H1-receptor antagonists: a critical reappraisal.

This review of second-generation H1-receptor antagonists aims to examine the therapeutic index of the different drugs that are available in light of the new criteria linked to specific and non-specific pharmacological activities.

Blood distribution of levocetirizine, a new non-sedating histamine H1-receptor antagonist, in humans.

The aim of the present study was to determine (1) the extent of levocetirizine binding to human blood cells, plasma and individual plasma proteins; (2) the parameters for levocetirizine binding to individual plasma proteins both at their physiological concentrations and, for human serum albumin (HSA), at a lower saturating concentration; and (3) to simulate levocetirizine distribution in human blood using the information obtained at physiological haematocrit (H) for blood cells and at physiological concentrations for individual plasma proteins. The nature of the main binding sites of HSA, i.e.

[H1 antihistaminics: can we precisely define the characteristics of the ideal molecule?].

The experience of the past twenty years in the field of H1 antihistamines prompts us to consider that these drugs are more dissimilar than has previously been reported in the scientific literature. In fact, the H1 antihistamines that are used in man seem to be effective, even if there are some differences in clinical efficacy. Nevertheless they may have marked differences as far as the following aspects are concerned: their possible binding to various biological targets, their pharmacokinetics, their metabolism and their volume of distribution.

Adhesion molecule profiles in atopic dermatitis vs. allergic contact dermatitis: pharmacological modulation by cetirizine.

Background: Experimental data suggest that there is an imbalance between Th1 and Th2 cells in atopic dermatitis (AD) skin compared to allergic contact dermatitis (ACD). This imbalance (Th2 and Th1 predominance, respectively) implies the production of different cytokines in these two conditions leading to different expression of adhesion molecules on skin endothelial cells.

Objective: The expression of VCAM-1 (IL-4/Th2-dependent) and ICAM-1 (INF-gamma/IL-1) on dermal vessels was compared in six patients with AD and six patients with ACD.

Cetirizine inhibits bradykinin-induced cutaneous wheal and flare in atopic and healthy subjects.

Background: Kinins are vasoactive mediators involved in allergic reactions. When applied on the skin or in the nose, bradykinin (BK) elicits inflammation that is poorly affected by previous H1-blockade. The aim of this study was to compare the possible effect of cetirizine (an H1-antagonist) on wheal and flare responses to BK, histamine, and compound 48/80 in atopic and healthy subjects.

Cetirizine inhibits bradykinin-induced cutaneous wheal and flare in atopic and healthy subjects.

Background: Kinins are vasoactive mediators involved in allergic reactions. When applied on the skin or in the nose, bradykinin (BK) elicits inflammation that is poorly affected by previous H1-blockade. The aim of this study was to compare the possible effect of cetirizine (an H1-antagonist) on wheal and flare responses to BK, histamine, and compound 48/80 in atopic and healthy subjects.

Cetirizine counter-regulates interleukin-8 release from human epithelial cells (A549).

Background: Cetirizine, a H1-receptor antagonist, exerts besides its well-known anti-allergic potential an array of anti-inflammatory activities. In particular epithelial cells activated in the presence of cetirizine showed a reduced ICAM-1 cell surface expression and a diminished release of sICAM-1.

Objective: We wondered whether cetirizine might influence the release of interleukin-8 (IL-8) from human epithelial cells activated with agonists distinct from histamine.

Therapeutic index of H1-antihistamines: example of cetirizine.

The second generation H1 antihistamines were considered to have an improved risk/benefit ratio because of their low penetration into the brain and their very low incidence of CNS depressant effects. Nevertheless, the cardiac rhythm disturbances described under terfenadine and astemizole intake drew the attention to the fact that the low penetration into the brain is only one limited item in the evaluation of their respective therapeutic indices. A correct evaluation of the therapeutic index should always comprise a large series of items: all desired and not desired effects and properties should be considered together with the physicobiochemical mechanisms of the drugs at cell and membrane levels.

CNS effects of histamine H1 antagonists.

An accurate evaluation of the functions of the human brain during the administration of drugs is one of the most complex tasks in medical science. In the case of H1 antihistamines, there are many biases that can explain why the interpretation of pharmacological data and those from clinical studies can be very difficult. First of all, the allergic disease itself may modify central nervous system (CNS) functioning and effective medical treatment may accordingly influence the self-reported CNS sensations of patients.

