piperidines and carebastine

To compare the anti-inflammatory effects of fexofenadine with other H(1)-receptor antagonists in vitro.. Published literature.. Recent experimental studies on anti-inflammatory effects of H(1)-receptor antagonists. Databases searched: Medline, Medscape.. 1990-2003. Search terms: second-, third-generation antihistamines; sedating, nonsedating antihistamines; in vitro anti-inflammatory activity; cetirizine; ebastine; loratadine; fexofenadine; desloratadine.. Second- and third-generation H(1)-receptor antagonists may demonstrate significant in vitro anti-inflammatory activity at concentrations considered to be clinically relevant. In some instances, higher (supraclinical) concentrations are required to achieve comparable effects.. Experimental research suggests that second- and third-generation H(1)-receptor antagonists may achieve anti-inflammatory effects in a clinical context. Further studies are required to support this conclusion.

Topics: Animals; Anti-Inflammatory Agents; Butyrophenones; Cells, Cultured; Histamine H1 Antagonists; Loratadine; Piperidines; Terfenadine

Although the new second-generation nonsedative antihistamines terfenadine and astemizole were launched as highly selective and specific H(1)-receptor antagonists, they were later found to cause prolongation of the QT-interval and severe cardiac arrhythmias. The prolongation of the QT-interval is caused by the blockade of one or more of the cardiac potassium channels, among which the delayed rectifier I(Kr), encoded by the HERG-gene, appears to be the most significant. The potency of the prokinetic drug cisapride to block I(Kr) appears to be similar to that of terfenadine (IC(50) about 50 nmol/l). These drugs cause problems when overdosed, used in combination with inhibitors of their CYP3A4-mediated metabolism, or when given to individuals with altered drug kinetics (the aged) or patients with existing cardiac disease (congenitally long QT). Moreover, interactions with other QT-interval prolonging drugs require special attention. Active hydrophilic metabolites of the second-generation antihistaminic compounds (ebastine-carebastine, loratadine-desloratadine, terfenadine-fexofenadine, astemizole-norastemizole) are new compounds with probably reduced risk for drug interactions and cardiac toxicity.

Topics: Arrhythmias, Cardiac; Astemizole; Benzimidazoles; Butyrophenones; Cetirizine; Cisapride; Heart Diseases; Histamine H1 Antagonists; Humans; Loratadine; Piperidines; Serotonin Receptor Agonists; Terfenadine; Triprolidine

Carebastine, a histamine H1 antagonist, is under development by Almirall Prodesfarma for the potential treatment of allergic rhinitis, asthma and conjunctivitis. A nasal formulation was submitted for registration in Spain in June 1999 [343595]. It is also in phase III trials for conjunctivitis and phase I trials for asthma [343144,343243]. In a multicentered, multinational, double-blind, placebo-controlled study in patients with symptomatic SAR, patients were assigned a nasal spray formulation of carebastine (2.5 mg/ml) or placebo. Severity scores decreased significantly with carebastine compared to placebo. This findings suggest that carebastine nasal spray has the potential to be of value in the treatment of SAR [282185]. In a multicenter, multinational, double-blind, randomized, placebo-controlled study, patients with seasonal allergic conjunctivitis (SAC) were assigned an eye drop formulation of carebastine (25 mg/ml) or placebo. Carebastine was significantly better than placebo at relieving the effects of SAC, as early as 15 min after administration and the effect lasted for 14 days. Carebastine was well-tolerated and there were no difference in adverse events between the two groups [282897].

Topics: Animals; Anti-Asthmatic Agents; Asthma; Butyrophenones; Clinical Trials as Topic; Contraindications; Drugs, Investigational; Humans; Piperidines; Structure-Activity Relationship

Topics: Animals; Bronchoconstriction; Butyrophenones; Guinea Pigs; Heart Diseases; Histamine H1 Antagonists; Piperidines; Potassium Channels; Rats; Structure-Activity Relationship; Terfenadine

The present study was performed to elucidate the effects of itraconazole and rifampin on the pharmacokinetics and pharmacodynamics of ebastine, a nonsedative H1 receptor antagonist. In a 3-way crossover sequential design with 2-week washouts, 10 healthy participants were pretreated with itraconazole for 6 days, rifampin for 10 days, or neither. After oral administration of 20 mg ebastine, blood and urine samples were collected for 72 and 24 hours, respectively, and histamine-induced wheal and flare reactions were measured to assess the antihistamine response for 12 hours. Itraconazole pretreatment decreased the oral clearance of ebastine to 10% (P < .001) and increased the AUC(infinity) of the active metabolite, carebastine, by 3-fold (P < .001). On the other hand, rifampin pretreatment decreased the AUC(infinity) of carebastine to 15% (P < .001), with an enormous reduction in the oral bioavailability of ebastine and significantly reduced histamine-induced skin reactions. From these results, the disposition of ebastine and carebastine seems to be significantly altered by coadministration of itraconazole or rifampin. The antihistamine response after ebastine dosing would be decreased following rifampin pretreatments.

Topics: Adult; Antifungal Agents; Butyrophenones; Cross-Over Studies; Drug Interactions; Enzyme Inhibitors; Histamine; Histamine H1 Antagonists; Humans; Hypersensitivity, Immediate; Itraconazole; Male; Piperidines; Rifampin; Skin; Young Adult

We describe a simple, rapid and sensitive high-performance liquid chromatography-electrospray ionization tandem mass spectrometric method that was developed for the simultaneous determination of carebastine and pseudoephedrine in human plasma using cisapride as an internal standard. Acquisition was performed in multiple-reaction monitoring mode by monitoring the transitions: m/z 500.43 > 167.09 for carebastine and m/z 166.04 > 147.88 for pseudoephedrine. The devised method involves a simple single-step liquid-liquid extraction with ethyl acetate. Chromatographic separation was performed on a C(18) reversed-phase chromatographic column at 0.2  mL/min by isocratic elution with 10  mM ammonium formate buffer-acetonitrile (30:70, v/v; adjusted to pH 3.3 with formic acid). The devised method was validated over 0.5-100  ng/mL of carebastine and 5-1000  ng/mL of pseudoephedrine with acceptable accuracy and precision, and was successfully applied to a bioequivalence study involving a single oral dose (10  mg of ebastine plus 120  mg of pseudoephedrine complex) to healthy Korean volunteers.

