piperidines and ebastine

The spread of the novel human respiratory coronavirus (SARS-CoV-2) is a global public health emergency. There is no known successful treatment as of this time, and there is a need for medical options to mitigate this current epidemic. SARS-CoV-2 uses the angiotensin-converting enzyme 2 (ACE2) receptor and is primarily trophic for the lower and upper respiratory tract. A number of current studies on COVID-19 have demonstrated the substantial increase in pro-inflammatory factors in the lungs during infection. The virus is also documented in the central nervous system and, particularly in the brainstem, which plays a key role in respiratory and cardiovascular function. Currently, there are few antiviral approaches, and several alternative drugs are under investigation. Two of these are Idelalisib and Ebastine, already proposed as preventive strategies in airways and allergic diseases. The interesting and evolving potential of phosphoinositide 3-kinase δ (PI3Kδ) inhibitors, together with Ebastine, lies in their ability to suppress the release of pro-inflammatory cytokines, such as IL-1β, IL-8, IL-6, and TNF-α, by T cells. This may represent an optional therapeutic choice for COVID-19 to reduce inflammatory reactions and mortality, enabling patients to recover faster. This concise communication aims to provide new potential therapeutic targets capable of mitigating and alleviating SARS-CoV-2 pandemic infection.

Topics: Angiotensin-Converting Enzyme 2; Angiotensin-Converting Enzyme Inhibitors; Anti-Inflammatory Agents; Antirheumatic Agents; Antiviral Agents; Betacoronavirus; Butyrophenones; Class I Phosphatidylinositol 3-Kinases; Coronavirus Infections; COVID-19; COVID-19 Drug Treatment; Drug Repositioning; Humans; Inflammation; Interleukin-6; Molecular Targeted Therapy; Pandemics; Peptidyl-Dipeptidase A; Piperidines; Pneumonia, Viral; Purines; Quinazolinones; SARS-CoV-2

Histamine, acting predominantly via the H1-receptor, is an important mediator of the symptoms of allergy. H1-antihistamines, which stabilize the receptor in its inactive form, are the treatment of choice for some chronic allergic conditions. Ebastine is a well-established secondgeneration oral H1-antihistamine that is administered once daily at a dose of 10-20 mg and is available both as a standard tablet and as a fast-dissolving tablet that disintegrates in the mouth. Ebastine has been shown to relieve symptoms in patients with allergic rhinitis or urticaria in multiple clinical trials. In addition to its antihistamine effects, the drug has modulating effects on the allergic inflammatory process, thus potentially explaining its beneficial effect on nasal obstruction in some patients. Ebastine is generally well tolerated at recommended doses and is one of the lowest-risk antihistamines with respect to adverse cognitive/psychomotor effects, as confirmed by decades of pharmacovigilance. New long-term data confirm its efficacy and tolerability during up to 1 year of treatment in patients with chronic urticaria.

Topics: Administration, Oral; Butyrophenones; Histamine; Histamine H1 Antagonists; Humans; Piperidines; Rhinitis, Allergic; Treatment Outcome; Urticaria

Allergic diseases are the most common conditions in children and the second most frequent in adults. Currently, there are two well-defined generations of antihistamines, those belonging to first generation, with inherent side effects such as drowsiness and anticholinergic effects. These side effects are often attributed to their high lipophilicity and high affinity for brain H1 receptors. The ebastine is a modern antihistaminic drug belongs to the second generation and has lower lipophilicity, which diminish the undesirable side effects. To ensure the quality, efficacy, safety, and effectiveness of ebastine drug products, efficient and reliable analytical methods are mandatory. Besides official compendial methods, alternative methods are often developed and used in quality control of pharmaceuticals as well as in pharmacokinetic studies. In this work, we present a critical review on characteristics, physicochemical properties, and analytical methods applied in the analysis of ebastine.

Topics: Butyrophenones; Chemistry, Physical; Humans; Molecular Structure; Piperidines

This review introduces the principles of visceral sensation and appraises the current approaches to management of visceral pain in functional GI diseases, principally IBS. These approaches include dietary measures including fibre supplementation, low fermentable oligosaccharides, disaccharides, monosaccharides and polyols diet, and pharmacological approaches such as antispasmodics, peppermint oil, antidepressants (tricyclic agents, selective serotonin reuptake inhibitors), 5-HT

Topics: Abdominal Pain; Anti-Infective Agents; Antidepressive Agents; Butyrophenones; Dipeptides; GABA Agents; Gastrointestinal Agents; Histamine H1 Antagonists; Humans; Imidazoles; Irritable Bowel Syndrome; Mentha piperita; Parasympatholytics; Phenylalanine; Piperidines; Plant Oils; Probiotics; Quaternary Ammonium Compounds; Rifamycins; Rifaximin; Serotonin 5-HT3 Receptor Antagonists; Thiophenes; Visceral Pain

Because of its burden on patient's lives and its impact on asthma, allergic rhinitis must be treated properly with more effective and safer treatments. According to guidelines by Allergic Rhinitis and Its Impact on Asthma (ARIA), the classification, pathogenesis, and treatment of allergic rhinitis are well defined. Currently, second-generation antihistamines and inhaled steroids are considered the cornerstone of first-line therapy. However, new formulations of available drugs (e.g., loratadine and rupatadine oral solution, ebastine fast-dissolving tablets, and the combination of intranasal fluticasone propionate and azelastine hydrochloride), recently discovered molecules (e.g., ciclesonide, bilastine, and phosphodiesterase-4 inhibitors), immunologic targets (e.g., omalizumab), and unconventional treatments (e.g., homeopathic treatments) are currently under investigation and represent a new frontier in modern medicine and in allergic rhinitis management. The aim of this review is to provide an update on allergic rhinitis treatment, paying particular attention to clinical trials published within the past 20 months that assessed the efficacy and safety of new formulations of available drugs or new molecules.

Topics: Administration, Intranasal; Androstadienes; Anti-Allergic Agents; Antibodies, Anti-Idiotypic; Antibodies, Monoclonal, Humanized; Benzimidazoles; Butyrophenones; Cyproheptadine; Fluticasone; Histamine H1 Antagonists; Humans; Omalizumab; Phthalazines; Piperidines; Pregnenediones; Rhinitis, Allergic; Rhinitis, Allergic, Perennial

Histamine is a key mediator in the development of allergy symptoms, and oral H(1)-antihistamines are among the most widely used treatments for symptomatic relief in conditions such as allergic rhinitis and chronic urticaria. Ebastine is a second-generation antihistamine which has been shown to be an effective treatment for both seasonal and perennial allergic rhinitis. In controlled clinical trials in adult and adolescent patients with allergic rhinitis, ebastine 10 mg once-daily improved symptoms to a significantly greater extent than placebo and to a similar extent as loratadine 10 mg and cetirizine 10 mg (both once-daily), while ebastine 20 mg proved to be more effective than these two comparator antihistamines. In addition, ebastine was significantly more effective than placebo at relieving the symptoms of chronic idiopathic urticaria. Ebastine provides efficacy throughout the 24-h dosing interval with once-daily administration and clinical benefit is seen from the first day of treatment. Small studies have found beneficial effects for ebastine in patients with other disorders, including cold urticaria, dermographic urticaria, atopic asthma, mosquito bites and (in combination with pseudoephedrine) the common cold. In addition to the regular ebastine tablet, a fast-dissolving tablet (FDT) formulation, which disintegrates in the mouth without the aid of a drink, is also available. It has been shown to be bioequivalent to the regular tablet, and to be significantly more effective than desloratadine at reducing histamine-induced cutaneous wheals. A number of patient surveys demonstrated that the majority of individuals who tried the fast-dissolving formulation reported it to be convenient for use, fast-acting and preferred it to their previous antihistamine medication. Perhaps most importantly, a large proportion of patients indicated that they would prefer to use this new formulation in the future. Ebastine has a rapid onset of action and it can be administered once-daily, with or without food. Dose modifications are not needed in elderly patients, or in those with renal or mild to moderate hepatic impairment. Ebastine is generally well-tolerated, and clinical studies showed that at usual therapeutic doses of 10 and 20 mg once-daily, it had no clinically relevant adverse effects on cognitive function and psychomotor performance or on cardiovascular function. In conclusion, ebastine is an effective and generally well-tolerated treatment for allergic rhini

Topics: Animals; Butyrophenones; Chronic Disease; Histamine H1 Antagonists; Humans; Piperidines; Rhinitis, Allergic, Perennial; Rhinitis, Allergic, Seasonal; Urticaria

Few randomized studies have compared the efficacy of ebastine and loratadine in the symptomatic treatment of seasonal allergic rhinitis (SAR).. A meta-analysis was performed on data from four randomized, double-blind, placebo-controlled, parallel-group clinical trials comparing the efficacy of ebastine 20 mg once daily versus loratadine 10 mg once daily in the symptomatic treatment of SAR symptoms. Primary efficacy variable was the mean change in the overall mean daily reflective total symptom score (TSS), i.e. the sum of five rhinitis symptom scores: nasal discharge, nasal congestion, nasal itching, sneezing and total eye symptoms (itchy/watery eyes) over the first 2 weeks of treatment compared to baseline.. There were 2,089 patients in the population analyzed: 749, 739 and 601 patients in the ebastine 20 mg, loratadine 10 mg and placebo groups, respectively. Compared to baseline, overall mean daily reflective TSS over the first 2 weeks of treatment was -3.61 (35.4% reduction from baseline) in the ebastine group, -3.05 (29.0% reduction) in the loratadine group and -2.30 (22.7% reduction) in the placebo group. Statistically significant differences in the mean change from baseline were found when comparing ebastine and loratadine (p<0.001), ebastine and placebo (p<0.0001), and loratadine and placebo (p<0.0001). The global effect (i.e. the difference in overall mean daily reflective TSS over the first 2 weeks of treatment) of ebastine compared with loratadine over the first 2 weeks of treatment was -0.56 (95% confidence interval, CI, -0.86 to -0.26), and it was sustained during the whole (4-week) period studied. The global effects of ebastine and loratadine compared with placebo were -1.30 (95% CI, -1.61 to -0.99) and -0.74 (95% CI, -1.05 to -0.43), respectively. Secondary variables (reflective and snapshot individual symptom scores) showed the same trend.. This meta-analysis confirms that ebastine 20 mg has a good efficacy profile, inducing a greater decrease from baseline in mean rhinitis symptom scores than loratadine 10 mg or placebo.

Topics: Adult; Butyrophenones; Female; Histamine H1 Antagonists, Non-Sedating; Humans; Loratadine; Male; Multicenter Studies as Topic; Piperidines; Placebos; Randomized Controlled Trials as Topic; Rhinitis, Allergic, Seasonal

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

Ebastine is a once-daily, non-sedating, selective, long-acting, second-generation antihistamine. The use of ebastine is indicated in patients suffering from intermittent and persistent allergic rhinitis and chronic idiopathic urticaria. Ebastine 10 mg/day, appears as effective as other second-generation antihistamines, such as cetirizine and loratadine. Ebastine 20 mg/day is indicated in patients with moderate and severe allergic symptoms. No cardiovascular effects of ebastine are described, although there is a pharmacokinetic interaction when ketoconazole or macrolides are co-administered. Ebastine has no relevant effects on the psychomotor performance. Even with ebastine 20 mg/day skilled performance does not appear to be impaired. Furthermore, ebastine 5-10 and 2.5 mg, appears to be efficient and can be used safely in children 6-11 and 2-5 years of age, respectively. Ebastine appears to be a safe, effective and well-tolerated second-generation antihistamine in the treatment of allergic rhinitis and chronic idiopathic urticaria.

Topics: Anti-Allergic Agents; Asthma; Butyrophenones; Clinical Trials as Topic; Histamine H1 Antagonists, Non-Sedating; Humans; Piperidines; Rhinitis, Allergic, Perennial; Rhinitis, Allergic, Seasonal; Urticaria

Topics: Animals; Butyrophenones; Cytokines; Histamine H1 Antagonists; Humans; Macrophages; Piperidines; T-Lymphocytes

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

The review summarizes recent progress in the study of the cardiac actions of second--generation antihistamines. Terfenadine and astemizole, two antihistamines of the second generation, are in vitro potent blockers of potassium channels (K+). It has been considered to be responsible for QT prolongation of the electrocardiogram and life--treating ventricular tachycardias called torsades de pointes. Loratadine and descarboethoxyloratadine, the major metabolite of loratadine were studied on a human cardiac K+ channel (hKv 1.5) cloned from human ventricle. Parent compound and its metabolite in high concentration blocked hKv1.5 channels. However, loratadine (10 mumol/L) failed to inhibit HERG potassium channel and HERG K+. Ebastine also inhibit potassium channels, cloned human Kv 1.5. Cetirizine was completely devoid of any inhibitory action on HERG K+ channels in concentration up to 30 mumd/L. On the other hand terfenadine and astemizole effectively blocked HERG K+ channels with nanomolar affinities (330 and 480 nmol/L, respectively), whereas loratadine was about 300-fold less potent. Fexofenadine--the major metabolite of terfenadine, does not block either HERG or Kv1.5. The quinea pig model (in vitro) revealed that only terfenadine, astemizole and ebastine produced significant QT interval prolongation and arrhythmogenic effects. The other nonsedating antihistamines including cetirizine, loratadine and the major metabolite of ebastine (carabastine), terfenadine (feksofenadine) and astemizole (norastemizole) were devoid of QT interval prolongation and other adverse ECG effects.

Topics: Animals; Area Under Curve; Astemizole; Butyrophenones; Electrocardiography; Heart; Histamine H1 Antagonists; Humans; Loratadine; Piperidines; Tachycardia; Terfenadine; Torsades de Pointes

Ebastine is a second-generation antihistamine which undergoes transformation to its active metabolite, carebastine. Its antihistaminic and antiallergic effects have been demonstrated in in vitro and in vivo studies, in addition to data obtained from clinical trials. Patients with allergic rhinitis or chronic idiopathic urticaria experienced significant improvement in their symptoms with ebastine 10 or 20 mg once daily. Some studies in patients with seasonal allergic rhinitis (SAR) have indicated trends towards greater efficacy with the 20 mg than the 10 mg dose, although only 1 study has shown statistically significant benefits. In comparative trials in patients with SAR, ebastine 10 mg was as effective as most other second-generation antihistamines, including astemizole, azelastine, cetirizine, loratadine and terfenadine. Ebastine 20 mg/day was significantly superior to loratadine 10 mg/day in patients with SAR according to effects on secondary efficacy variables in comparative studies; 1 study found significantly greater changes from baseline in mean total symptom score with ebastine 20 mg (-43 vs -36% with loratadine, p = 0.045). In patients with perennial allergic rhinitis, ebastine 10 or 20 mg daily was significantly more effective than loratadine in reducing total symptom scores from baseline 1 comparative study. There have been no reports of serious adverse cardiac effects during ebastine therapy. Increases in corrected QT interval have been observed during clinical trials; however, these have not been considered clinically significant and were generally of similar magnitude to those seen with loratadine. The normal diurnal variation in QTc interval and the problems associated in correcting for changes in heart rate also complicate assessment of this issue. The incidence of adverse events during ebastine treatment is not significantly greater than that observed with placebo or other second-generation antihistamines.. Ebastine 10 mg daily is a well tolerated and effective treatment for allergic rhinitis and chronic idiopathic urticaria. At this dosage, it is as effective as the other second-generation antihistamines against which it has been compared. Ebastine 20 mg has similar tolerability to the 10 mg dose, and trends towards greater efficacy with the higher dose have been shown in some studies. Ebastine does not appear to be associated with any significant cardiac adverse events. Ebastine is a useful treatment option for patients with allergic rhinitis or chronic idiopathic urticaria.

