ZYRTEC (cetirizine 10 mg)

Bibliography and References. Review.
List of selected scientific articles (abstracts). Experimental and clinical data.

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J Investig Allergol Clin Immunol. 2005;15(1):22-9.
Rupatadine 10 mg and cetirizine 10 mg in seasonal allergic rhinitis: a randomised, double-blind parallel study.
Martinez-Cocera C, De Molina M, Marti-Guadano E, Pola J, Conde J, Borja J, Perez I, Arnaiz E, Izquierdo I; Spanish Rupatadine Rhinitis Study Group.
Allergology Department, Hospital Clinico San Carlos, Madrid.

This randomised, double-blind, parallel-group, multicentre clinical trial evaluated the efficacy and safety of rupatadine, a new antihistamine with antiplatelet-activating factor (PAF) activity, and cetirizine in the treatment of patients with seasonal allergic rhinitis (SAR). A total 249 patients were randomised to receive rupatadine 10 mg once daily (127 patients) or cetirizine 10 mg (122 patients) for two weeks. The main efficacy variable was the mean total daily symptom score (mTDSS) and was based on the daily subjective assessment of the severity of each rhinitis symptom--nasal (runny nose, sneezing, nasal itching and nasal obstruction) and non-nasal (conjunctival itching, tearing, and pharyngeal itching)--recorded by patients in their diaries. The mTDSS was 0.7 for both treatment groups (intention to treat analysis). In the investigator's global evaluation of efficacy at the seventh day, 93.3% and 83.7% patients in the rupatadine and cetirizine groups, respectively, showed some or great improvement (p = 0.022). In the per protocol analysis (n = 181), runny nose at the seventh day of treatment was absent or mild in 81.1% of patients in the rupatadine group and in 68.6% of patients in the cetirizine group (p = 0.029). In any case statistical significance was not maintained at the second week. Overall, all treatments were well tolerated. Adverse events (AEs) were similar in both treatment groups, i.e. headache, somnolence and fatigue/asthenia as the most often reported. Somnolence was reported in 9.6% and 8.5% of patients treated with rupatadine or cetirizine, respectively. The most reported AEs (67%) were mild in intensity. Our results suggest that rupatadine 10 mg may be a valuable and safe alternative for the symptomatic treatment of SAR.

Ann Allergy Asthma Immunol. 2005 Apr;94(4):457-64.
The efficacy of short-term administration of 3 antihistamines vs placebo under natural exposure to Japanese cedar pollen.
Hyo S, Fujieda S, Kawada R, Kitazawa S, Takenaka H.
Department of Otorhinolaryngology, Osaka Medical College, Osaka, Japan. oto039@poh.osaka-med.ac.jp

BACKGROUND: Japanese cedar pollinosis, a common disease with morbidity of approximately 20% in the Japanese population, is characterized by subjectively irritating symptoms during an annual 3-month period. OBJECTIVE: To investigate the effectiveness of cetirizine hydrochloride, loratadine, and fexofenadine hydrochloride in reducing pollinosis symptoms induced while walking in a park during the pollen season. METHODS: A randomized, double-masked, placebo-controlled trial was conducted in 113 individuals with Japanese cedar pollinosis during 2 days in March 2003 in Osaka Expo Park, Osaka, Japan. Participants (aged 20-57 years) were divided into 4 groups according to treatment assignment: cetirizine hydrochloride, 10 mg/d; fexofenadine hydrochloride, 120 mg/d; loratadine, 10 mg/d; and placebo (lactose), twice daily. Symptoms were recorded hourly during the study. Furthermore, all the patients completed the Japanese version of the Rhinoconjunctivitis Quality of Life Questionnaire before and after the trial. RESULTS: Self-evaluated symptom scores in all 3 active treatment groups showed significant improvements compared with the placebo group. Furthermore, the cetirizine group showed significant improvement in the domains of frequency of nose blowing and nasal obstruction compared with placebo. In addition, improvement in Japanese Rhinoconjunctivitis Quality of Life Questionnaire scores was higher in the cetirizine group than in the loratadine and placebo groups. CONCLUSION: Cetirizine seems to be more effective than fexofenadine and loratadine at reducing subjective symptoms in this study population.

Eur J Clin Pharmacol. 2005 May 12;
Evaluation of pharmacokinetic interaction between cetirizine and ritonavir, an HIV-1 protease inhibitor, in healthy male volunteers.
Peytavin G, Gautran C, Otoul C, Cremieux AC, Moulaert B, Delatour F, Melac M, Strolin-Benedetti M, Farinotti R.
Service de Pharmacie Clinique et des Biomateriaux, Hopital Bichat-Cl Bernard, 46 rue Henri Huchard, 75018, Paris, France.

BACKGROUND: Serious adverse effects have been observed with some non-sedative H(1)-antihistamines (terfenadine and astemizole) when they were associated with drugs known to inhibit their metabolism. However, this is not a class effect, and this interaction should be considered on a case-by-case basis. The aim of this study was to evaluate the potential of pharmacokinetic interaction between cetirizine and ritonavir, the most potent cytochrome P( 450) (CYP) inhibitor.METHODS: An open-label, single-center, one-sequence crossover pharmacokinetic study was conducted in three running periods: cetirizine (CTZ) alone, ritonavir (RTV) alone and then CTZ plus RTV. For each period, steady-state pharmacokinetics were obtained. RTV and CTZ plasma concentrations were determined using validated liquid chromatography methods. The statistical method was based on a 90% confidence interval (CI) for the ratio of population geometric means (combination/drug alone) for each drug and for each parameter [area under the plasma concentration versus time curve (AUC(0-tau,ss)), value of maximum plasma concentration (C(max,ss))] and compared to bioequivalence ranges 80-125% and 70-143% for AUC(0-tau,ss) and C(max,ss), respectively.RESULTS: Among the 17 male subjects enrolled (26.4+/-8.6 years), 16 completed the study (1 withdrawal after the first period). The RTV pharmacokinetic parameter values were not affected by CTZ co-treatment. With RTV, a 42% increase in the CTZ AUC(0-tau,ss) (3406 versus 4840 mugh/l, 90% CI of 128-158%), a 53% increase in the CTZ elimination half-life (7.8 h versus 11.9 h, P = 0.001), a slight increase (15%) in the CTZ apparent volume of distribution (V(d,ss)/ f) (34.7 l versus 39.8 l, P = 0.035), a 29% decrease in the CTZ apparent total body clearance (49.9 ml/min versus 35.3 ml/min, P<0.001) and bioequivalent C(max,ss) (374 mug/l versus 408 mug/l) were observed. No serious drug related adverse effects were notified.CONCLUSIONS: CTZ does not significantly affect the pharmacokinetic parameters of RTV, and the association does not, thus, require a modification of the dosage of the protease inhibitor. The increased extent of exposure to CTZ in healthy subjects, in the presence of RTV administered at high doses, remained in the same range as previously observed in the elderly or in mildly renally impaired subjects.

Drugs. 2005;65(2):215-28.
Efficacy and tolerability of newer antihistamines in the treatment of allergic conjunctivitis.
Bielory L, Lien KW, Bigelsen S.
Department of Medicine, Pediatrics and Ophthalmology, Division of Allergy, Immunology and Rheumatology, UMDNJ-New Jersey Medical School, Immuno-Ophthalmology Service, 90 Bergen Street, DOC Suite 4700, Newark, NJ 07103, USA. bielory@umdnj.edu

Treatment for allergic conjunctivitis has markedly expanded in recent years, providing opportunities for more focused therapy, but often leaving both physicians and patients confused over the variety of options. As monotherapy, oral antihistamines are an excellent choice when attempting to control multiple early-phase, and some late-phase, allergic symptoms in the eyes, nose and pharynx. Unfortunately, despite their efficacy in relief of allergic symptoms, systemic antihistamines may result in unwanted adverse effects, such as drowsiness and dry mouth. Newer second-generation antihistamines (cetirizine, fexofenadine, loratadine and desloratadine) are preferred over older first-generation antihistamines in order to avoid the sedative and anticholinergic effects that are associated with first-generation agents. When the allergic symptom or complaint, such as ocular pruritus, is isolated, focused therapy with topical (ophthalmic) antihistamines is often efficacious and clearly superior to systemic antihistamines, either as monotherapy or in conjunction with an oral or intranasal agent.Topical antihistaminic agents not only provide faster and superior relief than systemic antihistamines, but they may also possess a longer duration of action than other classes including vasoconstrictors, pure mast cell stabilisers, NSAIDs and corticosteroids. Many antihistamines have anti-inflammatory properties as well. Some of this anti-inflammatory effect seen with 'pure' antihistamines (levocabastine and emedastine) may be directly attributed to the blocking of the histamine receptor that has been shown to downregulate intercellular adhesion molecule-1 expression and, in turn, limit chemotaxis of inflammatory cells. Some topical multiple-action histamine H(1)-receptor antagonists (olopatadine, ketotifen, azelastine and epinastine) have been shown to prevent activation of neutrophils, eosinophils and macrophages, or inhibit release of leukotrienes, platelet-activating factors and other inflammatory mediators. Topical vasoconstrictor agents provide rapid relief, especially for redness; however, the relief is often short-lived, and overuse of vasoconstrictors may lead to rebound hyperaemia and irritation. Another class of topical agents, mast cell stabilisers (sodium cromoglicate [cromolyn sodium], nedocromil and lodoxamide), may be considered; however, they generally have a much slower onset of action. The efficacy of mast cell stabilisers may be attributed to anti-inflammatory properties in addition to mast cell stabilisation. In the class of topical NSAIDs, ketorolac has been promoted for ocular itching but has been found to be inferior for relief of allergic conjunctivitis when compared with olopatadine and emedastine. Lastly, topical corticosteroids may be considered for severe seasonal ocular allergy symptoms, although long-term use should be avoided because of risks of ocular adverse effects, including glaucoma and cataract formation.

