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Electrophysiological effects of cetirizine, astemizole and D-sotalol in a canine model of long QT syndrome.

Weissenburger J, Noyer M, Cheymol G, Jaillon P.

Pharmacology Laboratory, Faculte de Medecine St Antoine, Universite Pierre et Marie Curie, Paris, France.

Observations of torsades de pointes during therapy with terfenadine and astemizole has raised concern about the cardiac safety of non-sedating H1-antagonist agents. We compared cetirizine, another compound of that class, to D-sotalol and to astemizole in a model of acquired long QT syndrome. Open-chest surgery was performed in adult beagle dogs anaesthetized with halothane and thiopental. Bradycardia was produced with beta-adrenergic blockade and sinus node crush. Four left ventricular intramyocardial unipolar monophasic action potentials (MAP) were recorded during atrial pacing at basic cycle lengths (BCL) 400-1500 msec, before and during three successive 1-h drug infusions (0.14, 0.45 and 1.4 mg/kg/h for astemizole and cetirizine and 1.1, 2.2 and 4.5 mg/kg/h for D-sotalol). Dose- and bradycardia-dependent prolongations of MAP duration (MAPD) were produced by D-sotalol (P < 0.001) and astemizole (P < 0.001) but not by cetirizine. At BCL 1500 ms, the three infusions of astemizole prolonged endocardial MAPD from 323 +/- 8 msec (mean +/- SE) at baseline to 343 +/- 10, 379 +/- 13 and 468 +/- 26 msec, respectively (n = 9). Sotalol prolonged that MAPD from 339 +/- 6 msec to 377 +/- 7, 444 +/- 15 and 485 +/- 24 msec (n = 7). In contrast, cetirizine did not prolong MAPD: 341 +/- 8 msec at baseline Vs 330 +/- 8, 324 +/- 9 and 323 +/- 11 msec (n = 9). Drug-induced increase in transmural dispersion reached +79 +/- 19 msec after astemizole, +59 +/- 21 msec after D-sotalol and only +7 +/- 11 msec after cetirizine. Runs of ventricular tachycardias and torsades de pointes occurred during dose three of astemizole (5/9 dogs) and D-sotalol (4/7 dogs) but never during cetirizine. In the present model, astemizole and D-sotalol but not cetirizine prolonged MAPD and transmural dispersions of repolarization and produced torsades de pointes. These results suggest that the halothane-anaesthetized bradycardic dog could be a valuable model to discriminate drugs for their class III effects and proarrhythmic potencies.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10444236&dopt=Abstract cetirizine Zyrtec



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Histamine receptors that influence blockage of the normal human nasal airway.

Taylor-Clark T, Sodha R, Warner B, Foreman J.

1Department of Pharmacology, University College London, Gower Street, London WC1E 6BT.

The aim of this study was to investigate the mechanisms by which histamine causes nasal blockage. Histamine, 40-800 mug, intranasally into each nostril, induced significant blockage of the nasal airway in normal human subjects, as measured by acoustic rhinometry.Oral pretreatment with cetirizine, 5-30 mg, the H(1) antagonist, failed to reverse completely the nasal blockage induced by histamine, 400 mug.Dimaprit, 50-200 mug, the H(2) agonist, intranasally, caused nasal blockage, which was reversed by oral pretreatment with ranitidine, 75 mg, the H(2) antagonist.A combination of cetirizine, 20 mg, and ranitidine, 75 mg, caused greater inhibition of the nasal blockage caused by histamine, 400 mug, than cetirizine alone. In the presence of both antagonists, there was residual histamine-induced nasal blockage.R-alpha-methylhistamine (R-alpha-MeH), 100-600 mug, the H(3) agonist, intranasally, caused nasal blockage, which was not inhibited by either cetirizine or ranitidine.Thioperamide, 700 mug, the H(3) antagonist, intranasally, reversed the R-alpha-MeH-induced nasal blockage. Thioperamide alone had no significant action on the nasal blockage induced by histamine, 400 and 1000 mug, but, in the presence of cetirizine, 20 mg, thioperamide further reduced the histamine-induced nasal blockage.Corynanthine, 2 mg, the alpha(1)-adrenoceptor antagonist, administered intranasally, caused nasal blockage.Corynanthine produced a greater increase in nasal blockage when in combination with bradykinin compared to its combination with R-alpha-MeH.There appears to be a contribution of H(1), H(2) and H(3) receptors to histamine-induced nasal blockage in normal human subjects. The sympathetic nervous system actively maintains nasal patency and we suggest that activation of nasal H(3) receptors may downregulate sympathetic activity.British Journal of Pharmacology advance online publication, 31 January 2005; doi:10.1038/sj.bjp.0706118.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15685206&dopt=Abstract cetirizine Zyrtec



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Effects of first- and second-generation histamine-h(1)-receptor antagonists on the pentobarbital-induced loss of the righting reflex in streptozotocin-induced diabetic mice.

Kamei J, Hirano S, Miyata S, Saitoh A, Onodera K.

Department of Pathophysiology and Therapeutics, School of Pharmacy and Pharmaceutical Sciences, Hoshi University.