Topics: Animals; Anti-Allergic Agents; Butyrophenones; Humans; Hypersensitivity; Piperidines

Most of the modern non-sedating H1 receptor antagonists (antihistamines) penetrate the brain poorly, allowing the use of doses large enough to counteract allergic processes in peripheral tissues without important central effects. The antihistamines reviewed here are acrivastine, astemizole, cetirizine, ebastine, fexofenadine, loratadine, mizolastine, and terfenadine. However, these drugs are not entirely free from central effects, and there are at least quantitative differences between them. Although psychomotor and sleep studies in healthy subjects in the laboratory may predict that an antihistamine does not cause drowsiness, the safety margin can be narrow enough to cause a central sedating effect during actual treatment. This might result from a patient's individual sensitivity, disease-induced sedation, or drug dosages that are for various reasons relatively or absolutely larger (patient's weight, poor response, reduced drug clearance, interactions). Mild to even moderate sedation is not necessarily a major nuisance, particularly if stimulants need be added to the regimen (e.g. in perennial rhinitis). Furthermore, patients can adjust doses themselves if needed. Sedating antihistamines are not needed for long-term itching, because glucocorticoids are indicated and more effective. It is wise to restrict or avoid using antihistamines (astemizole, terfenadine) that can cause cardiac dysrhythmias, because even severe cardiotoxicity can occur in certain pharmacokinetic drug-drug interactions. Histamine H1 receptor antagonists (antihistamines) are used in the treatment of allergic disorders. The therapeutic effects of most of the older antihistamines were associated with sedating effects on the central nervous system (CNS) and antimuscarinic effects causing dry mouth and blurred vision. Non-specific "quinidine-like" or local anaesthetic actions often led to cardiotoxicity in animals and man. Although such adverse effects varied from drug to drug, there was some degree of sedation with all old antihistamines. Non-sedating antihistamines have become available during the past 15 years. Some of them also have antiserotonin or other actions that oppose allergic inflammation, and they are not entirely free from sedative effects either. In small to moderate "clinical" concentrations they are competitive H1 receptor antagonists, although large concentrations of some of them exert non-competitive blockade. Daytime drowsiness and weakness are seldom really important,

Topics: Astemizole; Benzimidazoles; Butyrophenones; Central Nervous System; Cetirizine; Drug Interactions; Heart; Histamine H1 Antagonists; Humans; Hypnotics and Sedatives; Loratadine; Piperidines; Potassium Channel Blockers; Terfenadine; Triprolidine

Ebastine and its active metabolite carebastine show potent antagonism of histamine H1-mediated phenomena in a wide variety of in vitro and in vivo non-clinical experimental models. By contrast, activity is not seen against histamine H2- or H3-mediated, nor acetylcholine- or serotonin-mediated phenomena, and both compounds are virtually without effect in models measuring pharmacological effects on the central nervous system (CNS). Explanation of these observations is found in their high selectivity for the histamine H1 receptor and in their low in vivo potency in displacing [3H]-mepyramine from central histamine H1 receptors, indicating that they do not readily pass the blood-brain barrier. These findings have been mirrored in clinical experimental models where oral doses of ebastine (1-30 mg) showed clear dose-related inhibition of intradermal histamine-induced weal and flare responses, whereas doses of 90 mg were without anticholinergic effects on salivary flow, cardiovascular reflexes or pilocarpine-induced miosis. Furthermore, in an extensive series of controlled studies in specific clinical models for measuring objective effects on the CNS, ebastine in single doses of 10-90 mg and repeated doses of 10-30 mg once daily, had no clinically relevant effects on cognitive performance and visual co-ordination tests, nor on simulated car-tracking tests and real car-driving tests. Nor was their any interaction with ethanol or diazepam. On subjective test parameters (questionnaires and visual analogue scales) there were only a few isolated and random incidences of minor increases in some indices of sedation at the highest doses. Not surprisingly, therefore, the clear therapeutic benefit seen during the extensive and international use of ebastine (5-20 mg once daily) in the treatment of seasonal and perennial rhinitis and chronic idiopathic urticaria, has not been accompanied by signs of drug-induced anticholinergic effects (dry mouth, disturbances of visual accommodation) or sedation, making it an effective and well-tolerated first-line treatment alternative to other second-generation antihistamines.

Topics: Animals; Brain; Butyrophenones; Histamine H1 Antagonists; Humans; Piperidines; Psychomotor Performance

The cardiac safety of ebastine, a long-acting, non-sedating antihistamine, has been thoroughly assessed in phase I-III clinical studies. Ebastine alone at the recommended doses of 10 mg and 20 mg has no clinically relevant effect on QTc interval in adults and in special patient populations (elderly, children or subjects with hepatic or renal impairment). Ebastine administered at 60 and 100 mg/day (3-5 times the maximum recommended dose) for 1 week had statistically significantly smaller effects (3.7 and 10.3 msec, respectively) on the QTc interval than terfenadine (18 msec) at three times the recommended dose (360 mg/day). The mean QTc interval prolongation observed with ebastine 100 mg/day was small and not clinically meaningful, although the results were statistically significant vs. placebo. The effect of ebastine 60 mg/day was not statistically different from placebo. Steady-state drug interaction studies demonstrated that the co-administration of ebastine 20 mg with ketoconazole or erythromycin produced significant increases in systemic exposure for ebastine, which were accompanied by small increases in QTc (approximately 10 msec above ketoconazole or erythromycin alone). Results from individual studies suggest that, when coadministered with ketoconazole, ebastine produces similar changes in QTc interval measurements compared to loratadine and cetirizine. Pooled data from clinical efficacy trials of ebastine 1-30 mg/day administered for 2-3 weeks showed no clinically relevant cardiac effects as assessed by serial electrocardiographs and Holter monitoring. The overall cardiac safety profile based on currently available information suggests that ebastine, like loratadine and cetirizine, has a lower potential for causing adverse cardiovascular effects than terfenadine.

Topics: Adult; Butyrophenones; Child; Clinical Trials as Topic; Drug Interactions; Erythromycin; Heart; Histamine H1 Antagonists; Humans; Ketoconazole; Piperidines

Topics: Animals; Butyrophenones; Histamine H1 Antagonists; Humans; Long QT Syndrome; Piperidines; Torsades de Pointes

Topics: Animals; Butyrophenones; Cation Transport Proteins; DNA-Binding Proteins; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels; Histamine H1 Antagonists; Humans; Piperidines; Potassium Channel Blockers; Potassium Channels; Potassium Channels, Voltage-Gated; Torsades de Pointes; Trans-Activators; Transcriptional Regulator ERG

The electrocardiographic effects of ebastine and its active metabolite, carebastine, have been studied alone and in relevant drug-interaction studies in various patient populations. The overall cardiac tolerability of ebastine is excellent. In ebastine dose-ranging studies in adults and children, there were no meaningful dose-related changes in the QTc interval. At high doses of ebastine (5 to 10 times the recommended dose), a modest 10.3 msec increase in QTc was observed. Recommended doses of ebastine had no meaningful effect on QTc in the elderly or in patients with renal or hepatic insufficiency. Interaction studies involving ebastine with ketoconazole revealed a significant increase in the serum ebastine concentration and in the elimination half-life of ebastine, with a modest 18.1 msec increase in QTc (approximately 10 msec above ketoconazole alone) and a plateau QTc-ebastine relationship at higher ebastine levels. Similar, though more minor, QTc findings were observed during coadministration of ebastine with erythromycin. No QTc effects were noted when ebastine was administered with theophylline, and the QTc was similar when ebastine was administered with or without food. These findings indicate that ebastine is well tolerated and, in contrast to terfenadine and astemizole, has no clinically meaningful effect on the QTc interval even at high serum concentrations. As with other 'safe' antihistamines, which have shown similar modest increases in QTc when coadministered with ketoconazole, caution should be exercised when administering ebastine to patients having the long QT syndrome or hypokalaemia, and in patients receiving azole antifungals or macrolide antibacterials.

Topics: Aged; Butyrophenones; Child; Drug Interactions; Electrocardiography; Heart Diseases; Histamine H1 Antagonists; Humans; Piperidines

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

Oral antihistamines generally represent the first line of treatment (after allergen avoidance) in mild seasonal allergic rhinitis (SAR), and in perennial allergic rhinitis (PAR) where symptoms are intermittent. They are safe, effective and easily administered. First-generation antihistamines experienced problems mainly with sedation and anticholinergic activity. Second-generation antihistamines are safer and have largely eliminated these effects, although a very small number of patients taking terfenadine or astemizole have developed a characteristic ventricular dysrhythmia, 'torsade de pointes'. Ebastine is a potent second-generation H1-blocker that compares well with others in the class. It demonstrates no interaction with alcohol, does not induce sedation and has no clinically relevant effect on QTc interval at up to five times the maximum recommended dose. Ebastine acts rapidly to relieve symptoms of allergic rhinitis (including stuffiness) and has a long duration of action, allowing once-daily dosing. Whilst comparable in efficacy to other second-generation antihistamines at 10 mg, ebastine also has the advantage of flexible dosing. Thus, the lower dose of 10 mg is effective for treatment of mild SAR or PAR, and the dose can be increased to 20 mg once daily for control of patients with severe or chronic symptoms.

Topics: Butyrophenones; Histamine H1 Antagonists; Humans; Piperidines; Rhinitis, Allergic, Perennial; Rhinitis, Allergic, Seasonal; Sleep Stages; Torsades de Pointes

Ebastine is a long-acting nonsedating second generation histamine H1 receptor antagonist which binds preferentially to peripheral H1 receptors in vivo. It has shown antihistamine and antiallergic activity in healthy volunteers and patients with allergies, and protected against histamine-induced bronchoconstriction in patients with asthma. Significant symptom improvement is observed in patients with seasonal or perennial allergic rhinitis or chronic idiopathic urticaria following administration of ebastine 10 mg/day, or 20 mg/day in severe rhinitis. In clinical trials, the efficacy of ebastine 10 or 20 mg/day was generally similar to standard dosages of terfenadine, cetirizine, astemizole and loratadine in patients with seasonal allergic rhinitis, astemizole, terfenadine and ketotifen in patients with chronic idiopathic urticaria, and ketotifen, terfenadine, chlorpheniramine and mequitazine in patients with perennial allergic rhinitis. The most frequent adverse events reported during ebastine therapy are drowsiness, headache and dry mouth, the incidence being similar to that reported in placebo recipients. Serious adverse cardiac events, observed on rare occasions with some other histamine H1 receptor antagonists, have not been reported with ebastine, and there has been no evidence of QTc interval prolongation related to ebastine therapy. Thus, once-daily ebastine offers an effective and well-tolerated alternative to other second generation antihistamines in current use for the first-line treatment of seasonal and perennial allergic rhinitis and chronic idiopathic urticaria.

Topics: Animals; Butyrophenones; Histamine H1 Antagonists; Humans; Hypersensitivity; Piperidines

Ebastine is a novel histamine H1 receptor antagonist that combines potency with a rapid onset (fast absorption) and long duration (slow elimination) of action, at least partially mediated via the formation of an acid metabolite (carebastine) that is even more potent as an antihistamine. It shows clear selectivity for histamine H1 as opposed to H2 receptors, has moderate activity against other potential mediators of allergic phenomena such as leukotriene C4 and platelet-activating factor, and is clearly effective against anaphylactic reactions resulting from exposure of suitably sensitised tissues or animals to antigen. By contrast, ebastine has negligible activity against acetylcholine (no atropine-like adverse effects on secretions and visual accommodation) and only poorly penetrates the blood-brain barrier (no sedative adverse effects). Ebastine is without effects on the central nervous and cardiovascular systems, even after oral administration of high doses, and does not interact pharmacologically with a wide range of other drugs covering most areas of potential coadministration. Furthermore, ebastine showed no clinically relevant effects in a complete set of regulatory-required toxicity tests (including acute, chronic, reproductive, mutagenic and carcinogenic protocols) at doses giving blood concentrations representing high multiples of clinical exposure. In conclusion, ebastine has a preclinical profile indicative of an excellent therapeutic ratio of desired effects to undesired effects.

Topics: Animals; Butyrophenones; Drug Evaluation, Preclinical; Histamine H1 Antagonists; Humans; Hypersensitivity, Immediate; Piperidines

Topics: Administration, Intranasal; Anti-Allergic Agents; Butyrophenones; Double-Blind Method; Drug Therapy, Combination; Histamine H1 Antagonists; Humans; Mometasone Furoate; Piperidines; Rhinitis, Allergic; Rhinitis, Allergic, Seasonal

Histamine sensitizes the nociceptor transient reporter potential channel V1 (TRPV1) and has been shown to contribute to visceral hypersensitivity in animals. We investigated the role of TRPV1 in irritable bowel syndrome (IBS) and evaluated if an antagonist of histamine receptor H1 (HRH1) could reduce symptoms of patients in a randomized placebo-controlled trial.. By using live calcium imaging, we compared activation of submucosal neurons by the TRPV1 agonist capsaicin in rectal biopsy specimens collected from 9 patients with IBS (ROME 3 criteria) and 15 healthy subjects. The sensitization of TRPV1 by histamine, its metabolite imidazole acetaldehyde, and supernatants from biopsy specimens was assessed by calcium imaging of mouse dorsal root ganglion neurons. We then performed a double-blind trial of patients with IBS (mean age, 31 y; range, 18-65 y; 34 female). After a 2-week run-in period, subjects were assigned randomly to groups given either the HRH1 antagonist ebastine (20 mg/day; n = 28) or placebo (n = 27) for 12 weeks. Rectal biopsy specimens were collected, barostat studies were performed, and symptoms were assessed (using the validated gastrointestinal symptom rating scale) before and after the 12-week period. Patients were followed up for an additional 2 weeks. Abdominal pain, symptom relief, and health-related quality of life were assessed on a weekly basis. The primary end point of the study was the effect of ebastine on the symptom score evoked by rectal distension.. TRPV1 responses of submucosal neurons from patients with IBS were potentiated compared with those of healthy volunteers. Moreover, TRPV1 responses of submucosal neurons from healthy volunteers could be potentiated by their pre-incubation with histamine; this effect was blocked by the HRH1 antagonist pyrilamine. Supernatants from rectal biopsy specimens from patients with IBS, but not from the healthy volunteers, sensitized TRPV1 in mouse nociceptive dorsal root ganglion neurons via HRH1; this effect could be reproduced by histamine and imidazole acetaldehyde. Compared with subjects given placebo, those given ebastine had reduced visceral hypersensitivity, increased symptom relief (ebastine 46% vs placebo 13%; P = .024), and reduced abdominal pain scores (ebastine 39 ± 23 vs placebo 62 ± 22; P = .0004).. In studies of rectal biopsy specimens from patients, we found that HRH1-mediated sensitization of TRPV1 is involved in IBS. Ebastine, an antagonist of HRH1, reduced visceral hypersensitivity, symptoms, and abdominal pain in patients with IBS. Inhibitors of this pathway might be developed as a new treatment approach for IBS. ClinicalTrials.gov no: NCT01144832.

Topics: Abdominal Pain; Adolescent; Adult; Aged; Analgesics; Belgium; Biopsy; Butyrophenones; Calcium Signaling; Double-Blind Method; Female; Gastrointestinal Agents; Histamine H1 Antagonists; Humans; Irritable Bowel Syndrome; Male; Middle Aged; Neurons; Pain Measurement; Pain Threshold; Piperidines; Quality of Life; Receptor Cross-Talk; Receptors, Histamine H1; Rectum; Remission Induction; Surveys and Questionnaires; Time Factors; Treatment Outcome; TRPV Cation Channels; Young Adult

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

In dermographic urticaria (DU), shearing forces on the skin result in weals and itching. Second-generation antihistamines are recommended as the first-line treatment, but to date only a few have ever been tested for this condition. The objective of this pilot study was to assess the safety and efficacy of ebastine in preventing symptoms of DU. Seven adult patients with DU participated in a double-blind cross-over trial of ebastine 20 mg. Safety was assessed using a sensitive psychometric battery, testing cognitive performance and mood. Efficacy was assessed by rating weals, erythema, pruritus and burning after challenge. Ebastine had no negative effective on cognitive performance or mood. Weals, pruritus and burning were greatly reduced for most subjects. This pilot study suggests that ebastine is safe and effective in preventing the symptoms of DU and should be tested on a larger scale.