Br J Clin Pharmacol. 2004 Jul;58(1):34-9.
Single and short-term dosing effects of levocetirizine on adenosine monophosphate bronchoprovocation in atopic asthma.
Lee DK, Gray RD, Wilson AM, Robb FM, Soutar PC, Lipworth BJ.
Asthma & Allergy Research Group, Department of Clinical Pharmacology, Ninewells Hospital & Medical School, University of Dundee, Dundee DD1 9SY, Scotland, UK.
AIMS: Adenosine monophosphate (AMP) acts indirectly via primed airway mast cells to induce bronchial hyper-responsiveness, which in turn correlates with eosinophilic asthmatic inflammation and atopic disease expression. We evaluated single and short-term dosing effects of a modern histamine H1-receptor antagonist, levocetirizine, given at the usual clinically recommended dose, on the primary outcome of AMP bronchoprovocation. METHODS: Fifteen atopic asthmatics were randomized in double-blind, cross-over fashion to receive for 1 week either levocetirizine 5 mg or placebo. There was a 1-week washout period prior to each randomized treatment. The provocative concentration of AMP producing a 20% fall in FEV1 (PC20) was measured after each washout at baseline and at 4-6 h following the first and last doses of each randomized treatment. RESULTS: Baseline mean +/- SEM values after washout prior to each randomized treatment comparing levocetirizine vs placebo were not significantly different for prechallenge FEV1 (% predicted) 83 +/- 4 vs 82 +/- 4, or AMP PC20 (mg ml(-1)) 45 +/- 24 vs 45 +/- 22, respectively. Airway calibre as prechallenge FEV1 for levocetirizine vs placebo was not significantly different following the first dose 86 +/- 4 vs 82 +/- 4, or the last dose 85 +/- 4 vs 83 +/- 4, respectively. There were significant improvements (P < 0.05) in AMP PC20 comparing levocetirizine vs placebo following the first dose 123 +/- 73 vs 48 +/- 24, a 1.4 doubling dilution difference (95% CI 0.8, 1.9), and the last dose 127 +/- 74 vs 53 +/- 29, a 1.2 doubling dilution difference (95% CI 0.5, 2.0). AMP PC20 was also improved (P < 0.05) by the first and last doses of levocetirizine but not placebo, vs respective baseline values, with there being no difference in the degree of protection between first and last doses. CONCLUSIONS: Single and short-term dosing with levocetirizine conferred similar improvements in bronchial hyper-responsiveness to AMP challenge, which was unrelated to prechallenge airway calibre. Further studies are indicated to evaluate the longer-term effects of levocetirizine on asthma exacerbations.

Ophthalmology. 2004 Jul;111(7):1275-9.
Adverse ocular drug reactions recently identified by the National Registry of Drug-Induced Ocular Side Effects.
Fraunfelder FW, Fraunfelder FT.
Casey Eye Institute, Oregon Health and Science University, Portland, Oregon 97239, USA. eyedrug@ohsu.edu
PURPOSE: To report recent ocular adverse drug reactions identified by the National Registry of Drug-Induced Ocular Side Effects. METHODS: Case reports from the National Registry and the World Health Organization were collected and adverse drug reactions categorized as follows: certain, probable/likely, possible, unlikely, and conditional/unclassifiable. RESULTS: Bisphosphonates are associated with ocular inflammation, including the first reports of drug-related scleritis. Topiramate is shown to cause angle-closure glaucoma. Cetirizine can cause an oculogyric crisis, and there is strong evidence retinoids cause intracranial hypertension. CONCLUSION: Recent reports to the National Registry have led to identification of new ocular adverse drug reactions.

Allerg Immunol (Paris). 2004 Jun;36(6):237-40.
Cetirizine reduces cytokines and inflammatory cells in children with perennial allergic rhinitis.
Ciprandi G, Tosca MA, Milanese M, Ricca V.
Allergy and ENT Division, Head Neck Dpt., San Martino Hospital, Genoa.
Cetirizine has been demonstrated able of reducing nasal inflammatory infiltration in children with allergic rhinitis and cytokine production in in vitro studies. The aim of this double-blind, placebo-controlled, and randomized study was to evaluate cytokine pattern and inflammatory cells in children with perennial allergic rhinitis, before and after treatment with cetirizine or placebo. Twenty children with perennial allergic rhinitis were evaluated, 13 males and 7 females (mean age 13.4 years). Inflammatory cells and cytokines were evaluated by scraping and nasal lavage, before and after 2-weeks administration of cetirizine or placebo. IL4 and IL8 were measured by immunoassay and inflammatory cells were counted by conventional staining. Cetirizine treatment induced a significant decrease of IL4 (p<0.01) and IL8 levels (p=0.01). A significant reduction of the inflammatory cells was detected in actively-treated children, both concerning neutrophils and eosinophils (p<0.01). Moreover, cetirizine significantly reduced nasal obstruction score (p=0.007). This study shows the cetirizine effectiveness in exerting anti-inflammatory activity by modulating cytokine pattern and by reducing inflammatory infiltration in children with perennial allergic rhinitis.

Ann Allergy Asthma Immunol. 2004 Jun;92(6):635-40.
Comparative activity of cetirizine and desloratadine on histamine-induced wheal-and-flare responses during 24 hours.
Purohit A, Melac M, Pauli G, Frossard N.
INSERM U425 and EA3771, Service de Pneumologie, Hopitaux Universitaires, Strasbourg, France.
BACKGROUND: Cetirizine and desloratadine are antihistamines active in the treatment of symptoms associated with seasonal allergic rhinitis and chronic urticaria. OBJECTIVE: To compare the antihistamine activity of desloratadine, the active metabolite of loratadine, with that of cetirizine in the skin wheal-and-flare responses during 24 hours. METHODS: This was a double-blind, randomized, placebo-controlled, single oral dose, crossover study. Skin reaction to histamine (100 mg/mL), administered by prick tests, was measured by the wheal and flare surface areas for 24 hours (before treatment and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours). Eighteen healthy volunteers (mean age, 33.9 years; 13 women) participated in this study. The areas under the curves of the wheal-and-flare responses as a function of time (primary efficacy variables) were compared using analysis of variance. RESULTS: A highly significant overall treatment effect (P < .001) was detected for wheal and flare inhibition, with the activity of cetirizine and desloratadine significantly superior to that of placebo (P < .001). In addition, the activity of cetirizine was significantly superior to that of desloratadine (P < .001). With desloratadine, only 3 of the 18 subjects achieved a wheal inhibition of at least 70%, occurring between 2 and 4 hours, whereas all subjects using cetirizine reached a wheal inhibition of at least 70% between 0.5 and 3 hours (median time, 1.7 hours). The difference between the 2 active drugs was highly significant (P < .001). The median duration of wheal inhibition of at least 70% was zero with placebo and desloratadine and was 21.9 hours with cetirizine (P < .001). No serious adverse events were reported, and no subject withdrew from the study due to an adverse event. CONCLUSION: Cetirizine was associated with significantly greater suppression of skin reactivity to histamine compared with desloratadine during 24 hours after a single dose, with a consistent duration of action for cetirizine, as previously reported.

