[H1 antihistaminics: can we precisely define the characteristics of the ideal molecule?]. / Antihistaminiques H1: peut-on définir de manière précise les caractéristiques d'une molécule idéale?

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. All these differences must be taken into consideration when judging the real quality of each of these drugs.

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. METHODS: In a randomized, double-blind, crossover study, eight atopic and eight healthy subjects received cetirizine (10 mg/day) or placebo for 3 days before cutaneous tests. Intradermal tests (IDT) and prick tests (PT) were performed with BK (20 nmol/ml for IDT and 20 micromol/ml for PT), histamine (100 microg/ml IDT and 100 mg/ml PT), and compound 48/80 (100 microg/ml IDT and 100 mg/ml PT) as positive controls and saline as negative control. The skin responses were monitored by measurement of wheal and flare areas. RESULTS: BK, histamine, and 48/80 induced wheal and flare reactions in all placebo-treated subjects. Histamine elicited larger wheal and flare reactions than BK and 48/80. IDT with BK induced four- to six-fold larger wheal and flare reaction than PT. No differences in BK-induced wheal and flare were observed between atopic and healthy subjects. In atopic subjects, cetirizine induced a significant reduction of flare reactions after the BK test (80% for IDT, and 94% for PT [P<0.01]). Moreover, cetirizine reduced significantly BK-induced wheals by 70% for IDT (P<0.01) and 65% for PT (P<0.01). A similar inhibiting effect of cetirizine was also observed in healthy subjects. CONCLUSIONS: These findings showed that the wheal and flare reactions induced by BK challenge were markedly inhibited by previous intake of cetirizine. The mechanism by which this effect is mediated cannot be established at present.

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. METHODS: In a randomized, double-blind, crossover study, eight atopic and eight healthy subjects received cetirizine (10 mg/day) or placebo for 3 days before cutaneous tests. Intradermal tests (IDT) and prick tests (PT) were performed with BK (20 nmol/ml for IDT and 20 micromol/ml for PT), histamine (100 microg/ml IDT and 100 mg/ml PT), and compound 48/80 (100 microg/ml IDT and 100 mg/ml PT) as positive controls and saline as negative control. The skin responses were monitored by measurement of wheal and flare areas. RESULTS: BK, histamine, and 48/80 induced wheal and flare reactions in all placebo-treated subjects. Histamine elicited larger wheal and flare reactions than BK and 48/80. IDT with BK induced four- to sixfold larger wheal and flare reaction than PT. No differences in BK-induced wheal and flare were observed between atopic and healthy subjects. In atopic subjects, cetirizine induced a significant reduction of flare reactions after the BK test (80% for IDT, and 94% for PT [P < 0.01]). Moreover, cetirizine reduced significantly BK-induced wheals by 70% for IDT (P < 0.01) and 65% for PT (P < 0.01). A similar inhibiting effect of cetirizine was also observed in healthy subjects. CONCLUSIONS: These findings showed that the wheal and flare reactions induced by BK challenge were markedly inhibited by previous intake of cetirizine. The mechanism by which this effect is mediated cannot be established at present.

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. The effect of cetirizine, a highly selective H1-receptor antagonist on the expressions was studied. METHODS: Six patients with AD were challenged with Dermatophagoides pteronyssimus (DPT patch tests applied to clinically normal skin) and six patients with ACD challenged in the same way with allergens of the European standard series. Skin biopsies at challenged sites were performed before and 6, 24 and 48 h after challenge. The experiment was carried out under double-blind cross-over conditions during a 4-day treatment with a placebo and cetirizine. RESULTS: In AD patients, the scores for both VCAM-1 and ICAM-1 were high before and after challenge. In ACD patients, the ICAM-1 score was high at each experimental time, but the VCAM-1 score, which was significantly lower before challenge, increased at 6, 24 and 48 h after challenge. The administration of cetirizine significantly reduced the VCAM-1 expression in AD patients at each experimental time. CONCLUSION: It is concluded that the increased VCAM-1 expression in AD patients compared to ACD may reflect greater IL-4 and/or IL-13 production in situ. The study also confirms the existence of a modulating effect of cetirizine in vivo on adhesion molecule expression.

Therapeutic index of H1-antihistamines: example of cetirizine.

BACKGROUND: 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.