Topics: Adult; Affect; Aged; Butyrophenones; Cognition; Cross-Over Studies; Double-Blind Method; Female; Histamine H1 Antagonists; Humans; Male; Middle Aged; Physical Stimulation; Pilot Projects; Piperidines; Psychometrics; Treatment Outcome; Urticaria

Guidelines for allergic rhinitis are more effective than free-treatment choice in the control of seasonal allergic rhinitis.. To validate the ARIA (Allergic Rhinitis and its Impact on Asthma) guidelines in the treatment of intermittent and persistent allergic rhinitis induced by pollens.. A multicenter, open-label, parallel, pragmatic randomized study compared two therapeutic strategies during a 2-week treatment course. In the first strategy ('guidelines group'), 417 patients were treated according to ARIA with ebastine as oral antihistamine. In the second strategy ('free-choice treatment group'), investigators had a free choice for the treatment of 422 patients.. Quality of life measured using the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ), work productivity and daily symptom medication scores.. 94.2% patients returned the baseline visit questionnaires and 88.6% returned the posttreatment period questionnaires. RQLQ scores were similar in the two groups at baseline. After treatment, there were improvements in the overall score and in all domains in both treatment groups. According to pragmatic methodology, the improvements show that the guidelines group (-1.70 +/- 1.20) is more effective than the free-choice treatment group (-1.52 +/- 1.22) with a gamma risk of 2%. Individual RQLQ scores, work productivity, and daily symptom scores were significantly improved in the guidelines group by comparison to the free-choice treatment group.. A treatment based on ARIA guidelines offers patients a significant improvement in comparison to the use of a nonstandardized treatment regimen.

Topics: Adolescent; Adult; Butyrophenones; Female; Histamine H1 Antagonists; Humans; Male; Piperidines; Practice Guidelines as Topic; Practice Patterns, Physicians'; Quality of Life; Rhinitis, Allergic, Seasonal; Surveys and Questionnaires; Young Adult

Ebastine is a long-acting, second-generation selective histamine H(1) receptor antagonist. The pharmacodynamics of a new 10mg fast-dissolving tablet (FDT) oral lyophilisate tablet formulation of ebastine were compared with those of desloratadine and placebo following histamine skin intradermal test challenge. The acceptability of the FDT was also assessed.. This was a double-blind, double-dummy, placebo-controlled, randomised, crossover, three-period study in 36 healthy adults. The histamine skin intradermal test (0.05 mL of 100 microg/mL solution) was administered into volunteers' forearms, and wheal area was measured 15 minutes later. Ebastine 10 mg FDT, desloratadine 5mg capsule or placebo were given on days 1-5. On day 1, a skin intradermal test was performed at baseline, then every 20 minutes for 2 hours after administration and at 24 hours. The final skin intradermal test was on day 6, 24 hours after the last drug dose. Subjective symptoms (itching, heat and pain) were assessed on day 1 for 2 hours following the first drug dose. There was a washout period of 7-10 days between treatments. At study end, the acceptability of the new ebastine formulation was evaluated using a questionnaire.. Ebastine 10mg inhibited the wheal response to histamine significantly more than desloratadine 5 mg or placebo 24 hours after 5 days' treatment (mean difference between treatments in wheal area reduction from baseline: 26.7%, p < 0.0001; 46.9%, p < 0.0001, respectively), and after 24 hours on day 1 (mean difference: 16.2%, p = 0.0082; 34.2%, p < 0.0001, respectively). The results with desloratadine were also significantly different from placebo on day 1 and after 5 days, but less than with ebastine after 5 days (difference, desloratadine vs placebo: 20.2%, p = 0.0001). No differences in itching, heat and pain were observed between the treatments. Most participants (70%) preferred the FDT, and all reported that it made adherence easier.. Ebastine 10 mg FDT demonstrated significantly superior antihistamine activity compared with desloratadine and placebo.

Topics: Adult; Butyrophenones; Chemistry, Pharmaceutical; Dermatitis, Contact; Double-Blind Method; Female; Histamine; Histamine H1 Antagonists; Humans; Loratadine; Male; Pain Measurement; Patient Acceptance of Health Care; Piperidines; Skin; Tablets; Treatment Outcome

The guidelines of German and European associations of allergology recommend the treatment of severe allergic rhinitis with a combination of oral antihistamines and nasal steroids. Many patients face this option rather skeptically, so that ENT specialists mostly use antihistamine monotherapy with a higher dosage. This increased dose may cause drowsiness, as has been demonstrated for cetirizine and loratadine. However, ebastine is a non-sedating antihistamine. Furthermore, it has been shown that improved clinical efficacy can be attained with an increased dosage of 20 mg daily in comparison to the usual dosage of 10 mg/day without increasing the rate of side effects.. In this prospective post-marketing survey, the treatment of 4,307 patients with allergic rhinitis was documented during the pollen season 2005. The severity of rhinitis symptoms and satisfaction with the treatment were recorded.. Treatment with 20 mg ebastine daily as monotherapy led to a significantly greater reduction in symptoms (P=0.002) than the combination therapy.. This outcome could be attributed to an assumed better compliance in patients with monotherapy.

Topics: Adrenal Cortex Hormones; Adult; Butyrophenones; Conjunctivitis; Drug Combinations; Female; Germany; Histamine H1 Antagonists; Humans; Male; Piperidines; Practice Patterns, Physicians'; Prevalence; Rhinitis, Allergic, Seasonal; Treatment Outcome

Ebastine is a long-acting, second-generation, selective histamine H1-receptor antagonist. A fast-dissolving tablet formulation of ebastine has been developed at 10- and 20-mg doses, with the intention of facilitating administration to patients experiencing problems with swallowing, including those confined to bed and elderly people, as well as those who may need to use ebastine when they do not have easy access to water to aid swallowing a tablet.. This study was conducted to assess the pharmacodynamic effects (ie, inhibition of wheal response to cutaneous histamine challenge, and subjective assessments of itching, flare, and pain) and tolerability of the fast-dissolving 20-mg ebastine tablet formulation compared with desloratadine 5-mg capsule and placebo. Acceptability and convenience of the fast-dissolving tablet were also evaluated.. This double-blind, double-dummy, randomized, placebo-controlled, 3-period crossover study was conducted at the Drug Research Centre, Department of Clinical Pharmacology, the Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. Healthy, nonatopic, white adults aged 18 to 40 years were randomly assigned to 1 of 6 study sequences: ABC, ACB, BAC, BCA, CBA, or CAB, where A was the ebastine fast-dissolving 20-mg tablet, B was the desloratadine 5-mg capsule, and C was placebo. All study drugs were given orally once daily (8-9 AM) on days 1 to 5 of each study period. Study periods were separated by a washout period of 7 to 10 days. Histamine skin-prick test (SPT) challenge was performed before study drug administration on day 1 of each period (baseline), and then every 20 minutes for 2 hours after administration and again after 24 hours. The final SPT was 24 hours after the day-5 dose was administered. The primary end point was inhibition o f the histamine response, defined as the percentage reduction from baseline wheal area 24 hours after 5 days of administration. Subjective symptoms (itching, flare, and pain) were assessed by subjects using visual analog scales every 20 minutes for 2 hours after administration on day 1. At study end, acceptability (taste, convenience, and overall preference) of the fast-dissolving tablet and capsule formulations were assessed using a questionnaire completed by subjects. Tolerability was assessed using physical examination, laboratory analysis, physician questioning, and spontaneous reporting.. Thirty-six people were randomized (22 women, 14 men; mean [SD] age, 24.7 [4.1] years; mean [SD] weight, 63.2 [9.9] kg); 35 completed the study (1 subject was lost to follow-up after the second study period). Unadjusted mean (SD) wheal areas 24 hours after dose administration on day 5 were 72.9 (29.5), 115.0 (32.1), and 146.7 (32.2) mm(2), for ebastine, desloratadine, and placebo, respectively. Mean differences in reduction from baseline in wheal area were 29.0% for ebastine versus desloratadine and 43.7% for ebastine versus placebo (both, P < 0.001). Corresponding unadjusted mean (SD) wheal areas 24 hours after administration of the first dose on day 1 were 76.5 (22.5), 128.9 (24.0), and 140.5 (33.1) mm(2). Mean itching, flare, and pain ratings were not significantly different between study drugs. Results from the preference questionnaire indicated that the majority (80%) preferred the ebastine fast-dissolving tablet to the desloratadine capsule (and hypothetically also to tablets and oral solution, which were not tested in this study). Ninety-seven percent of subjects were of the opinion that compliance in the home setting would be facilitated by the fas-tdissolving tablet formulation. Fourteen adverse events (AEs) were reported in 9 (25%) volunteers; all AEs were of mild or moderate intensity. Five occurred with ebastine 20 mg (intermittent somnolence, back pain, pharyngolaryngeal pain, pyrexia, and oral pain [1 patient each]), 5 occurred with desloratadine 5 mg (asthenia [2 patients] and dry mouth, somnolence, and back pain [1 patient each]), and 4 occurred with placebo (diarrhea [2 patients] and somnolence and headache [1 patient each]). The relationship with the study drugs was considered unlikely in 6 cases and possible in the remaining 8 cases. An additional AE (back pain) occurred during a washout period.. In this small study in healthy, nonatopic white subjects, inhibition of the response to histamine injection was significantly greater with the ebastine 20-mg fast-dissolving tablet compared with desloratadine 5-mg capsule and placebo after 1 and 5 days of administration. Most participants expressed an overall preference for the fast-dissolving tablet formulation over capsules. All study drugs were well tolerated.

Topics: Adolescent; Adult; Butyrophenones; Cross-Over Studies; Double-Blind Method; Female; Histamine; Histamine H1 Antagonists; Humans; Loratadine; Male; Pain Measurement; Piperidines; Pruritus; Skin; Skin Tests

Acquired cold urticaria (ACU) is a skin condition, in which exposure to cold results in wheals and itching and sometimes general systemic complications. It has a profound impact on patient quality of life. Second-generation antihistamines are recommended as the first-line treatment, but to date only a few have been scientifically tested for this condition.. To assess the safety and efficacy of ebastine in preventing ACU symptoms.. Twenty-two adult ACU patients participated in a double-blind crossover trial of 20 mg ebastine. The safety of ebastine was sensitively assessed with a psychometric battery testing cognitive performance and mood. After cold challenge, wheal and erythema were assessed by the investigator and the intensities of pruritus and burning were rated by the subject.. Ebastine had no negative impact on any of the parameters of cognitive performance or mood. It dramatically reduced the number of patients who experienced wheals, pruritus, and burning after challenge.. Ebastine is safe and effective in preventing the symptoms of ACU.

Topics: Adult; Affect; Butyrophenones; Cold Temperature; Cross-Over Studies; Double-Blind Method; Female; Histamine H1 Antagonists; Humans; Male; Middle Aged; Piperidines; Psychometrics; Treatment Outcome; Urticaria

Two studies were conducted to evaluate the effects of coadministration of ketoconazole with two nonsedating antihistamines, ebastine and loratadine, on the QTc interval and on the pharmacokinetics of the antihistamines.. In both studies healthy male subjects (55 in one study and 62 in the other) were assigned to receive 5 days of antihistamine (ebastine 20 mg qd in one study, and loratadine 10 mg qd in the other) or placebo alone using a predetermined randomization schedule, followed by 8 days of concomitant ketoconazole 450 mg qd/antihistamine or ketoconazole 400 mg qd/placebo. Serial ECGs and blood sampling for drug analysis were performed at baseline and on study days 5 (at the end of monotherapy) and 13 (at the end of combination therapy). QT intervals were corrected for heart rate using the formula QTc = QT/RR(alpha) with special emphasis on individualized alpha values derived from each subject's own QT/RR relationship at baseline.. No significant changes in QTc interval from baseline were observed after 5 days administration of ebastine, loratadine or placebo. Ketoconazole/placebo increased the mean QTc (95% CI) by 6.96 (3.31-10.62) ms in the ebastine study and by 7.52 (4.15-10.89) ms in the loratadine study. Mean QTc was statistically significantly increased during both ebastine/ketoconazole administration (12.21 ms; 7.39-17.03 ms) and loratadine/ketoconazole administration (10.68 ms; 6.15-15.21 ms) but these changes were not statistically significantly different from the increases seen with placebo/ketoconazole (6.96 ms; 3.31-10.62 ms), P = 0.08 ebastine study, (7.52 ms; 4.15-10.89 ms), P = 0.26 loratadine study). After the addition of ketoconazole, the mean area under the plasma concentration-time curve (AUC) for ebastine increased by 42.5 fold, and that of its metabolite carebastine by 1.4 fold. The mean AUC for loratadine increased by 4.5 fold and that of its metabolite desloratadine by 1.9 fold following administration of ketoconazole. No subjects were withdrawn because of ECG changes or drug-related adverse events.. Ketoconazole altered the pharmacokinetic profiles of both ebastine and loratadine although the effect was greater for the former drug. The coadministration of ebastine with ketoconazole resulted in a non significant mean increase of 5.25 ms (-0.65 to 11.15 ms) over ketoconazole with placebo (6.96 ms) while ketoconazole plus loratadine resulted in a nonsignificant mean increase of 3.16 ms (-2.73 to 8.68 ms) over ketoconazole plus placebo (7.52 ms). Changes in uncorrected QT intervals for both antihistamines were not statistically different from those observed with ketoconazole alone. The greater effect of ketoconazole on the pharmacokinetics of ebastine was not accompanied by a correspondingly greater pharmacodynamic effect on cardiac repolarization.

Topics: Adolescent; Adult; Antifungal Agents; Butyrophenones; Double-Blind Method; Drug Combinations; Electrocardiography; Heart Rate; Histamine H1 Antagonists; Humans; Ketoconazole; Loratadine; Male; Piperidines

To assess the differences between patients with hepatic insufficiency and healthy subjects with regard to the pharmacokinetics, cardiac safety and overall safety of ebastine and its active metabolite carebastine.. Open-label parallel-group study.. 24 patients with varying degrees of hepatic insufficiency, as categorised by the Child-Pugh classification, and 12 healthy volunteers.. Healthy subjects and patients with Child-Pugh class A (n = 8) or B (n = 8) received ebastine 20 mg once daily for 7 days. Patients with Child-Pugh class C (n = 8) [single or repeated dose] received ebastine 10 mg. Plasma concentrations of ebastine and carebastine were determined for 23.5 hours following the initial dose on day 1 and for 96 hours following the dose on day 7 by using a sensitive liquid chromatography-tandem mass spectrometry assay with a minimum quantifiable limit of 0.05 microg/L for ebastine and 1.00 microg/L for carebastine. Hepatic function was assessed by blood clearance of indocyanine green 0.5 mg/kg administered intravenously on day 2. Cardiac and overall safety parameters were monitored.. Overall, the pharmacokinetics of ebastine were not modified by hepatic impairment. No correlation between ebastine pharmacokinetics and hepatic function, as expressed by indocyanine green clearance, was observed. Comparison of the effective half-life of ebastine and carebastine between groups did not show relevant differences. Therefore, no apparent accumulation of ebastine occurred, and steady-state concentrations of ebastine and carebastine were predictable from single-dose pharmacokinetics both in healthy subjects and in hepatically impaired patients. Finally, no apparent difference was noted in the safety of ebastine between patients with hepatic insufficiency and healthy subjects as assessed by evaluation of adverse events, vital signs and laboratory parameters.. Ebastine can be safely administered to patients with impaired hepatic function, as no clinically important differences can be anticipated from the pharmacokinetics and safety profile of ebastine/carebastine as compared with healthy subjects. Nevertheless, the dosage used in severely impaired patients (10mg daily) was half that used in patients with mild to moderate impairment, and any comedication did not include drugs affecting liver function; in clinical practice, both these factors should be taken into account.

