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.

Interference of cetirizine with the late eosinophil accumulation induced by either PAF or compound 48/80.

1. The effect of topical or systemic treatment with the histamine H1-receptor antagonist, cetirizine, on the rat pleural eosinophil accumulation induced by PAF or compound 48/80 was investigated. The number of pleural resident eosinophils increased 6 h after the intrathoracic (i.t.) injection of PAF (1 microgram/cavity), peaked within 24 h and persisted significantly augmented for at least 96 h. Compound 48/80 (25 micrograms/cavity) also produced a long lasting pleural eosinophilia but this was first noted only 24 h after stimulation. 2. Intraperitoneal pretreatment with cetirizine inhibited eosinophilia induced by either PAF (ED50 = 19 mg kg-1) or compound 48/80 (ED50 = 14 mg kg-1) whereas meclizine, another histamine H1-receptor antagonist, was inactive. 3. Administered locally, cetirizine (5 and 15 micrograms/cavity) also dose-dependently inhibited both PAF- and compound 48/80-induced eosinophilia, providing evidence that its inhibitory effect is not due to any action upon circulating eosinophils. Consistent with this result, incubation of isolated peritoneal eosinophils with cetirizine failed to modify in vitro eosinophil migration caused by PAF. 4. Since the late eosinophilia induced by PAF may depend on the synthesis of a transferable protein mediator, cetirizine was administered to donor or recipient rats in order to determine whether it interferes with the generation or with the expression of this protein. We showed that only the treatment of recipient rats abolished the transfer of the eosinophilotactic activity, indicating that cetirizine does not modify the generation but inhibits the expression of this activity. 5. Our findings indicate that cetirizine is able to inhibit eosinophil accumulation by acting locally. The mechanism is neither related to its recognized ability to antagonize histamine H,-receptors nor to a direct action upon circulating eosinophils.

Agonist-antagonist interactions in the skin: comparison of effects of loratadine and cetirizine on skin vascular responses to prick tests with histamine and substance P.

The skin vascular responses (weal, flare, blood flow measurements) elicited by intradermal administration by pricking of histamine (HS) and substance P (SP) were evaluated 6 h after a single intake of anti-H1 agents displaying different activity profile on skin tests at currently recommended dosages (loratadine 10 mg, cetirizine 10 mg) as compared to placebo (P). The weal and flare response and the increases of blood flow occurring in the usual flare area after HS and SP were almost completely abolished by cetirizine. Inhibition of HS- and SP-induced weal and flare reactions was less marked after loratadine and blood flow in the expanding flare after HS and SP showed significant fluctuations over time. In view of the present results and of data obtained in previous experiments with intradermal injection of agonists, we hypothesize that mode of administration of agonists significantly influences the size of the residual weal after anti-H1 agents. We demonstrate that SP weals induced by pricking are largely inhibited by a potent H1 blockade which supports the view that this phenomenon, as well as the SP-flare, is due to SP-induced histamine liberation. We also, for the first time, report on fluctuations recorded at the edge of the developing flare with laser Doppler flowmetry early after prick testing with a weak H1 blockade. This opens up new avenues in dynamically testing H1-receptor occupancy in vivo and in situ in human skin.

Suppression by cetirizine of pleurisy triggered by antigen in actively sensitized rats.

The efficacy of cetirizine in comparison with meclizine, another piperazine H1 receptor antagonist, in rat pleurisy caused by allergen or autacoid was investigated. Sensitization was achieved by subcutaneous injection of a mixture of ovalbumin and aluminium hydroxide. Fourteen days later, the animals were challenged with an intrathoracic injection of ovalbumin (12 micrograms/cavity), which caused drastic mast cell degranulation, followed by pleural oedema and leucocyte influx. Cetirizine and meclizine (2.5-30 mg/kg i.p.), 1 h before challenge, inhibited the exudatory response evoked by antigen, under conditions where neutrophil and eosinophil accumulation was affected only by the former. When administered intrathoracically 22 h after allergen, i.e. using a curative approach, cetirizine (15 micrograms/cavity) drastically reduced the pleural eosinophilia noted 24 h post-challenge, indicating that this drug can reverse an already established eosinophilia. Cetirizine (15 mg/kg i.p.) also restored, to about 39% (P < 0.001), the number of uninjured mast cells recovered from the pleural cavity following allergen stimulation. In normal rats, cetirizine (5-15 micrograms/cavity) completely inhibited the pleural exudation elicited by histamine and only partially the exudation caused by 5-hydroxytryptamine or bradykinin, but was quite inactive against platelet-activating factor. We conclude that the pleural exudation triggered by allergen, vasoactive amines or bradykinin is clearly sensitive to cetirizine. In addition, the ability of the drug to interfere with pleural neutrophil or eosinophil mobilization and mast cell degranulation seems not to be associated with its ability to block the histamine H1 receptor.

