT-interval is caused by the blockade of one or more of the cardiac potassium channels, among which the delayed rectifier I(Kr), encoded by the HERG-gene, appears to be the most significant. The potency of the prokinetic drug cisapride to block I(Kr) appears to be similar to that of terfenadine (IC(50) about 50 nmol/l). These drugs cause problems when overdosed, used in combination with inhibitors of their CYP3A4-mediated metabolism, or when given to individuals with altered drug kinetics (the aged) or patients with existing cardiac disease (congenitally long QT). Moreover, interactions with other QT-interval prolonging drugs require special attention. Active hydrophilic metabolites of the second-generation antihistaminic compounds (ebastine-carebastine, loratadine-desloratadine, terfenadine-fexofenadine, astemizole-norastemizole) are new compounds with probably reduced risk for drug interactions and cardiac toxicity.

Arrhythmias, Cardiac↗

PubMed1988

Identification and differentiation of alkylamine antihistamines and their metabolites in urine by computerized gas chromatography-mass spectrometry.

A gas chromatographic-mass spectrometric screening procedure is described for the identification and differentiation of the following alkylamine antihistamines and their metabolites in urine: azatadine, benzquinamide, brompheniramine, chlorphenamine, (clofedanol), cyproheptadine, dimetindene, ketotifen, mebhydroline, phenindamine, pheniramine, pyrrobutamine, terfenadine and tolpropamine. After acid hydrolysis of the conjugates, extraction and acetylation, the urine samples were analysed by computerized gas chromatography-mass spectrometry. Using ion chromatography with the selective ions m/z 58, 169, 203, 205, 230, 233, 262 and 337, the presence of alkylamine antihistamines and/or their metabolites was indicated. The identity of positive signals in the reconstructed ion chromatograms was confirmed by a visual or computerized comparison of the stored full mass spectra with the reference spectra. The ion chromatograms, reference mass spectra and gas chromatographic retention indices (OV-101) are documented. The procedure presented is integrated in a general screening procedure (general unknown analysis) for several groups of drugs.

Acetylation↗

PubMed2001

Retention pharmacokinetic and pharmacodynamic parameter relationships of antihistamine drugs using biopartitioning micellar chromatography.

Antihistamines are drugs which act by competitive inhibition of the H1 or H2 histamine receptors. Little has been known about their clinical pharmacokinetics and biological responses until the last few years. In this paper, we propose quantitative retention-activity relationship, QRAR, models based on the retention data of antihistamines in a biopartitioning micellar chromatography (BMC) system using a Brij35 mobile phase for describing pharmacokinetic parameters such as half-life and volume of distribution, or the pharmacodynamic parameters, therapeutic plasma levels, lethal doses and drug-receptor dissociation constant. The predictive ability of these models is statistically validated. These results are compared to traditional quantitative structure-activity relationship, QSAR, models using lipophilicity data. The adequacy of QRAR models can be explained taking into account the fact that the retention of compounds in BMC depends on their hydrophobic, electronic and steric characteristics which are of great importance in pharmacokinetic and pharmacodynamic behavior.

Chromatography, Liquid↗

PubMed1996

Torsade de pointes with an antihistamine metabolite: potassium channel blockade with desmethylastemizole.

OBJECTIVES: Proarrhythmic effects have been observed with the selective histamine1 (H1) receptor antagonist drug astemizole, a widely prescribed antihistamine. The metabolites of astemizole and those of other antihistamine compounds have not been implicated as causative agents of cardiac arrhythmias. The purpose of this study was to examine whether desmethylastemizole, the principal metabolite of astemizole, blocks delayed rectifier potassium (K+) channels. BACKGROUND: QT interval prolongation and torsade de pointes are associated with astemizole intake and have been ascribed to block the repolarizing K+ currents, specifically the rapidly activating component of the delayed rectifier iKr. Astemizole undergoes extensive first-pass metabolism, and its dominant metabolite, desmethylastemizole, has a markedly prolonged elimination time. We report the clinical observation of QT prolongation and torsade de pointes in a patient with undetectable serum concentrations of astemizole (< 0.5 ng/ml) and "therapeutic" concentrations of desmethylastemizole (up to 7.7 ng/ml or 17.3 nmol/liter). METHODS: The perforated patch clamp recording technique was used to study the effects of desmethylastemizole (20 nmol/liter) on action potentials and iKr in isolated rabbit ventricular myocytes. RESULTS: Desmethylastemizole produced action potential prolongation and the induction of plateau early afterdepolarizations. Under voltage clamp conditions, desmethylastemizole suppressed iKr amplitude by approximately 65%. The drug E-4031 (100 nmol/liter), which selectively blocks iKr, had a similar effect on current amplitude. CONCLUSIONS: Desmethylastemizole, the major astemizole metabolite, blocks the repolarizing K+ current iKr with high affinity. The clinical observation of QT prolongation and torsade de pointes found with astemizole intake may principally be caused by the proarrhythmic effects of its metabolite desmethylastemizole.