Topics: Adult; Area Under Curve; Butyrophenones; Case-Control Studies; Female; Half-Life; Histamine H1 Antagonists; Humans; Intestinal Absorption; Liver Diseases; Male; Metabolic Clearance Rate; Middle Aged; Piperidines

Few randomized studies have compared loratadine to ebastine in the symptomatic treatment of seasonal allergic rhinitis (SAR) patients.. This double-blind, placebo-controlled, randomized, parallel-group, comparative trial compared the efficacy and safety of ebastine 20 mg (E20), loratadine 10 mg (L10) and placebo (P), administered once daily, in the control of SAR symptoms over a 2-week period. An additional 2-week treatment period was included in order to check sustained efficacy and tolerability.. A total of 703 patients were enrolled: 282 patients in the E20 group, 279 in the L10 group and 142 in the P group. E20 showed a greater decrease from baseline in the main efficacy variable (mean daily reflective total symptom score) than L10 (p = 0.0018) or P (p = 0.0024), whereas the difference between L10 and P was not significant. Moreover, reductions from baseline in all composite/individual daily reflective rhinitis symptom scores were significantly larger in patients receiving E20 than in patients receiving L10 or P. Most significant differences between E20 and L10 or P were maintained after 4 weeks of treatment. Overall, all treatments were safe and well tolerated. There was no significant difference in the percentage of patients who reported one or more adverse events (AEs) between the groups, and most AEs were mild to moderate (89.9%).. E20 given once daily for 2 weeks was more effective in the treatment of SAR symptoms than L10 or P. E20 also showed a sustained efficacy after 4 weeks of treatment, and overall was well tolerated and proved safe.

Topics: Adolescent; Adult; Aged; Butyrophenones; Child; Double-Blind Method; Female; Histamine H1 Antagonists; Humans; Least-Squares Analysis; Loratadine; Male; Middle Aged; Piperidines; Rhinitis, Allergic, Seasonal

Few randomized studies have compared the H1-receptor antagonists loratadine and ebastine in seasonal allergic rhinitis (SAR) patients. The objective of this study was to compare the efficacy and safety of ebastine 20 mg (E20), ebastine 10 mg (E10), loratadine 10 mg (L10), and placebo (P), once daily, in controlling symptoms of SAR over a 4-week period. This was a double-blind, placebo-controlled, randomized, parallel-group study. Efficacy was assessed in 749 patients (12 to 70 years old) by SAR symptom scores (nasal discharge, congestion, itching, sneezing, and total eye symptoms) entered on diary cards every morning and every evening over the previous 12 hours (reflective score) and at the time of recording (snapshot score). The E20 group showed greater reductions from baseline compared with the L10 group in 2 daily reflective composite scores (nasal index [with or without congestion]) and in all 4 daily snapshot composite scores. E10 and L10 groups showed no significant differences in either the daily reflective or snapshot scores overall although E10 showed a greater improvement of nasal discharge snapshot score than L10. The efficacy of E20 at controlling the symptoms of SAR was well sustained during the fourth week of treatment, with significant differences over placebo in 22/36 total rhinitis symptom scores, followed by E10 (6/36), whereas L10 showed no differences (0/36). Patient and physician global evaluations at the final visit were not statistically significant for any treatment group compared with placebo. There was no significant difference among all groups in the number of patients who reported adverse events. In conclusion, ebastine 20 mg given once daily for 4 weeks in the treatment of SAR showed larger mean reductions from baseline in most rhinitis symptoms scores than loratadine 10 mg. Sustained efficacy was most frequently observed with ebastine 20 mg over placebo, whereas loratadine 10 mg did not provide a statistically significant improvement in any individual or composite symptom score at the end of the fourth week. Both ebastine 20 and 10 mg were well tolerated and proved safe in the treatment of SAR.

Topics: Administration, Oral; Butyrophenones; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Loratadine; Male; Multivariate Analysis; Patch Tests; Piperidines; Probability; Rhinitis, Allergic, Seasonal; Severity of Illness Index; Treatment Outcome

The aim of this study is to establish the efficacy and safety of rupatadine vs ebastine and placebo in the treatment of seasonal allergic rhinitis (SAR). Rupatadine is a new second generation H(1)-antihistamine with once-daily dosing that may provide better control of symptoms than the currently used H(1)-receptor blockers because of its dual pharmacological profile (anti-PAF and anti-H(1)).. In a multicentre study, 250 patients with SAR were included in a double-blind, randomized, parallel-group and placebo-controlled study. Patients received either rupatadine 10 mg, ebastine 10 mg or placebo once daily for 2 weeks. The main efficacy outcome was based on the patient's record of severity of nasal symptoms (sneezing, nasal itching, runny nose and nasal obstruction) and nonnasal symptoms (conjunctival itching, tearing and pharyngeal itching). The daily total symptom score (DTSS) was the mean of the DSS recorded for each of the seven symptoms assessed, and the mean DTSS (mDTSS) was the mean of the DTSS values for each study day.. Significant differences in mDTSS were detected between rupatadine and placebo (33% lower for rupatadine group; P = 0.005) after 2 weeks of treatment. The TSS for rupatadine were 22% lower than for ebastine, although the differences were not statistically significant. No serious adverse events were reported during the study period.. Rupatadine 10 mg once daily was clearly superior to placebo in alleviating the symptoms of SAR over a 2-week period. In comparison with ebastine, rupatadine shows a trend towards a better profile as regard several secondary efficacy variables.

Topics: Adolescent; Adult; Analysis of Variance; Anti-Allergic Agents; Butyrophenones; Cyproheptadine; Double-Blind Method; Female; Histamine H1 Antagonists; Humans; Male; Middle Aged; Piperidines; Rhinitis, Allergic, Seasonal; Severity of Illness Index; Treatment Outcome

Three similarly designed, multicenter, double-blind, randomized, placebo-controlled, parallel-group comparative studies were carried out in the United States in a total of 1,881 patients to evaluate the efficacy of ebastine 20 mg (E20), ebastine 10 mg (E10), loratadine 10 mg (L10), and placebo (P), all given once daily, in controlling the symptoms of ragweed-induced rhinitis over a 4-week treatment period. Efficacy was assessed, among other means, by nasal congestion symptom scores entered by patients on diary cards in the morning and before bedtime over the previous 12-h period (reflective score, R) and at the time of recording (snapshot score, SS). Mean value of both morning and evening score changes from baseline were analyzed in each study and for each treatment. E20 was more effective than placebo in all studies, in both R and SS symptom scores (6 of 6 scores), while E10 was effective in 4 of 6 scores (2 R and 2 SS). In contrast, L10 was effective in only 1 of 6 scores (1 R). In conclusion, the comparative analysis of the results from these three trials shows that ebastine is efficacious in the reduction of nasal congestion associated with seasonal allergic rhinitis. This symptomatic effect of ebastine may be accounted for by its ability to reduce inflammatory markers, as shown in preclinical studies, in addition to its primary effect of antagonizing histamine H1 receptors.

Topics: Adult; Ambrosia; Butyrophenones; Dose-Response Relationship, Drug; Double-Blind Method; Female; Histamine H1 Antagonists; Histamine H1 Antagonists, Non-Sedating; Humans; Loratadine; Male; Nasal Obstruction; Piperidines; Rhinitis, Allergic, Seasonal

Allergic rhinitis is a common disease altering quality of life. Its treatment is well established and guidelines have been proposed. However, their efficacy has never been tested. The aim of the study was to validate the guidelines of the International Consensus on Rhinitis in the treatment of seasonal allergic rhinitis.. A multicenter, multinational, open label, parallel, randomized study compared two therapeutic strategies in seasonal allergic rhinitis during a 3-week treatment. General practitioners were randomized into two groups. In the first group of 224 patients, doctors followed guidelines from the International Consensus on Rhinitis. Depending on the severity of nasal and ocular symptoms defined using visual analogue scales, patients received ebastine (an oral antihistamine), triamcinolone acetonide (a topical corticosteroid) and/or ophthalmic nedocromil sodium (a topical ocular cromone). In the second group of 241 patients, general practitioners had a free choice of treatment. The primary efficacy end points were quality of life measured using the standardized rhinoconjunctivitis quality of life questionnaire (RQLQ) and the symptom-medication scores assessed daily with an electronic dairy system.. Adjusted mean total symptom scores over 21 days were 4.93 in the guidelines strategy group compared with 7.48 in the free-choice treatment group (P = 0.0001). Mean total scores in the RQLQ decreased by 2.19 in the guidelines group compared with a decrease of 1.79 in the free-choice treatment group (P = 0.0001). At 21 days, the least square mean difference in improvement in overall scores for RQLQ in the guidelines group compared with the free-choice treatment group was 0.53, which was greater than the minimal important difference.. Patients with seasonal allergic rhinitis often present severe symptoms which are not well recognized or controlled by physicians using their own criteria of severity and treatment. Using a simple method for the evaluation of the severity and a simple therapeutic scheme based on International Guidelines, patients with seasonal allergic rhinitis presented a significant improvement by comparison with those receiving a non-standardized treatment.

Topics: Administration, Intranasal; Administration, Oral; Adult; Anti-Allergic Agents; Butyrophenones; Conjunctivitis, Allergic; Female; Glucocorticoids; Guideline Adherence; Histamine H1 Antagonists; Humans; Male; Nedocromil; Piperidines; Practice Guidelines as Topic; Quality of Life; Rhinitis, Allergic, Seasonal; Surveys and Questionnaires; Triamcinolone Acetonide

The aim of this double-blind, randomized, crossover, placebo-controlled clinical trial was to compare the inhibition of the histamine-induced skin reaction induced by ebastine 20 mg with respect to that induced by fexofenadine 120 mg or placebo.. Eighteen volunteers (10 males, 8 females) received the three treatments once daily for 5 days, with a mean 7-day washout period between treatments. Intradermal tests, using 0.05 ml from a solution containing 100 microg/ml of histamine, were performed at baseline and at 1, 1.5, 2, 3, 10 and 24 h after a single dose and repeated 5-day dose, and in addition after 34, 48, 58 and 72 h after repeated 5-day dose.. After 24 h of acute administration, ebastine 20 mg was significantly more effective than fexofenadine 120 mg in reducing the wheal and flare induced by histamine challenge (p<0.001). Although fexofenadine 120 mg had the shortest onset of action (1.5 vs. 3 h in ebastine 20 mg), the duration of its antihistamine effect was the shortest (24 vs. 58 h in ebastine 20 mg) and wheal reduction after 24 h was not significantly different from placebo. The overall effect after single and repeated 5-day dose, expressed as the AUC of reduction of wheal and flare area (%/h), showed the following order of magnitude: ebastine 20 mg>fexofenadine 120 mg>placebo. No significant differences in the incidence of adverse events were found between the three treatments.. The present results clearly show a superior and long-acting effect of ebastine 20 mg compared with fexofenadine 120 mg on the skin response to histamine 24 h after dosing.

Topics: Administration, Oral; Adolescent; Adult; Butyrophenones; Double-Blind Method; Female; Histamine Antagonists; Humans; Male; Middle Aged; Piperidines; Skin; Terfenadine

Few studies have compared the antihistaminic effect of ebastine at 20 mg/day (maximal recommended daily dose) with the effect found for other antihistamines in human pharmacologic models.. To compare the inhibition of the histamine-induced skin reaction produced by ebastine (20 mg/day) with that produced by cetirizine (10 mg/day), loratadine (10 mg/day), or placebo in a double-blind, randomized, crossover, placebo-controlled clinical trial.. Twenty volunteers (10 men and 10 women) received the four treatments once daily for 7 days, with a mean 7-day washout period between treatments. Three intradermal histamine challenges (0.05 mL of a 100 microg/mL histamine solution at 4, 8, and 24 hours after drug administration) were performed at baseline, day 1 (single dose), and day 7 (multiple doses). Wheal and flare areas were measured after 15 minutes.. All treatments yielded significant reductions of histamine-induced wheal in comparison to placebo (P < 0.001). Analysis of covariance revealed significant differences between treatments (P < 0.05). Ebastine had a significantly greater antihistaminic effect than did cetirizine or loratadine, except at 4 hours after a single dose versus cetirizine. Further, the effect of cetirizine was similar with single or multiple doses after both 4 and 24 hours, whereas the effect of ebastine showed significant increases in wheal reduction with multiple doses (P < 0.05). No serious adverse events or withdrawals occurred during the study.. This study shows that ebastine in a 20-mg dose is an effective once-daily antihistamine. Superior efficacy was found in comparison to cetirizine (10 mg) or loratadine (10 mg) on the overall skin wheal response after single and multiple doses.

Topics: Adolescent; Adult; Butyrophenones; Cetirizine; Cross-Over Studies; Double-Blind Method; Female; Histamine H1 Antagonists; Humans; Kinetics; Loratadine; Male; Middle Aged; Piperidines; Skin Tests

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

The objective of this double-blind, randomized, placebo-controlled, 5-way crossover study was to compare the pharmacodynamic effects of the H1 antihistamine ebastine (10 mg once daily, E10) with those of cetirizine (10 mg once daily, C10), loratadine (10 mg once daily, L10), fexofenadine (60 mg, twice daily, F60 x 2) and placebo (P) after 6 days of treatment in healthy volunteers. The pharmacodynamic variable was the mean percent reduction from baseline (pretreatment) of the wheal area induced by intradermal histamine 0.1% on the morning after 6 days' treatment. A secondary variable was the concentration of histamine required to produce a wheal of area 150 mm2. E10 reduced wheal size more than did P (p < 0.001) or F60 x 2 (p < 0.019). No significant differences were found among E10, C10 and L10. After E10, a significantly greater concentration of histamine was needed to induce a wheal of 150 mm2 than after P (p < 0.001), L10 (p < 0.001) or F60 x 2 (p < 0.001). No significant differences were found between E10 and C10. In conclusion, this study shows that, at the end of the conventional dosing interval, ebastine 10 mg and cetirizine 10 mg once daily in repeated doses suppressed the histamine wheal more effectively than did loratadine 10 mg once daily or fexofenadine 60 mg twice daily.

Topics: Adolescent; Adult; Butyrophenones; Cetirizine; Cross-Over Studies; Double-Blind Method; Female; Histamine; Histamine H1 Antagonists; Humans; Hypersensitivity, Immediate; Injections, Intradermal; Loratadine; Male; Piperidines; Skin Tests; Terfenadine

Levocetirizine is the active enantiomer of cetirizine, a potent drug with little metabolism widely used for allergic rhinitis and urticaria.. This study compares the potency, consistency, onset, and duration of action of levocetirizine with other popular antihistamines.. Levocetirizine 5 mg, ebastine 10 mg, fexofenadine 180 mg, loratadine 10 mg, mizolastine 10 mg, or placebo in single doses were given to 18 healthy male volunteers in a double-blind, crossover, randomized fashion. Wheal-and-flare responses to epicutaneous histamine dihydrochloride (100 mg/mL) challenge were measured at 0, 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hours after each dose.. The overall effect of each drug was evaluated by the area under the curve (0 to 24 hours). Levocetirizine was the most potent and consistently effective drug for inhibiting the histamine-induced wheal-and-flare surface areas. Ebastine, fexofenadine, and mizolastine ranked next and had almost identical effects for inhibiting the wheal. Loratadine was the least potent drug. Levocetirizine, fexofenadine, and mizolastine inhibited the wheal-and-flare response after 1 hour and reached their peak for inhibition after 4 hours. Ebastine and loratadine could be distinguished from placebo only after 4 hours. After treatment with levocetirizine, all 18 subjects had >95% inhibition of the wheal response at one timepoint. Fexofenadine, mizolastine, and ebastine were inhibitory in declining order. All treatments were considered safe and well tolerated.. Levocetirizine, the active enantiomer of cetirizine, is more potent and consistent than other popular H1 antihistamines for blocking the cutaneous response to histamine. These findings may predict the efficacy of this drug in treating allergic disorders.