Clin Exp Allergy. 2004 Jun;34(6):958-64.
Levocetirizine improves nasal obstruction and modulates cytokine pattern in patients with seasonal allergic rhinitis: a pilot study.
Ciprandi G, Cirillo I, Vizzaccaro A, Tosca MA.
Allergologia, Ospedale San Martino, Genoa, Italy. gio.cip@libero.it
BACKGROUND: Allergic rhinitis is characterized by an IgE-dependent inflammation. Nasal obstruction is related to allergic inflammation. Some antihistamines have been demonstrated to be capable of improving this nasal symptom. OBJECTIVE: The aim of this pilot study was to evaluate nasal symptoms, nasal airflow, inflammatory cells, and cytokine pattern in patients with seasonal allergic rhinitis (SAR), before and after treatment with levocetirizine, desloratadine, or placebo. METHODS: Thirty patients with SAR were evaluated, 27 males and three females (mean age 26.9+/-5.4 years). All of them received levocetirizine (5 mg/day), desloratadine (5 mg/day), or placebo for 2 weeks. The study was double-blind, parallel-group, placebo-controlled, and randomized. Total symptom score (TSS) (including: rhinorrhea, nasal itching, sneezing, and nasal obstruction) was assessed before and after treatment. Rhinomanometry, nasal lavage, and nasal scraping were performed in all subjects before and after treatment. Inflammatory cells were counted by conventional staining; IL-4 and IL-8 were measured by immunoassay on fluids recovered from nasal lavage. RESULTS: Levocetirizine treatment induced significant symptom relief (P=0.0009) and improved nasal airflow (P=0.038). Desloratadine also relieved TSS (P=0.01), but did not affect nasal airflow. Levocetirizine significantly reduced eosinophils (P=0.029), neutrophils (P=0.005), IL-4 (P=0.041), and IL-8 (P=0.02), whereas desloratadine diminished IL-4 only (P=0.044). Placebo treatment did not significantly affect any evaluated parameters. CONCLUSIONS: This pilot study demonstrates the effectiveness of levocetirizine in: (i) relieving nasal symptoms, (ii) improving nasal airflow, (iii) reducing leucocyte infiltration, and (iv) diminishing cytokine levels. These findings are the first evidence of the effectiveness of levocetirizine in SAR.

Curr Med Res Opin. 2004 Jun;20(6):891-902.
A direct comparison of the efficacy of antihistamines in SAR and PAR: randomised, placebo-controlled studies with levocetirizine and loratadine using an environmental exposure unit - the Vienna Challenge Chamber (VCC).
Stubner P, Zieglmayer R, Horak F.
ENT University Clinic Vienna, Austria. petra.stuebner@akh-wien.ac.at
OBJECTIVE: The Vienna Challenge Chamber (VCC) is an established method for the controlled exposure of patients to specific allergens, used to make valid comparisons between antihistamines. The aim of the significantly more than loratadine at all time two placebo-controlled, randomised studies reported here was to compare the efficacy and safety of levocetirizine 5 mg od and loratadine 10 mg od in subjects suffering from seasonal allergic rhinitis (SAR) or perennial allergic rhinitis (PAR). Subjects and methods: During each study period, SAR and PAR subjects were exposed to grass pollen or house-dust mite allergens, respectively for 6 h on 2 consecutive days in the VCC. Each day, medications were administered 2 h after the start of the challenge; with a washout of at least 5 days between each period. The main criterion for evaluation of efficacy was the major symptom complex (MSC) for SAR and the complex symptom score (CSS) for PAR. RESULTS: The pattern of patients' response was similar in SAR and PAR. Both levocetirizine and loratadine were superior to placebo in alleviating SAR and PAR symptoms at all time intervals evaluated during the two study days. Levocetirizine decreased the mean MSC score intervals in SAR subjects, with the most marked difference observed on day 2 (p = 0.002). In PAR patients, although with borderline significance (p = 0.08), levocetirizine decreased the mean CSS more than loratadine. Levocetirizine appeared to have a faster onset of action than loratadine in SAR (45 min versus 1 h 15 min) and PAR (1 h versus 1 h 30 min). However, these apparent differences were not tested for statistical significance. Both medications were well tolerated and no treatment-related adverse events were reported. This level of antihistamine efficacy was maintained regardless of whether the subjects' rhinitis was seasonal or perennial. CONCLUSION: This study demonstrated that levocetirizine is superior to loratadine in improving symptoms in SAR and that there is a similar trend in PAR.

Fundam Clin Pharmacol. 2004 Jun;18(3):281-6.
Is it important to correct apparent drug tissue concentrations for blood contamination in the dog?
Giudicelli C, Dricot E, Moati F, Strolin-Benedetti M, Giudicelli JF.
Departement de Pharmacologie, Faculte de Medecine Paris-Sud, 63, rue Gabriel Peri, 94276 Le Kremlin-Bicetre, France. christine.giudicelli@kb.u-psud.fr
The goal of this study was to quantify in the dog the error that is made in assessing drug tissue concentrations when no correction for blood contamination is performed and hence to determine in which organs such a correction should be made. The organs investigated were the heart, the brain, the liver and the skeletal muscle, and the test drug used was the H1-antihistamine, cetirizine (0.1 or 0.6 mg/kg/day for 3 days, orally, n = 6 dogs). Radiolabelled serum albumin was used to quantitate blood trapped in the tissues. Blood and tissue samplings were performed 2 h after the last drug administration. Mean (+/-SEM) volumes of blood trapped in the liver, heart, muscle and brain were 263 +/- 12, 91 +/- 3, 27 +/- 1 and 20 +/- 2 microL/g, respectively. Apparent tissue/blood concentration ratios of cetirizine were 2.39 +/- 0.33, 1.11 +/- 0.09, 0.77 +/- 0.07 and 0.37 +/- 0.05 in the four organs. When correction for residual blood is not performed, cetirizine concentrations are underestimated (-13.6 +/- 3.2%) in the liver, slightly overestimated (+4.7 +/- 1.5 to +6.3 +/- 2.8%) in the brain, and neither over nor underestimated in the heart and muscle. Simulation data over a wide range of theoretical drug tissue/blood concentration ratios indicate that in the dog: (a) for the liver, correction of apparent tissue concentration for residual blood should be performed when the drug tissue/blood concentration ratio achieved is <0.8 or >4, (b) for the heart, correction should be made when this ratio is < or =0.4 and (c) for the brain and muscle, no correction is necessary unless the ratio is < or =0.1.

J Am Acad Dermatol. 2004 Jun;50(6):953-6.
Cutaneous drug eruption from cetirizine and hydroxyzine.
Lew BL, Haw CR, Lee MH.
Department of Dermatology, College of Medicine, Kyunghee University, Seoul, Korea.
Topical application of the antihistamines commonly leads to sensitization for patients, but skin reactions provoked by their systemic use are very rare. The antihistamines cetirizine and hydroxyzine are piperazine derivatives, on the structural basis of an ethylenediamine, but the cross-reactions between the 2 have rarely been reported. A 44-year-old man visited because of the generalized morbilliform eruptions with pruritus over his whole body, after intake of hydroxyzine (Ucerax) and azelastine (Azeptine), administered during a 2-day period for chronic urticaria. Previously, he had presented the same cutaneous reactions after oral administration of cetirizine (Lotec). Oral challenge tests performed with cetirizine and hydroxyzine led to the same cutaneous reactions. He was given the diagnosis of drug eruption from cetirizine and hydroxyzine, which suggests that there were cross-reactions among cetirizine, hydroxyzine, and ethylenediamine.

Can Vet J. 2004 May;45(5):414-7.
Treatment of canine atopic dermatitis with cetirizine, a second generation antihistamine: a single-blinded, placebo-controlled study.
Cook CP, Scott DW, Miller WH Jr, Kirker JE, Cobb SM.
Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853, USA.
Cetirizine and placebo were administered orally as individual agents to 23 dogs with atopic dermatitis. The pruritus was satisfactorily reduced in 4/22 (18%) dogs that completed the trial with cetirizine. Two dogs vomited after administration of the active drug.

Drugs Today (Barc). 2004 May;40(5):415-21.
Levocetirizine: a new selective H1 receptor antagonist for use in allergic disorders.
Day JH, Ellis AK, Rafeiro E.
Division of Allergy and Immunology, Kingston General Hospital, Kingston, Ontario, Canada. dayj@kgh.kari.net
Levocetirizine is the active R-enantiomer of cetirizine and represents a new second-generation histamine H(1) antagonist. It has a high affinity and selectivity for H(1) receptors. Comparative studies have shown evidence of superior H(1) receptor binding affinity over its racemate, cetirizine. Levocetirizine has a favorable pharmacokinetic profile; it is rapidly and extensively absorbed, minimally metabolized, and has a lower volume of distribution (V(d)) than some other second-generation antihistamines. A number of studies using the histamine-induced wheal and flare model have repeatedly demonstrated marked suppressive effects for levocetirizine. Levocetirizine has also been found to be effective in relieving symptoms of seasonal and perennial allergic rhinitis, including nasal congestion, and its side effects are minor. (c) 2004 Prous Science. All rights reserved.

