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Serum tryptase in allergic rhinitis: effect of cetirizine and fluticasone propionate treatment.

Bruno G, Andreozzi P, Bracchitta S, Graf U, Santangelo G, Zaino S, Gaston N.

Dipartimento di Medicina Interna, Fondazione A. Cesalpino, Universita degli Studi La Sapienza, Roma, Italia. guglielmo.bruno uniroma1.it

PURPOSE: A specific reaction against several kinds of inhalant allergens characterizes allergic rhinitis. Mast cells play a crucial role in the allergic inflammation releasing histamine and other mediators. Tryptase is considered to be a specific marker of mast cell activation. This study was devoted to evaluate the serum tryptase in allergic rhinitis and to evaluate the effect of cetirizine and fluticasone propionate on mast cell activation. 13 subjects, suffering from perennial allergic rhinitis induced by Dermatophagoides pteronyssinus, were studied. MATERIALS AND METHODS: Tryptase serum levels were detected by the fluoroenzymeimmunoassay (Pharmacia & Upjohn AB, Uppsala, Sweden). Blood samples were taken four times: before starting the study, after two weeks of 10 mg cetirizine treatment once a day, after two weeks of wash-out, and again after 15 days of 100 micrograms intranasal fluticasone propionate therapy twice a day. RESULTS: In allergic rhinitis, the basal values of serum tryptase (M +/- SD: 6.1 +/- 2.4 micrograms/l) were significantly higher than in controls (M +/- SD: 3.0 +/- 1.2 micrograms/l). After the antihistamine treatment, tryptase values (M +/- SD: 4.4 +/- 1.8 micrograms/l) decreased significantly (p < 0.001). After the stop of antihistamine treatment, tryptase levels increased (M +/- SD: 5.5 +/- 2.6 micrograms/l, p < 0.001). After the topical corticosteroid treatment, tryptase values decreased again significantly (M +/- SD: 4.5 +/- 3.1 micrograms/l, p < 0.04). CONCLUSIONS: All these data seem to confirm the effective action of cetirizine and fluticasone propionate on tryptase serum levels. While the action of corticosteroid is well known, the action of cetirizine is still to define, considering the recent reports on anti-inflammatory effect of the second generation of H1 receptor antagonists. Further studies are necessary to understand if the pharmacological effect on tryptase is a specific one of cetirizine, or if it is common to other anti-H1 molecules.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11794849&dopt=Abstract cetirizine Zyrtec



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Binding characteristics of cetirizine and levocetirizine to human H(1) histamine receptors: contribution of Lys(191) and Thr(194).

Gillard M, Van Der Perren C, Moguilevsky N, Massingham R, Chatelain P.

UCB S.A. Pharma Sector, In Vitro Pharmacology, Braine l'Alleud, Belgium. michel.gillard ucb-group.com

Competition experiments with [(3)H]mepyramine showed that cetirizine and its enantiomers, levocetirizine and (S)-cetirizine, bound with high affinity and stereoselectivity to human H(1) histamine receptors (K(i) values of 6, 3, and 100 nM, respectively). Cetirizine and levocetirizine were 600-fold more selective for H(1) receptors compared with a panel of receptors and channels. Binding results indicated that the interaction between cetirizine, its enantiomers, and histamine is compatible with a competitive behavior, in contrast with the noncompetitive profile of cetirizine and levocetirizine observed in isolated organs. Binding kinetics provided a suitable explanation for this observation, because levocetirizine dissociated from H(1) receptors with a half-time of 142 min; that of (S)-cetirizine was only 6 min, implying that the former could act as a pseudo-irreversible antagonist in functional studies. The carboxylic function of levocetirizine seemed responsible for its long dissociation time. Indeed, hydroxyl or methyl ester analogs dissociated more rapidly from H(1) receptors, with half-times of 31 min and 7 min, respectively. The importance of the carboxylic function of levocetirizine for the interaction with the H(1) receptor was further supported by the results from the mutation of Lys(191) to Ala(191). This mutation decreased the dissociation half-time of levocetirizine from 142 to 13 min and reduced its affinity from 3 to 12 nM, whereas the affinity and dissociation kinetics of hydroxyl and methyl ester analogs were hardly affected. The mutation of Thr(194) reduced the binding stereoselectivity by selectively enhancing the affinity of the distomer.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11809864&dopt=Abstract cetirizine Zyrtec



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Lack of Clinically Relevant Interaction of Cetirizine on Theophylline Disposition in Healthy Subjects: A Placebo-Controlled Study.

Hulhoven R, Desager JP, Harvengt C.

Laboratoire de Pharmacotherapie, Universite Catholique de Louvain, B-1200 Brussels, Belgium.

The possible interaction of a steady-state cetirizine treatment, a nonsedating H(1) antihistamine, on the disposition of a single I.V. infusion of theophylline was studied in six healthy male volunteers. As a corollary, it was checked whether this single theophylline administration modified the steady-state condition of cetirizine. A three-period, two-treatment, crossover design was used, each period being separated by a washout of 1 week. Each period consisted of the oral administration of 10 mg cetirizine or of a matching placebo every 12 h for 3(1/2) days, the last intake being followed, 1 hour later, by a single 1-h I.V. infusion of 240 mg theophylline or of placebo. The sequence of treatments (A = cetirizine + theophylline placebo, B = cetirizine placebo + theophylline, C = cetirizine + theophylline) was alloted by a double Latin-square randomization. The repeated administration of cetirizine induced a 3% decrease of the urinary elimination of unchanged theophylline; the total body clearance of theophylline was marginally (+5%) and not significantly modified. Theophylline slightly lengthened the elimination half-life of cetirizine (from 8.3 to 9.9 h), without modification of its apparent total body clearance; the half-life of cetirizine remaining in the normal range. These subtle modifications are not clinically relevant and it may, thus, be considered that cetirizine exerts no pertinent interaction on theophylline disposition.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11850652&dopt=Abstract cetirizine Zyrtec



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Cetirizine decreases interleukin-4, interleukin-5, and interferon-gamma gene expressions in nasal-associated lymphoid tissue of sensitized mice.

