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Mast cell mediators other than histamine induce pruritus in atopic dermatitis patients: a dermal microdialysis study.

Rukwied R, Lischetzki G, McGlone F, Heyer G, Schmelz M.

Department of Physiology and Experimental Pathophysiology, University of Erlangen/Nurnberg, Universitatsstr. 17, D-91054 Erlangen, Germany.

While histamine is the crucial mediator of pruritus in type 1 allergic reactions, its role in atopic dermatitis (AD) is unclear. In this study, the role of mast cell mediators in protein extravasation and pruritus was evaluated using intradermal microdialysis. The microdialysis capillaries were used to apply the mast cell degranulating substance compound 48/80 (C48/80; 0.05%) or histamine (0.01%) and also to deliver H1-blockers (cetirizine, 200 microg mL-1) in nine AD patients and nine controls. Large pore size membranes (3000 kDa) enabled simultaneous analysis of protein extravasation. Itch sensation was measured psychophysically and weal and flare reaction were evaluated planimetrically. Protein extravasation induced by histamine and C48/80 was significantly reduced in AD patients. Blockade of H1-receptors by cetirizine significantly reduced C48/80-induced protein extravasation in AD patients and controls to an identical level. C48/80-induced pruritus was abolished by cetirizine in controls, whereas pruritus in AD patients was unchanged after H1 blockade. We conclude that mast cell mediators others than histamine are involved in C48/80-induced pruritus in AD patients. Whether the reduced capacity of AD patients to induce protein extravasation is of pathophysiological relevance for pruritus remains to be established.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10848733&dopt=Abstract cetirizine Zyrtec



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Effect of a novel anti-allergic agent, HSR-609, on antigen-induced airway hyperresponsiveness in mice.

Musoh K, Maeda Y, Tanaka H, Inagaki N, Nagai H.

Department of Pharmacology, Gifu Pharmaceutical University, Gifu, Japan.

The effects of a newly synthesized anti-allergic agent, HSR-609, on allergic airway hyperresponsiveness and airway inflammation have been studied in sensitized mice. The effects were compared with those of two histamine H(1) receptor antagonists, cetirizine and terfenadine, and prednisolone. Three inhalations of antigen caused an increase in leukocytes (including eosinophils) with increases in IL-5 in BALF and airway hyperresponsiveness to acetylcholine in BALB/c mice. All drugs were orally administered once a day for 10 days from the day before the first inhalation of antigen. HSR-609 (10 mg/kg) and prednisolone (5 mg/kg) significantly inhibited the antigen-induced airway hyperresponsiveness, whereas cetirizine (10 mg/kg) or terfenadine (100 mg/kg) did not affect this airway response. At the same time HSR-609 inhibited the antigen-induced eosinophilia and IL-5 production in BALF. Prednisolone also showed an inhibitory effect on the airway eosinophilia and IL-5 production but not cetirizine and terfenadine in the same experiments. In addition, HSR-609 (p.o.) dose-dependently suppressed the accumulation of eosinophils elicited by antigen-stimulated D10G4.1 cells, a murine Th2 clone, in peritoneal cavity lavage fluid in AKR/J mice. These results suggest that HSR-609 inhibits allergic airway hyperresponsiveness to acetylcholine probably because of the inhibition of Th2-dependent eosinophilia caused by IL-5. In addition, effects of HSR-609 were different from those of cetirizine and terfenadine concerning the inhibition of antigen-induced airway hyperresponsiveness in mice. Copyright 2000 S. Karger AG, Basel

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10940779&dopt=Abstract cetirizine Zyrtec



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Stereoselective determination of cetirizine and studies on pharmacokinetics in rat plasma.

Choi SO, Lee SH, Kong HS, Kim EJ, Choo HY.

Department of Drug Evaluation, Korea Food and Drug Administrations, Seoul, South Korea. sunok7 daum.net

Enantiomers may confer benefits over racemates in therapeutic uses and we developed a chiral separation method of cetirizine enantiomers, a second generation H1 histamine receptor antagonist, in rat plasma. alpha1-Acidglycoprotein based chiral stationary phase(AGP-CSP), monitored with UV at 230 nm was used to separate the enantiomers. Observed enantioselectivity (alpha) was 2.0. The AGP-CSP was also used at a preparative scale to isolate the enantiomers with an optical purity of greater than ee 99%. In addition, an analysis was carried out for the cetirizine enantiomers in rat plasma to study the differences of enantiomers in pharmacokinetics. Both (+)- and (-)-cetirizine were separated using a reversed-phase column of AGP, and were detected at the range of 2.5-200 microg ml(-1) in plasma. Although there was no recognizable differences in pharmacokinetics between the enantiomers in rat, the method appears to be useful for their pharmacokinetic studies.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10985583&dopt=Abstract cetirizine Zyrtec



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Stability indicating HPTLC method for the simultaneous determination of pseudoephedrine and cetirizine in pharmaceutical formulations.

Makhija SN, Vavia PR.