J Med Assoc Thai. 2004 May;87(5):551-6.
Comparative efficacy of wheal-and-flare suppression among various non-sedating antihistamines and the pharmacologic insights to their efficacy.
Roongapinun S, Wajajamreon S, Fooanant S.
Department of Pharmacology, Faculty of Medicine, Chiang Mai University, Thailand.
BACKGROUND AND OBJECTIVE: Non-sedating antihistamines (loratadine, fexofenadine, and cetirizine) have been widely used in Thailand. This study examined the time-of-onset and compared the 95% inhibitory effect of these agents on histamine-induced cutaneous reaction so as to understand the diversity of their efficacy. PATIENTS AND METHOD: Thirty-one atopic patients were randomized into 4 treatment groups, placebo (n = 7), loratadine (n = 8), fexofenadine (n = 8), and cetirizine (n = 8). They were pricked with histamine every 30 min for 4 hrs. The percentage change of the wheal/flare area was calculated. RESULTS: All active treatments showed wheal suppression superior to placebo after 210 min for loratadine (P = 0.04); 90 min for fexofenadine (P = 0.009); and 60 min for cetirizine (P = 0.02), while flare suppression was significantly marked after 150 min (P = 0.0008) for loratadine; 90 min for fexofenadine (P = 0.0001), and 60 min for cetirizine (P = 0.006). All drugs except loratadine demonstrated a 95% suppression of wheal superior to the placebo (P = 0.001 for fexofenadine; P = 0.0001 for cetirizine). Only fexofenadine exhibited a 95% suppression of flare statistically superior to placebo (P = 0.02). Discrepancies among the effects of these 3 antihistamines were also detected. DISCUSSION AND CONCLUSION: All antihistamines tested repressed the wheal-and-flare area superbly over the placebo within 4 hours. Cetirizine exerted the fastest onset, and it also appeared to be the most efficacious inhibitor. The heterogeneity of their efficacy probably stems from their diverse physicochemical properties, which have also been discussed.

Clin Infect Dis. 2004 Apr 15;38(8):e66-72. Epub 2004 Mar 29.
Assessment of cetirizine, an antihistamine, to prevent cutaneous reactions to nevirapine therapy: results of the viramune-zyrtec double-blind, placebo-controlled trial.
Launay O, Roudiere L, Boukli N, Dupont B, Prevoteau du Clary F, Patey O, David F, Lortholary O, Devidas A, Piketty C, Rey E, Urbinelli R, Allaert FA, Treluyer JM, Caumes E; Viramune-Zyrtec Study Group.
Service de Medecine Interne, Hopital Cochin-Port Royal-Saint-Vincent de Paul, AP-HP, Paris, France. odile.launay@cch.ap-hop-paris.fr
We conducted a 12-week, multicenter, randomized, double-blind, placebo-controlled trial of cetirizine to assess the ability of antihistamines to prevent nevirapine-associated rash in patients infected with human immunodeficiency virus type 1. Patients initiating treatment with nevirapine were randomized to receive either cetirizine, 10 mg q.d. (104 patients), or placebo (96 patients) during the first 6 weeks of therapy. Rash occurred in 22 (11%) of 200 patients; 10 (9.6%) were in the cetirizine group and 12 (12.5%) were in the placebo group (odds ratio [OR], 0.75; 95% confidence interval [CI], 0.31-1.81; P=.5). Five of 22 rashes were cases of hypersensitivity syndrome. The rate of nevirapine discontinuation due to rash was similar in the 2 groups (7.7% and 6.25% in the cetirizine and placebo groups, respectively; P=.4). Multivariate analysis showed no treatment-group effect but indicated that age >40 years (OR, 3.83; 95% CI, 1.4-10.46; P=.008) was associated with an increased risk of rash. Cetirizine has no preventive effect on nevirapine-associated rash.

Br J Clin Pharmacol. 2004 Apr;57(4):402-11.
Retrospective population pharmacokinetic analysis of cetirizine in children aged 6 months to 12 years.
Pitsiu M, Hussein Z, Majid O, Aarons L, de Longueville M, Stockis A.
Medeval Ltd, Manchester, UK.
AIMS: To evaluate retrospectively the population pharmacokinetics of cetirizine, a second-generation antihistamine, in children. METHODS: Data were pooled from six clinical trials, in which cetirizine was administered orally in various formulations and in single and multiple dosage regimens. The population consisted of 112 children (33 female and 79 male) aged 6 months to 12 years. A one-compartment open model with first-order absorption and elimination was fitted to the plasma concentration-time profiles using nonlinear mixed effects modelling with first-order estimation. RESULTS: A linear association was found between apparent clearance (CL/F) and age with the former increasing by 0.12 l h(-1) per year. The intercept of the relationship was slightly lower for female children (0.59 vs. 0.77 l h(-1) in male). The population estimate of CL/F for an average age of 7 years was 1.61 and 1.43 l h(-1) for male and female children, respectively. A linear association was found between apparent volume of distribution (V/F) and age with the former increasing by 1.4 l year(-1), with an intercept of 4.0 l. The population estimate of V/F for an average age of 7 years was 13.9 l. The magnitudes of interpatient variability were 35.6% for CL/F and 19.7% for V/F. The magnitude of residual variability in cetirizine concentrations was 26.9%. CONCLUSIONS: Population analysis predicts a linear increase in cetirizine CL/F and V/F with age, with CL/F being slightly lower in female children, relative to males of the same age. However, this gender difference probably has no clinical consequences. Since V/F increased more rapidly with age than CL/F, a nonlinear increase in half-life was seen, from < 4 h in infants to near the adult value at 12 years of age. The current recommended dosing regimens that younger children should receive lower but more frequent doses, are confirmed by the present analysis.

Clin Exp Allergy. 2004 Apr;34(4):650-3.
Comparative effects of desloratadine, fexofenadine, and levocetirizine on nasal adenosine monophosphate challenge in patients with perennial allergic rhinitis.
Lee DK, Gardiner M, Haggart K, Fujihara S, Lipworth BJ.
Asthma & Allergy Research Group, Ninewells Hospital & Medical School, University of Dundee, Dundee, Scotland, UK.
Summary Background There are no data directly comparing the relative efficacy of modern H(1)-antihistamines in allergic rhinitis using nasal provocation challenge. Objective We elected to study the comparative effectiveness of usual clinically recommended doses of desloratadine (DES), fexofenadine (FEX), and levocetirizine (LEV), on nasal adenosine monophosphate (AMP) challenge in patients with perennial allergic rhinitis (PAR). Methods 16 patients with PAR were randomized in double-blind cross-over fashion to receive single doses of DES 5 mg, FEX 180 mg, LEV 5 mg, or placebo (PL), with nasal AMP challenge performed 12 h after dosing. Measurements of peak nasal inspiratory flow (PNIF) were made over 60 min after nasal AMP challenge. Results Pre-challenge values (mean+/-SEM) for PNIF (L/min) were not significantly different comparing all groups; DES (129+/-9), FEX (128+/-11), LEV (128+/-13), and PL (128+/-12). The maximum % PNIF fall from baseline over 60 min after nasal AMP challenge was significantly attenuated (P<0.05) compared to PL (50+/-4), with DES (32+/-5), FEX (36+/-4), and LEV (36+/-4). The area under the 60-min time-response curve (%.min) was also significantly attenuated (P<0.05) compared to PL (2110+/-268), with DES (1126+/-285), FEX (1225+/-255), and LEV (1261+/-194). There were no significant differences between the three H(1)-antihistamines for any outcomes. Conclusion DES, FEX, and LEV were equally effective in attenuating the response to nasal AMP challenge. However, further long-term studies will be required to study their comparative effects on nasal symptoms, quality of life, as well as on nasal inflammatory cells.

J Allergy Clin Immunol. 2004 Apr;113(4):669-76.
Levocetirizine better protects than desloratadine in a nasal provocation with allergen.
Deruaz C, Leimgruber A, Berney M, Pradervand E, Spertini F.
Division of Allergy and Immunology, Centre Hospitalier Universitaire Vaudois, Rue du Bugnon, 1011 Lausanne, Switzerland.
BACKGROUND: Direct comparisons of antihistamines are rare but very much needed. Newly available antihistamine preparations, levocetirizine, the R-enantiomer of racemate cetirizine, and desloratadine, an active metabolite of loratadine, have been recently released for allergic rhinitis. OBJECTIVE: We sought to compare levocetirizine and desloratadine in a nasal provocation test (NPT) with grass pollen. METHODS: Twenty-four volunteers with grass pollen allergy and a history of rhinitis were enrolled in a double-blind, placebo-controlled, crossover study. Three NPTs were performed in a dose-escalating manner during the out-of-season period 4 hours after a single dose of levocetirizine (5 mg), desloratadine (5 mg), or placebo. RESULTS: CONCLUSIONS: This study demonstrates a better overall protection of a single dose of levocetirizine compared with desloratadine in an NPT with grass pollen allergen. In contrast to late-phase inflammatory markers, which were unaffected, extravascular leakage of the early-phase marker albumin was significantly limited by levocetirizine.