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. Skin prick tests were performed with histamine 100 mg/ml. RESULTS: Plasma cetirizine levels increased within 30 min to reach peak values of 315+/-10 and 786+/-45 ng/ml 90-120 min after administration of 10 and 20 mg of cetirizine. This was followed by a slow decline. In the skin, dialysate cetirizine levels (non-protein-bound fraction only) peaked at 1.6+/-0.1 and 2.4+/-0.3 ng/ml at 120-180 min. In vivo recovery of cetirizine was 14.4+/-4.3%. It was estimated that the non-protein-bound concentration of cetirizine in the skin was 50-70% of corresponding plasma values. Both 10- and 20-mg doses of cetirizine inhibited wheal and flare reactions over 240 min. The time vs concentration profile of cetirizine in skin dialysate paralleled the inhibition of skin reactions, but no significant correlations were found between individual cetirizine levels in skin or plasma with wheal and flare reactions. CONCLUSIONS: Cetirizine concentrations in the skin could be monitored by the microdialysis technique. The results indicate no simple linear correlation between cetirizine skin levels and inhibition of skin reactions.

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, 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 h after doses. RESULTS: Epinastine inhibited the wheal and flare after 30 min. Cetirizine commenced acting at 1 h and was superior to other treatments. Ebastine was no better than placebo until 4 h, but was efficacious thereafter until 24 h. Terfenadine induced potent inhibition after 1 h and was superior to its metabolite fexofenadine. Loratadine was the least potent inhibitor. Inhibition of the flare response paralleled the patterns seen for wheals. The rank order for area under the curve (0-24 h) was cetirizine, epinastine, terfenadine, ebastine, fexofenadine, loratadine, and placebo. CONCLUSIONS: The inhibition of histamine effects in the skin may be useful in predicting the clinical utility of newly introduced antihistamines in treating allergic disorders.

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. Moreover, the carefully selected populations that are enrolled both in pharmacological and clinical studies do not reflect the profile of patients who are treated with such drugs on an everyday basis. Finally, studies of performance impairment and those relying on self-reported sensations may give different and indeed conflicting results. It may be concluded that the various pronouncements on the CNS properties of H1 antihistamines must be treated with some caution.

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.e a down-regulating effect on the nuclear factorKappaB (NFkappaB). This hypothesis was tested on human endothelial cells and a human epithelial pulmonary cell line using different experimental methods. The results showed that CTZ down-regulates the TNF-alpha-induced hyperactivation of NFKappaB in these two different resident cells at physiological concentrations.

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.

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. In this pH range, its octanol/water lipophilicity is constant and low compared to cationic antihistamines (log D = log PZ = 1.5), whereas its H-bonding capacity is relatively large (delta log PZ > or = 3.1). Conformational, electronic, and lipophilicity potential calculations revealed that zwitterionic cetirizine experiences partial intramolecular charge neutralization in folded conformers of lower polarity. Pharmacokinetic investigations have shown the drug to be highly bound to blood proteins, mainly serum albumin, and to have a low brain uptake, explaining its lack of sedative effects. As such, cetirizine does not differ from "second-generation" antihistamines. In contrast, its very low apparent volume of distribution in humans (0.4 L kg-1, smaller than that of exchangeable water) implies a low affinity for lean tissues such as the myocardium and is compatible with the absence of cardiotoxicity of the drug. The zwitterionic nature and modest lipophilicity of cetirizine may account for this pharmacokinetic behavior. The suggestion is offered that cetirizine and analogous zwitterions, whose physicochemical, pharmacokinetic, and pharmacodynamic properties differ from those of "first-" and "second-generation" drugs in this class, could be considered as "third-generation" antihistamines.

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. METHODS: Dialysate was collected at 2 min intervals for 4 min before and 20 min after codeine injection and histamine assayed spectrofluorometrically. Weal and flare responses to codeine were assessed in the opposite arm. RESULTS: Histamine concentrations in the microdialysis fibre outflow with 3 and 10 mg/ml codeine were maximal at 2-4 min when 910 +/- 156 and 1194 +/- 304 nM respectively were found in the placebo group. Cetirizine and loratadine did not modify either the kinetics or total histamine release while significantly (p < 0.01) inhibiting weal and flare responses. CONCLUSIONS: Neither cetirizine nor loratadine inhibited codeine-induced histamine release or modified the time course of its release in human skin in vivo when given in clinically used doses which are sufficient to significantly reduce weal and flare responses.