Aged↗

PubMed2003

H1-receptor blocker antihistamine, terfenadine durably influences the glucocorticoid receptor, and lymphocyte histamine content of weanling rats.

Hormonal imprinting takes place perinatally when a hormone and its maturing target receptor meet. As a consequence of imprinting the receptor accomplishes its maturation reaching the binding capacity characteristic to the adult age. In this critical period the presence of foreign molecules which are able to bind to the receptor can cause faulty imprinting with life-long consequences. In the recent years it was cleared that not only receptors are influenced by faulty imprinting, however, also the hormone production of the given cell. In addition imprinting was provoked at non-perinatal periods (adolescence and adult age) in cytogenic organs. In the present experiment the prolonged effect of a non-perinatal imprinting by an antihistamine to the histamine content of white blood cells and glucocorticoid receptors of liver and thymus was studied. Two weeks after 3-day terfenadine treatment at weaning, flow cytometry of peritoneal cells and blood lymphocytes for histamine, and receptor kinetic analysis of dexamethasone binding were done. Histamine content of blood lymphocytes and glucocorticoid receptor density of liver cells were significantly decreased. This means that a short treatment with a H(1)-receptor blocker antihistamine durably influences physiological indexes which were not known till now. This means that not only the acute effects, but the prolonged side-effects must be considered.

Animals↗

PubMed2002

Does potency predict clinical efficacy? Illustration through an antihistamine model.

OBJECTIVE: The concepts of potency and efficacy are often confused and used interchangeably within the scientific and pharmaceutical industry. It is important that the distinction between the two is understood, and that the terms are defined within their correct context. After reading this article, readers should have an understanding of the relationships between receptor potency and clinical efficacy. DATA SOURCES: Following a comprehensive review of the literature using MEDLINE, the author observed a lack of relevant references that relate measurements of potency to clinical efficacy. Therefore, the author reviewed the basic pharmacologic principles of potency using examples from the recent antihistamine literature. RESULTS: Potency is an expression of the activity of a drug in terms of the concentration or amount of the drug required to produce a defined effect, whereas clinical efficacy judges the therapeutic effectiveness of the drug in humans. The differing methods of evaluating the activity of antihistamines in vitro and in vivo can lead to inconsistent results, which complicate the use of potency to predict clinical efficacy. Further, as therapeutic behavior is modulated by pharmacokinetic and pharmacodynamic parameters and by further interactions at sites other than the target receptor, it does not necessarily follow that more potent drugs have greater clinical efficacy. CONCLUSIONS: Although potency can be a good preclinical marker of the therapeutic potential of a drug, clinical efficacy should only be evaluated within the patient population using appropriate outcome measures.

Histamine Antagonists↗

PubMedDate not supplied

Second-generation antihistamines: the OTC debate.

OBJECTIVE: To demonstrate that the safety profiles of second-generation antihistamines (SGAs) meet the criteria set by the Food and Drug Administration (FDA) for switching these products to over-the-counter (OTC) status. DATA SOURCES: MEDLINE search of articles published from 1970 through 2000. SUMMARY: Most patients with allergic rhinitis treat their symptoms with first-generation antihistamines (FGAs), which are available over-the-counter (OTC). Yet FGAs are generally considered less safe than the newer drugs. FGAs cause central nervous system (CNS) adverse effects and may increase users' risk for work-related injuries and motor vehicle accidents and, in children, for learning impairment. SGAs cause fewer CNS effects, do not appear to affect learning in children, and do not have significant drug interactions. Several other countries have made SGAs available OTC. Blue Cross of California petitioned FDA in July 1998 to make this class of drugs available OTC in the United States. This petition will finally be heard in May 2001. The 1951 Durham-Humphrey amendment to the original Federal Food, Drug and Cosmetic Act of 1938 requires that "a drug be made available without a prescription if, by following the labeling, consumers can use it safely and effectively without professional guidance." If judged according to this and other criteria promulgated by FDA, SGAs should be strongly considered for being switched to OTC status. CONCLUSION: The safety and efficacy of SGAs have been adequately established. Consumers should have the option of self-treating mild allergic rhinitis symptoms with these products.

