Antihistamines in children and adolescents: A practical update

Histamine is a chemical mediator, released predominantly by tissue mast cells, circulating basophils, and neurons, which are activated in response to various immunological and non-immunological stimuli. Histamine has to bind to specific receptors to exert its physiological and pathophysiological functions. Endogenous histamine is the main mediator of the immediate allergic response, which moreover, performs other multiple functions, including regulation of gastric secretion, neurotransmission in the central nervous system, and immunomodulatory activity. The involvement of histamine in various disorders and the importance of receptors in the clinical features have relevant implications in clinical practice. Anti-H1 antihistamines contrast the histamine-dependent effects, mainly concerning nasal symptoms and cutaneous itching and wheal. Antihistamines are among the most prescribed drugs in pediatric care. This review updates the practical use of antihistamines in children and adolescents

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Histamine Antagonists for Treatment of Peripheral Vertigo: A Meta-Analysis.

OBJECTIVE: Vertigo, the hallucination of movement of oneself or one's surroundings, can have substantial adverse effects on the quality of life of affected patients. It is essential to decrease the frequency, severity, and duration of vertigo attacks using effective medications with minimal debilitating adverse effects. We performed a meta-analysis of available clinical trials to evaluate the efficacy of histamine antagonists in the treatment of vertigo compared to the rate of resolution in untreated control groups. MATERIALS AND METHODS: A systematic search of articles in any language from January 1970 to March 2015 was performed through the following databases: the Cochrane Central Register of Controlled Trials, Medical Literature Analysis and Retrieval System Online, the Excerpta Medica Database, Cumulative Index to Nursing and Allied Health Literature, Latin American and Caribbean Health Sciences Literature, Allied and Complementary Medicine Database, Web of Science, ClinicalTrials.gov, and Google. Randomized controlled trials comparing each kind of antihistamine to untreated control participants in the treatment of vertigo (blinded/unblinded) were screened for inclusion. Three reviewers separately performed data extraction from the included trials using a standard data abstraction form. Three other researchers read the final list of all articles retained. Discrepancies were settled by mutual consensus between the authors. Random effects models were applied to estimate the pooled odds ratio (OR) and 95% confidence interval (CI) using the Review Manager software. The evaluation of publication bias was performed by Egger's test and Begg's funnel plot. RESULTS: We identified 13 eligible citations. The pooled OR was 5.370, 95% CI (3.263-8.839), and I2=56.0%, with no obvious evidence of publication bias. CONCLUSION: Our results provide clarification of the effectiveness of several categories of histamine antagonists compared with placebos in controlling peripheral vertigo.

Differential thermodynamic driving force of first- and second-generation antihistamines to determine their binding affinity for human H1 receptors.

Differential binding sites for first- and second-generation antihistamines were indicated on the basis of the crystal structure of human histamine H1 receptors. In this study, we evaluated differences between the thermodynamic driving forces of first- and second-generation antihistamines for human H1 receptors and their structural determinants. The binding enthalpy and entropy of 20 antihistamines were estimated with the van't Hoff equation using their dissociation constants obtained from their displacement curves against the binding of [(3)H]mepyramine to membrane preparations of Chinese hamster ovary cells expressing human H1 receptors at various temperatures from 4°C to 37°C. Structural determinants of antihistamines for their thermodynamic binding properties were assessed by quantitative structure-activity relationship (QSAR) analyses. We found that entropy-dependent binding was more evident in second- than first-generation antihistamines, resulting in enthalpy-entropy compensation between the binding forces of first- and second-generation antihistamines. QSAR analyses indicated that enthalpy-entropy compensation was determined by the sum of degrees, maximal electrostatic potentials, water-accessible surface area and hydrogen binding acceptor count of antihistamines to regulate their affinity for receptors. In conclusion, it was revealed that entropy-dependent hydrophobic interaction was more important in the binding of second-generation antihistamines, even though the hydrophilicity of second-generation antihistamines is generally increased. Furthermore, their structural determinants responsible for enthalpy-entropy compensation were explored by QSAR analyses. These findings may contribute to understanding the fundamental mechanisms of how the affinity of ligands for their receptors is regulated.

The conventional antihistamine drug cyproheptadine lacks QT-interval-prolonging action in halothane-anesthetized guinea pigs: comparison with hydroxyzine.

Antihistamines are known to belong to the chemical class that may induce long QT syndrome. Among them, cyproheptadine has been shown to exert multifaceted actions on the ventricular repolarization phase; namely, shortening of the action potential duration at supra-therapeutic concentrations of 2 - 8 µM and prolongation of the QT interval at ≥ 10 µM. Since information is limited regarding the in vivo electrophysiological effects of cyproheptadine, we assessed it using the halothane-anesthetized guinea-pig model, which was compared with effects of another antihistamine drug, hydroxyzine. Sub-therapeutic to therapeutic doses of hydroxyzine at 1 and 10 mg/kg, i.v. prolonged the QT interval and duration of monophasic action potential, whereas therapeutic to supra-therapeutic doses of cyproheptadine at 0.1 and 1 mg/kg, i.v. hardly affected the indices of ventricular repolarization. These results suggest that cyproheptadine may be categorized into antihistamines with little effect on the ventricular repolarization.

Managing hay fever during the exam period.

Hay-fever symptoms are common and debilitating and can have a detrimental effect on students' examination results. It is important to provide effective treatment using medication that optimises symptom control while ensuring drug side-effects are minimised. Research has confirmed that uncontrolled hay fever or medication side-effects can have a detrimental outcome on exam results. Ideally treatment should commence shortly before the start of the hay-fever season.

Chemometric exploration of the dependencies between molecular modeling descriptors and analytical chemistry data of antihistaminic drugs.