Topics: Butyrophenones; Chromatography, High Pressure Liquid; Cisapride; Cross-Over Studies; Humans; Hydrogen-Ion Concentration; Male; Piperidines; Pseudoephedrine; Reproducibility of Results; Republic of Korea; Sensitivity and Specificity; Spectrometry, Mass, Electrospray Ionization; Therapeutic Equivalency; Young Adult

The efficacy and safety of ebastine 20 mg once daily given with and without food were compared in patients ages 12 to 70 years with seasonal allergic rhinitis (SAR) caused by mountain cedar allergen. This double-blind, placebo-controlled study was conducted at six centers in Texas. Efficacy and safety analyses were performed on the intent-to-treat population, which comprised 652 patients; 540 patients completed the study. Following 2 weeks' treatment, no significant differences (p > or = 0.91) were found between the ebastine with and without food groups in the percentage change from baseline of daily "reflective" total rhinitis symptom scores (i.e., patients' assessment of severity over the previous 12 h), but both ebastine groups exhibited significantly greater reductions versus patients receiving placebo (p < 0.0001). There were also no significant differences in the percentages of patients experiencing adverse events between the ebastine with and without food groups. Mean steady-state plasma concentrations of ebastine and its active metabolite carebastine were, respectively, 5.5% (ns) and 15.1% (p < 0.05) higher when ebastine was given with food versus its administration without food. Overall, these results indicate that in clinical practice, ebastine does not need to be administered with reference to food.

Topics: Adolescent; Adult; Aged; Butyrophenones; Child; Double-Blind Method; Female; Food-Drug Interactions; Histamine H1 Antagonists; Humans; Male; Middle Aged; Piperidines; Rhinitis, Allergic, Seasonal; Severity of Illness Index; Treatment Outcome

Ebastine is a potent and selective H1-receptor antagonist indicated for allergic rhinitis which undergoes extensive first pass metabolism by CYP3A4 to form an active metabolite, carebastine. The purpose of the study was to determine age- and gender-related differences in the pharmacokinetics of ebastine and carebastine.. The upper recommended oral dose of 20 mg once daily was administered to 12 healthy young (22 to 38 years) and 12 healthy elderly (50 to 92 years; 8 m and 4 f) subjects for 5 days. Plasma concentrations of ebastine and carebastine were determined for 24 hours following the initial dose on Day 1 and for 72 hours following the dose on Day 5 using a sensitive LC/MS/MS assay. The minimum quantifiable limit (MQL) for the assay was 0.05 ng/ml and 1.0 ng/ml for ebastine and carebastine, respectively.. Mean area under the curve and Cmax values on Day 1 and Day 5 were similar for ebastine but approximately doubled for carebastine due to its longer half-life. Mean carebastine concentrations were approximately 10 to 20 fold higher than mean ebastine concentrations. For young subjects, the mean (%CV) ebastine t(1/2) was 5.76 (28.47) h and 20.38 (46.19) h on Day 1 and Day 5, respectively. Similarily, for young subjects, the mean (%CV) for carebastine t(1/2) was 7.03 (23.21) h and 26.12 (23.39) h on Day 1 and Day 5, respectively. This apparent prolongation of t(1/2) was probably due to lack of proper estimation of terminal half-life on Day 1 as fewer samples were collected for a shorter duration on Day 1. Using a multicomparison test for Cmin values, it was determined that steady state conditions were achieved by Day 5 for both age groups for ebastine and in young subjects for carebastine. The variability in ebastine pharmacokinetic parameters was higher than carebastine. A 50% increase in ebastine AUC(0-24) and Cmax values in elderly subjects, with no changes in t(1/2), could be explained by either increased absorption of ebastine in elderly subjects or due to a decrease in first pass metabolism. As ebastine shows a high first-pass effect, even a small change in this first pass can cause large changes in plasma exposure. The ebastine pharmacokinetic parameters for elderly subjects in this study lie between the values reported in young subjects in earlier studies. Hence, the apparent age-related pharmacokinetic difference for ebastine is probably due to the inherent variability in ebastine pharmacokinetics. There were no gender-related differences in either young or elderly subjects for mean AUC, Cmax, tmax and t(1/2) ebastine and carebastine values. Ebastine was absorbed rapidly with a median tmax of 1.25 to 2.25 h for both healthy young and elderly males and females on Day 1 and Day 5. There was a delayed appearance of carebastine as expressed by median tmax of 4.0 to 5.0 h, which did not change with age, gender or repeated administration. There were no clinically relevant differences between the groups of subjects with respect to adverse events or safety parameters.. Thus, ebastine can be safely administered to elderly subjects with no clinically important age- or gender related differences in the pharmacokinetics of ebastine/carebastine.

Topics: Administration, Oral; Adult; Age Factors; Aged; Aged, 80 and over; Area Under Curve; Butyrophenones; Drug Administration Schedule; Female; Histamine H1 Antagonists; Humans; Male; Mass Spectrometry; Middle Aged; Piperidines; Sex Factors

The influence of different weighting methods in non-linear regression analysis was evaluated in the pharmacokinetics of carebastine after a single intravenous dose of 10 mg in 8 healthy volunteers. Plasma concentrations were measured by HPLC using an on-line solid-phase extraction method and automated injection. The analytical method was fully validated and the function of the analytical error subsequently determined. The parametric approach was performed using different weighting methods, including the homoscedastic method (W = 1) and heteroscedastic methods using weights of 1/C, 1/C2, and the inverse of the concentration variance calculated through the analytical error function (1/V), and the results were statistically evaluated according to the normal distribution. Statistically significant differences were observed in the representative parameters of the disposition kinetics of carebastine. The use of a multiple comparison test for statistical analysis of all differences among group means indicated that differences were generated between the homoscedastic method (W = 1) and the heteroscedastic methods (1/C, 1/C2, and 1/V). The results obtained in the present study confirmed the utility of the analytical error function as a weighting method in non-linear regression analysis and reinforced the importance of the correct choice of weights to avoid the estimation of imprecise or erroneous pharmacokinetic parameters.

