Inhibition of cytokine-induced expression of T-cell cytokines by antihistamines.
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OBJECTIVE: To investigate immunomodulatory properties of 4 antihistamines available in Japan. METHOD: Isolated peripheral blood T cells from healthy volunteers were preincubated with cetirizine, loratadine, olopatadine, or fexofenadine for 30 minutes and then stimulated with interleukin (IL)-1 2 or IL-4 to skew immune response towards type 1 or type 2 helper T cells. RNA was extracted 6 hours later and semiquantitative reverse transcription polymerase chain reaction (RT-PCR) was performed using primers for IL-5 and interferon (IFN) gamma. Supernatants were collected 24 hours after stimulation, and cytokine production was quantified by enzyme-linked immunosorbent assay (ELISA). RESULTS: RT-PCR revealed that IL-12-induced expression of IFN-gamma was partially suppressed by loratadine and fexofenadine and that all 4 agents tested inhibited IL-4-induced expression of IL-5. ELISA demonstrated that IL-12-induced IFN-gamma production was significantly suppressed by cetirizine and fexofenadine and IL-4-induced IL-5 production was downregulated by three agents with the exception of cetirizine. This study demonstrates that antihistamines have varying immunomodulatory properties, suggesting treatment choice for atopic dermatitis can be directed by disease signs and symptoms. (+info)
Influences of histamine H1 receptor antagonists on maximal electroshock seizure in infant rats.
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The influences of histamine H1 receptor antagonists on maximal electroshock seizure were studied using infant rats. In this study, electroconvulsion was induced by stimulating rats using ear-clip electrodes, and the durations of electroencephalogram (EEG) seizure, tonic extensor (TE) seizure and clonic (CL) seizure induced by maximal electroshock were measured. Diphenhydramine, chlorpheniramine, cyproheptadine and ketotifen caused a dose-dependent and significant prolongation of both EEG seizure and TE seizure induced by maximal electroshock. On the other hand, epinastine and fexofenadine caused no such effects, even at a dose of 50 mg/kg. All drugs used in this study showed no significant effect on CL seizure induced by maximal electroshock. From these findings, it is suggested that epinastine and fexofenadine may cause no harmful influence on epilepsy, even when used in a little child. (+info)
Histamine and spontaneously released mast cell granules affect the cell growth of human hepatocellular carcinoma cells.
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The role of mast cells in tumor growth is still controversial. In this study we analyzed the effects of both histamine and pre-formed mediators spontaneously released by mast cells on the growth of two human hepatocellular carcinoma cell lines, HA22T/VGH and HuH-6, with different characteristics of differentiation, biological behavior and genetic defects. We showed that total mast cell releasate, exocytosed granules (granule remnants) and histamine reduced cell viability and proliferation in HuH-6 cells. In contrast, in HA22T/VGH cells granule remnants and histamine induced a weak but significant increase in cell growth. We showed that both cell lines expressed histamine receptors H(1) and H(2) and that the selective H(1) antagonist terfenadine reverted the histamine-induced inhibition of HuH-6 cell growth, whereas the selective H(2) antagonist ranitidine inhibited the histamine-induced cell growth of HA22T/VGH cells. We demonstrated that histamine down-regulated the expression of beta-catenin, COX-2 and survivin in HuH-6 cells and that this was associated with caspase-3 activation and PARP cleavage. On the contrary, in HA22T/VGH cells expression of survivin and beta-catenin increased after treatment with granule remnants and histamine. Overall, our results suggest that mediators stored in mast cell granules and histamine may affect the growth of liver cancer cells. However, mast cells and histamine may play different roles depending on the tumor cell features. Finally, these data suggest that histamine and histamine receptor agonists/antagonists might be considered as "new therapeutic" drugs to inhibit liver tumor growth. (+info)
Bioequivalence of two fexofenadine formulations in healthy human volunteers after single oral administration.
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AIM: A randomized, two-way, crossover, bioequivalence study was conducted in 25 fasting, healthy, male volunteers to compare two brands of fexofenadine 180 mg tablets, FEXOFENADINE 180 mg Film Tablet (Drogsan A.S., Ankara, Turkey) as test and Telfast 180 mg Tablet (Aventis Pharma, Frankfurt am Main, Germany) as a reference product. METHOD: One tablet of either formulation was administered after 10 h of overnight fasting. After dosing, serial blood samples were collected during a period of 48 hours. Plasma samples were analysed for fexofenadine by a validated HPLC method. The pharmacokinetic parameters AUC(0-48), AUC(0-alpha), C(max), T(max), K(el), T(1/2), and CL were determined from plasma concentration-time profiles for both formulations and were compared statistically. RESULTS AND CONCLUSIONS: The analysis of variance (ANOVA) did not show any significant difference between the two formulations and 90% confidence intervals (CI) fell within the acceptable range, satisfying the bioequivalence criteria of the FDA. Based on these statistical inferences it was concluded that the two brands exhibited comparable pharmacokinetics profiles and that Drogsan's Fexofenadine is equivalent to Telfast of Aventis Pharma, Frankfurt am Main, Germany. (+info)
Detection and reporting of drug-induced proarrhythmias: room for improvement.
