Zyrtec
Leukotriene B4 production by blood neutrophils in allergic rhinitis--effects of cetirizine.

Cheria-Sammari S, Aloui R, Gormand F, Chabannes B, Gallet H, Grosclaude M, Melac M, Rihoux JP, Perrin-Fayolle M, Lagarde M, et al.

Centre Hospitalier Lyon-Sud, Laboratoire D'Immuno-allergologie, Unite INSERM U352, Pierre-Benite, France.

BACKGROUND: Mucosal inflammatory processes in late phase of allergic diseases involve cytokine production, cell adhesion molecule overexpression and release of inflammatory mediators with chemotactic activity, such as leukotriene B4 (LTB4). We had previously observed increased production of LTB4 by neutrophils in patients with allergic rhinitis and discussed the role of granulocyte macrophage-colony stimulating factor (GM-CSF) priming. Some antihistaminic compounds were shown to diminish the production of leukotrienes by neutrophils. OBJECTIVES: In a first step, we evaluated in ex vivo and in vitro studies, the effects of cetirizine on LTB4 production by blood neutrophils from allergic and healthy subjects. In a second step, we studied the in vitro effect of cetirizine on LTB4 production by neutrophils from healthy subjects during GM-CSF priming of these cells. METHODS: Neutrophils from both populations were purified from venous blood and LTB4 production was measured using high performance liquid cromatography (HPLC) method. RESULTS: In ex vivo studies, cetirizine treatment induced a decreased LTB4 production by neutrophils in allergic rhinitis. This effect of decreased LTB4 production was reproduced in vitro with 10(-8)-10(-6)M cetirizine. Nevertheless, this anti-H1 compound had no effect on neutrophil priming with GM-CSF. CONCLUSION: As LTB4 is an important chemotactic factor, Cetirizine could act on inflammatory cell recruitment by inhibiting LTB4 production by neutrophils.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7584684&dopt=Abstract cetirizine Zyrtec



Zyrtec
Cetirizine pharmacokinetics and pharmacodynamics in primary biliary cirrhosis.

Simons FE, Watson WT, Minuk GY, Simons KJ.

Health Sciences Clinical Research Centre, Faculty of Medicine, University of Manitoba, Winnipeg, Canada.

The new H1-receptor antagonist, cetirizine, is eliminated primarily unchanged by renal excretion and is thus potentially useful for relief of pruritus in patients with hepatic dysfunction, in whom many H1-receptor antagonists are contraindicated. The authors studied the elimination of cetirizine in six patients with primary biliary cirrhosis. In contrast to data obtained in healthy adults with normal hepatic function reported in the medical literature, they found that the mean serum elimination half-life value of cetirizine, 13.8 +/- 1.8 hours, was longer, and the mean clearance rate, 0.44 +/- 0.10 mL/min/kg, was lower (P < .05). The mean peak serum cetirizine concentration, 498 +/- 118 ng/mL, was higher, the mean area under the curve, 6438 +/- 1621 ng/mL/hr, was larger, and the mean fraction of the dose excreted as unchanged cetirizine in the urine, .32 +/- .14, was lower (P < .05). The duration of action of cetirizine was prolonged, as evidenced by significant suppression of the histamine-induced wheal and flare for 48 and 72 hours, respectively, after a single dose. Cetirizine elimination was impaired in patients with hepatic dysfunction.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7693767&dopt=Abstract cetirizine Zyrtec



Zyrtec
In vitro effect of cetirizine on PGE2 release by rat peritoneal macrophages and human monocytes.

Roch-Arveiller M, Tissot M, Idohou N, Sarfati G, Giroud JP, Raichvarg D.

Departement de Pharmacologie, CNRS URA 1534, Paris, France.