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.

Pharmacological modulation of cutaneous reactivity to histamine: a double-blind acute comparative study between cetirizine, terfenadine and astemizole.

In a double-blind study performed in 81 healthy volunteers, 10 mg cetirizine and 60 mg terfenadine given orally in a single administration significantly inhibited skin reactivity to histamine. Astemizole (10 mg) was completely ineffective. The inhibitory effect of cetirizine was potent and regular whereas 6/28 (21%) volunteers did not respond to terfenadine. The difference observed between cetirizine and terfenadine might be due to differences in the metabolism of the two drugs after administration: terfenadine is rapidly and extensively metabolized whereas cetirizine is directly active without the need for biotransformation and, indeed is poorly metabolized.

The effect of clemastine and hydroxyzine on cutaneous histamine response in man.

Histamine-induced cutaneous wheals were measured in five healthy volunteers 2, 4, 8 and 24 hours after per os administration of a single dose of clemastine 1 mg and hydroxyzine 25 mg. Clemastine produced a mean wheal suppression of 9%, 18% and 6%, while hydroxyzine produced a mean wheal suppression of 49%, 73%, 82% and 77%. This experiment demonstrates the potent and long-lasting anti-H1 effect of hydroxyzine.

Inhibitory effects of orally or sublingually administered cetirizine on histamine-induced weals and flares and their correlation with cetirizine plasma concentrations.

In an open, randomized crossover study, the inhibition of histamine-induced weals and flares after one dose of 10 mg cetirizine administered orally or sublingually to seven healthy volunteers was compared. Formation of both weals and flares was significantly inhibited by cetirizine administered by either route; weals were inhibited as early as 20 min after oral intake but not clearly inhibited until 90 min after sublingual intake. There was no clinically relevant difference between the effects of the two routes of administration on flare area. Cetirizine was not well tolerated when given sublingually: two patients reported a burning sensation in the tongue and one reported a local anaesthetic effect. Plasma cetirizine concentrations showed no clear difference between the two routes of administration.

Astemizole and cetirizine in the treatment of seasonal allergic rhinitis: a comparative double-blind, multicentre study.

In a double-blind, multicentre trial, 105 patients with seasonal allergic rhinitis were treated with 10 mg astemizole or 10 mg cetirizine once daily for 4 days. Patients were thereafter allowed to change their treatment if not satisfied with the clinical efficacy. In the cetirizine-treated group, there were significantly fewer (P = 0.02) patients who asked to change their treatment compared to patients receiving astemizole for 4 days. At day 4, there was a significant improvement in the clinical scores for the patients who did not want to change treatment but scores were hardly altered in those patients that wished to change. After treatment for a further 10 days, there was a decrease in all the scored symptoms but this was less marked in the two groups of patients who wanted to change treatment.

Pharmacological modulation by cetirizine and loratadine of antigen and histamine-induced skin weals and flares, and late accumulation of eosinophils.

In a double-blind, randomized, crossover study performed in atopic subjects, the inhibitory effects of single doses of 10 mg cetirizine and 10 mg loratadine on histamine- and grass pollen-induced skin reactions were evaluated 4 h after drug intake. Cetirizine significantly inhibited histamine- and antigen-induced skin reactions, as well as the accumulation of eosinophils measured 24 h after antigen challenge. Loratadine, however, did not significantly inhibit the skin reactions induced by histamine and grass pollen, nor eosinophil accumulation.

A comparison of central and peripheral effects of cetirizine and loratadine.

In a double-blind, crossover, randomized clinical pharmacological study performed on 10 healthy volunteers, peripheral and central effects of 10 mg cetirizine and 10 and 40 mg loratadine were compared. Cetirizine (10 mg) significantly (P less than 0.001) inhibited 10 or 100 mg/ml histamine-induced weals 2 and 6 h after drug intake. Cetirizine was more potent than 10 mg loratadine after 2 and 6 h, and was even more potent than 40 mg loratadine after 6 h. Neither drug affected subjective evaluation of central effects and cetirizine was completely devoid of electro-encephalographic (EEG) changes, whereas 10 and 40 mg loratadine induced only slight and limited EEG changes.

[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.

[Understanding allergy]. / Comprendre l'allergie.

