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Effects of second generation of histamine H1 antagonists, cetirizine and ebastine, on the antitussive and rewarding effects of dihydrocodeine in mice.

Kamei J, Morita K, Miyata S, Onodera K.

Department of Pathophysiology & Therapeutics, School of Pharmacy and Pharmaceutical Sciences, Hoshi University, Shinagawa-ku, 142-8501, Tokyo, Japan.

RATIONALE: Little information is available about the interaction between dihydrocodeine and second-generation antihistamine drugs such as cetirizine and ebastine, with particular reference to the rewarding effect of dihydrocodeine. OBJECTIVE: The effects of second generation histamine H(1) antagonists, such as cetirizine and ebastine on the antitussive and rewarding effect of dihydrocodeine were examined in mice. METHODS: Mice were exposed to a nebulized solution of capsaicin (30 micromol/l) under conscious and identical conditions, using a body plethysmograph. The coughs produced during a 3-min exposure period were counted. Effects of H(1) antagonists on the reinforcing effect of dihydrocodeine were assessed by using the conditioned place preference procedure in mice. RESULTS: The antitussive effect of dihydrocodeine was enhanced by the simultaneous administration of either cetirizine or ebastine. There was no statistical difference between the ED(50) of dihydrocodeine in combination with ebastine and that of dihydrocodeine in combination with cetirizine. Concurrent dosing of dihydrocodeine and ebastine produced a significant place preference. This behavioral potentiation was antagonized by SCH23390, a dopamine D(1) antagonist. Moreover, ebastine enhanced the central dopamine turnover ratio, but cetirizine could not, in this study. CONCLUSION: Taken together, the potentiation of place preference of dihydrocodeine with ebastine may be due, at least in part, to stimulation of the central dopaminergic system via D(1) receptors. However, combination of dihydrocodeine with cetirizine does not potentiate place preference at all, nor does it potentiate the central dopaminergic system. Thus, it is likely that cetirizine may be a useful constituent in opioid-containing, antitussive preparations that would not potentiate the development of psychological dependence.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12536265&dopt=Abstract cetirizine Zyrtec



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P-glycoprotein limits the brain penetration of nonsedating but not sedating H1-antagonists.

Chen C, Hanson E, Watson JW, Lee JS.

Pfizer Global Research and Development, Pfizer Inc., Groton, Connecticut 06340, USA. cuiping_chen groton.pfizer.com

The present study evaluates the impact of P-glycoprotein (P-gp) on plasma-brain disposition and transepithelial transport of sedating versus nonsedating H1-antagonists using multidrug-resistant (mdr) gene 1a and 1b (mdr1a/b) knockout (KO) mice and human MDR1-transfected Madin-Darby canine kidney (MDCK) cells. Three nonsedating (cetirizine, loratadine, and desloratadine) and three sedating (diphenhydramine, hydroxyzine, and triprolidine) H1-antagonists were tested. Each compound was administered to KO and wild-type (WT) mice intravenously at 5 mg/kg. Plasma and brain drug concentrations were determined by liquid chromatography-mass spectrometry analysis. Mean pharmacokinetic parameters (CL, V(ss), and t(1/2)) were obtained using WinNonlin. In addition, certirizine, desloratadine, diphenhydramine, and triprolidine (2 microM) were tested as substrates for MDR1 using MDR1-MDCK cells. The bidirectional apparent permeability was determined by measuring the amount of compound at the receiving side at 5 h. The brain-to-plasma area under the curve (AUC) ratio was 4-, 2-, and >14-fold higher in KO compared with WT mice for cetirizine, loratadine, and desloratadine, respectively. In contrast, the brain-to-plasma AUC ratio between KO and WT was comparable for hydroxyzine, diphenhydramine, and triprolidine. Likewise, the efflux ratio between basolateral to apical and apical to basolateral was 4.6- and 6.6-fold higher in MDR1-MDCK than the parental MDCK for certirizine and desloratadine, respectively, whereas it was approximately 1 for diphenhydramine and triprolidine. Our results demonstrate that sedating H1-antagonists hydroxyzine, diphenhydramine, and triprolidine are not P-gp substrates. In contrast, nonsedating H1-antagonists cetirizine, loratadine, and desloratadine are P-gp substrates. Affinity for P-gp at BBB may explain the lack of central nervous system side effects of modern H1-antagonists.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12584158&dopt=Abstract cetirizine Zyrtec



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Cetirizine, a second-generation H1 antagonist, modulates Rantes and MCP-1 levels in allergic rhinitis.

Bruno G, Andreozzi P, Graf U, Tega F, Santangelo G, Barucco M, Bruno A, Bracchitta S.