Allergy Asthma Proc. 2004 Mar-Apr;25(2):81-3.
Onset of action for the relief of allergic rhinitis symptoms with second-generation antihistamines.
Greisner WA 3rd.
Allergy and Asthma Associates of the Bluegrass, Lexington, Kentucky, USA.
Onset of action for relief of allergic rhinitis symptoms is of clinical significance to both the physician and the patient. Using either subjective or objective methods, the onset of action after a single, oral dose of an antihistamine can be measured. Multicenter studies, outdoor studies, and pollen challenge systems have been used to measure the onset of action. A literature search from 1985 to May 2002 was performed. All published, randomized, placebo-controlled clinical studies pertaining to the onset of action for relief of allergic rhinitis symptoms after a single, oral dose of a second-generation antihistamine (not combined with a decongestant) including cetirizine, desloratadine, fexofenadine, and loratadine, were reviewed. The onset of action for cetirizine ranged from 59 minutes to 2 hours and 6 minutes and for loratadine onset of action ranged from 1 hour and 42 minutes to none identified during the duration of the study. Cetirizine had a shorter onset of action than loratadine for all comparisons. Fexofenadine had an onset of action within 60 minutes. The literature search did not reveal any published onset of action studies for desloratadine. The onset of action for a given second-generation antihistamine depends on how it is defined and subsequently measured.

Yao Xue Xue Bao. 2004 Mar;39(3):204-7.
[Study on the enantiomer separation of cetirizine dihydrochloride using proteinate- and amylose-based chiral stationary phase]
[Article in Chinese]
Zhang ZF, Yang GL, Liang GJ, Zhou Y, Chen Y.
College of Chemistry and Environmental Science, Hebei University, Baoding 071002, China.
AIM: To study the chromatographic behavior of cetirizine dihydrochloride on the proteinate- and amylose- based chiral stationary phases so as to optimizate the chromatographic condition of its enantiomers separation. METHODS: When using amylose-based, alpha1-acid glycoprotein and ovomucoid protein chiral stationary phase, the mobile phase was hexane-isopropyl alcohol-alcohol-trifluoroacetic acid (430:45:25:1), acetonitrile-10 mmol x L(-1) phosphate buffer solution (adjusted to pH 7.0 with sodium hydroxide) (4:96) and acetonitrile-20 mmol x L(-1) KH, PO4 solution (adjusted to pH 7.0 with triethylamine) (12.7:87.3), respectively. The temperature of proteinate column was 25 degrees C. The detective wavelength was 230 nm. RESULTS: The two enantiomers could be separated on the two kinds of chiral stationary phases without derivatization and the resolution was above 2.0. The methods developed on the two kinds of chiral stationary phases are accurate, sensitive and specific. CONCLUSION: Both the proteinate- and amylose-based chiral stationary phases can be used to separate the enantiomers of cetirizine.

Allerg Immunol (Paris). 2004 Feb;36(2):67-70, 72.
Antihistamines added to an antileukotriene in treating seasonal allergic rhinitis: histamine and leukotriene antagonism.
Ciprandi G, Tosca MA, Milanese M, Schenone G, Ricca V.
Allergy & ENT Unit, Head-Neck Dpt., San Martino Hospital, Genoa, Italy.
Cysteinyl leukotrienes (CysLTs) are a key element of allergic inflammation. Thus, the antagonism of CysLTs appears a potential target of allergic rhinitis management. Antileukotrienes and antihistamines combined showed a synergistic effect in treating seasonal allergic rhinitis (SAR). This double blind, parallel group, randomized study aimed at evaluating the clinical and anti-inflammatory effects exerted by two combinations of antihistamine plus antileukotriene in patients with SAR and mild intermittent asthma. Thirty patients were treated with montelukast added to cetirizine (M-C group) or desloratadine (M-D group) for 2 weeks. The visits, including spirometry, nasal scraping and lavage, were performed in all subjects before and directly after the treatment. Evaluation parameters were: i) nasal symptoms, ii) number of eosinophils and neutrophils, and iii) IL5 and IL8 levels. Both combinations significantly reduced: nasal symptoms (p<0.001), eosinophils and neutrophils (p<0.001), IL5 (p<0.001 for M-C groupand p<0.01 for M-D group), and IL8 levels (p<0.001 for M-C group and p<0.05 for M-D group). M-C combination reduced more significantly than M-D combination: nasal symptoms (p<0.01), inflammatory cells (p<0.01), and cytokines (p<0.01). The present study demonstrates that these antileukotriene-antihistamine combinations are effective in relieving nasal symptoms in SAR. Moreover, these combinations exert additional anti-inflammatory activity as provided by reduction of inflammatory infiltrate and cytokine levels. Finally, cetirizine might exert more beneficial activity than desloratadine when added to montelukast.

Am J Ophthalmol. 2004 Feb;137(2):355-7.
Oculogyric crisis in patients taking cetirizine.
Fraunfelder FW, Fraunfelder FT.
Casey Eye Institute, Oregon Health and Science University, Portland, Oregon 97201, USA. eyedrug@ohsu.edu
PURPOSE: To report oculogyric crisis in patients receiving cetirizine and inform clinicians on the characteristics of this drug-induced ocular side effect. METHODS: For this retrospective, observational case series, case reports were collected from the National Registry of Drug-Induced Ocular Side Effects (Casey Eye Institute, Portland, Oregon). The World Health Organization Causality Assessment Guide of Suspected Adverse Reactions was used to categorize the cases. RESULTS: Nine cases were reported, with eight occurring in the pediatric age group. Dosage ranged from 5 to 10 mg orally and onset of symptoms ranged from 3 to 184 days. Six cases of oculogyric crisis had positive rechallenge data. Eight cases had complete neurologic consultation including radiographic studies. CONCLUSIONS: Cetirizine can cause oculogyric crisis, especially in the pediatric age group. Extensive neurologic workups may be avoided if clinicians recognize this drug-induced ocular side effect.

Clin Exp Allergy. 2004 Feb;34(2):259-67.
Randomized placebo-controlled trial comparing fluticasone aqueous nasal spray in mono-therapy, fluticasone plus cetirizine, fluticasone plus montelukast and cetirizine plus montelukast for seasonal allergic rhinitis.
Di Lorenzo G, Pacor ML, Pellitteri ME, Morici G, Di Gregoli A, Lo Bianco C, Ditta V, Martinelli N, Candore G, Mansueto P, Rini GB, Corrocher R, Caruso C.
Dipartimento di Medicina Clinica e delle Patologie Emergenti, Universita di Palermo, Italy.
BACKGROUND: Corticosteroids are considered to be particularly effective in reducing nasal congestion and are therefore recommended as first-line treatment in allergic rhinitis patients with moderate to severe and/or persistent symptoms. OBJECTIVE: We compared the clinical efficacy of fluticasone propionate aqueous nasal spray (FPANS) 200 microg given once daily, administered in mono-therapy or combined therapy with a H1 receptor antagonist (cetirizine, CTZ) or with a leukotriene antagonist (montelukast, MSK), and the combined therapy of CTZ plus MSK in the treatment of patients affected by allergic rhinitis to Parietaria during natural pollen exposure. In addition, we examined the effect of the treatment on eosinophil counts and eosinophil cationic protein (ECP) in nasal lavage performed at beginning of season, during season and at the end of the season. METHODS: One hundred patients aged 12-50 years (mean+/-SD 31.8+/-9.6) with a history of moderate to severe Parietaria pollen-induced seasonal allergic rhinitis were selected. A randomized, double-blind, double dummy, placebo (PLA)-controlled, parallel-group study design was used. Patients were treated FPANS 200 microg once daily (n=20) or with FPANS 200 microg once daily, plus CTZ (10 mg) in the morning (n=20), or with FPANS 200 microg once daily, plus MSK (10 mg) in the evening (n=20) or with CTZ (10 mg) in the morning plus MSK in the evening (n=20) or matched PLA (n=20). Assessment of efficacy was based on scores of daily nasal symptoms and on eosinophil counts and ECP in nasal lavage. RESULTS: All treatments showed significant differences (P<0.001) compared with PLA in terms of total symptom, rhinorrhea, sneezing and nasal itching scores. Concerning nasal congestion on waking and daily only the groups treated with FPANS in mono-therapy or in combined therapy showed significant differences compared with PLA. Comparing the group treated with FPANS alone and the groups treated with FPANS plus CTZ, we found significant differences for total symptom score (P=0.04) and for nasal itching (P=0.003). The comparison between FPANS plus CTZ and FPANS plus MSK showed significant difference for nasal itching (P=0.003). Finally, there were significant differences between the group treated with FPANS and the group treated with CTZ plus MSK for total symptom score (P=0.009), for nasal congestion on waking (P<0.001) and nasal congestion daily (P<0.001). Also the comparisons between the group treated with FPANS plus CTZ and the group treated with CTZ plus MSK demonstrated significant differences (P<0.001) for total symptom, for nasal congestion on waking and for nasal congestion on daily, for rhinorrhea (P=0.04) and for nasal itching (P=0.003) scores. Concerning the comparison between the group treated with FPANS plus MSK and the group treated with CTZ plus MSK we found significant differences for total symptom score (P=0.005), for nasal congestion on waking (P<0.001) and for nasal congestion on daily (P<0.001). No other differences were observed between the groups. Concerning blood eosinophil counts, significant differences were found between the treatments with FPANS in mono-therapy or in combined therapy with PLA group during and at the end of the season (P=0.0003 and P<0.0001, respectively). Concerning eosinophils and ECP in nasal lavage, all treatments showed significant differences (P<0.001) compared with PLA. Besides, there were significant differences (P<0.001) between the groups treated with FPANS alone or in combined therapy and the group treated with CTZ plus MSK. CONCLUSION: The results of this comparative study demonstrate that FPANS is highly effective for treating patients affected by allergic rhinitis, with efficacy exceeding that of CTZ plus MSK in combined therapy. In addition, the regular combined therapy of FPANS plus CTZ or plus MSK would not seem to offer substantial advantage with respect to FPANS in mono-therapy in patients affected by seasonal allergic rhinitis.