Topics: Adult; Area Under Curve; Butyrophenones; Histamine H1 Antagonists; Humans; Infusions, Intravenous; Linear Models; Male; Metabolic Clearance Rate; Pharmacology; Piperidines

1. We have given 12 healthy subjects the H1-antihistamine ebastine (20 mg) or placebo in a randomized double-blind and crossover study for 1 week each. The subjects were tested for drug effects on day 6 of each period, and for interactions of ebastine with oral 15 mg diazepam (DZ) on day 7. On both days, the testing runs were at baseline and 1.5, 3, 4.5 and 6 h after intake. 2. The performance was evaluated both objectively (digit symbol substitution, flicker fusion, Maddox wing, simulated driving, body balance) and subjectively (visual analogue scales, questionnaires). Venous blood was sampled daily during the maintenance and during each testing round for the assay of plasma carebastine (the active metabolite of ebastine) by high pressure liquid chromatography and plasma diazepam by radioreceptor assay. Three-way ANOVA, paired t-test, Wilcoxon rank sign test and Fisher's fourfold table test were used for data analysis. 3. Plasma carebastine reached steady levels from day 3 onwards. The mean concentrations in the morning were 82 micrograms l-1 on day 6 and 85 micrograms l-1 on day 7. The rise (+ 150%) in plasma carebastine after an extra 20 mg ebastine was not modified by DZ. Ebastine did not affect performance objectively or subjectively, yet borderline drowsiness was recorded during the first 3 h. On day 7, plasma DZ concentrations peaked (mean 480 micrograms l-1) at 1.5 h after the intake. DZ produced impaired performance in various objective tests, and drowsiness, weakness, clumsiness, mental slowness and poor performance were reported on visual analogue scales.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Oral; Adult; Analysis of Variance; Butyrophenones; Chromatography, High Pressure Liquid; Diazepam; Double-Blind Method; Drug Interactions; Female; Histamine H1 Antagonists; Humans; Male; Piperidines; Psychomotor Performance

Ebastine is an H1-receptor antagonist with a relative lack of sedating properties. It is almost completely converted to carebastine, and it is this metabolite which is responsible for the antihistaminic effect. Twelve healthy subjects received a single 20 mg dose of ebastine on day 2 of a multiple oral dosing regimen of either cimetidine (400 mg three times daily and 800 mg in the evening on the day preceding ebastine administration and 400 mg four times daily on the 2 following days) or placebo in a randomised cross-over design. Significant plasma concentrations of ebastine were not detected after either treatment. The AUC of carebastine was not affected by cimetidine coadministration (4049 +/- 985 ng ml-1 h after cimetidine vs 3795 +/- 959 ng ml-1 h after placebo; 95% confidence interval of the difference: -412 to 919). Cimetidine coadministration did not induce any effect of ebastine on blood pressure and heart rate or cause sedation.

Topics: Adult; Blood Pressure; Butyrophenones; Chromatography, High Pressure Liquid; Cimetidine; Drug Interactions; Half-Life; Heart Rate; Histamine H1 Antagonists; Humans; Male; Piperidines

1. The kinetics and effects of ebastine 10 and 50 mg were studied after oral dosing in healthy subjects. 2. The parent drug was extensively metabolised during the first pass to its carboxylic acid derivative, carebastine. 3. The pharmacokinetics of carebastine were linear over the dose range studied and the terminal elimination half-life was 10.6 +/- 2.6 and 12.5 +/- 1.9 h respectively after 10 and 50 mg of ebastine. 4. Antihistamine (H1-receptor) activity was examined with intradermal histamine (2 micrograms). Oral ebastine reduced the histamine wheal area for up to 24 h and also reduced subjective local pain. 5. Antihistamine activity correlated well with plasma levels of carebastine in individual subjects. 6. Ebastine appears to have potential as an antihistamine for once a day dosing.

Topics: Adult; Butyrophenones; Dose-Response Relationship, Drug; Histamine H1 Antagonists; Humans; Hypersensitivity, Immediate; Male; Piperidines; Time Factors

Topics: Animals; Butyrophenones; Chronic Urticaria; Female; Fetal Blood; Histamine H1 Antagonists; Humans; Infant; Lactation; Milk, Human; Piperidines; Pregnancy

Histamine H(1) receptor (H1R) expression influences the severity of allergy symptoms. We examined the effect of inverse agonists on H1R gene expression. Two inverse agonists (carebastine and mepyramine), but not the neutral antagonist oxatomide, decreased inositol phosphate accumulation. The inverse agonists also decreased H1R gene expression and down-regulated H1R mRNA below basal expression, while basal H1R mRNA expression was maintained after oxatomide treatment. These results suggest that inverse agonists more potently alleviate allergy symptoms by not only inhibiting stimulus-induced up-regulation of H1R gene expression but also by suppressing basal histamine signaling through their inverse agonistic activity.

Topics: Animals; Butyrophenones; CHO Cells; Cricetinae; Cricetulus; Drug Inverse Agonism; Gene Expression Regulation; HeLa Cells; Histamine Antagonists; Histamine H1 Antagonists; Humans; Inositol Phosphates; Piperazines; Piperidines; Pyrilamine; Receptors, Histamine H1; RNA, Messenger

Topics: Butyrophenones; Cells, Cultured; Granulocyte-Macrophage Colony-Stimulating Factor; Histamine; Histamine H1 Antagonists; Humans; Inflammation; Inflammation Mediators; Interleukin-17; Interleukin-8; Keratinocytes; Piperidines; Receptors, Histamine H1; Tumor Necrosis Factor-alpha