Topics: Adult; Benzimidazoles; Butyrophenones; Cetirizine; Cross-Over Studies; Double-Blind Method; Histamine; Histamine H1 Antagonists; Humans; Loratadine; Male; Piperidines; Terfenadine; Treatment Outcome; Urticaria

It has been widely recognized that classical antihistamines induce sedation as an adverse effect, while second-generation antihistamines have few if any sedative effects. In order to evaluate the sedative properties of ebastine, a second-generation antihistamine, its effect on cognitive performance in healthy subjects was compared with placebo and (+)-chlorpheniramine.. Twelve healthy male subjects were instructed to perform six types of attention-demanding cognitive tasks, and objective measurements of reaction times and accuracy was made before and after drug administration. Their sleepiness levels were also monitored. Test drugs were ebastine 10 mg, placebo and two doses of (+)-chlorpheniramine 2 mg and 6 mg, as positive controls. Plasma drug concentrations at the end of the study were analysed.. After treatments with (+)-chlorpheniramine, the reaction times of the tasks were significantly prolonged (e.g. ratios of after/before dosing: placebo (0.998 +/- 0.113) vs (+)-chlorpheniramine 2 mg (1.103 +/- 0.083; P<0.05) or (+)-chlorpheniramine 6 mg (1.170 +/- 0.139; P<0.001) in a 7 ms visual discrimination time task) and the accuracy was significantly decreased (e.g. ratios: placebo (1.038 +/- 0.158) vs (+)-chlorpheniramine 2 mg (0.792 +/- 0.202; P<0.01) or (+)-chlorpheniramine 6 mg (0.837 +/- 0.222; P<0.05) in a 7 ms task). On the other hand, performance was not affected by ebastine or placebo treatment (e.g. ebastine 10 mg (reaction time ratio; 1.014 +/- 0.067 and accuracy ratio; 0.990 +/- 0.146) in a 7 ms task). Subjective sleepiness was also not affected by ebastine but (+)-chlorpheniramine significantly increased sedation. With respect to the relationship between plasma drug concentrations and task performance, the latter deteriorated with an increase in plasma (+)-chlorpheniramine concentration (e.g. r=0.439 (P=0.007) in a 5 ms and r = 0.352 (P=0.039) in a 7 ms task), but it did not correlate with the plasma concentration of carebastine, an active metabolite of ebastine.. Ebastine 10 mg did not cause any cognitive impairment or subjective sleepiness. On the other hand, (+)-chlorpheniramine impaired cognitive function and induced sleepiness even at 2 mg, the recommended dose in over-the-counter medication. In addition, impaired CNS performance was significantly correlated with plasma (+)-chlorpheniramine concentration.

Topics: Administration, Oral; Adult; Butyrophenones; Chlorpheniramine; Cognition; Dose-Response Relationship, Drug; Histamine H1 Antagonists; Humans; Male; Piperidines; Reaction Time; Sleep; Stereoisomerism; Visual Perception

Placebo-controlled outdoors clinical study was performed at the Utsunomiya City Forest Park surrounded by many cryptomerias on March 5, 2000, at the season of most cedar pollens, to evaluate the efficacy and its timing and duration of Ebastine. It was a fine weather on the day of the study, and so much cedar pollens as 235 pollens/cm2 were spreading at the park when it was measured at the park. In particular, the amount of cedar pollen for 2 hours from 10:00 a.m. when Ebastine was administered exceeded 50 pollens/cm2 per hour. The nasal symptoms of the placebo-treated subjects promptly aggravated during the time, while the symptoms of the subjects who received oral Ebastine showed the tendency to improve from 2 hours after oral administration under exposure of a large amount of cedar pollens, and the efficacy maintained until 10:00 a.m. at the next morning that passed 24 hours after administration. The results suggest that Ebastine promptly inhibited the symptom induced by the exposure of a large amount of pollens at the season of most cedar pollens and that once daily oral administration of Ebastine maintained the efficacy at least for 24 hours. It was also suggested that outdoors comparative clinical study at the season of cedar pollen was effective to observe and evaluate the natural clinical course of a patient's symptom and was useful for evaluation of clinical efficacy of anti-pollinosis drugs of various types, including an anti-allergic reagent.

Topics: Adult; Butyrophenones; Female; Histamine H1 Antagonists; Humans; Male; Piperidines; Pollen; Rhinitis, Allergic, Seasonal; Single-Blind Method

People frequently experience whealing and delayed papules from mosquito bites. Whealing is mediated by antisaliva immunoglobulin (Ig)E antibodies and histamine. Cetirizine, ebastine and loratadine have earlier shown effects on mosquito-bite reactions but no comparative studies exist.. A double-blind, placebo-controlled, cross-over study was performed with cetirizine 10 mg, ebastine 10 mg and loratadine 10 mg in 29 mosquito-bite-sensitive adults exposed to Aedes aegypti mosquito-bites. The size of the bite lesion and the intensity of pruritus (visual analog scale) were measured at 15 min and 2, 6 and 24 h.. Cetirizine and ebastine, but not loratadine, decreased significantly the size of whealing (P < 0.01) and accompanying pruritus (P < 0.001) compared to placebo. Cetirizine was most effective on pruritus but caused more often sedation than ebastine or loratadine. The delayed bite symptoms remained too faint for any statistical comparison.. This comparative study in mosquito-bite-sensitive adults shows that cetirizine and ebastine decrease significantly whealing and accompanying pruritus, and that cetirizine seems to be the most effective against pruritus.

Topics: Adult; Animals; Butyrophenones; Cetirizine; Conscious Sedation; Cross-Over Studies; Culicidae; Double-Blind Method; Finland; Histamine H1 Antagonists; Humans; Hypersensitivity, Immediate; Insect Bites and Stings; Loratadine; Middle Aged; Piperidines; Pruritus; Severity of Illness Index; Time Factors; Treatment Outcome

Estimation of QT interval prolongation belongs to safety assessment of every drug. Among unresolved issues, heart rate correction of the QT interval may be problematic. This article proposes a strategy for heart rate correction in drug safety studies and demonstrates the strategy using a study of ebastine, a nonsedating antihistamine.. Four-way cross-over Phase I study investigated 32 subjects on placebo, ebastine 60 mg once a day, 100 mg once a day, and terfenadine 180 mg twice a day. Repeated ECGs were obtained before each arm and after 7 days of treatment. The changes in heart rate-corrected QTc interval were investigated using (A) 20 published heart rate correction formulas, (B) a correction formula optimized by QT/RR regression modeling in all baseline data, and (C) individual corrections optimized for each subject by drug-free QT/RR regression modeling. (A) Previously published correction formulas found QTc interval increases on terfenadine. The results with ebastine were inconsistent. For instance, Bazett's and Lecocq's correction found significant QTc increase and decrease on ebastine, respectively. The results were related (absolute value(r) > 0.95) to the success of each formula (independence of drug-free QTc and RR intervals). (B) The pooled drug-free QT/RR regression found an optimized correction QTc = QT/RR(0.314). QTc interval changes on placebo, ebastine 60 mg, ebastine 100 mg, and terfenadine were -1.95 +/- 6.87 msec (P = 0.18), -3.91 +/- 9.38 msec (P = 0.053), 0.75 +/- 8.23 msec (P = 0.66), and 12.95 +/- 14.64 msec (P = 0.00025), respectively. (C) Individual QT/RR regressions were significantly different between subjects and found optimized corrections QTc = QT/RR(alpha) with alpha = 0.161 to 0.417. Individualized QTc interval changes on placebo, ebastine 60 mg, ebastine 100 mg, and terfenadine were -2.76 +/- 5.51 msec (P = 0.022), -3.15 +/- 9.17 msec (P = 0.11), -2.61 +/- 9.55 msec (P = 0.19), and 12.43 +/- 15.25 msec (P = 0.00057, respectively. Drug-unrelated QTc changes up to 4.70 +/- 8.92 msec reflected measurement variability.. Use of published heart rate correction formulas in the assessment of drug-induced QTc prolongation is inappropriate, especially when the drug might induce heart rate changes. Correction formulas optimized for pooled drug-free data are inferior to the formulas individualized for each subject. Measurement imprecision and natural variability can lead to mean QTc interval changes of 4 to 5 msec in the absence of drug treatment.

Topics: Butyrophenones; Cross-Over Studies; Drug Evaluation; Electrocardiography; Heart Rate; Histamine H1 Antagonists; Humans; Long QT Syndrome; Models, Cardiovascular; Piperidines; Regression Analysis

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 inhibitory effect of antihistamines on allergen-induced skin reactions can impair the results of allergen skin testing, which are necessary for the diagnosis of atopic diseases. This study was designed to determine the time period required for the inhibitory effect of ebastine on allergen-induced skin reactivity to disappear completely.. This was a double-blind, placebo-controlled, parallel-group study including 23 out of 27 randomized patients. They received either ebastine 20 mg or placebo once daily for 7 days. At the end of treatment, allergen challenge was performed daily for 7 days. Histamine challenge was performed on day 1 (6 and 24 h) and day 5 after treatment. The wheal and flare surface areas were measured and analyzed.. Highly significant inhibition of the wheal and flare response induced by allergen was observed after ebastine treatment on days 1 and 2 as compared with placebo (P < 0.01 for both). The inhibition was reduced, although still significant, by day 3 (P < 0.05). No significant difference was observed by day 4 between the ebastine and the placebo groups. The effects of histamine challenge were significantly reduced in the ebastine compared with the placebo group at day 1 (6 and 24 h), and were similar at day 5 after treatment.. Our results show that the wheal and flare response to allergen after ebastine discontinuation returns to placebo values after 4 days. Therefore, patients using ebastine need to be antihistamine-free for 4 days before the skin prick test. This is valuable information for the allergologist seeking to diagnose allergen sensitivity.

Topics: Adolescent; Adult; Butyrophenones; Confidence Intervals; Dose-Response Relationship, Drug; Double-Blind Method; Female; Histamine H1 Antagonists; Humans; Male; Middle Aged; Piperidines; Time and Motion Studies; Time Factors

The objective of this study was to compare the effects of high doses of ebastine with terfenadine and placebo on QTc.. Thirty-two subjects were randomly assigned to four treatments (ebastine 60 mg x day(-1), ebastine 100 mg x day(-1), terfenadine 360 mg x day(-1), placebo) administered for 7 days. Serial ECGs were performed at baseline and day 7 of each period. QT interval was analysed using both Bazett (QTcB) and Fridericia (QTcF) corrections.. Ebastine 60 mg (+ 3.7 ms) did not cause a statistically significant change in QTcB compared with placebo (+ 1.4 ms). The mean QTcB for ebastine 100 mg was increased by + 10.3 ms which was significantly greater than placebo but was significantly less (P < 0.05) than with terfenadine 360 mg (+ 18.0 ms). There were no statistically significant differences in QTcF between ebastine 60 mg (-3.2 ms) or ebastine 100 mg (1.5 ms) and placebo (-2.1 ms); although terfenadine caused a 14.1 ms increase which was significantly different from the other three treatments. The increase in QTcB with ebastine most likely resulted from overcorrection of the small drug-induced increase in heart rate.. Ebastine at doses up to five times the recommended therapeutic dose did not cause clinically relevant changes in QTc interval.

Topics: Adolescent; Adult; Butyrophenones; Cross-Over Studies; Dose-Response Relationship, Drug; Electrocardiography; Heart Rate; Histamine H1 Antagonists; Humans; Male; Piperidines; Terfenadine

Sedation induced by antihistamines is widely recognized to be caused by their penetration through the blood-brain-barrier and the consequent occupation of brain histamine H1-receptors. We previously studied the mechanism of sedation caused by antihistamines using positron emission tomography (PET). Recently, we revealed the nonsedative characteristic of ebastine, a second-generation antihistamine, with cognitive performance tests. In the present study, H1-receptor occupation by ebastine was examined in the human brain using PET.. Ebastine 10 mg and (+)-chlorpheniramine 2 or 6 mg were orally given to healthy male volunteers. PET scans with [11C]-doxepin, a potent H1-receptor antagonist, were conducted near tmax of respective drugs. Other volunteers in the control group also received PET scans. The binding potential of doxepin (BP = Bmax/Kd) for available brain H1-receptors was imaged on a voxel-by-voxel basis through graphical analysis. By setting regions of interest, the H1-receptor occupancy of drugs was calculated in several H1-receptor rich regions.. Brain distribution of radioactivity after ebastine treatment was similar to that without any drugs. However, after the oral administration of 2 mg (+)-chlorpheniramine, the level was lower than after ebastine and nondrug treatments. Graphical analysis followed by statistical parametric mapping (SPM96) revealed that H1-receptor rich regions such as cortices, cingulate gyrus and thalamus were regions where the BPs after ebastine were significantly higher than after (+)-chlorpheniramine (2 mg). H1-receptor occupancies in cortex were approximately 10% by ebastine and > or = 50% by either dose of (+)-chlorpheniramine (95% confidence interval for difference in the mean receptor occupancies: 27%, 54% for 2 mg and 35%, 62% for 6 mg vs ebastine, respectively). Receptor occupancies increased with increasing plasma concentration of (+)-chlorpheniramine, but not with concentration of carebastine, an active metabolite of ebastine.. Ebastine (10 mg orally) causes brain histamine H1-receptor occupation of approximately 10%, consistent with its lower incidence of sedative effect, whereas (+)-chlorpheniramine occupied about 50% of brain H1-receptors even at a low but sedative dose of 2 mg; occupancy of (+)-chlorpheniramine was correlated with plasma (+)-chlorpheniramine concentration.

Topics: Adult; Butyrophenones; Carbon Radioisotopes; Cerebral Cortex; Chlorpheniramine; Cross-Over Studies; Histamine H1 Antagonists; Humans; Male; Models, Biological; Piperidines; Receptors, Histamine H1; Single-Blind Method; Thalamus; Tomography, Emission-Computed; Treatment Outcome

The cognitive and psychomotor effects of 10 mg, 20 mg and 30 mg ebastine, a second generation H1-receptor antagonist, were compared with sustained release triprolidine 10 mg (as a verum) and placebo in 10 healthy volunteers in a double-blind, randomised cross-over study.. Following each dose, subjects were required to perform a series of tests of cognitive function and psychomotor performance at 1 h, 2 h, 4 h and 8 h post-dose on days 1 and 5. The test battery consisted of critical flicker fusion, choice reaction time, simulated car tracking task, Sternberg memory scanning task, assessment of subjective sedation (LARS) and subjective evaluation of sleep (LSEQ).. Ebastine at all doses investigated was not statistically significant from placebo in any of the objective tests used. However, as expected for a positive internal control, a number of objective measures were significantly disrupted by triprolidine (p < 0.05). Triprolidine produced an overall increase of the peripheral reaction time component of the simulated car tracking task (SCTT), the difference with placebo reaching statistical significance on day 1, 8 h post-dose (p < 0.05). The mean tracking accuracy scores were also significantly impaired following the administration of triprolidine after 8h on day 1 (p < 0.05). Triprolidine also produced a clear decrement on the SMST (Sternberg Memory Scanning Task), which was significantly different from placebo, at 4 h and 8 h post-dose on day 1. Subjective reports of sedation (LARS) were significantly greater at 2 h and 4 h following triprolidine administration on day 1 and ebastine (30 mg) was rated as sedative 4 h following administration on day 5. The perceived sedative activity of ebastine 30 mg was also reflected in the subjective reports on the LSEQ on day 1 (p < 0.05).. These results allow the conclusion that ebastine, at its recommended therapeutic doses of 10-20 mg, is demonstrably free from impairment on objective aspects of psychomotor and cognitive function in a study where the psychometric assessments were shown to be sensitive to disruptive effects, as evidenced by the action of the positive control, triprolidine 10 mg.

Topics: Adult; Analysis of Variance; Butyrophenones; Cognition; Cross-Over Studies; Double-Blind Method; Female; Histamine H1 Antagonists; Humans; Piperidines; Psychomotor Performance; Triprolidine

Ebastine and loratadine are 2 nonsedating second-generation H(1) antihistamines with once-daily dosing.. We compared the efficacy and safety of ebastine 20 mg and 10 mg, loratadine 10 mg, and placebo administered once daily for 4 weeks in controlling the symptoms of seasonal allergic rhinitis (SAR).. In a double-blind, placebo-controlled, randomized, parallel-group study, 565 patients with ragweed SAR, ages 12 to 70 years, received either ebastine 20 mg, ebastine 10 mg, loratadine 10 mg, or placebo once daily for 4 weeks. Patients recorded morning and evening reflective scores (past 12 hours) as well as snapshot scores (at time of recording) for nasal discharge, congestion, sneezing, itching, and total eye symptoms. Total symptom score (TSS) is the sum of these 5 scores.. Ebastine 20 mg produced significantly greater (P <.05) reductions from baseline compared with loratadine 10 mg over the entire treatment period in the mean daily reflective (42.5% vs 36.3%) and mean morning snapshot (40.3% vs 31.3%) TSS. The overall improvement in daily reflective and morning snapshot TSS was comparable between ebastine 10 mg and loratadine 10 mg and significantly better than placebo (P <.05). The total percent of patients with adverse events was similar among all 4 treatment groups (P =.78).. Ebastine 20 mg given once daily was significantly superior to loratadine 10 mg given once daily at improving the rhinitis total symptom score throughout the day and at awakening over a 4-week period. Ebastine 20 mg and 10 mg doses were both efficacious and well tolerated in the treatment of SAR.