A double-blind, single-dose, crossover comparison of cetirizine, ebastine, epinastine, fexofenadine, terfenadine, and loratadine versus placebo: suppression of histamine-induced wheal and flare response for 24 h in healthy male subjects.

Background: New H1-antagonists have become available, but there has been no comparison of their potency for inhibiting histamine in the skin.

Methods: Cetirizine 10 mg, ebastine 10 mg, epinastine 20 mg, fexofenadine 60 mg, terfenadine 60 mg, loratadine 10 mg, or placebo was given to 14 healthy male volunteers in a double-blind, crossover randomized manner. Inhibition of the wheal and flare response to epicutaneous histamine phosphate (100 mg/ml) challenge was measured at 0, 0.

Measurement of interstitial cetirizine concentrations in human skin: correlation of drug levels with inhibition of histamine-induced skin responses.

Background: The purpose of the present study was to measure the concentrations of cetirizine in the extracellular water compartment in intact human skin and assess simultaneously inhibition of histamine-induced wheal and flare reactions.

Methods: Skin cetirizine levels were collected by the microdialysis technique and analyzed by high-pressure liquid chromatography with mass spectrometry detection. Skin levels in 20 subjects were compared to plasma levels for 4 h after a single oral dose of 10 or 20 mg of cetirizine.

Hypothetical mechanisms of action of an H1-antihistamine in asthma.

Some recent clinical studies carried out with the potent H1-antihistamine cetirizine (CTZ) suggest that this drug could be useful for the treatment of mild to moderate asthma and even for the prevention of the disease. Besides a potent antagonism of H1-receptors at bronchial level, this drug was also shown to exert a large series of anti-inflammatory effects in in vitro, ex vivo and in vivo pharmacological models and also in clinical situations in atopic subjects. All the data collected up to now suggest the possible existence in the molecule of a central key mechanism of action on resident cells especially involved in cell trafficking and bronchial inflammation, i.

Molecular properties and pharmacokinetic behavior of cetirizine, a zwitterionic H1-receptor antagonist.

The ionization and lipophilicity behavior of the antihistamine (H1-receptor antagonist) cetirizine was investigated, showing the drug to exist almost exclusively as a zwitterion in the pH region 3.5-7.5.

G proteins as biological targets for anti-allergic drugs?

The inhibiting effect of the H1 antihistamine cetirizine on the release of mediators (LTB4, arachidonic acid and phospholipase A2) was measured in different cells in vitro (human PMN, deltaF508 cells, chinese hamster ovary cells and rabbit chondrocytes) using different agonists (fMLP, NaF, calcium ionophore A 23187, bradykinin, adrenaline and IL-1). It was shown that physiological concentrations of the drug inhibited the release when activation of receptor-coupled G proteins was involved. By contrast, there was no inhibiting effect of cetirizine when the release was induced by a calcium ionophore which bypasses the G proteins coupled to cell membrane receptors.

The effect of cetirizine and loratadine on codeine-induced histamine release in human skin in vivo assessed by cutaneous microdialysis.

Objective And Design: To determine whether or not cetirizine and loratadine inhibit codeine- induced histamine release in human skin in vivo, we conducted a placebo-controlled double-blind trial in which histamine release was assessed by dermal microdialysis.

Subjects: A group of ten normal volunteers were studied, each subject visiting the laboratory on three occasions with intervals of at least 2 weeks between visits.

Treatment: Cetirizine, loratadine (both 10 mg) or placebo was given orally 4 h before provocation of weal and flare responses in the skin by intradermal injection of 25 microliters of 3 or 10 mg/ml codeine 1 mm from the centre of individual 216 microns diameter microdialysis fibres inserted in the dermis.

Cetirizine exerts anti-inflammatory effects on human neutrophils.

Leukotrienes are potent lipid mediators involved in acute and chronic inflammatory processes and allergic inflammation. Cetirizine is an H1-receptor antagonist used in the treatment of allergic symptoms. We analyzed the effect of cetirizine on the formation of leukotriene B4 (LTB4) after stimulation of human peripheral blood neutrophils.