Ebastine is a well-known selective second-generation histamine H(1) receptor antagonist, which is used for seasonal and perennial allergic rhinitis and chronic urticaria. Angiogenesis plays a crucial role in the development of airway inflammation and remodelling in allergic rhinitis and asthmatic patients, in whom, indeed, the mucosa displays increased vascularity and overexpression of vascular endothelial growth factor (VEGF). The aim of the present study was to evaluate the anti-angiogenic properties of carebastine, the active metabolite of ebastine. The effects of carebastine on human umbilical vein endothelial cell (EC) (HUVEC) and human pulmonary artery EC (HPAEC) proliferation, migration and capillary-like tube formation were investigated in vitro, and in the chick embryo chorioallantoic membrane (CAM) assay in vivo. Moreover, the effect of carebastine on phosphorylation of the cell VEGF receptor fetal liver kinase-1, or VEGF receptor 2 (VEGFR-2), and Akt kinase (Akt) was evaluated by Western blotting. Carebastine inhibited VEGF-induced HUVEC and HPAEC proliferation, migration and angiogenesis in a dose-dependent manner in vitro. Cell proliferation was inhibited by 42 and 64% in HUVECs and 62 and 75% in HPAECs upon exposure for 48 and 72 h, respectively, to 20 microM carebastine (p < or = 0.03), and even more with 30 microM carebastine. Cell migration was inhibited by 37 and 70% in HUVECs (p < or = 0.03) and 60 and 78% in HPAECs (p < or = 0.01) in the presence of 10 and 30 microM carebastine, respectively. Carebastine (20 microM) caused a significant reduction (70-86%; p<0.01) in topological parameters of the capillary network produced in vitro by both EC lines on a basement membrane extract. Carebastine (30 and 50 microM) inhibited the VEGF-induced angiogenesis in the CAM assay in vivo two- and three-fold, respectively (p<0.001). Finally, both EC lines, on exposure to 10 and 20 microM carebastine, showed a four- to six-fold reduction (p < or = 0.01) in both VEGF- and H1 receptor-induced VEGFR-2 and Akt phosphorylation. Overall, these data provide the first evidence regarding the anti-angiogenic activity of ebastine, and suggest its potential use as an anti-angiogenic molecule, besides its antihistaminic activity for the treatment of allergic diseases in which angiogenesis takes place.

Topics: Airway Remodeling; Animals; Anti-Asthmatic Agents; Butyrophenones; Capillaries; Cell Division; Cell Movement; Cells, Cultured; Chick Embryo; Chickens; Chorioallantoic Membrane; Endothelial Cells; Humans; Neovascularization, Pathologic; Phosphorylation; Piperidines; Proto-Oncogene Proteins c-akt; Pulmonary Artery; Receptors, Histamine H1; Signal Transduction; Umbilical Veins; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2

Topics: Butyrophenones; Cells, Cultured; Histamine H1 Antagonists; Humans; Interleukin-6; Macrophage Migration-Inhibitory Factors; Monocytes; Piperidines; Tumor Necrosis Factor-alpha

CC chemokines have been shown to play an important role in inducing selective recruitment of inflammatory cells into local allergic inflammatory sites. CC chemokines are also known as histamine releasing factors. We previously showed that histamine enhances transcription of CC chemokines from nasal mucosa which leads to further induction of histamine release. This cyclic cascade may cause prolonged allergic inflammation. The aim of this study is to clarify the relationship between histamine and CC chemokine production by using human nasal epithelial cells (HNECs) and to examine the potential of H1 receptor (H1R) antagonists in new therapeutic approaches for the treatment of nasal allergy.. HNECs were isolated from the nasal turbinates of patients diagnosed with nasal allergy. HNEC monolayers were cultured for 48 hours with or without histamine (10(-3) to 10(-5) mol/L). Furthermore, an H1R antagonist, either carebastine or olopatadine, was added to the supernatant (10(-3) to 10(-7) mol/L) 30 minutes before incubation with histamine. The expression of Regulated on Activation, Normal T-cell Expressed and Secreted (RANTES) and monocyte chemotactic protein-1 (MCP-1) in the culture media were measured by ELISA.. The release of RANTES and MCP-1 was significantly upregulated by histamine compared with the control group. Both carebastine and olopatadine inhibited the release of CC chemokine production to the control level in both groups.. This study suggests that the interaction between histamine and CC chemokines may prolong allergic inflammation in human nasal mucosa. We also demonstrate the potential use of H1R antagonists in new therapeutic approaches to the treatment of nasal allergy through inhibiting this histamine-CC chemokine interaction.

Topics: Adolescent; Adult; Anti-Inflammatory Agents; Butyrophenones; Cells, Cultured; Chemokine CCL2; Chemokine CCL5; Chemokines, CC; Child; Dibenzoxepins; Dose-Response Relationship, Drug; Epithelial Cells; Female; Histamine; Histamine H1 Antagonists; Humans; Male; Middle Aged; Nasal Mucosa; Olopatadine Hydrochloride; Piperidines; Rhinitis; Rhinitis, Allergic, Perennial; Rhinitis, Allergic, Seasonal

To assess the differences in the pharmacokinetics and cardiac safety of ebastine and its active metabolite, carebastine, in patients with normal and impaired renal function.. Twenty-four patients with varying degrees of renal impairment (mild, moderate or severe: n = 8 per group) and 12 healthy subjects participated in an open-label, parallel-group, multicentre study. Ebastine 20mg was administered orally once daily for 5 days. Plasma concentrations of ebastine and carebastine were determined for 24 hours on day 1 and for 72 hours on day 5 by using a validated sensitive liquid chromatography-tandem mass spectrometry assay with a minimum quantifiable limit of 0.05 ng/mL for ebastine and 1.00 ng/mL for carebastine. Renal function was assessed by measuring 24-hour creatinine clearance (CL(CR)) at baseline. Cardiac and general safety parameters were also monitored.. The pharmacokinetics of ebastine were not modified by renal impairment. No correlation between ebastine pharmacokinetics and renal function, as expressed by CL(CR) assessed 2 days prior to dosing, was observed. Comparison of the plasma exposure and the elimination half-life of ebastine and carebastine between groups showed no significant differences. Therefore, no apparent accumulation of ebastine and carebastine occurred, and steady-state concentrations of ebastine and carebastine were predictable from single-dose pharmacokinetics for both healthy subjects and patients with renal impairment, even though the variability between the groups was large. In addition, no differences were observed in the safety of ebastine between patients with renal impairment and healthy subjects when assessing adverse events, vital signs, laboratory parameters or ECGs.. Ebastine was generally well tolerated in subjects with impaired renal function. No clinically important pharmacokinetic or safety differences were observed between patients with renal impairment and healthy subjects with normal renal function.