Pharmaceutical Division, University Department of Chemical Technology (Autonomous), University of Mumbai, Nathalal Parikh Marg, Matunga, 400 019, Mumbai, India.

The combination of pseudoephedrine and cetirizine is widely used in the treatment of allergic rhinitis. A rapid, selective and stability indicating high performance thin layer chromatographic method was developed and validated for their simultaneous estimation in pharmaceutical dosage forms. The method employed TLC aluminium plates precoated with silica gel 60F-254 as the stationary phase. The solvent system consisted of ethyl acetate-methanol-ammonia (7:1.5:1, v/v/v). This system was found to give compact spots for both pseudoephedrine (Rf value of 0.69+/-0.01) and cetirizine (Rf value of 0.38+/-0.01). Also the degraded products were well separated from the pure drugs. Spectrodensitometric scanning-integration was performed at a wavelength of 240 nm. The polynomial regression data for the calibration plots showed good linear relationship with r(2)=0.9947 in the concentration range of 10-26 microg for pseudeophedrine and 200-1200 ng for cetirizine with r(2)=0.9973. The method was validated for precision, accuracy, ruggedness and recovery. The minimum detectable amounts were found to be 2 microg and 500 pg for pseudoephedrine and cetirizine, respectively. The limits of quantitation were found to be 6 microg for pseudoephedrine and 800 pg for cetirizine. Both the drugs do not undergo degradation under acidic and basic conditions. The samples degraded with hydrogen peroxide showed additional peaks at Rf values of 0.75 and 0.28 for pseudoephedrine and cetirizine, respectively. This indicates that both the drugs are susceptible to oxidation. Statistical analysis proves that the method is reproducible and selective for the simultaneous estimation of pseudoephedrine and cetirizine. As the method could effectively separate the drugs from their degradation products, it can be employed as a stability indicating one.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11377047&dopt=Abstract cetirizine Zyrtec



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Lipophilicity behaviour of the Zwitterionic antihistamine cetirizine in phosphatidylcholine liposomes/water systems.

Plember van Balen G, Caron G, Ermondi G, Pagliara A, Grandi T, Bouchard G, Fruttero R, Carrupt PA, Testa B.

Institut de Chimie Therapeutique, Section de Pharmacie, Universite de Lausanne, Switzerland.

PURPOSE: The partitioning of cetirizine in a phosphatidylcholine liposomes/water system was compared with that of hydroxyzine and acrivastine to gain insight into the mechanisms of interaction of its various electrical species with membranes. METHODS: The lipophilicity profiles of the compounds were obtained from equilibrium dialysis and potentiometry, and compared with changes in NMR relaxation rates. RESULTS: The neutral form of hydroxyzine interacted mainly via hydrophobic interactions with the bilayer lipid core of the membrane, whereas for the cationic form both hydrophobic and electrostatic interactions were involved. Zwitterionic and anionic cetirizine were less lipophilic than its cation, which behaved like the corresponding species of hydroxyzine. Zwitterionic cetirizine interacted more by weak electrostatic interactions with the polar headgroups of phospholipids than by hydrophobic interactions with the membrane interior. The lipophilicity of its anion reflected the balance of repulsive electrostatic interactions between the carboxylate and phosphate groups and the hydrophobic interactions with the lipid core. CONCLUSION: The study confirms that various mechanisms influence the interaction of solutes with liposomes. Combining experimental techniques and using suitable reference compounds proves useful.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11465428&dopt=Abstract cetirizine Zyrtec



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Dissociable effects of histamine H1 antagonists on reaction-time performance in rats.

Blokland A, Scholtissen B, Vermeeren A, Ramaekers J.

Maastricht Brain and Behaviour Institute, Faculty of Psychology, Section Neurocognition, Maastricht University, PO Box 616, 6200 MD Maastricht, The Netherlands. a.blokland psychology.unimaas.nl

The most pronounced side effect of antiallergic histaminergic drugs (H1 antagonists) is sedation. These effects have been linked with the effects of histaminergic drugs on central H1 receptors. In the present study, we investigated the dose-response relationship of different antihistamines on the performance in a reaction-time task that has been developed for rats. The dose-response relationship of diphenhydramine, cetirizine and terfenadine were examined for the various behavioural measures in this task (i.e., reaction time, motor time, premature responses and number of trials completed). In addition, the effects of scopolamine were assessed to evaluate the cholinergic profile in this task. Diphenhydramine did not reliably affect the reaction time, but increased the motor time and the proportion of premature responses, and decreased the number of trials completed in a session. A low dose of cetirizine decreased the reaction time, whereas an increase in reaction time was found for the high dose. The motor time was increased after both doses of cetirizine. Terfenadine did not affect the responding of rats in the reaction-time task at the doses tested. The effects of scopolamine were very similar to those of diphenhydramine. The reaction-time task used in this study was able to dissociate different types of antihistamines on aspects of psychomotor function, which were likely to be related to central muscarinic or H1 antagonism. These findings suggest that the reaction-time task may be a sensitive tool for assessing effects of drugs on psychomotor function.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11701216&dopt=Abstract cetirizine Zyrtec