Effect of cetirizine, levocetirizine, and dextrocetirizine on histamine-induced nasal response in healthy adult volunteers.

BACKGROUND: Cetirizine, an effective H1-receptor antagonist, is a racemate mixture of two enantiomers: levocetirizine (R enantiomer) and dextrocetirizine (S enantiomer). METHODS: To investigate the pharmacologic activity of the two enantiomers of cetirizine, we conducted a randomized, double-blind, four-way, crossover study to assess the effect of treatment with 5 mg levocetirizine, 5 mg dextrocetirizine, and 10 mg cetirizine and matched placebo, on histamine-induced changes in the nasal airways of 24 healthy volunteers. Four hours after a single oral intake, all subjects were challenged by nasal aerosol application with increasing doubling concentrations (from 0.25 to 32 mg/ml) of histamine in both nostrils. Nasal resistance was measured by passive anterior rhinomanometry (PAR), and changes in histamine threshold were calculated together with the absolute number of sneezes after each challenge. RESULTS: Both levocetirizine and cetirizine significantly attenuated the histamine-induced increase in nasal airway resistance by nearly 50% (from a median resistance of 2.51 Pa per cm3/s to 1.29 and 1.31 Pa per cm3/s, respectively) at the maximal concentration, and they concomitantly increased the histamine threshold by fourfold (from 8 to 32 mg/ml), compared with placebo. Sneezing was also attenuated by both levocetirizine and cetirizine. However, these antihistaminic effects were not seen with dextrocetirizine. CONCLUSIONS: This study shows a similar activity of levocetirizine and cetirizine on the inhibition of histamine-induced increase in nasal resistance, indicating that the antihistaminic properties of cetirizine are probably attributable to levocetirizine.

A randomized, double-blind, crossover comparison among cetirizine, levocetirizine, and ucb 28557 on histamine-induced cutaneous responses in healthy adult volunteers.

BACKGROUND: Cetirizine is a highly efficacious and long-acting second-generation H1-receptor antagonist for the treatment of allergic diseases, such as allergic rhinitis and chronic idiopathic urticaria, in adults and children. Pharmacologic studies have demonstrated that cetirizine, a racemate mixture composed of equal amounts of two enantiomers, does not undergo hepatic metabolism to any significant level. The enantiomers are excreted mainly unchanged, predominantly in the urine and to a lesser extent in the faeces. METHODS: The pharmacologic activity and potency of the two enantiomers of cetirizine in the management of allergic skin conditions were investigated by studying the effect of treatment with 5.0 mg cetirizine; 2.5 mg levocetirizine, the (R)-enantiomer; and 2.5 mg ucb 28557, the (S)-enantiomer, on histamine-induced wheal and flare response in 18 healthy volunteers. Each treatment was administered as a single oral dose in randomized, double-blind, and crossover manner, and the efficacy of treatment was assessed over a period of 32 h, as per cent inhibition of the histamine-induced wheal and flare areas before treatment. Blood and urine samples were collected in a time-dependent manner and analyzed for the total amounts of each study drug, to elucidate their pharmacokinetic profiles. RESULTS: Both cetirizine and levocetirizine caused a marked inhibition of histamine-induced wheal and flare, whereas ucb 28557 was inactive in this model. Inhibition of the wheal response observed for cetirizine and levocetirizine was apparent by 1 h after dosage and lasted for mean durations of 24.4 and 28.4 h, respectively. In addition, the response for cetirizine and levocetirizine became maximal by 6 h after treatment, rising to 79.5% and 83.8%. Similarly, cetirizine and levocetirizine also markedly inhibited the histamine-induced flare response. This effect was evident for both drugs by 1 h after dosage and lasted over a mean period of 28.4 and 26.0 h, respectively, for cetirizine and levocetirizine. The inhibitory effect of these compounds on histamine-induced flare response was also maximal by approximately 6 h after dosage, peaking at 88.5%) and 83.6%, respectively. Statistical evaluation showed that cetirizine and levocetirizine were equivalent for maximum inhibition of histamine-induced wheal and flare. However, levocetirizine was found to be superior to cetirizine when area under the curve was compared. In contrast, ucb 28557 was not found to inhibit histamine-induced wheal and flare responses at any time during the study period. Plasma concentrations of levocetirizine were found to be approximately double those of ucb 28557 at 4 and 8 h after dosing, and 50-60% of the drugs were excreted unchanged in urine over a period of 32 h. CONCLUSIONS: The finding that, in this model, levocetirizine 2.5 mg has comparable antihistaminic activity to cetirizine 5 mg, whereas its other enantiomer ucb 28557 has no pharmacodynamic effect, suggests that the antihistaminic properties of cetirizine observed in the management of allergic skin conditions are likely to be attributable to levocetirizine.

A comparison of the effects of oral cetirizine and inhaled beclomethasone on early and late asthmatic responses to allergen and the associated increase in airways hyperresponsiveness.

BACKGROUND: Cetirizine is a non-sedating H1 antihistamine which is effective in the treatment of allergic rhinitis and urticaria. It inhibits eosinophil and basophil chemotaxis in late cutaneous allergic reactions in skin windows. Its effect on early (EAR) and late asthmatic reactions (LAR) is less certain. METHODS: We examined the effect on EAR and LAR of 3 days treatment with oral cetirizine (15 mg twice daily) compared with a single dose of inhaled beclomethasone 10 min prior to allergen challenge in a placebo-controlled (oral and inhaled) double-blind cross-over design with three treatment arms separated by 14 days. RESULTS: Cetirizine did not significantly inhibit either the EAR or LAR documented by maximum percentage fall in FEV1 (0-3 and 6-9 h) or as area under the curve (AUC between 0 and 3 and 6-9 h). Beclomethasone inhibited the LAR compared with placebo (P = 0.02) when expressed as AUC (6-9 h). This did not quite reach statistical significance (P = 0.06) when expressed as maximal percentage late fall in FEV1 between 6 and 9 h. A greater than twofold increase in airways responsiveness to methacholine was observed 3 h after challenge which was significantly reduced by beclomethasone compared with placebo (P < 0.02) and cetirizine (P < 0.05). The data suggest that oral cetirizine does not significantly inhibit either the EAR or LAR. Beclomethasone inhibited both the early increase in airways responsiveness and the subsequent LAR. Our study also confirms the view that early increases in airway responsiveness precede the late response and suggests that these associated events are not dissociable by the pharmacological treatments employed in this study.