Histamine Antagonists↗

PubMed1986

Studies on 1,2,3-triazoles. 13. (Piperazinylalkoxy) [1]benzopyrano[2,3-d]-1,2,3-triazol-9(1H)-ones with combined H1-antihistamine and mast cell stabilizing properties.

Several N-benzylpiperazino derivatives of [1]benzopyrano[2,3-d]-1,2,3-triazol-9(1H)-one and its 5-methyl homologue have been prepared and evaluated for H1-antihistamine activity on guinea pig ileum. The most potent compounds were also evaluated for their ability to stabilize mast cells in the rat passive peritoneal anaphylaxis (PPA) system and were shown to inhibit histamine release at concentrations below those required to inhibit extravasation, suggesting that this might be relevant to their antianaphylactic activity in this system. The compound tested with the most potent H1-antihistamine activity was 6-[3-[4-(4-chlorobenzyl)-1-piperazinyl]propoxy][1]benzopyrano[2,3- d]-1,2,3-triazol-9(1H)-one, 28, which had a pA2 of 9.1 against histamine on guinea pig ileum, comparable to that of mepyramine, and inhibited histamine release in the rat PPA system with an IC50 value of 5.4 X 10(-6) M.

Anaphylaxis↗

PubMed1977

(+)- and (-)-3-Methoxycyproheptadine. A comparative evaluation of the antiserotonin, antihistaminic, anticholinergic, and orexigenic properties with cyproheptadine.

The synthesis and resolution of (+/-)-3-methoxycyproheptadine [(+/-)-4] are described. As a peripheral serotonin antagonist, (+/-)-4 was found to be one-half as potent as cyproheptadine (1b). The peripheral anticholinergic and antihistaminic activities as well as the orexigenic property of (+/-)-4 are less than those of 1b. A further comparison of the enantiomers (+)-4 and (-)-4 shows that all of the anticholinergic activity of (+/-)-4 resides solely in the dextrorotatory enantiomer, (+)-4, while the antiserotonin activity, which is similar to that of 1b, resides in the levorotatory enantiomer, (-)-4. Antihistaminic and orexigenic activity also resides in (-)-4 but these properties are reduced compared to those of 1b.

Animals↗

PubMed2005

Norpiperidine imidazoazepines as a new class of potent, selective, and nonsedative H1 antihistamines.

Clinical doses of available H(1) antihistamines are limited mainly by sedative side effects. However, higher doses are often required to obtain optimal therapeutic activity, especially in dermatology. We report the synthesis of three norpiperidine imidazoazepines representative of a new class of selective and nonsedating H(1) antihistamines. The compounds were at least as potent as cetirizine and loratadine as measured by H(1) receptor binding affinity, by protection against compound 48/80- and histamine-induced lethality in rats and guinea pigs, respectively, and by skin reaction tests in rats, guinea pigs, and dogs. The compounds, in particular 3a, were less prone than the reference compounds to penetrate the brain and to occupy central H(1) receptors, suggesting absence of sedative side effects. In vitro and in vivo cardiovascular safety tests showed that 3a had no intrinsic potential to prolong ventricular repolarization or induce cardiac arrhythmias. Compound 3a has been selected for further clinical development, mainly for application in dermatology.

Anaphylaxis↗

PubMed1985

New antihistaminic theophylline or theobromine derivatives.