Clin Exp Allergy. 2004 Feb;34(2):250-8.
A dose-ranging study of the effects of mequitazine on actual driving, memory and psychomotor performance as compared to dexchlorpheniramine, cetirizine and placebo.
Theunissen EL, Vermeeren A, van Oers AC, van Maris I, Ramaekers JG.
Experimental Psychopharmacology Unit, Brain and Behaviour Institute, Faculty of Psychology, Maastricht University, The Netherlands. e.theunissen@psychology.unimaas.nl
BACKGROUND: Mequitazine is a so-called 'non-sedative' second-generation antihistamine even though it has never been firmly established that this drug's sedative potential actually differs from that of the 'sedative' first-generation antihistamines. OBJECTIVE: The present study compares the sedative effects of three doses of mequitazine on actual driving, psychomotor performance and memory with those of a first- and a second-generation antihistamine. METHODS: Eighteen healthy volunteers received on separate days a single dose of 5, 10 and 15 mg mequitazine, 10 mg cetirizine, 6 mg dexchlorpheniramine and placebo. Drug effects were assessed using two actual driving tests (highway-driving test and car-following test), cognitive and psychometric tests (tracking, divided attention, memory, reasoning and critical flicker fusion), pupil size and questionnaires. RESULTS: Highway-driving data revealed an overall effect of Treatment on the standard deviation of lateral position (SDLP). Dexchlorpheniramine impaired driving performance as indicated by a significant rise in SDLP. Mequitazine significantly increased SDLP in a dose-related manner, but the separate dose effects failed to reach statistical significance. Divided attention performance was also affected by Treatment. Reaction time (RT) during mequitazine treatments increased in a dose-related manner and significantly differed from placebo at the highest dose. Subjects reported to be less alert after treatment with dexchlorpheniramine. Cetirizine did not affect performance in any of the tasks. CONCLUSION: It was concluded that mequitazine is mildly sedating. The effects of mequitazine are comparable to those of other second-generation antihistamines, in that it causes mild driving impairment, particularly at higher doses.

Int J Clin Pract. 2004 Feb;58(2):109-18.
Comparative clinical efficacy, onset and duration of action of levocetirizine and desloratadine for symptoms of seasonal allergic rhinitis in subjects evaluated in the Environmental Exposure Unit (EEU)
Day JH, Briscoe MP, Rafeiro E, Ratz JD.
Division of Allergy and Immunology, Kingston General Hospital, Kingston, Ontario, Canada. dayj@kgh.kari.net
The Environmental Exposure Unit, an indoor pollen challenge system to test anti-allergic medications, was used to compare the onset and duration of action and the efficacy of levocetirizine and desloratadine, two recently developed H1-antagonists. In this double-blind, placebo-controlled, parallel-group study, qualified subjects were randomised to once-daily levocetirizine 5 mg (n = 141), desloratadine 5 mg (n = 140) or placebo (n = 92) and exposed to ragweed pollen on two consecutive days (7 h and 6 h). Symptoms were self-rated every 30 min. On both days, levocetirizine produced a greater improvement in the major symptom complex score (primary efficacy variable) than desloratadine (p = 0.015); both were better than placebo (p < 0.001). Levocetirizine acted earlier (1 h vs. 3 h) and produced greater symptom relief at 24 h than desloratadine (p = 0.003). Levocetirizine also alleviated nasal obstruction better than desloratadine (p = 0.007) on day 1; and better than placebo (p = 0.014) after the second dose on day 2, which was not observed with desloratadine. Levocetirizine and desloratadine were safe and well tolerated.

Manag Care Interface. 2004 Feb;17(2):29-34.
Assessing patient satisfaction with desloratadine after conversion from loratadine, fexofenadine, or cetirizine.
Glass D, Harper A.
Harris Interactive Healthcare Division, New York City, New York 10003, USA. dglass@harrisinteractive.com
A number of prescription and nonprescription nonsedating antihistamines are available for the treatment of allergic rhinitis. From a managed care perspective, determining the extent to which a medication conversion to desloratadine from loratadine, fexofenadine, or cetirizine results in maintained or increased patient satisfaction with allergy care would be informative for formulary decision makers and other budget holders. To that end, a survey was undertaken of patient medication assessments after a switch in antihistamines. On average, patients who converted to desloratadine from loratadine, fexofenadine, or cetirizine reported increased satisfaction with desloratadine treatment.

Pediatrics. 2004 Feb;113(2):e116-21.
Central nervous system side effects of first- and second-generation antihistamines in school children with perennial allergic rhinitis: a randomized, double-blind, placebo-controlled comparative study.
Ng KH, Chong D, Wong CK, Ong HT, Lee CY, Lee BW, Shek LP.
Department of Paediatrics, National University of Singapore, Singapore.
OBJECTIVE: Allergic rhinitis is common and on the rise. Antihistamines are the mainstay of treatment and are the most commonly prescribed drugs in Singapore. Treatment-related sedation and its effect on cognition are a major concern. First- and second-generation antihistamines show varying degrees of sedation, but to date, objective studies in children are lacking. The objective of this study was to assess the sedating effect of cetirizine (second-generation antihistamine) and chlorpheniramine (first-generation antihistamine) compared with placebo using an objective neurophysiological test. METHODS: This was a prospective, double-blind, placebo-controlled, randomized, single-dose, 3-way crossover study. Twenty-four children aged 7 to 14 years with allergic rhinitis completed the study. All children were randomly allocated to medication sequences and received 3 different drugs on 3 different days, at least 1 week apart. The P300 event-related potential was used as an objective test of sedation. Subjective assessment was by a visual analog scale. RESULTS: Chlorpheniramine and cetirizine increased P300 latency when compared with baseline. No significant increase was obtained with placebo. The significant increase in P300 latency was not accompanied by significant change in subjective somnolence as measured by the visual analog scale. CONCLUSION: We have shown that cetirizine has sedative properties in children. The lack of correlation between P300 latency and the visual analog scale indicates that sedation induced by these drugs may not be subjectively noted.

Allergy Asthma Proc. 2004 Jan-Feb;25(1):59-68.
Randomized double-blind comparison of cetirizine and fexofenadine after pollen challenge in the Environmental Exposure Unit: duration of effect in subjects with seasonal allergic rhinitis.
Day JH, Briscoe MP, Rafeiro E, Hewlett D Jr, Chapman D, Kramer B.
Division of Allergy and Immunology, Department of Medicine, Queen's University and Kingston General Hospital, Kingston, Ontario, Canada.
There is published evidence that cetirizine has a longer duration of effect than fexofenadine. This study compared duration of effect and other measures of efficacy of cetirizine, 10 mg; fexofenadine, 180 mg; and placebo in allergic subjects exposed to pollen in the Environmental Exposure Unit. Eligible subjects (n = 575) were exposed to ragweed pollen (day 1, 7 hours; day 2, 5 hours) and randomized in double-blind fashion to once-daily cetirizine, 10 mg; fexofenadine, 180 mg; or placebo. The total symptom severity complex (TSSC) score, the primary efficacy variable, was based on four rhinoconjunctivitis symptoms rated at 20-minute intervals. Treatment evaluation was divided into three periods: period 1 TSSC, average of 15 scores obtained 0-5 hours after the first dose; period 2 TSSC, average of 9 scores obtained 21-24 hours after the first dose; and period 3 TSSC, average of 6 scores obtained 0-2 hours after the second dose. The primary efficacy end point was the change from baseline TSSC at period 2. Baseline TSSC was the final pretreatment score on day 1 and was 9.7 for cetirizine, 9.8 for fexofenadine, and 9.7 for placebo. For the primary efficacy end point, the reduction in baseline TSSC at period 2 was greater for cetirizine (-3.6) compared with fexofenadine (-2.7; p < 0.001) and placebo (-2.0; p < 0.001), representing a 33% greater reduction for cetirizine versus fexofenadine. Cetirizine continued to reduce TSSC more than fexofenadine (-5.2 versus -4.6; p = 0.017) and placebo (-3.9; p < 0.001) (period 3). Similar efficacy was observed in period 1 for both active treatments. Treatment-related adverse events were similar in all groups with an incidence of somnolence of 1.3% for both active medications. In conclusion, cetirizine produced a 33% greater reduction in SAR symptoms over the 21- to 24-hour interval after the first dose and for 40 minutes after the second dose, indicating a superior and longer duration of effect, which is relevant because both are once-daily medications. Onset of action was comparable and both treatments were safe and well tolerated.