Topics: Administration, Oral; Adult; Aged; Area Under Curve; Butyrophenones; Drug Administration Schedule; Drug Monitoring; Electrocardiography; Female; Half-Life; Histamine H1 Antagonists; Humans; Kidney Function Tests; Male; Middle Aged; Piperidines; Renal Insufficiency

To determine the effect of gender and the genetic polymorphisms of CYP2J2, CYP3A4, CYP3A5 and MDR1 on the urinary excretion of the H(1) antihistamine ebastine in healthy subjects.. Eighty-nine Caucasians were studied. The presence of polymorphisms in genes known to be involved in ebastine metabolism and transport (CYP2J2*2,*3,*4,*6,*7, CYP3A4*1B, CYP3A5*3, *6 and MDR1(ABCB1)(C3435T)) was assessed by means of PCR-restriction fragment length polymorphism and sequencing methods. Genotype was correlated with the urinary excretion of the main ebastine metabolites (desalkylebastine and carebastine) under basal conditions and after administration of grapefruit juice.. Women excreted statistically greater amounts of desalkylebastine in urine (mean +/- SD (95% confidence intervals, 95% CI), 23.0 +/- 19.5 (18.1, 27.9) micromol) than men (12.4 +/- 11.0 (7.9, 16.9)), (mean difference: 10.6 (2.4, 18.7), P < 0.005). The CYP2J2, CYP3A4 and CYP3A5 analysed polymorphisms did not greatly affect ebastine metabolite excretion. The MDR1(C3435T) polymorphism was found to affect both the urinary excretion of the active metabolite carebastine (32.3 +/- 18.3 (23.1, 41.4), 22.8 +/- 14.7 (18.6, 27.0) and 21.5 +/- 15.3 (14.7, 28.3) for CC, CT and TT carriers, respectively; P < 0.05) and the grapefruit juice-induced inhibition of its transport/formation (mean fold-decrease +/- SD (95% CI), 1.5 +/- 0.8 (1.0, 2.0), 1.1 +/- 0.9 (0.7, 1.4) and 0.9 +/- 0.4 (0.6, 1.2) for CC, CT and TT carriers, respectively; P = 0.01).. Gender and the presence of the MDR1(C3435T) polymorphism both influence the excretion of ebastine metabolites in urine.

Topics: Administration, Oral; Adolescent; Adult; ATP Binding Cassette Transporter, Subfamily B, Member 1; Beverages; Body Weight; Butyrophenones; Citrus paradisi; Cytochrome P-450 CYP2J2; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Female; Genotype; Histamine H1 Antagonists; Humans; Male; Oxygenases; Pilot Projects; Piperidines; Polymorphism, Restriction Fragment Length; Sex Factors

Ebastine undergoes extensive metabolism to form desalkylebastine and hydroxyebastine. Hydroxyebastine is subsequently metabolized to carebastine. Although CYP3A4 and CYP2J2 have been implicated in ebastine N-dealkylation and hydroxylation, the enzyme catalyzing the subsequent metabolic steps (conversion of hydroxyebastine to desalkylebastine and carebastine) have not been identified. Therefore, we used human liver microsomes (HLMs) and expressed cytochromes P450 (P450s) to characterize the metabolism of ebastine and that of its metabolites, hydroxyebastine and carebastine. In HLMs, ebastine was metabolized to desalkyl-, hydroxy-, and carebastine; hydroxyebastine to desalkyl- and carebastine; and carebastine to desalkylebastine. Of the 11 cDNA-expressed P450s, CYP3A4 was the main enzyme catalyzing the N-dealkylation of ebastine, hydroxyebastine, and carebastine to desalkylebastine [intrinsic clearance (CL(int)) = 0.44, 1.05, and 0.16 microl/min/pmol P450, respectively]. Ebastine and hydroxyebastine were also dealkylated to desalkylebastine to some extent by CYP3A5. Ebastine hydroxylation to hydroxyebastine is mainly mediated by CYP2J2 (0.45 microl/min/pmol P450; 22.5- and 7.5-fold higher than that for CYP3A4 and CYP3A5, respectively), whereas CYP2J2 and CYP3A4 contributed to the formation of carebastine from hydroxyebastine. These findings were supported by chemical inhibition and kinetic analysis studies in human liver microsomes. The CL(int) of hydroxyebastine was much higher than that of ebastine and carebastine, and carebastine was metabolically more stable than ebastine and hydroxyebastine. In conclusion, our data for the first time, to our knowledge, suggest that both CYP2J2 and CYP3A play important roles in ebastine sequential metabolism: dealkylation of ebastine and its metabolites is mainly catalyzed by CYP3A4, whereas the hydroxylation reactions are preferentially catalyzed by CYP2J2. The present data will be very useful to understand the pharmacokinetics and drug interaction of ebastine in vivo.

Topics: Butyrophenones; Cytochrome P-450 CYP2J2; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Histamine H1 Antagonists; Humans; In Vitro Techniques; Microsomes, Liver; Oxygenases; Piperidines

The oxidation of tert-butyl-phenyl group of title compounds by some microorganisms was studied. We have optimized the conditions of culture to increase the formation of acid metabolites and to avoid the formation of side products. We showed that an oxidative activity is induced by soybean peptones in Streptomyces platensis. The biologically active compounds, fexofenadine and carebastine, are produced in good yield (86-95%) by Absidia corymbifera.

Topics: Absidia; Biotransformation; Butyrophenones; Cunninghamella; Histamine H1 Antagonists; Oxidation-Reduction; Piperidines; Streptomyces griseus; Terfenadine

The effects of ebastine and its active metabolite carebastine on brain dopamine uptake and the accessibility to brain were compared with those for a classical antihistaminic agent chlorpheniramine by using the microdialysis technique. Both carebastine and chlorpheniramine potently inhibited brain [(3)H]dopamine uptake and increased the extracellular concentration of dopamine in the striatum after local perfusion via microdialysis probes, although systemic injection of ebastine but not chlorpheniramine did not change the dopamine level. These findings suggest that neither ebastine nor carebastine affects central dopamine metabolism because of a limited access to brain, in spite of having a potent inhibitory action on neuronal dopamine uptake.