The relationships between experimental and computational descriptors of antihistamine drugs were studied using principal component analysis (PCA). Empirical data came from UV and IR spectroscopic measurements. Nonempirical data, such as structural molecular descriptors and chromatographic data, were obtained from HyperChem software. Another objective was to test whether the parameters used as independent variables (nonempirical and empirical-spectroscopic) could lead to attaining classification similar to that developed on the basis of the chromatographic parameters. To arrive at the answer to the question, a matrix of 18x49 data, including HPLC and UV and IR spectroscopic data, together with molecular modeling studies, was evaluated by the PCA method. The obtained clusters of drugs were consistent with the drugs' chemical structure classification. Moreover, the PCA method applied to the HPLC retention data and structural descriptors allowed for classification of the drugs according to their pharmacological properties; hence it may potentially help limit the number of biological assays in the search for new drugs.

Rotationally constrained 2,4-diamino-5,6-disubstituted pyrimidines: a new class of histamine H4 receptor antagonists with improved druglikeness and in vivo efficacy in pain and inflammation models.

A new structural class of histamine H 4 receptor antagonists (6-14) was designed based on rotationally restricted 2,4-diaminopyrimidines. Series compounds showed potent and selective in vitro H 4 antagonism across multiple species, good CNS penetration, improved PK properties compared to reference H 4 antagonists, functional H 4 antagonism in cellular and in vivo pharmacological assays, and in vivo anti-inflammatory and antinociceptive efficacy. One compound, 10 (A-943931), combined the best features of the series in a single molecule and is an excellent tool compound to probe H 4 pharmacology. It is a potent H 4 antagonist in functional assays across species (FLIPR Ca (2+) flux, K b < 5.7 nM), has high (>190x) selectivity for H 4, and combines good PK in rats and mice (t 1/2 of 2.6 and 1.6 h, oral bioavailability of 37% and 90%) with anti-inflammatory activity (ED 50 = 37 micromol/kg, mouse) and efficacy in pain models (thermal hyperalgesia, ED 50 = 72 micromol/kg, rat).

Validation of a histamine H3 receptor model through structure-activity relationships for classical H3 antagonists.

Histamine H(3) receptor is a G protein-coupled receptor whose activation inhibits the synthesis and release of histamine and other neurotransmitters from nerve endings and is involved in the modulation of different central nervous system functions. H(3) antagonists have been proposed for their potential usefulness in diseases characterized by impaired neurotransmission and they have demonstrated beneficial effects on learning and food intake in animal models. In the present work, a 3D model of the rat histamine H(3) receptor, built by comparative modeling from the crystallographic coordinates of bovine rhodopsin, is presented with the discussion of its ability to predict the potency of known and new H(3) antagonists. A putative binding site for classical, imidazole-derived H(3) antagonists was identified by molecular docking. Comparison with a known pharmacophore model and the binding affinity of a new rigid H(3) antagonist (compound 1, pK(i)=8.02) allowed the characterization of a binding scheme which could also account for the different affinities observed in a recently reported series of potent H(3) antagonists, characterized by a 2-aminobenzimidazole moiety. Molecular dynamics simulations were employed to assess the stability and reliability of the proposed binding mode. Two new conformationally constrained benzimidazole derivatives were prepared and their binding affinity was tested on rat brain membranes; compound 9, designed to reproduce the conformation of a known potent H(3) antagonist, showed higher potency than compound 8, as expected from the binding scheme hypothesized.

G-protein coupled receptors: SAR analyses of neurotransmitters and antagonists.

BACKGROUND: From the deductive point of view, neurotransmitter receptors can be divided into categories such as cholinergic (muscarinic, nicotinic), adrenergic (alpha- and beta-), dopaminergic, serotoninergic (5-HT1 approximately 5-HT5), and histaminergic (H1 and H2). Selective agonists and antagonists of each receptor subtype can have specific useful therapeutic applications. For understanding the molecular mechanisms of action, an inductive method of analysis is useful. OBJECTIVE: The aim of the present study is to examine the structure-activity relationships of agents acting on G-protein coupled receptors. METHOD: Representative sets of G-PCR agonists and antagonists were identified from the literature and Medline [P.M. Walsh (2003) Physicians' Desk Reference; M.J. O'Neil (2001) The Merck Index]. The molecular weight (MW), calculated logarithm of octanol/water partition coefficient (C log P) and molar refraction (CMR), dipole moment (DM), E(lumo) (the energy of the lowest unoccupied molecular orbital, a measure of the electron affinity of a molecule and its reactivity as an electrophile), E(homo) (the energy of the highest occupied molecular orbital, related to the ionization potential of a molecule, and its reactivity as a nucleophile), and the total number of hydrogen bonds (H(b)) (donors and receptors), were chosen as molecular descriptors for SAR analyses. RESULTS: The data suggest that not only do neurotransmitters share common structural features but their receptors belong to the same ensemble of G-protein coupled receptor with seven to eight transmembrane domains with their resultant dipoles in an antiparallel configuration. Moreover, the analysis indicates that the receptor exists in a dynamic equilibrium between the closed state and the open state. The energy needed to open the closed state is provided by the hydrolysis of GTP. A composite 3-D parameter frame setting of all the neurotransmitter agonists and antagonists are presented using MW, Hb and mu as independent variables. CONCLUSION: It appears that all neurotransmitters examined in this study operate by a similar mechanism with the G-protein coupled receptors.

[Urticaria and antihistamines]. / L'urticaire et les anti-histaminiques.

Urticaria is often incapacitating, yet it is not always easy to know whether a patient should undergo testing and what treatment should be prescribed. This article provides a systematic approach to urticaria and its treatment.