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Recently adopted guidelines mandate the inclusion of detailed non-clinical and clinical QT data in future drug labels. As a result of increasing recognition of drug-induced proarrhythmias, and the bias introduced by the prescribing physician's awareness of these events, it is likely that the number of adverse drug reaction (ADR) reports of life-threatening ventricular arrhythmias and sudden death, allegedly caused by the drug, will increase. To illustrate how different approaches have been used to assess proarrhythmic liability and validate ADR reports on serious ventricular arrhythmias, this overview assesses pharmacoepidemiology studies on terfenadine and cisapride, the quality of ADR reports and the effect of label changes on prescribing patterns and other information to prescribing physicians. Clinical and pharmacoepidemiology studies, which in most cases did not demonstrate an increased risk for proarrhythmias with these two drugs, are discussed with emphasis on limitations, studied endpoints, and populations. Recommendations are made on how to improve the effectiveness of labelled precautions and contraindications, which may include the implementation of more effective alert systems. Given the low incidence of drug-induced proarrhythmias, 'signal' generation through ADR reports will continue to have a key role for early identification of proarrhythmic liability of newly marketed drugs. The quality of these reports varies widely, and can be improved through implementation of procedures by which complementary information is captured and events are adjudicated and classified into confidence categories using a consistent scheme across different classes of drugs. (+info)
Effects of H1-receptor blockade with terfenadine in nocturnal asthma.
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1. In a single-blind placebo controlled study we have measured peak flow (PEFR) at 04.00 h and 16.00 h in eight asthmatics 6 h after placebo or terfenadine 120 mg, to determine if diurnal variation in histamine mediated effects contribute to nocturnal bronchoconstriction in asthma. 2. On placebo there was a significant diurnal variation in mean PEFR of 41 l min-1 (P less than 0.05). Terfenadine improved 04.00 h baseline mean PEFR from 242 to 278 l min-1 (P less than 0.05) but a 38 l min-1 diurnal variation in mean PEFR persisted (P less than 0.05). 3. We conclude that H1-receptor blockade with terfenadine may produce modest nocturnal bronchodilatation but does not influence the diurnal variation in PEFR in asthma suggesting that H1-receptor mediated effects are not important in the pathogenesis of nocturnal asthma. (+info)
Possible involvement of 5-lipoxygenase metabolite in itch-associated response of mosquito allergy in mice.
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This study investigated endogenous mediators involved in mosquito allergy-associated itching in mice. An intradermal injection of an extract of mosquito salivary gland elicited marked scratching in sensitized mice. The 5-lipoxygenase inhibitor zileuton (100 mg/kg), the 5-lipoxygenase activating peptide inhibitor MK-886 (10 mg/kg), and the glucocorticoid betamethasone 17-valerate (3 mg/kg) inhibited the scratching. The scratching was not affected by the cyclooxygenase inhibitors indomethacin and ketoprofen, the TP prostanoid receptor antagonist SQ-29548, the leukotriene B(4) antagonist ONO-4057, the cysteinyl leukotriene antagonist pranlucast, the leukotriene D(4) antagonist MK-571, the platelet-activating factor antagonist CV-3988, the nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester, the H(2) histamine-receptor antagonist cimetidine, the H(1) histamine-receptor antagonist terfenadine plus cimetidine, and cypoheptadine that blocks the 5-HT(1/2) serotonin receptors. Zileuton (100 mg/kg) inhibited the increased activity of the cutaneous nerve branch induced by an intradermal injection of the extract, suggesting the peripheral action. Zileuton and MK-886 (10 and 100 microM) did not affect high K(+)-induced increase in intracellular Ca(2+) concentration in cultured dorsal root ganglion neurons. The results suggest that 5-lipoxygenase metabolite(s) other than leukotriene B(4) and cysteinyl leukotrienes are involved in mosquito allergy-associated itching. (+info)
Multidrug resistance-associated protein 2 is primarily responsible for the biliary excretion of fexofenadine in mice.
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Previous studies implicated P-glycoprotein (P-gp) as the major transport protein responsible for the biliary excretion of fexofenadine (FEX). However, FEX biliary excretion was not impaired in P-gp- or breast cancer resistance protein (Bcrp)-knockout mice or multidrug resistance-associated protein 2 (Mrp2)-deficient rats. The present study tested the hypothesis that species differences exist in the transport protein primarily responsible for FEX biliary excretion between mice and rats. Livers from Mrp2-knockout (Mrp2KO) mice and Mrp2-deficient (TR(-)) rats were perfused in a single-pass manner with 0.5 muM FEX. N-(4-[2-(1,2,3,4-Tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dih ydro-5-methoxy-9-oxo-4-acridine carboxamide (GF120918) (10 muM) was employed to inhibit P-gp and Bcrp. The biliary excretion rate of FEX was decreased 85% in Mrp2KO relative to wild-type mice (18.4 +/- 2.2 versus 122 +/- 34 pmol/min/g liver). In mice, more than 50% of FEX unbound intrinsic biliary clearance (CL(bile, int)(') = 3.0 ml/h/g liver) could be attributed to Mrp2 (Mrp2-dependent CL(bile, int)(') approximately 1.7 ml/h/g liver), with P-gp and Bcrp playing a minor role (P-gp- and Bcrp-dependent CL(bile, int)(') approximately 0.3 ml/h/g liver). Approximately one third of FEX CL(bile, int)(') was attributed to unidentified mechanisms in mice. In contrast to mice, FEX biliary excretion rate (245 +/- 38 and 250 +/- 25 pmol/min/g liver) and CL(bile, int)(') (9.72 +/- 2.47 and 6.49 +/- 0.68 ml/h/g liver) were comparable between TR(-) and control Wistar rats, respectively, suggesting that unidentified transport mechanism(s) can completely compensate for the loss of Mrp2 function in rats. Mrp2 clearly plays a major role in FEX biliary excretion in mice. In conclusion, remarkable species differences exist in FEX hepatobiliary transport mechanisms. (+info)