Topics: Adolescent; Adult; Aged; Butyrophenones; Child; Double-Blind Method; Female; Histamine H1 Antagonists; Humans; Loratadine; Male; Middle Aged; Piperidines; Rhinitis, Allergic, Seasonal

This double-blind, placebo-controlled, multicentre study investigated the ability of ebastine, 10 and 20 mg once daily, to control symptoms of perennial allergic rhinitis (PAR) over a 12-week period, and assessed additional benefits of the 20-mg dose. Following a 2-week baseline period, patients (12-63 years) were randomized to treatment with ebastine 10 mg (n=88) or 20 mg (n=102), or placebo (n=100). Patients scored symptom severity (0-3) twice daily, and mean changes from baseline scores showed ebastine to be significantly effective in week 1. Control of symptoms persisted over the 12 weeks, the average daily total nasal symptom score for nasal stuffiness plus nasal discharge plus sneezing plus itchy nose being reduced by both doses, with statistical significance at 20 mg (P=0.015 vs placebo) despite decreased usage of sodium cromoglycate rescue medications. Patient and clinician final opinions of treatment also significantly favoured ebastine, both 10 and 20 mg, over placebo. No serious adverse events occurred, and study treatments were well tolerated with a low incidence of central nervous system-related adverse events and headache. In conclusion, ebastine 10 or 20 mg once daily was rapidly effective in relieving symptoms of PAR in adult and adolescent patients; additional benefits of the 20-mg dose became apparent in the longer term.

Topics: Adolescent; Adult; Butyrophenones; Child; Double-Blind Method; Female; Histamine H1 Antagonists; Humans; Male; Middle Aged; Piperidines; Rhinitis, Allergic, Perennial; Treatment Outcome

New H1-antagonists have become available, but there has been no comparison of their potency for inhibiting histamine in the skin.. Cetirizine 10 mg, ebastine 10 mg, epinastine 20 mg, fexofenadine 60 mg, terfenadine 60 mg, loratadine 10 mg, or placebo was given to 14 healthy male volunteers in a double-blind, crossover randomized manner. Inhibition of the wheal and flare response to epicutaneous histamine phosphate (100 mg/ml) challenge was measured at 0, 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 h after doses.. Epinastine inhibited the wheal and flare after 30 min. Cetirizine commenced acting at 1 h and was superior to other treatments. Ebastine was no better than placebo until 4 h, but was efficacious thereafter until 24 h. Terfenadine induced potent inhibition after 1 h and was superior to its metabolite fexofenadine. Loratadine was the least potent inhibitor. Inhibition of the flare response paralleled the patterns seen for wheals. The rank order for area under the curve (0-24 h) was cetirizine, epinastine, terfenadine, ebastine, fexofenadine, loratadine, and placebo.. The inhibition of histamine effects in the skin may be useful in predicting the clinical utility of newly introduced antihistamines in treating allergic disorders.

Topics: Adult; Butyrophenones; Cetirizine; Cross-Over Studies; Dibenzazepines; Double-Blind Method; Histamine; Histamine H1 Antagonists; Histamine Release; Humans; Hypersensitivity, Immediate; Imidazoles; Loratadine; Male; Piperidines; Skin Tests; Terfenadine; Urticaria

We compared the consistency and efficacy of the two antihistamines, cetirizine (10 mg) and ebastine (20 mg) on histamine skin reactivity 4 h after treatment.. Twenty-four healthy volunteers participated in a randomised double-blind cross-over study. The areas of wheals and flares induced by increasing (0, 5, 10, 50, 100, 200, 300 mg/ml) histamine concentrations, administered by prick tests, were measured before and 4 h after intake of cetirizine or ebastine.. Before treatment, concentration-response curves were similar and threshold concentrations identical (0.57 mg/ml and 0.57 mg/ml for cetirizine and ebastine, respectively). Both treatments exerted a significant effect. However, cetirizine was significantly more efficient than ebastine 20 mg (P < 0.01 both for wheals and flares). After cetirizine, the threshold concentration inducing a 3-mm(2 )wheal was significantly higher (266 mg/ml) than after ebastine (77 mg/ml) (P < 0.01), and total inhibition of the wheal was obtained in 18 of 24 patients for cetirizine and in 4 of 24 for ebastine (P < 0.001). The variation coefficient for the wheal reaction was 31% for cetirizine and 159% for ebastine, indicating a much lower variability after cetirizine.. Our study shows clearly that the efficacy of a single therapeutic dosage of cetirizine is greater and consistently better than that of ebastine for suppression of cutaneous reactivity to histamine 4 h after treatment in healthy volunteers. The need for ebastine to metabolise into the active carebastine might explain this difference.

Topics: Adolescent; Adult; Anti-Allergic Agents; Butyrophenones; Cetirizine; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Female; Histamine H1 Antagonists; Humans; Male; Middle Aged; Piperidines; Skin; Skin Tests

Ebastine is a nonsedating and selective histamine H1 receptor antagonist without anticholinergic or sedative effects at therapeutic doses. It has shown a rapid onset and long duration of action, and doses of 10 and 20mg once daily are effective in relieving the nasal and non-nasal symptoms of seasonal and perennial allergic rhinitis (SAR and PAR, respectively). In 3 randomised double-blind, multicentre clinical trials in patients with SAR, ebastine 10 and 20mg once daily for 2 to 3 weeks significantly reduced symptoms (nasal discharge, stuffiness, sneezing, itchy nose, itchy/watery eyes) when compared with placebo. Similarly, in patients with PAR, two 3-week studies demonstrated that ebastine 10mg twice daily and 20mg once daily significantly relieved the symptoms of PAR, as measured by the Perennial Index. Ebastine was well tolerated in these studies and had no effect on the QTc interval.

Topics: Adolescent; Adult; Aged; Butyrophenones; Child; Double-Blind Method; Electrocardiography; Electrocardiography, Ambulatory; Female; Histamine H1 Antagonists; Humans; Male; Middle Aged; Piperidines; Rhinitis, Allergic, Perennial; Rhinitis, Allergic, Seasonal

At therapeutic dosage, cetirizine and ebastine induce significant inhibition of skin reactivity to histamine. The consistency of their efficacy, that is, efficacy with the least interindividual variability among subjects, has not been carefully assessed, however.. To compare the consistency and efficacy of these antihistamines on skin reactivity.. Twenty-four healthy volunteers participated in a randomized double-blind crossover study. The areas of wheals and flares induced by increasing (0, 5, 10, 50, 100, 200, and 300 mg/mL) histamine concentrations, administered by prick tests, were measured before and four hours after intake of 10 mg of each antihistamine, allowing concentration-response curves to be established. The threshold histamine concentrations inducing wheal areas of 3 mm2 (positivity) were calculated by interpolation. The coefficient of variation (SD/mean %) was used to evaluate the consistency of the response.. Pretreatment concentration-response curves were similar, and threshold concentrations identical (0.29 mg/mL and 0.34 mg/mL for cetirizine and ebastine, respectively). For both, curves were lower after treatment than before. After cetirizine, the threshold concentration was significantly higher (217 mg/mL) than after ebastine (0.82 mg/mL) (P < .001), and total inhibition of the wheal reaction was observed in 21 of 24 patients at the lowest histamine concentration and in 17 of 24 at the highest. Ebastine never totally inhibited reaction, even to 5 mg/mL of histamine. Over the entire concentration-response curve, the coefficient of variation for the wheal reaction was 6.3% for cetirizine and 72.6% for ebastine, and, for flares, 11.0% and 83.7%, respectively. Hence, variability was much lower after cetirizine.. Our study shows clearly that the efficacy of a single therapeutic dosage of cetirizine is consistently good for suppression of cutaneous reactivity to histamine in healthy volunteers. The need for ebastine to metabolize into the active carebastine might explain its lesser consistency.

Topics: Adult; Anaphylaxis; Butyrophenones; Cetirizine; Cross-Over Studies; Dermatitis, Allergic Contact; Dose-Response Relationship, Drug; Double-Blind Method; Female; Histamine; Histamine H1 Antagonists; Humans; Male; Piperidines; Safety; Skin; Skin Tests

Cetirizine and ebastine are two second-generation histamine H1 antagonists undergoing evaluation for treatment of perennial rhinitis.. The clinical efficacy and safety of once daily cetirizine 10 mg were compared with ebastine 10 mg in patients with perennial allergic rhinitis in a 4-week, double-blind, parallel-group, randomized, multicenter study.. Two hundred fourteen patients (120 females, 94 males, aged 17 to 70 years, mean 31.2 years) were selected on the basis of perennial allergic rhinitis history, positive skin test for perennial allergens and a minimum rhinitis symptom score of 6/12. Patients recorded nasal symptom severity (nasal stuffiness, nasal discharge, sneezing, and itching) once daily on diary cards using a rating scale of 0 (none) to 3 (severe). Clinicians made an overall evaluation after 4 weeks of treatment. An intent-to-treat-analysis was performed comparing cetirizine (106 patients) and ebastine groups (108 patients).. The individual and total baseline symptom scores were comparable in both treatment groups. During the first week, the percentage mean decrease in the total nasal symptom score from baseline (sum of nasal stuffiness, discharge, sneezing, and itching) was significantly higher for cetirizine 46.2% than for ebastine 32.8% (P = .037). After 4 weeks of treatment, total symptom score improvement was 53.7% for cetirizine and 44.7% for ebastine (P = .12), and the clinician's overall evaluation showed that the percentage of symptom-free patients was significantly higher for cetirizine 17.8% than for ebastine 6.9% (P = .02). Cetirizine also significantly improved nasal stuffiness. An associated antiinflammatory effect is suggested. Commonly reported drug-related side effects were similar in both groups.. This study shows that both antihistamines, cetirizine 10 mg and ebastine 10 mg once a day, improved symptom scores of patients with perennial allergic rhinitis. Cetirizine, however, provided faster improvement and total relief in a greater number of patients after 4 weeks.

Topics: Adolescent; Adult; Aged; Butyrophenones; Cetirizine; Double-Blind Method; Female; Histamine H1 Antagonists; Humans; Male; Middle Aged; Piperidines; Rhinitis, Allergic, Perennial

The administration of histamine with iontophoresis is an alternative method to skin prick tests or intradermal injections. Skin reactions obtained with this method can be recorded with laser Doppler flowmetry (LDF) and previous studies with this method have shown histamine-induced laser Doppler changes in the wheal area.. In order to compare the influence of two H1 receptor antagonists (cetirizine 10 mg vs. ebastine 10 mg) on the skin vascular responses to histamine introduced by iontophoresis, we designed a double-blind, randomized, two-period crossover trial in which 18 volunteers were randomized.. Before and 2, 5 and 7 h after drug administration, iontophoresis (30 s, 1.4 mA/cm2) of histamine 10% was performed and followed by (1) monitoring of skin vascular responses with LDF at the administration site and at 1 cm from it, and (2) wheal and flare area measurements.. 2, 5 and 7 h after intake of the antihistaminic drug, there were significant differences between both drugs. Concerning LDF recordings, we noted at the histamine administration site an increase in perfusion unit (PU) values which is an effect known to be in proportion to the degree of inhibition of wheal reaction, and at 1 cm distal to the histamine administration site, there was a decrease in PU values. These changes were more marked under cetirizine. A greater suppressive effect of cetirizine on the wheal and flare reaction was consistently observed at all time points during the study, demonstrating its superior efficacy.. We conclude that (1) cetirizine demonstrated a stronger antihistaminic effect compared to ebastine at all time points; (2) iontophoresis appears to be an appropriate method to study specific microvascular changes at the delivery site of histamine and hence to detect the earliest changes occurring at the site of agonist-antagonist competition in the skin.

Topics: Adult; Butyrophenones; Cetirizine; Cross-Over Studies; Double-Blind Method; Female; Histamine; Histamine H1 Antagonists; Humans; Iontophoresis; Laser-Doppler Flowmetry; Male; Piperidines; Skin; Skin Diseases; Skin Tests; Time Factors

The objective of this study was to compare the single- and multiple-dose pharmacokinetics and electrocardiographic effect of a 10-mg oral dose of ebastine in elderly (ages, 65-85 years) and young (ages, 18-35 years) healthy volunteers. Thirty-seven subjects completed this randomized, double-blind, multiple-dose, placebo-controlled, parallel group study. The elderly group consisted of 18 subjects, with 13 subjects receiving 10 mg ebastine and 5 receiving matching placebo. The young group consisted of 19 subjects, with 13 subjects receiving 10 mg ebastine and 6 receiving matching placebo. On study days 1 and 3 through 10, each subject received a single 10-mg dose of ebastine or matching placebo in the morning with a standard breakfast. No drug was administered on study day 2 because of pharmacokinetic sampling. Blood samples were collected at selected times postdose on study days 1, 2, and 10. Plasma samples were analyzed for ebastine and its active metabolite, carebastine, using a validated high-performance liquid chromatography method. No plasma ebastine concentrations were detected, suggesting essentially complete metabolic conversion of ebastine to its metabolites. Analysis of variance showed no statistically significant differences between young and elderly single- and multiple-dose carebastine pharmacokinetics with respect to area under the plasma concentration-time curve, maximum concentration (Cmax ), terminal elimination rate constant, apparent oral clearance, or apparent volume of distribution. The mean time of maximum concentration value for young subjects was 1 hour longer than that for elderly subjects after single-dose administration but was comparable after multiple-dose administration. Within-group comparisons of both the young and elderly showed that pharmacokinetics between single dose and steady state were not statistically different. However, the mean steady-state carebastine Cmax values were approximately twofold greater than the mean Cmax values obtained after single-dose administration. A twofold increase in Cmax values between single-dose and steady-state administration is predicted for drugs such as carebastine, because its input interval is approximately equal to its elimination half-life. Twelve-lead electrocardiography was performed before dosing on day 1 and repeated 4 hours postdose on days 1, 5, and 10. Twenty-four hour Holter monitoring was also performed before and at the end of the study. No clinically relevant findings wer

Topics: Administration, Oral; Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Analysis of Variance; Butyrophenones; Chromatography, High Pressure Liquid; Double-Blind Method; Drug Monitoring; Electrocardiography; Electrocardiography, Ambulatory; Female; Histamine H1 Antagonists; Humans; Male; Middle Aged; Piperidines

Mosquito bites usually cause wealing and delayed bite papules. Cetirizine decreases wealing, bite papules and pruritus but the effect of other antihistamines on mosquito bites is unknown. We studied the effect of ebastine in 30 mosquito bite-sensitive adult subjects. Ebastine 10 mg or 20 mg and placebo were given for 4 days in a cross-over fashion. Aedes aegypti bites were given on forearms. The size of the bite lesions and pruritus (visual analogue score) were measured at 15 min, 2, 6, and 24 h after the bites. Twenty-five subjects were evaluable in the study. At 15 min ebastine decreased significantly the size of the bite lesion (p = 0.0017) and pruritus (p<0.0001). The effects of 10 mg and 20 mg of ebastine were similar. No significant effect was found at 2, 6 or 24 h, but when the measurements at all four time points were compiled the size of the bite lesion and pruritus score decreased significantly. Sedation occurred during ebastine treatment in 6 (21%) and during placebo treatment in 2 (7%) subjects. The present results show that prophylactically given ebastine is effective against immediate mosquito bite symptoms.

