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Br J Clin Pharmacol. 1999 Mar;47(3):307-13.
Risk of ventricular arrhythmias associated with nonsedating antihistamine drugs.
de Abajo FJ, Rodriguez LA.
Area de Farmacovigilancia, Centro Nacional de Farmacobiologia, Madrid, Spain.
AIMS: To quantify and compare the incidence of ventricular arrhythniias associated with the use of five nonsedating antihistamines: acrivastine, astemizole, cetirizine, loratadine and terfenadine. The effects of age, sex, dose, duration of treatment, and the interaction with P450 inhibitor drugs were also examined. METHODS: We carried out a cohort study with a nested case-control analysis using the UK-based General Practice Research database (GPRD). The study cohort included persons aged less than 80 years old who received their first prescription for any of the five study drugs between January 1, 1992 and September 30, 1996. We estimated relative risks and 95% confidence intervals of idiopathic ventricular arrhythmias with current use of antihistamines as compared with non use. RESULTS: The study cohort included 197425 persons who received 513012 prescriptions. Over the study period 18 valid cases of idiopathic ventricular arrhythmias were detected. Nine occurred during the current use of any antihistamine, resulting in a crude incidence of 1.9 per 10000 person-years (95%CI: 1.0-3.6) and a relative risk of 4.2 (95%CI: 1.5-11.8) as compared with non use. Astemizole presented the highest relative risk (RR= 19.0; 95%CI: 4.8-76.0) of all study drugs, while terfenadine (RR=2.1; 95%CI:0.5-8.5) was in the range of other nonsedating antihistamines. Older age was associated with a greater risk of ventricular arrhythmias (RR=7.4; 95%CI: 2.6-21.4) and seemed to increase the effect of antihistamines (RR=6.4; 95%CI: 1.7-24.8). The proportions of high dose terfenadine and the concomitant use with P450 inhibitors among current users of terfenadine were 2.7% and 3.4%, respectively over the study period with no single case of ventricular arrhythmias occurring in the presence of these two risk factors. CONCLUSIONS: The use of nonsedating antihistamines increases the risk of ventricular arrhythmias by a factor of four in the general population. Yet, the absolute effect is quite low requiring 57000 prescriptions, or 5300 person-years of use for one case to occur. The risk associated with terfenadine was no different from that with other nonsedating antihistamines.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10215756&dopt=Abstract
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Mol Pharmacol. 2000 Nov;58(5):1115-28.
Pharmacological blockade of ERG K(+) channels and Ca(2+) influx through store-operated channels exerts opposite effects on intracellular Ca(2+) oscillations in pituitary GH(3) cells.
Secondo A, Taglialatela M, Cataldi M, Giorgio G, Valore M, Di Renzo G, Annunziato L.
Unit of Pharmacology, Department of Neuroscience, School of Medicine, University of Naples Federico II, Naples, Italy.
In the present study, the effects on intracellular calcium concentration ([Ca(2+)](i)) oscillations of the blockade of ether-a-go-go-related gene (ERG) K(+) channels and of Ca(2+) influx through store-operated channels (SOC) activated by [Ca(2+)](i) store depletion have been studied in GH(3) cells by means of a combination of single-cell fura-2 microfluorimetry and whole-cell mode of the patch-clamp technique. Nanomolar concentrations (1-30 nM) of the piperidinic second-generation antihistamines terfenadine and astemizole and of the class III antiarrhythmic methanesulfonanilide dofetilide, by blocking ERG K(+) channels, increased the frequency and the amplitude of [Ca(2+)](i) oscillations in resting oscillating GH(3) cells. These compounds also induced the appearance of an oscillatory pattern of [Ca(2+)](i) in a subpopulation of nonoscillating GH(3) cells. The effects of ERG K(+) channel blockade on [Ca(2+)](i) oscillations appeared to be due to the activation of L-type Ca(2+) channels, because they were prevented by 300 nM nimodipine. By contrast, the piperazinic second-generation antihistamine cetirizine (0.01-30 microM), which served as a negative control, failed to affect ERG K(+) channels and did not interfere with [Ca(2+)](i) oscillations in GH(3) cells. Interestingly, micromolar concentrations of terfenadine and astemizole (0.3-30 microM), but not of dofetilide (10-100 microM), produced an inhibition of the spontaneous oscillatory pattern of [Ca(2+)](i) changes. This effect was possibly related to an inhibition of SOC, because these compounds inhibited the increase of [Ca(2+)](i) achieved by extracellular calcium reintroduction after intracellular calcium store depletion with the sarcoplasmic or endoplasmic reticulum calcium ATPase pump inhibitor thapsigargin (10 microM) in an extracellular calcium-free medium. The same inhibitory effect on [Ca(2+)](i) oscillations and SOC was observed with the first-generation antihistamine hydroxyzine (1-30 microM), the more hydrophobic metabolic precursor of cetirizine. Collectively, the results of the present study obtained with compounds that interfere in a different concentration range with ERG K(+) channels or SOC suggest that 1) ERG K(+) channels play a relevant role in controlling the oscillatory pattern of [Ca(2+)](i) in resting GH(3) cells and 2) the inhibition of SOC might induce an opposite effect, i.e., an inhibition of [Ca(2+)](i) oscillations.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11040061&dopt=Abstract
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Pharmacology. 2000 Nov;61(4):230-7.
Effects of an amphoteric antiallergic agent, HSR-609, on antigen-induced late phase nasal eosinophilia in brown Norway rats.
Musoh K, Nakamura N, Nagai H.
Department of Pharmacology, Gifu Pharmaceutical University, Gifu, Japan.
The effect of a newly synthesized compound, HSR-609, on rat experimental rhinitis was investigated. In the first part of the study, a new experimental nasal allergic late phase eosinophilia model in Brown Norway (BN) rats was investigated. The increase in the number of antigen inhalations resulted in the proportional increase in the number of inflammatory cells such as macrophages, eosinophils and neutrophils in the nasal cavity lavage fluid (NCLF) at 5 h after each inhalation. The number of inflammatory cells reached a maximum 8 h after the antigen perfusion. Submaximum response was observed at 5 h after the antigen provocation. In this system, the serum IgG and IgE antibody titers measured by homologous passive cutaneous anaphylaxis were 160 and 640, respectively. In the second part of the study, the effects of prednisolone, cetirizine and a newly synthesized amphoteric antiallergic agent, HSR-609, on this allergic late nasal eosinophilia and neutrophilia in BN rats were investigated. Prednisolone and HSR-609 significantly inhibited the increase in the number of eosinophils in the NCLF but not cetirizine. Furthermore, prednisolone showed the inhibition of the increase in the number of macrophages and neutrophils in NCLF. These results suggest that this late phase eosinophilia model in the nose of BN rats may be useful for investigating the therapeutic drugs for nasal allergy and a newly synthesized amphoteric antiallergic agent, HSR-609, may be useful for the treatment of allergic rhinitis with eosinophilia. Copyright 2000 S. Karger AG, Basel.
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