Topics: Animals; Butyrophenones; Chlorpheniramine; Corpus Striatum; Dopamine; Dopamine Uptake Inhibitors; Dose-Response Relationship, Drug; Histamine H1 Antagonists; In Vitro Techniques; Male; Microdialysis; Nomifensine; Piperidines; Rats; Rats, Wistar

Allergic rhinitis is characterized by tissue accumulation of inflammatory cells. CC chemokines, including monocyte chemotactic protein (MCP) 1, MCP-3, RANTES, and eotaxin, are thought to play an important role in inducing selective recruitment of these cells to the allergic inflammatory site. Furthermore, MCPs have been indicated as histamine-releasing factors. Histamine is an important mediator in the pathogenesis of nasal allergy. The regulation of histamine may have a role in the management of allergic inflammation.. The objectives of this study were to investigate the expression of MCP-1, MCP-3, RANTES, and eotaxin in the nasal mucosa of patients with allergic rhinitis and to clarify the effect of histamine and antihistamine on the regulation of the expression of these CC chemokines.. By using a semiquantitative reverse transcriptase PCR technique, the numbers of copies of messenger RNA encoding MCP-1, MCP-3, RANTES, and eotaxin were measured in explant cultures of human nasal mucosa. In culture medium, specific antigen or histamine was added. Furthermore, the effect of preincubation with the antihistamine carebastine was estimated.. Mite antigen (1:2 x 10(4) dilution) and histamine (10(-4) to 10(-3) mol/L) upregulated the messenger RNA expression of these CC chemokines at 3- to 10-fold increases. Carebastine (10(-7) to 10(-6) mol/L) inhibited this upregulation.. Our results suggest that histamine may induce CC chemokine production in the nasal mucosa of patients with allergic rhinitis. This indicates that there may be a prolonged inflammatory cycle in the histamine-MCP axis in allergic rhinitis. The regulation of histamine-CC chemokine interaction could lead to new therapeutic approaches in the treatment of nasal allergy.

Topics: Adult; Animals; Antigens; Butyrophenones; Chemokines, CC; Female; Gene Expression Regulation; Histamine; Histamine H1 Antagonists; Humans; Male; Mites; Nasal Mucosa; Piperidines; RNA, Messenger

Ebastine (CAS 90729-43-4) is an antiallergic agent which selectively and potently blocks histamine H1-receptors in vivo. A simple and sensitive high-performance liquid chromatography (HPLC) method is described for the simultaneous determination of ebastine and its two oxidized metabolites, carebastine (CAS 90729-42-3) and hydroxyebastine (M-OH), in human plasma. After a pretreatment of plasma sample by solid-phase extraction, ebastine and its metabolites were analyzed on an HPLC system with ultraviolet detection at 254 nm. Chromatography was performed on a cyano column (250x4.0 mm I.D.) at 40 degrees C with the mobile phase of acetonitrile-methanol-0.012 M ammonium acetate buffer (20:30:48, v/v/v) at a flow rate of 1.2 ml/min. Accurate determinations were possible over the concentration range of 3-1000 ng/ml for the three compounds using 1 ml plasma samples. The intra- and inter-day assay accuracy of this method were within 100+/-15% of nominal values and the precision did not exceed 12.4% of relative standard deviation. The lower limits of quantitation were 3 ng/ml for ebastine and its metabolites in human plasma. This method was satisfactorily applied to the determination of ebastine and its two oxidized metabolites in human plasma after oral administration of ebastine.

Topics: Butyrophenones; Chromatography, High Pressure Liquid; Histamine H1 Antagonists; Humans; Piperidines; Reproducibility of Results; Sensitivity and Specificity

Topics: Anti-Inflammatory Agents; Butyrophenones; Cells, Cultured; Cetirizine; Chymases; Eosinophils; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoietic Cell Growth Factors; Histamine; Histamine H1 Antagonists; Humans; Hypersensitivity; Intercellular Adhesion Molecule-1; Interleukin-3; Interleukin-8; Loratadine; Mast Cells; Piperidines; Potassium Channel Blockers; Potassium Channels; Prostaglandin D2; Pyridines; Recombinant Fusion Proteins; Recombinant Proteins; Serine Endopeptidases; Terfenadine; Time Factors; Tryptases

The transport mechanism of the non-sedative H1-antagonist ebastine and its first-pass carboxylic acid metabolite carebastine at the blood-brain barrier (BBB) was studied. In rats, the brain uptake index (BUI) value of [14 C]carebastine was significantly lower than that of [14 C]ebastine. The BUI value of [14 C]carebastine was greatly increased by the addition of non-labeled carebastine. The steady-state uptake of [14 C]carebastine by P-glycoprotein-overexpressing K562/ADM cells was significantly lower than that by their parental drug-sensitive cell line K562. The decreased steady-state uptake of [14 C]carebastine by K562/ADM cells was reversed by verapamil. Steady-state uptake of [14 C]carebastine by primary cultured bovine brain capillary endothelial cells (bovine BCECs) was increased in the presence of metabolic inhibitors and verapamil. Non-labeled carebastine increased the steady-state uptake of a P-glycoprotein substrate, [3 H]vincristine, by bovine BCECs. The initial uptake of [3 H]mepyramine by bovine BCECs and RBEC1 (an immortalized cell line from rat brain capillary endothelial cells) was strongly inhibited by ebastine, while zwitterionic carebastine was slightly inhibitory. The values of brain-to-plasma unbound concentration ratio (Kp,f) in mdr1a(-/-) mice were increased 5.3-fold and 4.2-fold for [14 C ebastine and for [14 C]carebastine, respectively, compared with those in mdr1a(+/+) mice. Non-radiolabeled carebastine increased the Kp,f values of [14 C]carebastine in both types of mice. In conclusion, carebastine was shown to be a substrate for P-glycoprotein-mediated efflux from the brain at the BBB. A second efflux system may also be involved. The relatively low affinity of the uptake transport system for carebastine also limits the brain distribution of ebastine/carebastine.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; Blood-Brain Barrier; Butyrophenones; Cattle; Endothelium, Vascular; Histamine H1 Antagonists; Humans; Male; Mice; Mice, Mutant Strains; Piperidines; Rats; Rats, Sprague-Dawley; Tumor Cells, Cultured

Ebastine (EBS), a novel nonsedative antiallergic agent, is similar to terfenadine in its chemical structure. However, clinical arrhythmogenicity of EBS remains controversial. In this study, we evaluated the possible arrhythmogenic potency of EBS as assessed by QT prolongation from a pharmacokinetic-pharmacodynamic viewpoint in comparison with that of terfenadine. EBS was intravenously infused into anesthetized rats at a rate of 3.0 or 10 mg/kg/h for 60 min, and electrocardiographic effects were continuously monitored from lead II. The plasma concentrations of EBS and its major metabolite, carebastine, were also measured under the same conditions. When intravenously administered, EBS exhibited QT prolongation in an infusion rate-dependent manner, with a lag time. Pharmacokinetic-pharmacodynamic analysis of EBS based on the effect-compartment model revealed values of EC50, Emax and EC(10 ms), (where 10 ms of QT prolongation was evoked) of 0.73 microg/mL, 12.5 ms and 2.90 microg/mL, respectively. The EC(10 ms) value of EBS was five times higher than that of terfenadine reported previously (Ohtani et al., J. Pharm. Pharmacol., 49, 458-462 (1997)). In conclusion, EBS was suggested to be less arrhythmogenic than terfenadine.