J Dermatolog Treat. 2004 Jan;15(1):55-7.
Comparative efficacy of cetirizine and fexofenadine in the treatment of chronic idiopathic urticaria.
Handa S, Dogra S, Kumar B.
Department of Dermatology, Venereology and Leprology, Postgraduate Institute of Medical Education and Research, Chandigarh, India.
OBJECTIVES: Antihistamines are the first line of therapy for chronic idiopathic urticaria (CIU). The present study was designed considering the lack of reports comparing the efficacy and safety of commonly prescribed cetirizine and fexofenadine in the treatment of CIU. METHODS: A total of 116 patients, aged 17 to 65 years, with CIU (urticarial wheals for at least two days per week for six consecutive weeks before entry) were enrolled in this randomised double-blind study. Study period was 28 days with patient visits on days 14 and 28 for investigator evaluation of the clinical response. Patient evaluation was on the basis of an analogue scale. Final response to treatment was judged as symptom free, partial improvement, and no improvement. RESULTS: Ninety-seven patients (52 cetirizine, 45 fexofenadine) completed the study. The response to treatment in both the groups at the end of treatment period was as follows; symptom free [cetirizine 27(51.9%), fexofenadine 2(4.4%)], partial improvement [cetirizine 19(36.5%), fexofenadine 19(42.2%)], no improvement [cetirizine 6(11.5%), fexofenadine 24(53.3%)]. Side effects noted were mild with no significant difference between the two. CONCLUSION: Cetirizine seems to have therapeutic advantage over fexofenadine in the treatment of CIU.

Clin Exp Allergy. 2004 Jan;34(1):103-9.
Cetirizine, an H1-receptor antagonist, suppresses the expression of macrophage migration inhibitory factor: its potential anti-inflammatory action.
Shimizu T, Nishihira J, Watanabe H, Abe R, Ishibashi T, Shimizu H.
Departments of Dermatology Molecular Biochemistry, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
BACKGROUND: H1-receptor antagonists are often effective in the treatment of allergic disorders such as atopic dermatitis. Cetirizine, a putative H1-receptor antagonist, has recently been shown to have anti-inflammatory properties through the inhibition of leucocyte recruitment and activation, and by the reduction of ICAM-1 expression on keratinocytes. OBJECTIVE: To further elucidate the anti-inflammatory properties of cetirizine, we first examined its effects on antigen-induced eosinophilia and neutrophila in vivo. We then examined the anti-inflammatory effects of cetirizine on a human keratinocyte A431cell line. METHODS: Mice were sensitized subcutaneously with ragweed pollen and were challenged intraperitoneally with the allergen. Cetirizine diluted in sterile water (0-20 mg/kg) or only sterile water was administered orally. Peritoneal cells were obtained at 8 and 24 h after challenge. The eosinophilia and neutrophilia induced by ragweed pollen extract were quantitated. Macrophage migration inhibitory factor (MIF), macrophage inflammatory protein 2 (MIP-2) and eotaxin contents of peritoneal fluid were also measured by mouse ELISA. The effects of cetirizine on MIF-induced IL-8 production in A431 cells were examined by ELISA. The effects of cetirizine on MIF expression and production in A431 cells were examined by human MIF ELISA and Northern blot analysis. RESULTS: Eosinophilia and neutrophilia induced by ragweed pollen extract were found to be significantly reduced in cetirizine-treated mice (20 mg/kg). MIF, a pleuripotent cytokine, was significantly decreased at 8 and 24 h in the peritoneal fluid by cetirizine treatment. MIP-2 and eotaxin were also decreased 8 and 24 h, respectively, after challenge in the peritoneal fluid with cetirizine treatment. MIF stimulates IL-8 production in A431 cells. We found that MIF production in A431 cells was inhibited by 10 microm cetirizine. Consistent with this, cetirizine significantly inhibited MIF-induced IL-8 production. CONCLUSION: These results suggest that cetirizine exerts its anti-inflammatory effects by inhibiting MIF as well as IL-8 production, such as those involved in inflammatory allergic skin disease, suggesting a broad spectrum of action beyond its mere H1-receptor-antagonistic function.

Expert Opin Pharmacother. 2004 Jan;5(1):125-35.
Review of cetirizine hydrochloride for the treatment of allergic disorders.
Portnoy JM, Dinakar C.
Childrens Mercy Hospital, 2401 Gillham Road, Kansas City, MO 64108, USA.
Cetirizine hydrochloride is an orally-active and selective histamine (H(1))-receptor antagonist. It is a second-generation antihistamine and a human metabolite of hydroxyzine. Therefore, its principal effects are mediated via selective inhibition of peripheral H(1) receptors. The antihistaminic activity of cetirizine has been documented in a variety of animal and human models. In vivo and ex vivo animal models have shown negligible anticholinergic and antiserotonergic activity. In clinical studies, however, dry mouth has been seen more commonly with cetirizine than with placebo. In vitro receptor binding studies have shown no measurable affinity for receptors other than H(1) receptors. Auto-radiographical studies with radiolabelled cetirizine in the rat have shown negligible penetration into the brain. Ex vivo experiments in the mouse have shown that systemically administered cetirizine does not significantly occupy cerebral H(1) receptors. Impairment of CNS function is comparable to other low-sedating antihistamines at the recommended dose of 10 mg/day for adults. It has anti-inflammatory properties that may play a role in asthma management. It does not interact with concomitantly administered medications, it has no cardiac adverse effects, and it does not appear to be associated with teratogenicity. Cetirizine is predominantly eliminated by the kidneys with a mean elimination half-life is 8.3 h. It is rapidly absorbed, and significant clinical inhibition of a wheal and flare response occurs in infants, children and adults within 20 min of a single oral dose and persists for 24 h. No tolerance to the wheal and flare response occurs even after 1 month of daily treatment. The clinical efficacy of cetirizine for allergic respiratory diseases has been established in numerous trials. There is evidence that cetirizine improves symptoms of urticaria. Concomitant use of cetirizine also decreases the duration and amount of topical anti-inflammatory preparations needed for the treatment of atopic dermatitis. Interestingly, several clinical studies suggest that cetirizine may be useful in the treatment and prevention of mild asthma.

J Am Acad Dermatol. 2003 Oct;49(4):714-6.
Treatment of acquired cold urticaria with cetirizine and zafirlukast in combination.
Bonadonna P, Lombardi C, Senna G, Canonica GW, Passalacqua G.
Allergy Service, Verona General Hospital, Verona, Italy.
Acquired cold urticaria is an infrequent physical urticaria that can provoke severe systemic reactions. Histamine is the primary mediator, but leukotrienes are also involved in the pathogenesis. H(1) antihistamines are recommended as first-choice treatment, but their efficacy is sometimes unsatisfactory. On the basis of pathogenic knowledge, it can be hypothesized that a combination therapy with antihistamines and leukotriene receptor antagonists is more effective than each drug given alone. We tested this hypothesis in 2 patients with severe systemic cold urticaria poorly responsive to conventional therapy. The patients underwent 3 consecutive treatment regimens (each of 2 weeks): cetirizine (10 mg once a day); zafirlukast (20 mg twice a day); and their combination. They were clinically evaluated, after each regimen, by means of a visual analog scale and ice-cube test. The combination therapy was superior to the 2 drugs given alone, as testified by subjective and objective evaluations.