A series of 3,4-dihydro-1,3-dimethyl-7-[3-(4-substituted-piperazin-1-yl)- substituted-alkyl]-1H-purine-2,6-diones and 3,7-dihydro-3,7-dimethyl-1-[3-(4-substituted-piperazin-1-yl)- substituted-alkyl]-1H-purine-2,6-diones was synthesized and evaluated for antihistaminic activity. Some of them displayed good inhibition of both histamine-induced bronchospasm in the anesthetized guinea pig at 10 micrograms/kg by the intravenous route and of passive cutaneous anaphylaxis in the rat at 10 mg/kg by the oral route. Comparison of the two most active compounds revealed a higher antihistaminic activity with the compounds containing a (phenylthio)propyl group (1 and 2) as compared with that containing a phenoxy group. Compound 2 [RS-49014, 3,4-dihydro-1,3-dimethyl-7-[3-[4-[3-(phenylthio)propyl]piperazin-1 -yl]- 2-hydroxypropyl]-1H-purine-2,6-dione] was selected for clinical trials on the basis of a comparative pharmacological study with chlorpheniramine, ketotifen, promethazine, and theophylline.

Acetylcholine↗

PubMed2001

Optimization of a mathematical topological pattern for the prediction of antihistaminic activity.

Molecular topology was used to develop a mathematical model capable of classifying compounds according to antihistaminic activity. The equations used for this purpose were derived using multilinear regression and linear discriminant analysis. The topological pattern of activity obtained allows the reliable prediction of antihistaminic activity in drugs frequently used for other therapeutic purposes. Based on the results, the proposed pattern is seemingly only valid for drugs that interact with histamine through competitive inhibition with H1 receptors.

Histamine H1 Antagonists↗

PubMed1999

Continuous antihistamine treatment controls allergic inflammation and reduces respiratory morbidity in children with mite allergy.

BACKGROUND: Allergic reaction is characterized by a complex inflammatory process. Some of the new antihistamines have antiallergic effects and can affect the inflammatory cell recruitment via adhesion molecule downregulation. We aimed to assess in a 12-month study whether continuous treatment with an antihistamine (terfenadine) can reduce respiratory symptoms and local inflammation in children with mite allergy. METHODS: The study was double-blind and placebo-controlled: it involved two parallel groups of children suffering from rhinoconjunctivitis and/or mild intermittent asthma due to mite allergy. They received either terfenadine (1 mg/kg per body weight per day) or placebo for 1 year. Nasal, conjunctival, and bronchial symptoms were recorded by diary cards; at each of the programmed control visits, a nasal scraping for inflammatory cells and ICAM-1 was performed. Some additional clinical parameters were also recorded: days of school absence, extra visits for acute respiratory symptoms, and days of hospital admission. RESULTS: Only children treated with terfenadine achieved significant control of symptoms (P<0.05 in 8 out of 12 months) and allergic inflammation, as shown by inflammatory cell infiltrate and ICAM-1 expression at nasal level (P<0.001), and had significantly fewer extra visits and school absences than the placebo group (P<0.03). No side-effects were reported in either group. CONCLUSIONS: The present study demonstrates that continuous terfenadine treatment (1 mg/kg body weight per day) could decrease respiratory symptoms and allergic inflammation, and it had an additional antiallergic effect in reducing ICAM-1 expression on nasal epithelial cells. Therefore, the present results confirm the efficacy of a long-term therapeutic strategy in controlling allergic inflammation.

Adolescent↗

PubMed2000

A comparison of the anti-inflammatory properties of intranasal corticosteroids and antihistamines in allergic rhinitis.

Allergic rhinitis manifests itself clinically due to the local release of mediators from activated cells within the nasal mucosa. Treatment strategies aim either to reduce the effects of these mediators on the sensory neural and vascular end organs, or to reduce the tissue accumulation of the activated cells that generate them. Corticosteroids intervene at a number of steps in the inflammatory pathway, and, by reducing the release of cytokines and chemokines, inhibit cell recruitment and activation. These effects are evident both in vivo and in vitro. While antihistamines also have some anti-inflammatory effects in vitro, these require higher concentrations than with corticosteroids and are not consistently reproduced in vivo. In addition, although antihistamines and corticosteroids might appear to have complementary mechanisms of action, clinical trials suggest that their co-administration does not confer any additional long-term benefits compared with that achieved with corticosteroids alone. Topical corticosteroids are therefore the preferred anti-inflammatory therapy for persistent allergic rhinitis.

Administration, Intranasal↗