Topics: Animals; Arrhythmias, Cardiac; Butyrophenones; Electrocardiography; Histamine H1 Antagonists; Male; Piperidines; Rats; Rats, Sprague-Dawley; Terfenadine

53 compounds with clinically established ability to cross or not to cross the blood-brain barrier by passive diffusion were characterized by means of surface activity measurements in terms of three parameters, i.e., the air-water partition coefficient, Kaw, the critical micelle concentration, CMCD, and the cross-sectional area, AD. A three-dimensional plot in which the surface area, AD, is plotted as a function of K-1aw and CMCD shows essentially three groups of compounds: (i) very hydrophobic compounds with large air-water partition coefficients and large cross-sectional areas, AD > 80 A2 which do not cross the blood-brain barrier, (ii) compounds with lower air-water partition coefficients and an average cross-sectional area, AD congruent with 50 A2 which easily cross the blood-brain barrier, and (iii) hydrophilic compounds with low air-water partition coefficients (AD < 50 A2) which cross the blood-brain barrier only if applied at high concentrations. It was shown that the lipid membrane-water partition coefficient, Klw, measured previously, can be correlated with the air-water partition coefficient if the additional work against the internal lateral bilayer pressure, pibi = 34 +/- 4 mN/m is taken into account. The partitioning into anisotropic lipid membranes decreases exponentially with increasing cross-sectional areas, AD, according to Klw = const. Kaw exp(-ADpibi/kT) where kT is the thermal energy. The cross-sectional area of the molecule oriented at a hydrophilic-hydrophobic interface is thus the main determinant for membrane permeation provided the molecule is surface active and has a pKa > 4 for acids and a pKa < 10 for bases.

Topics: Air; Amiodarone; Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; Blood-Brain Barrier; Brain; Butyrophenones; Diffusion; Domperidone; Histamine H1 Antagonists; Humans; Kinetics; Loperamide; Micelles; Models, Biological; Piperidines; Surface Properties; Thermodynamics; Water

The effects of ebastine and terfenadine, long-acting nonsedating histamine H1 receptor antagonists, were studied on hKv1.5 channels using the whole-cell voltage-clamp configuration of the patch-clamp technique in Ltk- cells transfected with the gene encoding the hKv1.5 channel. Upon depolarization to +60 mV, terfenadine, 1 microM and 3 microM, inhibited the hKv1.5 current by 42.4 +/- 6.4% and 69.3 +/- 4.2% (P < 0.01). In contrast, at the same range of concentrations, ebastine-induced inhibition of this K+ current averaged 6.5 +/- 2.0% and 13.0 +/- 2.0 (P < 0.05). At the highest concentration tested (3 microM) neither terfenadine carboxylate nor carebastine significantly modified hKv1.5 current. All these results suggest that ebastine could represent a safer alternative to terfenadine in the clinical practice.

Topics: Animals; Butyrophenones; Cells, Cultured; Drug Evaluation, Preclinical; Histamine H1 Antagonists; Humans; Membrane Potentials; Mice; Patch-Clamp Techniques; Piperidines; Potassium Channels; Terfenadine

The microbial oxidation of ebastine to carebastine was investigated. Among the 15 micro-organisms examined, only the Cunninghamella strains showed the desired biotransformation. Cunninghamella blakesleeana oxidised the substrate within 7 days, via the intermediates alcohol and aldehyde, mainly to carebastine, the corresponding carboxylic acid. Optimisation of the culture conditions increased the yield from initially 10% up to a reproducible 40%. For the synthesis of carebastine a substrate concentration of 200 mg/l, a starting pH of 5.0 and the addition of 1% poly(vinyl alcohol) is favourable. The results achieved in experiments with shaking flasks are transferable to the fermentation scale and yielded 270 mg carebastine in a 3-1 fermentation of 600 mg ebastine. The progress of the reaction was detected by TLC and HPLC, the products were identified by mass spectrometry and NMR.

Topics: Biotransformation; Butyrophenones; Histamine H1 Antagonists; Mucorales; Oxidation-Reduction; Piperidines

The anti-allergic activity of ebastine, a novel antihistamine, was assessed in comparison with several antihistamines. 1) Orally administered ebastine dose-dependently inhibited 7-day homologous passive cutaneous anaphylaxis (PCA), experimental allergic rhinitis and experimental asthma in guinea pigs or rats (ED50-values were 2.17, 0.29 and 0.35 mg/kg, respectively); and its anti-allergic activity was more potent than those of terfenadine and mequitazine. Moreover, its PCA-inhibitory activity was still observed 24 hr after the administration. 2) Orally administered ebastine also inhibited histamine-induced skin reaction in rats (ED50: 1.10 mg/kg). 3) In isolated guinea pig trachea, ebastine had no effect on histamine-induced contraction, but carebastine, a main metabolite of ebastine, inhibited this contraction (IC50: 0.12 microM). 4) Carebastine (30-100 microM) suppressed the histamine release from rat peritoneal mast cells and human basophils. 5) Ebastine at a high oral dose showed slight inhibition of the specific binding of 3H-mepyramine to the histamine H1-receptor in rat brain. This binding-inhibitory activity of ebastine was little more potent than that of terfenadine, but much less potent than those of mequitazine and ketotifen. These results indicated that ebastine has potent and long acting anti-allergic activity with few side effects based on the antihistaminic activity in the central nervous system. Furthermore, it was suggested that these effects of ebastine are due to the action of a main metabolite, carebastine.