Cetirizine was first described as a specific anti-H1 molecule displaying potent antiallergic activity. It was later found that its pharmacological properties extended to cellular actions as on eosinophil recruitment at inflammatory sites in allergic patients. Monocytes and macrophages participate in allergic mechanisms, particularly through high affinity H1 and H2 membrane receptors and generation of pro- and anti-inflammatory agents; among them histamine-induced factors, IL-1 and prostanoids are of importance. The aim of this work was to investigate the effect exerted by various concentrations of cetirizine (0.1-10 micrograms/ml) applied in vitro to human monocytes and peritoneal rat macrophages cultured for 24 h. Peritoneal macrophages were collected either from normal or experimentally inflamed rats. Human monocytes, isolated from peripheral blood, were studied either in a resting state or after stimulation by LPS from Escherichia coli (1 and 10 micrograms/ml). Cetirizine (10 micrograms/ml) significantly enhanced IL-1 release by human monocytes stimulated by a weak LPS concentration (1 microgram/ml) but could not modify the maximal increase of IL-1 release induced by 10 micrograms/ml of LPS. It did not exert any effect on resting cells. Cetirizine (0.1-10 micrograms/ml) enhanced PGE2 release by resting human monocytes. Concentrations of 1 and 10 micrograms/ml enhanced PGE2 release by LPS-stimulated monocytes, and by healthy and inflamed rat macrophages. This effect was concentration-dependent. Our findings point to an anti-inflammatory action of cetirizine via PGE2 release and histamine H2 interactions. Cetirizine did not directly modify IL-1 generation by resting monocytes but the IL-1 production observed after LPS stimulation could promote the mechanisms by which PGE2 is released.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7741033&dopt=Abstract cetirizine Zyrtec



Zyrtec
Effect of ZCR-2060, an antiallergic agent, on antigen-induced immediate- and late-phase increases in airway resistance in sensitized guinea pigs.

Abe T, Yoshida K, Omata T, Segawa Y, Matsuda K, Nagai H.

Department of Pharmacology, Gifu Pharmaceutical University, Japan.

The effect of 2-[2-[4-(diphenylmethyl)-1-piperadinyl]ethoxy] benzoic acid maleate (ZCR-2060) on passive systemic anaphylaxis (PSA) and antigen-induced immediate- and late-phase increase in airway resistance (Rrs) in either passively or actively sensitized guinea pigs were investigated. ZCR-2060 inhibited PSA in guinea pigs. ID50 values of ZCR-2060, ketotifen, terfenadine and cetirizine on PSA were 0.03, 0.02, 0.8 and 0.3 mg/kg, respectively, when administered orally 1 h before the antigen challenge. The protective effect of ZCR-2060 was observed until 12 h before the antigen challenge. Aeroantigen-induce immediate increase in Rrs in passively sensitized guinea pigs with and without metyrapone treatment was inhibited by ZCR-2060, ketotifen, terfenadine and cetirizine. In contrast, prednisolone did not affect the aeroantigen-induced immediate increase in Rrs in animals not treated with metyrapone, but significantly inhibited the metyrapone-induced enhanced immediate response. In actively sensitized animals, the immediate- and late-phase increases in Rrs were observed within 30 min and between 3 and 8 h after the aeroantigen challenge. Pretreatment with metyrapone accelerated both antigen-induced responses. ZCR-2060 (1 mg/kg) significantly inhibited both responses. Ketotifen (1 mg/kg), terfenadine (10 mg/kg) and prednisolone (10 mg/kg) significantly the inhibited the late-phase response, but did not affect the immediate-phase response. In contrast, Cetirizine (10 mg/kg) did not affect either response. The effect of ZCR-2060 on late-phase response was stronger than that of ketotifen, terfenadine and cetirizine, and was almost the same as that of prednisolone. These results suggest that ZCR-2060 has a potent protective effect on immediate- and late-phase increases in Rrs.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7812169&dopt=Abstract cetirizine Zyrtec



Zyrtec
[Effect of cetirizine therapy on the rate of adverse reactions to specific desensitization]

[Article in Polish]

Kruszewski J, Zaras E.

Kliniki Chorob Zakaznych Instytutu Medycyny Wewnetrznej Centralnego Szpitala Klinicznego WAM, Warszawie.