There is a correlation between the clinical expression of various allergic disorders and an abnormal production of IgEs. A series of factors were recently described which are probably involved in this hyperproduction of IgEs: the IgE binding factors SFA and EFa, the glycosylation enhancing or inhibiting factors GEF and GIF and interleukin 4. It seems that there is also a correlation between the incidence of viral infections of the respiratory tract and an abnormal production of IgEs. Finally there are hereditary predispositions for the development of allergic diseases. It is interesting to try to group in an hypothetical scheme all the different factors which seem to act in conjunction to produce a shift to an IgE overproduction by atopic B lymphocytes.

[Allergic reaction and vascular permeability]. / Réaction allergique et perméabilité vasculaire.

The allergic reaction is characterized by an inflammatory phenomenon that comprises a cellular aspect and a vascular aspect. The vascular aspect is linked to the production of several mediators able to induce a vascular hyperpermeability. Among these mediators it is possible to find histamine, prostaglandins, leukotrienes, PAF, neuromediators, kinins, anaphylatoxins.

[Skin reactions to bradykinin]. / La réactivité cutanée à la bradykinine.

A large series of experiments carried out in animals and humans suggest that histamine release is not involved in the leakage phenomenon induced by bradykinin (BK) challenge. These experiments comprise in vitro studies on skin and bronchial human mast cells and in vivo studies on guinea pig airways and human skin using mepyramine, chlorpheniramine and terfenadine as reference H1-anti-histamines. Nevertheless, it has been shown recently that the H1 antagonist cetirizine 10 mg p.o. markedly inhibits skin reactions induced by BK challenge (intradermal injection of 212 micrograms BK in 10 microL saline and prick test with a solution of 21.2 micrograms/microL). In a guinea pig model, this drug also inhibited the bronchospasm induced by increasing concentrations of BK given by iv route (0.25 to 2 micrograms/Kg) and aerosol (3 to 300 micrograms/Kg). This inhibition was similar to the one obtained with the specific BK antagonist HOE 140 (15 pM/Kg). New data in the literature suggest the existence of various pharmacological mediators possibly involved in the BK-induced reaction: neuromediators, nitric oxyde and PAF. They also suggest that this reaction presents itself as a well defined sequence of pharmacological events. Since we could show that there is no binding of cetirizine to a human recombinant B2 receptor in vitro, some hypotheses are raised in order to explain this unexpected inhibiting effect of cetirizine.

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.

The inhibiting effect of cetirizine 2 HC1 on eosinophil migration and its link to H1 blockade.

Since the demonstration of an inhibiting effect of cetirizine on an antigen induced eosinophils' migration in the skin of atopic subjects, a series of in vitro and in vivo studies were performed in order to clarify the mechanism of action of this new H1-blocker. The studies used FMLP and PAF as agonists, and BN 52021, dexchlorpheniramine, terfenadine and loratadine as reference compounds. The results suggest that the inhibiting effect of cetirizine on the eosinophils' migration is independent of its specific H1 blocking activity.

Inhibition of the cutaneous response to histamine by H1-blocking agents. Quantitative evaluation of microvascular changes in the skin after histamine challenge and a comparison of the effects of a single intake of cetirizine and terfenadine.

A controlled, randomized, double-blind, cross-over study was performed in 10 healthy volunteers in order to compare changes of cutaneous blood flow values (CBFV, laser Doppler flowmetry, Periflux, Perimed, S) in histamine-challenged skin before and after administration of a capsule containing either 10 mg cetirizine or 60 mg terfenadine. The overall pattern of the basal cutaneous wheal and flare response to the agonists (histamine: aqueous solution: Hsol, or Phazet: Hprick) and control saline solution, showed the expected range of clinical effects, i.e. Hsol greater than Hprick greater than saline. Similarly, the increase of CBFV on the flare area was higher around the histamine injections as compared with saline. Surprisingly, CBFV was decreased at the site of Hsol and Hprick injections as compared with the levels recorded at the control injections. The following changes were noted after intake of H1-blocking agents. (1) There was a reduction of the areas of wheal and flare at all injection sites after administration of the H1 blockers, this reduction being consistently greater under cetirizine than terfenadine. (2) CBFV, measured 1 cm from the site of Hsol injection (i.e., within the area of normal flare response), was decreased only with cetirizine. In the smaller flare area induced by Hprick, CBFV was equally suppressed by both drugs. (3) At the site of agonist injection, along with a reduction of the size of the wheal, we observed significant increases in CBFV after drug intake. Under these experimental conditions, this quantitative pharmacologic in vivo assay of agonist-antagonist interactions suggests that after initial administration of normally prescribed doses, cetirizine may possess more anti-H1 activity than terfenadine.