J Pharm Sci. 2003 Oct;92(10):2082-9.
P-glycoprotein influences the brain concentrations of cetirizine (Zyrtec), a second-generation non-sedating antihistamine.
Polli JW, Baughman TM, Humphreys JE, Jordan KH, Mote AL, Salisbury JA, Tippin TK, Serabjit-Singh CJ.
Preclinical Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Inc., P.O. Box 13398, Room: MAI.2213.2G, Research Triangle Park, North Carolina 27709, USA.
Recent in vitro studies have suggested that P-glycoprotein (Pgp) and passive membrane permeability may influence the brain concentrations of non-sedating (second-generation) antihistamines. The purpose of this study was to determine the importance of Pgp-mediated efflux on the in vivo brain distribution of the non-sedating antihistamine cetirizine (Zyrtec), and the structurally related sedating (first-generation) antihistamine hydroxyzine (Atarax). In vitro MDR1-MDCKII monolayer efflux assays demonstrated that cetirizine was a Pgp substrate (B-->A/A-->B + GF120918 ratio = 5.47) with low/moderate passive permeability (PappB-->A = 56.5 nm/s). In vivo, the cetirizine brain-to-free plasma concentration ratios (0.367 to 4.30) were 2.3- to 8.7-fold higher in Pgp-deficient mice compared with wild-type mice. In contrast, hydroxyzine was not a Pgp substrate in vitro (B-->A/A-->B ratio = 0.86), had high passive permeability (PappB-->A + GF120918 = 296 nm/s), and had brain-to-free plasma concentration ratios >73 in both Pgp-deficient and wild-type mice. These studies demonstrate that Pgp-mediated efflux and passive permeability contribute to the low cetirizine brain concentrations in mice and that these properties account for the differences in the sedation side-effect profiles of cetirizine and hydroxyzine. Copyright 2003 Wiley-Liss, Inc. and the American Pharmacists Association.

Biochem Pharmacol. 2003 Oct 1;66(7):1123-6.
Compared pharmacological characteristics in humans of racemic cetirizine and levocetirizine, two histamine H1-receptor antagonists.
Tillement JP, Testa B, Bree F.
Laboratoire de Pharmacologie, Faculte de Medecine de Paris XII, F-94010 Creteil, France.
The potent histamine H(1)-receptor antagonist cetirizine (Zyrtec) is a racemic mixture of levocetirizine (now available under the trademark Xyzal and dextrocetirizine. In this Commentary, we examine somebiological properties of cetirizine and levocetirizine, namelyenantioselectivity in pharmacological activity and pharmacokinetic properties, with emphasis on the possibility of racemization, the compared behavior of the two enantiomers, and the potential for interactions with other drugs. Recent data demonstrate that the antihistaminergic activity of the racemate is primarily due to levocetirizine. Levocetirizine is rapidly and extensively absorbed, poorly metabolized, and not subject to racemization. Its pharmacokinetic characteristics are comparable after administration alone or in the racemate. Its apparent volume of distribution is smaller than that of dextrocetirizine (0.41 L kg(-1) vs. 0.60 L kg(-1)). Moreover, the non-renal (mostly hepatic) clearance of levocetirizine is also significantly lower than that of dextrocetirizine (11.8 mL min(-1) vs. 29.2 mL min(-1)). Our conclusion is that levocetirizine is indeed the eutomer of cetirizine. The evidence reviewed here confirms preclinical findings and offers a rationale for the chiral switch from the racemate to levocetirizine.

J Allergy Clin Immunol. 2003 Jun;111(6):1244-8.
Safety of cetirizine in infants 6 to 11 months of age: a randomized, double-blind, placebo-controlled study.
Simons FE, Silas P, Portnoy JM, Catuogno J, Chapman D, Olufade AO, Pharmd.
Section of Allergy and Clinical Immunology, Department of Pediatrics and Child Health, Faculty of Medicine, The University of Manitoba, 820 Sherbrook Street, Winnipeg, Manitoba, Canada R3A 1R9.
BACKGROUND: H(1)-antihistamines are widely used for symptom relief in allergic disorders in infants and children; however, there are few prospective, randomized, double-blind, controlled studies of these medications in young children, and to date, no such studies have been conducted in infants. OBJECTIVE: This prospective, randomized, parallel-group, double-blind, placebo-controlled study was designed to evaluate the safety of the H(1)-antihistamine cetirizine, particularly with regard to central nervous system and cardiac effects, in infants age 6 to 11 months, inclusive. METHODS: Infants who met the entry criteria for age and had a history of treatment with an H(1)-antihistamine for an allergic or other disorder were randomized to receive 0.25 mg/kg cetirizine orally or matching placebo twice daily orally for 1 week. RESULTS: The mean daily dose in cetirizine-treated infants was 4.5 +/- 0.7 mg (SD).No differences in all-cause or treatment-related adverse events were observed between the cetirizine- and placebo-treated groups. A trend was observed toward fewer adverse events and sleep-related disturbances in the cetirizine group compared with the placebo group. No prolongation in the linear corrected QT interval was observed in cetirizine-treated infants compared with either baseline values or with values in placebo-treated infants. CONCLUSIONS: We have documented the safety of cetirizine in this short-term investigation, the first randomized, double-blind, placebo-controlled study of any H(1)-antihistamine in infants. Additional prospective, randomized, double-blind, placebo-controlled, long-term studies of cetirizine and other H(1)-antihistamines are needed in this population.

Cutis. 2003 May;71(5):396.
High dose cetirizine: a case report.
Nordness M, Zacharisen MC.
Medical College of Wisconsin, Milwaukee, USA.
We report the case of a 46-year-old man who tolerated 50 mg per day of cetirizine for the treatment of chronic idiopathic urticaria. The patient denied any sedation or somnolence and had no difficulty performing routine daily functions including driving. He had tried other antihistamines, including fexofenadine, loratadine, and hydroxyzine without improvement.

Arzneimittelforschung. 2003;53(2):93-7.
Comparative antiallergic effects of second-generation H1-antihistamines ebastine, cetirizine and loratadine in preclinical models.
Llupia J, Gras J, Llenas J.
Department of Pharmacological Development, Almirall Prodesfarma, Research Centre, Cardener 68-74, 08024-Barcelona, Spain.
Ebastine (CAS 90729-43-4), cetirizine (CAS 83881-51-0) and loratadine (CAS 79794-75-5) are second generation H1-antihistamines of proven efficacy for treating allergy. Recent clinical studies have found ebastine to be more effective than cetirizine or loratadine in alleviating the symptoms of seasonal allergic rhinitis. The objective of this study was to compare the efficacy of these compounds in three guinea-pig modeles of bronchoconstriction, elicited either by histamine, allergen or leukotriene C4 in order to shed light onto the mechanisms that might explain differences found in clinical studies. In the present experiments, ebastine and cetirizine were equipotent against aerosol histamine-induced bronchospasm in guinea pigs (ED50 115 and 100 micrograms/kg p.o., respectively), while loratadine was three-fold less potent. In the same model the effects of ebastine, loratadine and cetirizine lasted 21, 19 and 15 h, respectively. Ebastine (ED50 334 micrograms/kg p.o.) was the most potent compound in inhibiting allergen-induced bronchospasm in conscious guinea pigs. In vitro studies in tracheally perfused guinea pig lungs demonstrated that ebastine and loratadine inhibited with equal potency the bronchoconstriction induced by leukotriene C4 whilst cetirizine was significantly less potent. Finally, in another in vivo study, ebastine reverted the changes in pulmonary resistance induced by leukotriene C4 in anaesthetised guinea pigs, whereas cetirizine and loratadine were devoid of activity in this model. In accordance with the clinical data, ebastine proved to be the substance with the widest range of application in animal experiments, too.

Clin Exp Allergy. 2003 Mar;33(3):351-8.
The health-related quality of life effects of once-daily cetirizine HCl in patients with seasonal allergic rhinitis: a randomized double-blind, placebo-controlled trial.
Noonan MJ, Raphael GD, Nayak A, Greos L, Olufade AO, Leidy NK, Champan D, Kramer B.
Allergy Associates, PC, 545 NE 47th Street, Suite 310, Portland, OR 97213, USA.
BACKGROUND: Seasonal allergic rhinitis (SAR) is characterized by subjectively irritating symptoms that can have a substantial impact on the patient's health-related quality of life (HRQL), adversely affecting physical and social or work activity, interpersonal relationships, and general psychological well-being. The objective of this study was to test the effect of cetirizine HCl 10 mg once daily on the HRQL of adult patients 18-65 years of age with SAR, concurrently assessing safety and efficacy. METHODS: Randomized double-blind, placebo-controlled, parallel group trial conducted during the 1999 spring SAR season at 19 centers in the US. Following a 1-week placebo run-in period, qualified patients were randomized to cetirizine 10 mg, or placebo once daily for a 2-week treatment period. Change in Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) and Total Symptom Severity Complex (TSSC) scores from baseline were the primary outcomes of interest. RESULTS: Of the 611 patients enrolled, 403 (66%) were randomized. Cetirizine-treated patients reported significantly greater improvement in overall HRQL (P < 0.001) and in each of the seven domains of the RQLQ at all time-points (P < 0.05 to < 0.001) than the placebo group. They also experienced significantly greater symptom relief (P < 0.001) and were more satisfied with treatment (65% vs. 44%) compared to the placebo group. Correlations between symptomatic relief and overall HRQL improvement were moderate to strong and statistically significant (r = 0.49-0.68, P < 0.01). CONCLUSIONS: Results of this study are consistent with previous investigations, suggesting cetirizine HCl 10 mg taken once daily in the morning offer symptomatic relief that improves the HRQL of adults suffering from SAR.