The second-generation histamine-H(1)-receptor antagonists, such as epinastine and cetirizine, are used as non-sedating antihistamines for treating allergic symptoms due to their poor ability to penetrate blood-brain barrier. Because it has been reported that the blood-brain barrier system is disturbed in diabetes, it is possible that second-generation histamine-H(1)-receptor antagonists may easily penetrate the blood-brain barrier and cause potent sedation in diabetics. In the present study, we investigated the effects of first-generation (diphenhydramine) and second-generation (epinastine and cetirizine) histamine-H(1)-receptor antagonists on the duration of pentobarbital-induced loss of the righting reflex (LORR) in non-diabetic and diabetic mice. Systemic treatment with diphenhydramine (3 - 30 mg/kg, s.c.), and intracerebroventricular treatment with epinastine (0.03 - 0.3 mug/mouse) and cetirizine (0.03 - 0.3 mug/mouse) dose-dependently and significantly increased the duration of pentobarbital-induced LORR in both non-diabetic and diabetic mice. Although systemic treatment with epinastine (3 - 30 mg/kg, s.c.) and cetirizine (3 - 30 mg/kg, s.c.) did not affect the duration of pentobarbital-induced LORR in non-diabetic mice, these treatments significantly prolonged it in diabetic mice. Our results suggest that the systemic administration of second-generation histamine-H(1)-receptor antagonists may produce a central nervous system depressant effect in diabetes.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15699576&dopt=Abstract cetirizine Zyrtec



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Narrow-bore high performance liquid chromatographic method for the determination of cetirizine in human plasma using column switching.

Kim CK, Yeon KJ, Ban E, Hyun MJ, Kim JK, Kim MK, Jin SE, Park JS.

Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, San 56-1, Shillim-dong Kwanak-gu, Seoul 151-742, South Korea.

An improved column switching high performance liquid chromatographic (HPLC) method was developed for determination of cetirizine in human plasma. Plasma samples were prepared by liquid-liquid extraction using methylene chloride. The samples extracted were initially injected into a clean-up Capcell Pak MF C(8) column and the peaks of cetirizine and internal standard were separated to an analytical C(18) micro-column via column switching device. This analysis showed highly sensitive and selective results. Also, it was successfully applied to evaluate the pharmacokinetics of cetirizine in human volunteers after single oral administration.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15740923&dopt=Abstract cetirizine Zyrtec



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Inhibitory effect of cetirizine on cytokine-enhanced in vitro eosinophil survival.

Sedgwick JB, Busse WW.

Department of Medicine, University of Wisconsin, Madison, USA.

BACKGROUND: Cetirizine is an antihistamine that inhibits in vivo eosinophil influx into the inflamed airways following allergen challenge, and in vitro eosinophil chemotaxis and adhesion. Since eosinophils are proposed to have an important role in the pathophysiology of asthma and allergic disease, the effects of cetirizine on eosinophil function may be a mechanism of this agent's therapeutic regulation of the allergic reaction. OBJECTIVE: To determine the effect of cetirizine on in vitro eosinophil survival. METHODS: Using human eosinophils isolated from patients with allergic rhinitis, the cells were cultured in vitro for 48 to 72 hours with medium, cetirizine, or dexamethasone in the presence of IL-5, IL-3, or GM-CSF. Eosinophil survival was assessed by trypan blue exclusion. RESULTS: In the presence of IL-5, but not GM-CSF or IL-3 100 microM cetirizine significantly inhibited eosinophil survival at 48 and 72 hours; the magnitude of this inhibition was dependent on cytokine concentration. Although cetirizine significantly suppressed cytokine promotion of eosinophil survival, it was not as potent as dexamethasone. CONCLUSIONS: Although the in vitro concentration of cetirizine was required to be quite high, cetirizine may affect in vivo airway inflammation through its inhibition of IL-5-dependent eosinophil survival.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9207722&dopt=Abstract cetirizine Zyrtec



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Central effects of the H1-antihistamine, cetirizine.

Nicholson AN, Turner C.

Royal Air Force School of Aviation Medicine, Farnborough, Hampshire, United Kingdom.

BACKGROUND: Effects of the H1-antihistamine, cetirizine, were studied on daytime alertness and performance to establish whether the drug would be suitable for use by air personnel and others involved in skilled activity. METHODS: The investigation was carried out in six healthy volunteers, and the effects of the drug (5, 10, and 15 mg) were studied on sleep latency, subjective sleepiness, digit symbol substitution, tracking and vigilance from 0.5 h to 7.5 h after ingestion. The study was placebo-controlled and double-blind with a six-way cross-over design. Promethazine (10 mg) was used as an active control to establish the sensitivity of the experimental procedures. RESULTS: Promethazine (10 mg) decreased the mean level of vigilance over the day, increased objective and subjective sleepiness from 1.5 to 5.5 h, and impaired tracking 5.5 h after ingestion. Cetirizine (10 and 15 mg) led to shortened sleep latencies over the day, and at 7.5 h sleep latencies were shorter with 10 mg cetirizine than with placebo. Subjective sleepiness with cetirizine was increased compared with placebo after 5 mg at 1.5 h, 10 mg at 7.5 h, and 15 mg at 5.5 h and when meaned over the day. Tracking was impaired with 5 and 15 mg cetirizine 0.5 h after ingestion. CONCLUSION: The study failed to establish dose-response effects of cetirizine, but it is evident that cetirizine is not free of central activity over the therapeutic range, and so its use by air personnel is not recommended.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9491258&dopt=Abstract cetirizine Zyrtec