Jin HR, Okamoto Y, Matsuzaki Z, Endo S, Ito E.

Department of Otolaryngology, College of Medicine, Chungbuk National University, Korea.

Although the action of cetirizine dihydrochloride (cetirizine), a potent histamine H1 receptor antagonist, has been well known, its effect on the cytokine profiles in the nasal immune inductive site has not been elucidated yet. We studied the effect of cetirizine on the cytokine profiles in the nasal-associated lymphoid tissue (NALT), which is a principal mucosal lymphoid tissue of the respiratory tract in rodents. Two different doses of cetirizine were given intraorally for 5 days before the nasal challenge of ovalbumin in sensitized mice. The sensitized group was given normal saline instead of cetirizine, and the nonsensitized group had no sensitization or medication. The cytokine gene expressions in the NALT taken from the mice were investigated with real-time quantitative reverse-transcription polymerase chain reaction. The effect of cetirizine on the allergic symptom score, histamine threshold, and the eosinophil count in the nasal septal mucosa were examined also. Compared with the normal mice, the sensitized mice showed significantly increased levels of interleukin (IL)-4 and IL-5 gene expression although the increase of interferon (INF)-gamma gene expression was not significant. In the cetirizine groups, the levels of expression of IL-4, IL-5, and INF-gamma in the NALT were significantly decreased compared with the sensitized group. The cetirizine groups also showed decreased allergic symptom score, histamine threshold, and eosinophil count in the nasal septal mucosa compared with the sensitized group. In conclusion, cetirizine reduced the levels of expression of IL-4, IL-5, and INF-gamma in the NALT of ovalbumin-sensitized mice. Cetirizine also reduced the acute allergic symptom, histamine sensitivity, and eosinophil count in the nasal septal mucosa.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11895193&dopt=Abstract cetirizine Zyrtec



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Applications of derivative UV spectrophotometry for the determinations of cetirizine dihydrochloride in pharmaceutical preparations.

Drozd J, Hopkala H, Misztal G, Paw B.

Department of Medicinal Chemistry, Medical University, Lublin, Poland.

A method for the determination of cetirizine dihydrochloride in pharmaceuticals by first-, second-, third- and fourth- order derivative spectrophotometry is described, using "peak-peak" (P-P), and "peak-zero" (P-0) measurements. The calibration curves are linear within the concentration range of 7.5-22.5 microg ml(-1) for cetirizine dihydrochloride. The procedure is simple, rapid and the results are reliable.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12026109&dopt=Abstract cetirizine Zyrtec



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Cetirizine and levocetirizine inhibit eotaxin-induced eosinophil transendothelial migration through human dermal or lung microvascular endothelial cells.

Thomson L, Blaylock MG, Sexton DW, Campbell A, Walsh GM.

Department of Medicine & Therapeutics, University of Aberdeen Medical School, Aberdeen, UK.

BACKGROUND: Several second-generation antihistamines have documented anti-inflammatory effects which appear independent of H1-receptor blockade. We investigated the inhibitory effect of cetirizine and its active enantiomer levocetirizine on eosinophil transendothelial migration (TEM) through monolayers of normal human dermal microvascular endothelial cells (HMVEC-d) or human lung microvascular endothelial cells (HMVEC-l). METHODS: HMVEC-d or HMVEC-l were grown to confluence on micropore filters in transwells inserted into a 24-well tissue culture dish. Eosinophils were isolated by density gradient centrifugation and negative immunomagnetic selection. Untreated eosinophils or eosinophils pre-incubated (30 min at 37 degrees C) with a concentration range of cetirizine or levocetirizine (10-5 to 10-9 m) were added to the upper chamber of the transwell which was incubated for 60 min at 37 degrees C. Both spontaneous eosinophil TEM and TEM to 100 ng/mL of human eotaxin in the lower chamber were assessed. RESULTS: Between 8 and 10% of the eosinophils added to the upper chamber underwent spontaneous TEM through HMVEC-d or HMVEC-l. The addition of eotaxin to the lower chamber enhanced eosinophil TEM through HMVEC-d or HMVEC-l monolayers to over 20%, i.e. an enhanced TEM of approximately 100% in each case. Pre-incubation of eosinophils with cetirizine or levocetirizine dose-dependently inhibited eosinophil TEM to eotaxin through both HMVEC-d or HMVEC-l with total inhibition of eotaxin-induced TEM observed at 10-8 m for HMVEC-d and 10-7 m for HMVEC-l. Both drugs gave a reduced but significant inhibition of eosinophil TEM at lower concentrations. No concentration of cetirizine or levocetirizine had any significant effect on expression of CD11b, CD18 or CD49d by either resting or eotaxin-stimulated eosinophils. Furthermore, no effect on spontaneous eosinophil TEM, or eosinophil viability was seen with any concentration of cetirizine or levocetirizine. CONCLUSION: Levocetirizine inhibits eotaxin-induced eosinophil TEM through both dermal and lung microvascular endothelial cells suggesting that, like cetirizine, levocetirizine has potential anti-inflammatory effects.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12190657&dopt=Abstract cetirizine Zyrtec