Topics: Adult; Aedes; Animals; Butyrophenones; Cross-Over Studies; Double-Blind Method; Female; Histamine H1 Antagonists; Humans; Hypersensitivity; Insect Bites and Stings; Male; Middle Aged; Piperidines; Premedication

Second-generation histamine H1-receptor antagonists are accepted first-line systemic therapy for seasonal allergic rhinitis. Ebastine is a new histamine H1-receptor blocker that may differ in efficacy from currently used second-generation agents.. To compare the efficacy of daily treatment with ebastine, 10 mg, ebastine, 20 mg, or cetirizine, 10 mg, for relieving symptoms of seasonal allergic rhinitis in adults.. In this multicenter, double-blind study, outpatients were randomized to one of three parallel treatment groups: ebastine, 10 mg, ebastine, 20 mg, or cetirizine, 10 mg once daily in the morning for a 2-week period. Patients were evaluated clinically according to symptoms, discomfort, and a global assessment at baseline and on days 8 and 15 of treatment. The total symptom score, defined as the sum of the total morning score on the day of evaluation and the total evening score on the preceding day, was the primary efficacy parameter.. Ebastine, 20 mg (n = 111), ebastine, 10 mg (116), and cetirizine, 10 mg (116), were all effective for improving nasal and ocular symptoms. There was, however, a general trend towards more rapid relief of symptoms with ebastine, 20 mg, and this reached statistical significance in some efficacy parameters after the first week of treatment. In a subpopulation of 158 patients who presented with more severe symptoms, statistically significantly greater improvement was seen with ebastine, 20 mg, compared with ebastine, 10 mg, as indicated by the mean change from baseline in the total symptom score averaged over the treatment period (-13.7 +/- 4.7 vs -11.8 +/- 3.8; P =.027) and in the morning symptom score (-6.7 +/- 2.7 vs -5.7 +/- 2.2; P = .042). All three treatments were well tolerated. Dry mouth, headache, and somnolence were the most common adverse events.. Ebastine (10 mg), cetirizine (10 mg), and ebastine (20 mg) administered orally once daily for 2 weeks all appear to be effective for relieving the symptoms of seasonal allergic rhinitis. Ebastine, 20 mg, may have advantages over ebastine, 10 mg, and cetirizine, 10 mg, in terms of a reduced time to achieve maximal efficacy and a superior level of efficacy in patients with more severe symptoms.

Topics: Adult; Butyrophenones; Cetirizine; Double-Blind Method; Female; Histamine H1 Antagonists; Humans; Male; Piperidines; Rhinitis, Allergic, Seasonal

396 adult and adolescent patients with seasonal allergic rhinitis participated in this randomised double-blind parallel-group study in which the efficacy and tolerability of ebastine 10 or 20mg administered once daily in the morning or evening for 3 weeks were compared with those of placebo. Clinical efficacy was assessed by measuring improvement in rhinitis symptoms (nasal discharge, nasal stuffiness, sneezing, itchy nose and itchy/watery eyes) recorded by patients twice daily on diary cards. The improvement in individual and total symptom scores at the end of the 3-week treatment period in patients treated with ebastine 10mg in the morning or ebastine 20mg in the morning or evening was significantly greater than the improvement in placebo recipients. The 20mg dose of ebastine administered in the morning was associated with the greatest improvement in symptom scores. There was no significant effect with the 10mg evening dose compared with placebo. Ebastine was well tolerated by the majority of patients - the incidence of adverse events, including headache, dry mouth, somnolence and asthenia being similar to that reported in placebo recipients. Electrocardiograms showed no evidence of any clinically relevant changes in QTc intervals. In a subsequent nonblinded 4-month study that included 230 patients from the initial study, global evaluations at monthly intervals showed overall symptom improvement in > or = 72% of patients who received ebastine 10mg or 20mg once daily. The drug was well tolerated during prolonged therapy, with adverse events being similar in nature and incidence to those reported in the 3-week double-blind study. In conclusion, ebastine 10mg once daily in the morning is an appropriate starting dose for the treatment of rhinitis, and this can be increased to 20mg as required.

Topics: Adolescent; Adult; Butyrophenones; Child; Double-Blind Method; Female; Histamine H1 Antagonists; Humans; Male; Middle Aged; Piperidines; Rhinitis, Allergic, Seasonal; United States

Topics: Adolescent; Adult; Aged; Anti-Allergic Agents; Butyrophenones; Cetirizine; Double-Blind Method; Female; Histamine H1 Antagonists; Humans; Male; Middle Aged; Piperidines; Rhinitis, Allergic, Seasonal

Ebastine is a new second generation histamine H1 receptor antagonist that has shown clinical efficacy in the treatment of seasonal and perennial allergic rhinitis and chronic urticaria after once-daily administration. This double-blind multicentre randomised placebo-controlled study has investigated the long term efficacy of ebastine 10mg once daily in the treatment of chronic urticaria compared with that of terfenadine 60mg twice daily. At the end of a 3-month treatment period, ebastine was significantly superior to placebo in improving symptoms of chronic urticaria (including severity of itching, number of wheals per day), and its efficacy was similar to that of terfenadine. In a global assessment of efficacy, investigators considered chronic urticaria to have improved in 73% of ebastine recipients compared with 68% and 52% of patients treated with terfenadine or placebo, respectively. The patients' assessments of efficacy were similar to those of the investigators. Ebastine was well tolerated, the incidence and nature of adverse events with this agent being similar to those reported in patients treated with terfenadine or placebo. The most common adverse events were headache and dry mouth. Thus, these results, which show ebastine to be an effective and well tolerated agent, indicated that the drug should be considered for the first-line therapy of chronic urticaria.

Topics: Adult; Anti-Allergic Agents; Butyrophenones; Chronic Disease; Double-Blind Method; Histamine H1 Antagonists; Humans; Piperidines; Terfenadine; Urticaria

The efficacy of the second generation antihistamine ebastine has been investigated in the treatment and prevention of seasonal allergic rhinitis (SAR). In a double-blind randomised study, patients treated with a single daily dose of ebastine 10mg (n = 116) for 2 weeks showed a significant improvement in symptoms of SAR compared with those treated with placebo (n = 85). Sneezing, rhinorrhoea, tears and conjunctival irritation were all significantly improved, but not blocked nose. The overall efficacy of treatment was judged to be significantly superior in the ebastine group. There was no increase in bodyweight at the end of the study in either of the groups. There was no increase bodyweight at the end of the study in either of the groups. The percentage of patients reporting adverse events were headache, somnolence, nausea, dry mouth, stomach upset and increased appetite. The efficacy of ebastine 10 mg/day (n = 111) was similar to that of astemizole 10 mg/day (n = 106) over a 4-month period in preventing the symptoms of SAR in the open randomised study. The efficacy of both drugs in preventing the onset of sneezing, rhinorrhoea, blocked nose and tears was significant, when symptoms were compared with those during the previous year. At the end of the study, the astemizole-treated patients had a significant increase in bodyweight, which was not observed in the ebastine group. The percentage of patients reporting adverse events was significantly greater in the astemizole group (34.9% versus 20.7%; p = 0.02). Thus, ebastine is a useful alternative treatment for seasonal allergic rhinitis. It has also shown efficacy comparable to that of astemizole in the prevention of onset of symptoms of this allergic condition, and appears to be better tolerated than this agent.

Topics: Astemizole; Butyrophenones; Double-Blind Method; Histamine H1 Antagonists; Humans; Piperidines; Rhinitis, Allergic, Seasonal; Seasons

Histamine antagonists together with topical steroids are the treatment of choice in allergic rhinitis. Many of these histamine antagonists exhibit effects in addition to blockade of the histamine receptor. In this study we have investigated the effects of ebastine and carebastine on the release of eicosanoids and cytokines from human dispersed polyp cells and the effect of these compounds on the release of inflammatory mediators into nasal lavage fluid after allergen challenge. Ebastine was shown to block the release of anti-IgE-induced prostaglandin D2 (PGD2) and leukotriene C4/D4 from human nasal polyp cells (IC30 values of 2.57 and 9.6 mumol/L, respectively) and to inhibit the release of cytokines. Carebastine inhibited the release of PGD2 (IC30 8.14 mumol/L) but had little effect on cytokine release. When patients underwent nasal provocation tests with allergen, ebastine significantly increased the mean number of pollen grains required to induce an allergic response. In addition, the drug inhibited the release of granulocyte-macrophage colony-stimulating factor but had no effect on any other mediators measured.

Topics: Adolescent; Adult; Allergens; Butyrophenones; Cross-Over Studies; Double-Blind Method; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Histamine H1 Antagonists; Humans; Leukotriene C4; Male; Middle Aged; Nasal Polyps; Piperidines; Pollen; Prostaglandin D2; Rhinitis, Allergic, Seasonal

Ebastine is H1 receptor antagonist, powerful and selective for histamine. Its efficacy has been evaluated in control of symptoms of persistent rhinitis, appearance of secondary effects and tolerance of the drug, in 30 children who were suffering from persistent rhinitis, of which the diagnosis included:- clinical history, skin tests (prick test) nasal and conjunctival provocation tests, total and specific IgE. All the children had treatment for 30 days. The parameters followed were:- clinical score, skin tests, nasal and conjunctival provocations and evaluation of secondary effects, of the start and 10 days after the end of treatment. The results obtained were a disappearance or reduction of the weals from histamine and specific antigens, disappearance or reduction of the response in nasal and conjunctival provocation with carbachol or specific antigens, clear clinical improvement in 22 patients, in 2 small improvement and no response in 6 patients. We conclude that Ebastine improved the clinical symptoms in persistent rhinitis, the skin test is inhibited and sensitivity of the shock organ is reduced. No secondary effects were seen on the Central Nervous System (SNC) and the tolerance of the drug was very good.

Topics: Adolescent; Butyrophenones; Carbachol; Child; Conjunctivitis, Allergic; Female; Histamine H1 Antagonists; Humans; Male; Nasal Provocation Tests; Piperidines; Rhinitis, Allergic, Perennial; Skin Tests; Treatment Outcome

The review summarizes the major results of eight double-blind, placebo-controlled, volunteer studies undertaken by three independent institutions for showing the effects on actual driving performance of "sedating" and "nonsedating" antihistamines (respectively, triprolidine, diphenhydramine, clemastine and terfenadine, loratadine, cetirizine, acrivastine, mizolastine, and ebastine). A common, standardized test was used that measures driving impairment from vehicular "weaving" (i.e., standard deviation of lateral position (SDLP)). Logical relationships were found between impairment and dose, time after dosing, and repeated doses over 4-5 days. The newer drugs were generally less impairing, but differences existed among their effects, and none was unimpairing at doses 1-2x the currently recommended levels. One or possibly two of the newer drugs possessed both performance-enhancing and -impairing properties, depending on dose, suggesting two mechanisms of action.

Topics: Automobile Driving; Benzimidazoles; Butyrophenones; Cetirizine; Clemastine; Diphenhydramine; Dose-Response Relationship, Drug; Histamine H1 Antagonists; Humans; Loratadine; Netherlands; Piperidines; Psychomotor Performance; Terfenadine; Triprolidine

Ebastine is a nonsedating histamine H-1 antagonist undergoing evaluation for treatment of allergic rhinitis and urticaria.. To compare the suppression of prick and intradermal skin reactions to histamine over a period of 24 hours produced by a single dose of ebastine. Also to record side effects and assess changes in the electrocardiogram, particularly the QTc interval.. Single doses of 1, 3, 10, and 30 mg of ebastine or placebo were administered double-blind at approximately 8 AM after baseline measurement of the reaction to intradermal testing with 5 micrograms histamine base and prick skin testing with three concentrations of histamine. Intradermal testing with histamine was repeated hourly for four hours, every two hours for eight hours, and after 24 hours. Titrated prick skin testing with histamine was performed at 6, 12, and 24 hours. Potential side effects were recorded each time skin testing was performed. Electrocardiograms were repeated at 4 and 24 hours.. Intradermal skin test reactions were suppressed between 4 and 24 hours and prick skin tests to 10 mg/mL histamine base were suppressed between 6 and 24 hours with all doses of ebastine. Prick skin test reactions were significantly smaller at 12 and 24 hours in the group receiving the 30 mg dose of ebastine than in all other groups.. Ebastine is a potent antihistamine that suppresses skin reactions to histamine for 24 hours following single doses in the doses tested (1 to 30 mg). No differences from placebo were noted in either the incidence of side effects or in the QTc intervals of serial electrocardiograms.

Topics: Adult; Anaphylaxis; Butyrophenones; Dermatitis, Allergic Contact; Dose-Response Relationship, Drug; Double-Blind Method; Female; Histamine H1 Antagonists; Humans; Male; Middle Aged; Piperidines; Skin; Skin Tests

The efficacy and safety of the nasally administered histamine H1 receptor blocking drug azelastine was investigated in a randomized comparative trial with ebastine. Patients were treated for 14 days and efficacy was assessed by the physician using a rating scale measuring 10 nasal and ocular symptoms of seasonal rhinitis (0 = absent, 1 = mild, 2 = moderate, 3 = severe). Tolerability was measured on the basis of reported adverse events. Data from a total of 59 patients were included in the efficacy analysis. Both treatment groups had dramatic reductions in the physician's total symptom score following treatment. Mean scores in the azelastine group decreased from 12.4 pretreatment to 5.6, while the mean ebastine scores decreased from 13.6 to 6.6. There was no significant difference between the two groups (p = 0.86). Changes in individual rhinitis symptoms showed no differences between the two groups. The majority of patients in both treatment groups reported an initial relief of symptoms within 1 h of dosing. For seven patients treated with azelastine, the initial effect was already seen after 10 min (ebastine: two patients). Eight adverse events were reported in each treatment group; all were mild except one report of sedation in an ebastine patient, which was of moderate severity. Three patients reported somnolence during treatment with ebastine. A bitter taste was mentioned by four patients in the azelastine group, but neither somnolence nor sedation was reported with azelastine. In conclusion, the results of the study suggest that both azelastine and ebastine are effective treatments of the symptoms of seasonal allergic rhinitis. Both drugs were well tolerated.

Topics: Administration, Intranasal; Administration, Oral; Adolescent; Adult; Butyrophenones; Female; Histamine H1 Antagonists; Humans; Male; Middle Aged; Phthalazines; Piperidines; Rhinitis, Allergic, Seasonal; Treatment Outcome

In order to assess the antihistaminic power of cetirizine and ebastine, we designed a randomized, double-blind, crossover study, measuring their capacity to modify skin blood flow induced by a histamine prick test. The vasomotor response was compared using a laser Doppler flowmeter. Two hours after intake of the antihistaminic drug, there were significant differences between both drugs: at 4 h, the antihistaminic effect of cetirizine persists, whereas ebastine only showed moderate activity. The reduction of the cutaneous blood flow values (CBFV) showed good activity in both groups, but cetirizine was more potent and showed faster activity than ebastine.

Topics: Adolescent; Adult; Butyrophenones; Cetirizine; Double-Blind Method; Erythema; Female; Histamine; Histamine H1 Antagonists; Humans; Laser-Doppler Flowmetry; Male; Piperidines; Prospective Studies; Regional Blood Flow; Skin

Ebastine is a new piperidine-containing, relatively nonsedating second-generation H1-receptor antagonist. In a double-blind, parallel-group study of a single 5 mg or 10 mg dose of ebastine syrup used to treat allergic rhinitis in 20 children aged 6 to 12 years, we tested the hypothesis that the medication would have a duration of action of at least 24 hours. We measured plasma concentrations of carebastine, the pharmacologically active metabolite of ebastine, and the wheals and flares produced by epicutaneous tests with histamine phosphate, 1.0 mg/ml. Ebastine was absorbed well; peak carebastine concentrations occurred approximately 3 hours after dosing. Mean plasma elimination half-life values of carebastine ranged from 10 to 14 hours. The pharmacokinetics of carebastine were linear and dose independent in the dosage range studied. After the 5 or 10 mg dose, there were no significant differences between mean plasma elimination half-life values, mean oral clearance values, or mean apparent volumes of distribution. Mean peak plasma carebastine concentrations and mean areas under the plasma carebastine concentration-time curve after the 10 mg dose were 1.93 and 1.76 times, respectively, the values obtained after the 5 mg dose. Both doses significantly reduced the histamine-induced wheal-and-flare areas for up to 28 hours compared with predose values. The differences in effect between the doses generally were not statistically or clinically significant. No adverse effects were noted. We conclude that ebastine, an effective H1-receptor antagonist with a prompt onset of action and a long duration of action, is suitable for once-daily administration to children.