An effect of cetirizine--one of antihistaminic agents--on the rate of adverse reactions to the specific desensitization has been evaluated in patients with atopic respiratory diseases. The study included 270 patients desensitized in 1988-1993 for the atopic diseases due to hypersensitivity to grass pollens and Dermatophagoides pteronyssinus. Standard Alvac-P. Pollinex, and Alvac-S HDM vaccines have been used. Occurrence and severity of the adverse reactions noted during 3,368 injections of vaccines have been analysed. Frequency and adverse reactions severity have been compared for two periods--1988-1990 when patients have not been given antihistaminic agent, and 1991-1993--when ceterizine has been administered during the whole period of desensitization. It has been found that simultaneous cetirizine administration decreases frequency and severity of adverse reaction to the used vaccines. Such a procedure may be recommended to patients with advance hypersensitivity given vaccines in out-patient clinics.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7854995&dopt=Abstract cetirizine Zyrtec



Zyrtec
Enhanced cancer growth in mice administered daily human-equivalent doses of some H1-antihistamines: predictive in vitro correlates.

Brandes LJ, Warrington RC, Arron RJ, Bogdanovic RP, Fang W, Queen GM, Stein DA, Tong J, Zaborniak CL, LaBella FS.

Department of Medicine, Manitoba Institute of Cell Biology, University of Manitoba, Winnipeg, Canada.

BACKGROUND: Present studies of drug-induced tumor growth promotion have evolved from earlier investigations into the mechanism of action of N,N-diethyl-2-[4-(phenylmethyl)phenoxy[ethanamine.HCl, a tamoxifen derivative which potently inhibits lymphocyte mitogenesis in vitro and stimulates tumor growth in vivo. It is thought that potency to bind to intracellular histamine receptors (HIC), some of which are on cytochromes P450, may correlate with tumor growth-promoting activity. PURPOSE: We assessed the effectiveness of five in vitro assays in predicting in vivo tumor growth stimulation by the H1-antihistamines loratadine, astemizole, cetirizine, hydroxyzine, and doxylamine. METHODS: Potency of each agent was ranked 1-5 in each of the following in vitro assays: 1) inhibition of [3H]histamine binding to microsomal HIC, 2) inhibition of histamine binding to microsomal P450, 3) inhibition of the P450-catalyzed demethylation of aminopyrine, 4) inhibition of lymphocyte mitogenesis, and 5) stimulation of tumor colony formation. An overall rank score was assigned to each drug and correlated with tumor growth stimulation in vivo. Two laboratories conducted in vivo studies in a blinded fashion. Female C57BL and C3H mice were given a subcutaneous injection on day 1 of syngeneic B16F10 melanoma cells (5 x 10(5)) or C-3 fibrosarcoma cells (1 x 10(5)), respectively. Mice were randomly assigned to treatment groups, then received a single, daily intraperitoneal injection of an estimated human-equivalent dose (or range of doses) of antihistamine or vehicle control for 18-21 days before being killed. Tumors were surgically removed and wet weights compared statistically among groups. RESULTS: The cumulative potency of each drug in affecting tumor growth or growth mechanisms in the five in vitro assays ranked as follows: Loratidine and astemizole ranked highest and were equally potent, followed in decreasing order by hydroxyzine, doxylamine, and cetirizine. A significant correlation (r = .97; P < .02) was observed between the rank order of potency of the antihistamines in all five in vitro assays and the rank order to enhance tumor growth in vivo: Loratidine and astemizole significantly (P < .001) promoted the growth of both melanoma and fibrosarcoma, hydroxyzine significantly (P < .001) promoted the growth of melanoma, while doxylamine and cetirizine did not promote the growth of either tumor. CONCLUSION: Data demonstrate that the in vitro assays predicted the propensity of each H1-antihistamine to stimulate cancer growth in vivo. IMPLICATION: These in vitro tests may prove valuable to screen potential tumor growth promoters.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7909571&dopt=Abstract cetirizine Zyrtec