Allergologia e Immunologia Clinica, Dip Medicina Clinica, Università di Roma, Italy.

Chemokines and their receptors are involved in several allergic diseases. We measured RANTES and MCP-1 levels in sera of allergic rhinitis patients, and also we evaluated the effect of cetrizine, a second-generation H1 antagonist, on these chemoattractant proteins. 15 subjects were studied (10 males and 5 females; mean age: 26.7 years). They were suffering from perennial or seasonal allergic rhinitis induced by Dermatophagoides pteronyssinus (8 patients) or by grasses (7 patients). RANTES and MCP-1 serum levels were detected with an enzyme immunoassay before and after two weeks of treatment with 10 mg of cetirizine daily, and again after two weeks of washout. Baseline serum levels of RANTES and MCP-1 chemokines were significantly higher (p < 0.02 and p = 0.007, respectively) in allergic patients than in the healthy control group. Cetirizine resulted in a significant decrease in RANTES (p < 0.02) and MCP-1 (p = 0.003) versus baseline values. There is an increase in RANTES and MCP-1 in allergic rhinitis, which is counteracted by cetirizine.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12590873&dopt=Abstract cetirizine Zyrtec



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Serum tryptase in allergic rhinitis: effect of cetirizine treatment.

Bruno G, Andreozzi P, Magrini L, Santangelo G, Graf U, Angelino A.

Dept Internal Medicine, University of Rome, La Sapienza, Rome, Italy.

Activated mast cells release a large range of potent mediators of allergic inflammation, including proteases. The tryptase serum levels were evaluated in 13 subjects suffering from allergic perennial rhinitis. Moreover the effects of cetirizine treatment on serum tryptase were studied using the UniCap™ tryptase fluoroenzymeimmunoassay. In allergic patients the serum tryptase values (M±SD: 6.1 ± 2.4 μg/L) were significantly (p < 0.02) higher than the values detected in controls (3.0 ± 1.2 μg/L). In allergic rhinitis, after antihistamine treatment, tryptase values (4.4 ± 1.8 μg/L) decreased significantly (p < 0.001). After two weeks from the cetirizine stop, the tryptase levels increased again (5.5 ± 2.6 μg/l). The results demonstrate that mast cells are constantly activated in perennial allergic rhinitis. The antihistamine treatment is effective in reducing the tryptase release from mast cells, but the mechanism of action of cetirizine is still to understand.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12604015&dopt=Abstract cetirizine Zyrtec



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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. jllupia almirallprodesfarma.com

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.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12642964&dopt=Abstract cetirizine Zyrtec



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Blood distribution of levocetirizine, a new non-sedating histamine H1-receptor antagonist, in humans.

Bree F, Thiault L, Gautiers G, Benedetti MS, Baltes E, Rihoux JP, Tillement JP.

Laboratoire de Pharmacologie, Faculte de Medecine, Creteil-Cedex, France. bree univ-paris12.fr

The aim of the present study was to determine (1) the extent of levocetirizine binding to human blood cells, plasma and individual plasma proteins; (2) the parameters for levocetirizine binding to individual plasma proteins both at their physiological concentrations and, for human serum albumin (HSA), at a lower saturating concentration; and (3) to simulate levocetirizine distribution in human blood using the information obtained at physiological haematocrit (H) for blood cells and at physiological concentrations for individual plasma proteins. The nature of the main binding sites of HSA, i.e. site I (warfarin) and site II (diazepam), preferentially involved in levocetirizine binding was also investigated. Over the range of therapeutic concentrations and multiples thereof, levocetirizine is extensively bound to blood components, the free fraction remaining constant (6.45%) and the fraction bound to blood cells and to plasma proteins accounting for 27.43 and 66.11%, respectively. The binding of levocetirizine to HSA in the presence of physiological concentrations of non-esterified fatty acids (NEFAs) is the main interaction of levocetirizine in blood (50.68% of overall blood binding). This interaction is fatty acid sensitive, with decreasing concentrations of NEFA increasing the amount of bound drug and vice versa. Levocetirizine is also bound to alpha1-acid-glycoprotein and high-density lipoproteins (5.17 and 6.89% of overall blood binding, respectively). The displacement of levocetirizine by diazepam is consistent with the binding of this drug to HSA at site II, as diazepam is a specific marker for this site. The binding of levocetirizine to HSA at site II being characterized by a low association constant, other drugs sharing the same site with high association constants cannot displace levocetirizine except at very high plasma concentrations. In any case, at therapeutic concentrations of levocetirizine and at physiological protein concentrations, the observation that none of the levocetirizine binding proteins is saturated suggests that very little or no variation of the free fraction will occur although a different distribution of its bound forms is possible.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12685505&dopt=Abstract cetirizine Zyrtec