Topics: Administration, Oral; Animals; Butyrophenones; Disease Models, Animal; Dose-Response Relationship, Drug; Guinea Pigs; Histamine H1 Antagonists; Histamine Release; Humans; Hypersensitivity; In Vitro Techniques; Male; Phenothiazines; Piperidines; Pyrilamine; Rats; Rats, Wistar; Terfenadine

The pharmacokinetics of ebastine (CAS 90729-43-4), a new histamine H1-receptor antagonist, was investigated in rats, guinea pigs, dogs and monkeys. Plasma levels of ebastine and its active carboxylated metabolite, carebastine (CAS 90729-42-3), were determined after an intravenous dose (2 mg/kg) or an oral dose (10 mg/kg). After intravenous administration to dogs, plasma levels of the unchanged ebastine showed a bi-phasic decrease with a t1/2 alpha of 0.16 h and t1/2 beta of 4.2 h. In contrast, after oral administration, the unchanged ebastine was scarcely detected in plasma of 4 animal species examined, indicating extensive first-pass metabolism of ebastine. There were marked interspecies differences in the plasma concentration-time profiles of carebastine after oral administration of ebastine. The Cmax of carebastine in guinea pigs (2820 ng/ml) was markedly higher than that in rats (311 ng/ml), dogs (465 ng/ml) and monkeys (1036 ng/ml). Guinea pig also showed the slower elimination of carebastine (t1/2 of 9.4 h) than rat (0.92 h), dog (2.4 h) and monkey (1.2 h). After oral administration of carebastine to rats, the Cmax and AUC were approximately 3/4 of those after administration of ebastine. Once daily 7-day repeated oral administrations of ebastine did not affect the pharmacokinetics of ebastine and carebastine in rats. These findings strongly indicate that carebastine is responsible for the antihistamine activity after oral administration of ebastine.

Topics: Administration, Oral; Animals; Butyrophenones; Dogs; Guinea Pigs; Histamine H1 Antagonists; Injections, Intravenous; Macaca fascicularis; Male; Piperidines; Protein Binding; Rats; Rats, Wistar; Species Specificity

Pharmacokinetics of ebastine (CAS 90729-43-4), a histamine H1-receptor antagonist, was evaluated in healthy male volunteers. The subjects were given single oral doses of 5, 10, 20 and 40 mg of ebastine (5 or 6 subjects) and repeated oral doses of 20 mg once daily for 7 days (6 subjects). Administration of ebastine resulted in a negligible level of the unchanged drug in plasma and urine. Mean plasma concentration of carebastine (CAS 90729-42-3), an active carboxylated metabolite, reached maximum levels of 40, 112, 195 and 388 ng/ml at 4-6 h after single oral administration of ebastine at doses of 5, 10, 20 and 40 mg, respectively. Plasma levels of carebastine showed a first-order decrease with apparent half-lives of 13.8 to 15.3 h. The Cmax and AUC of carebastine increased in proportion to the dose. Urinary excretion of carebastine during 72 h after single administration accounted for 1.3-1.8% of the dose. Food intake did not affect the pharmacokinetics and gastrointestinal absorption of ebastine. Repeated administrations of ebastine once daily for 7 days did not cause any change in the pharmacokinetics of ebastine and carebastine. Plasma concentration of carebastine reached the steady state on day 4. The Cmax (360-396 ng/ml) was 1.6- to 1.7-fold greater than that after the first administration (229 ng/ml). These results strongly suggest that carebastine is responsible for the antihistamine activity after administration of ebastine.

Topics: Adult; Butyrophenones; Food; Half-Life; Histamine H1 Antagonists; Humans; Male; Middle Aged; Piperidines; Protein Binding

Absorption, distribution, metabolism and excretion of ebastine (4'-tert-butyl-4-[4-(diphenylmethoxy)piperidino]butyrophenone, LAS-90, CAS 90729-43-4), a novel antihistamine, were investigated with 14C-labeled compound in rats after a single oral or intravenous administration, in comparison with [14C]carebastine, an active metabolite of ebastine. After intravenous administration of [14C]ebastine at 2 mg/kg, the plasma level of radioactivity decreased biphasically with alpha-phase half-life (t1/2 alpha) of 1.6 h and beta-phase half-life (t1/2 beta) of 3.1 h. After administration of [14C]carebastine, a similar plasma level-time profile was observed with t1/2 alpha of 0.7 h and t1/2 beta of 2.1 h. Following oral administration of [14C]ebastine at a dose of 2 mg/kg, the plasma level reached the maximum (Cmax) of 102 ng eq./ml at 2 h and decreased monophasically with t1/2 of 3.9 h. At 20 mg/kg, a monophasic decrease was also observed with Cmax of 1110 ng eq./ml at 4 h and with t1/2 of 4.0 h. After oral administration of [14C]carebastine at 2 mg/kg, the plasma level reached Cmax of 129 ng eq/ml at 2 h, followed by a monophasic decrease with t1/2 of 2.9 h. Half-lives after administration of [14C]ebastine were somewhat longer than those after administration of [14C]carebastine. The level of [14C]ebastine radioactivity in the liver was about 36 times higher, and in kidney, mesenteric lymph nodes, lung, adrenal, submaxillary gland or pancreas 2-4 times higher than in plasma at 2 h after oral administration. The brain level was lower than the reliable limit of measurement. Other tissue levels were similar to or lower than plasma level. Radioactivity in most tissues decreased essentially in parallel with that in plasma. In pregnant rats, [14C]ebastine radioactivity level in fetus was about 1/4 of the maternal plasma level 1 h after administration. In lactating rats, milk levels of [14C]ebastine radioactivity were similar to maternal plasma levels over 8 h. Serum protein binding of [14C]ebastine was more than 99.8%. After intravenous administration of [14C]ebastine, about 6% of the dose was excreted in the urine and about 93% in the feces. Similar results were observed after oral administration at 0.2, 2 and 20 mg/kg. Following administration of [14C]carebastine, the recovery of radioactivity in urine and feces were around 2% and 96% of the dose, respectively, irrespective of administration route. In the plasma 2 h after oral administration of [14C] ebastine, carebasti

Topics: Administration, Oral; Animals; Autoradiography; Bile; Blood Proteins; Butyrophenones; Chromatography, Thin Layer; Feces; Female; Half-Life; Histamine H1 Antagonists; Humans; Injections, Intravenous; Intestinal Absorption; Male; Milk; Piperidines; Pregnancy; Protein Binding; Rats; Rats, Wistar; Tissue Distribution