Topics: Butyrophenones; Child; Double-Blind Method; Drug Administration Schedule; Female; Histamine H1 Antagonists; Humans; Male; Piperidines; Rhinitis, Allergic, Perennial; Skin Tests

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 effects of a new antihistamine, ebastine (10, 20 and 30 mg), on several parameters of driving performance in actual traffic were studied in 15 healthy male volunteers. Subjects were treated for 5 days, and their driving performance tested on day 1 and day 5. The study was double-blind, placebo controlled and included the antihistamine triprolidine (10 mg sustained release) as an active drug control. 2. General tolerability was good except in one case following the reference compound triprolidine. No significant changes in driving performance were found with the new antihistamine ebastine at any dosage, on day 1 or day 5. Triprolidine (10 mg) significantly increased both the amount of weaving and the delay in following speed manoeuvres of a leading car, compared with placebo. 3. The results suggest that ebastine in doses up to 30 mg may be relatively safe for use by those who drive motor vehicles while under medication. The results do not warrant such a conclusion for triprolidine 10 mg.

Topics: Adult; Automobile Driving; Butyrophenones; Double-Blind Method; Histamine H1 Antagonists; Humans; Male; Piperidines; Psychomotor Performance; Triprolidine

The effects of single oral doses of 10 and 20 mg ebastine were compared with placebo and 2 mg clemastine in a double-blind cross-over study in 16 healthy male volunteers. Clemastine produced the known pattern of changes, namely impairment of psychomotor performance, drowsiness, and a selective effect on cognitive processes. Earlier encoding in a perceptual stage was slowed whereas abstract classification processes were not affected. Electrophysiological measures of vigilance showed a general decrease in vigilance especially 2.5 and 4.5 h after dosing. In contrast at no time was any effect of ebastine different from that of the placebo. Ebastine 10 and 20 mg differed positively from clemastine in its effect on pursuit tracking, subjective rating of drowsiness and general discomfort. Ebastine 10 mg also differed positively from clemastine in the EEG features of vigilance. It is concluded that 10 and 20 mg ebastine were free from sedative adverse effects.

Topics: Adult; Butyrophenones; Clemastine; Cognition; Double-Blind Method; Electroencephalography; Histamine H1 Antagonists; Humans; Male; Piperidines; Psychomotor Performance; Reference Values; Sleep; Surveys and Questionnaires; Wakefulness

We have given 12 healthy subjects the H1-antihistamine ebastine (20 mg) or placebo in a double-blind, crossover study for one week each. The subjects were tested for drug effects on Day 6 of each period, and for interactions of ebastine with ethanol (0.8 g.kg-1) on Day 7. On both days, the testing runs were done at baseline and at 2, 4, and 6 h after the drug. Performance was evaluated both objectively (digit symbol substitution, flicker fusion, Madox wing, nystagmus, simulated driving, body balance) and subjectively (visual analogue scales) and with questionnaires. Venous blood samples were taken daily during maintenance and during each test run for assay of plasma carebastine. Blood ethanol concentrations were assayed with an Alcolmeter in the breath and directly in the blood. Plasma carebastine concentration reached a steady-state from Day 3 on; the mean concentrations in the morning were 92 micrograms.l-1 on Day 6 and 104 micrograms.l-1 on Day 7. The rise in plasma carebastine after an extra 20 mg of ebastine was accelerated but not increased by ethanol. Ebastine did not impair performance objectively or subjectively. It slightly improved body balance and reduced errors during simple tracking at 4 h. Blood ethanol concentrations peaked (mean 0.76 g.l-1) at 1.5 h after ethanol intake. Ethanol impaired performance in most objective tests and produced clumsiness, muzziness, and mental slowness, but little drowsiness. Ebastine neither modified the blood ethanol concentrations nor increased the effects of ethanol.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Butyrophenones; Double-Blind Method; Drug Interactions; Ethanol; Female; Histamine H1 Antagonists; Humans; Male; Piperidines; Psychomotor Performance

The peripheral H1-inhibiting effects of cetirizine 10 mg and ebastine 10 mg were compared at the skin level after single oral administration. The study was performed in 9 healthy subjects under double-blind randomized crossover conditions. Both drugs were significantly effective up to 24 h. The suppressive effect of cetirizine was significantly more rapid and more marked.

Topics: Administration, Cutaneous; Administration, Oral; Adult; Butyrophenones; Capsules; Cetirizine; Double-Blind Method; Female; Histamine; Histamine H1 Antagonists; Humans; Hydroxyzine; Hypersensitivity; Male; Multivariate Analysis; Piperidines; Placebos; Skin; Skin Tests; Time Factors

Oral ebastine, 10 mg once daily for seven days, and placebo were compared as treatment for active perennial allergic rhinitis in 151 patients in a multicenter, randomized, double-blind trial. Ebastine treatment produced a significant reduction in the incidence and severity of most symptoms associated with perennial rhinitis. Tolerability was similar in the two treatment groups. The incidences of drowsiness and dry mouth were not more frequent in the patients treated with the active drug.

Topics: Adult; Butyrophenones; Double-Blind Method; Female; Histamine H1 Antagonists; Humans; Male; Piperidines; Rhinitis, Allergic, Perennial; Time Factors

In a double blind, randomised, placebo controlled trial in a group of extrinsic asthmatics, we have evaluated the potency and selectivity of ebastine, a new piperidine-type H1-receptor antagonist, against histamine and methacholine-induced bronchoconstriction. The median histamine PC20FEV1 value following placebo was 3.15 mg/ml (0.24-58.84). When compared with placebo, ebastine produced significant protection at 10 mg (median PC20 = 31.36 mg/ml, p = 0.008) and 30 mg (median PC20 = 42.14 mg/ml, p = 0.001) but there appeared to be no significant dose effect. Ebastine also produced a small shift in the methacholine concentration-response curves to the right. We conclude that ebastine is an effective antagonist of histamine-induced bronchoconstriction in the asthmatic airway with evidence of minor blockade of methacholine-induced bronchoconstriction.

Topics: Adult; Asthma; Bronchi; Butyrophenones; Dose-Response Relationship, Drug; Female; Forced Expiratory Volume; Histamine; Histamine H1 Antagonists; Humans; Male; Methacholine Compounds; Middle Aged; Piperidines

Ebastine is an H1 antihistamine. Using a double-blind, parallel group randomized study design, the efficacy and the tolerability of oral ebastine (10 mg daily escalating to 40 mg daily according to clinical need) was compared over 4 weeks during 1986 with matching placebo in 40 general practice patients suffering from hayfever. Ebastine (19 patients) was more effective (P less than 0.05) than placebo (21 patients) against symptoms of running nose, itching nose, sneezing and blocked nose. Ebastine was superior to placebo in respect of the total symptom score as well as when judged by the investigators' and the patients' opinion of overall efficacy. Ebastine caused few adverse events, none of which resulted in a patient being withdrawn from treatment. Significantly more patients were withdrawn because of inefficacy from the placebo (n = 12) than from the ebastine (n = 3) treatment group (P less than 0.02). It is concluded that ebastine (10-40 mg daily) is an effective and well tolerated treatment for hayfever.

Topics: Adult; Butyrophenones; Double-Blind Method; Female; Histamine H1 Antagonists; Humans; Male; Piperidines; Rhinitis, Allergic, Seasonal

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

1. Ebastine, through its carboxylic acid metabolite has antihistamine (H1-receptor) activity in man. 2. We have examined in a single blind placebo controlled study the effects of 10 mg and 50 mg of ebastine on cardiovascular, autonomic and psychomotor function in healthy subjects. 3. Ebastine had no effect on blood pressure or heart rate and there was no evidence of any anticholinergic activity on circulatory reflexes or salivation. 4. Ebastine did not impair psychomotor performance as assessed by critical flicker fusion at either dose. 5. Ebastine 10 mg had no effect on sedation measured by visual analogue scale or direct questioning, however ebastine 50 mg did cause a modest increase in indices of sedation. 6. Ebastine did not have detectable sedative properties at the 10 mg dose where long-lasting antihistamine effects can be demonstrated.

Topics: Adult; Autonomic Nervous System; Blood Pressure; Butyrophenones; Flicker Fusion; Heart Rate; Histamine H1 Antagonists; Humans; Hypnotics and Sedatives; Male; Piperidines; Psychomotor Performance; Reaction Time; Salivation; Surveys and Questionnaires; Time Factors

Antihistamines are among the most widely used medications in the world. Ebastine is an antihistaminic which is long-acting, second-generation, and selective H1-receptor inverse agonist. I report a twelve-year-and-six-month-old girl with temporary prolongation of the QTc interval caused by acute ebastine intoxication due to TikTok challenge. Initial electrocardiogram showed sinus arrhythmia (72 beats/min) and prolongation of the QTc interval (QTc 482 milliseconds). Gastric lavage was performed. Intravenous fluid was administered, and activated charcoal (1 g/kg/per dose) was given. Electrocardiogram 9 h after drug ingestion showed sinus rhythm and normal QTc interval (QTc 414milliseconds). During follow-up, no electrocardiogram abnormalities were detected with electrocardiogram monitoring. She was discharged on day 2 without any complications. This case report is the first in the literature to show acute intoxication with ebastine due to challenge video on TikTok, which leads to a temporary prolongation of the QTc interval. Also, with this case report, I assert the fact that it is important to properly supervise the use of social media, such as TikTok and to review the content of TikTok videos.

Topics: Arrhythmias, Cardiac; Drug Inverse Agonism; Electrocardiography; Female; Histamine H1 Antagonists; Humans; Infant; Long QT Syndrome; Piperidines; Social Media

Topics: Acrylic Resins; Administration, Cutaneous; Animals; Butyrophenones; Chemistry, Pharmaceutical; Disease Models, Animal; Drug Carriers; Drug Liberation; Drug Stability; Emulsions; Gels; Histamine H1 Antagonists; Hydrogen-Ion Concentration; Male; Piperidines; Rabbits; Rheology; Urticaria; Viscosity

The second-generation antihistamines at licensed doses are first-line treatment in urticaria and up-dosing is recommended as second-line treatment. To assess the efficacy and safety of escalated doses of ebastine in patients with chronic urticaria (CU), we designed this study. Recruited patients with CU were treated with increasing doses of ebstine. Treatment started at the daily dose of 10 mg. The symptom is assessed weekly, and if there is no significant improvement, the dose is increased from 10 mg to 20 mg, and if still no significant improvement, up to 40 mg. Pruritus, number, diameter, duration and frequency of wheals, and adverse reactions were assessed. One hundred and forty (76.50%) patients achieved marked effect with ebastine 10 mg/day, 27 (14.75%) patients with ebastine 20 mg/day and 13 (7.10%) patients with ebastine 40 mg/day, while 3(1.64%) patients did not get marked effect. There was no significant difference of effect between factitious urticaria, CSU, cholinergic urticaria and CSU with factitious urticaria in different dose (all p > 0.05). Common adverse reactions of ebstine treatment, included dry mouth, somnolence, tiredness and headache, were mild or moderate. There was no significant difference between the degree score of dry mouth with different doses of ebastine, and the same to somnolence, tiredness and headache (all p > 0.05). Doses escalation of ebastine should be effective in treatment of factitious urticaria, CSU and cholinergic urticaria with poorly treated by standard of double doses. Increasing ebastine dose did not increase the incidence of adverse reactions.

Topics: Butyrophenones; Cholinergic Agents; Chronic Disease; Chronic Urticaria; Headache; Histamine H1 Antagonists; Humans; Piperidines; Prospective Studies; Sleepiness; Urticaria; Xerostomia

Cytochrome P450s (P450s) have been identified and analyzed in dogs and pigs, species that are often used in preclinical drug studies. Moreover, P450s are clinically important for drug therapy not only in humans, but also in species under veterinary care, including dogs and cats. In the present study, seven P450s homologous to human CYP2J2, namely, dog CYP2J2; cat CYP2J2; and pig CYP2J33, CYP2J35, CYP2J91, and CYP2J93, were newly identified and characterized, along with pig CYP2J34 previously identified. The cDNAs of these CYP2Js contain open reading frames of 502 amino acids, except for CYP2J35 (498 amino acids), and share high sequence identity (77%-80%) with human CYP2J2. Phylogenetic analysis revealed that dog and cat CYP2J2 were closely related, whereas pig CYP2Js formed a cluster. All seven

Topics: Animals; Astemizole; Butyrophenones; Cats; Cytochrome P-450 CYP2J2; Cytochrome P-450 Enzyme System; Dogs; Humans; Phylogeny; Piperidines; Swine; Terfenadine

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

Topics: Butyrophenones; Chemistry, Pharmaceutical; Drug Liberation; Drug Stability; Drug Storage; Humidity; Nonlinear Dynamics; Piperidines; Solubility; Tablets; Temperature; Time Factors

Cytochrome P450 2J2 (CYP2J2) is responsible for the epoxidation of endogenous arachidonic acid, and is involved in the metabolism of exogenous drugs. To date, no crystal structure of CYP2J2 is available, and the proposed structural basis for the substrate recognition and specificity in CYP2J2 varies with the structural models developed using different computational protocols. In this study, we developed a new structural model of CYP2J2, and explored its sensitivity to substrate binding by molecular dynamics simulations of the interactions with chemically similar fluorescent probes. Our results showed that the induced-fit binding of these probes led to the preferred active poses ready for the catalysis by CYP2J2. Divergent conformational dynamics of CYP2J2 due to the binding of each probe were observed. However, a stable hydrophobic clamp composed of residues I127, F310, A311, V380, and I487 was identified to restrict any substrate access to the active site of CYP2J2. Molecular docking of a series of compounds including amiodarone, astemizole, danazol, ebastine, ketoconazole, terfenadine, terfenadone, and arachidonic acid to CYP2J2 confirmed the role of those residues in determining substrate binding and specificity of CYP2J2. In addition to the flexibility of CYP2J2, the present work also identified other factors such as electrostatic potential in the vicinity of the active site, and substrate strain energy and property that have implications for the interpretation of CYP2J2 metabolism.

Topics: Arachidonic Acid; Astemizole; Butyrophenones; Catalytic Domain; Cytochrome P-450 CYP2J2; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Humans; Hydrophobic and Hydrophilic Interactions; Kinetics; Molecular Docking Simulation; Oxidation-Reduction; Piperidines; Protein Binding; Substrate Specificity

Although ebastine (EBT) can impede histamine-induced skin allergic reaction and persuade long acting selective H1 receptor antagonistic effects but its poor water solubility circumscribed its clinical application. The main objective of this research work was to improve the aqueous solubility and oral bioavailability of EBT by preparing EBT-loaded bilosomes (EBT-PC-SDC-BS). A thin film hydration method was used to prepare ebastine loaded bilosomes. The prepared-formulations were optimized considering size, morphology and entrapment efficiency. The SEM images revealed regular and spherical shape of bilosomes. Average size of the prepared EBT-PC-SDC-BS was 665.8 nm and zeta potential was around-32.9 mV with 89.05 % average entrapment efficiency (EE).Importantly, the solubility of EBT in water was amplified up to 17.9 μg/ml compared to pure drug (2 μg/mL) reflecting a highest solubility increase of 751 %. In vitro drug release results of prepared EBT-PC-SDC-BS exhibited improved release behavior. Finally, it is established from the results that the EBT-PC-SDC-BS could function as a favorable nano-carrier system to improve the solubility as well as dissolution of EBT.

Topics: Administration, Oral; Bile Acids and Salts; Biological Availability; Butyrophenones; Drug Compounding; Drug Liberation; Histamine H1 Antagonists; Liposomes; Nanoparticles; Phosphatidylcholines; Piperidines; Solubility

1. The objective of our study was to develop and validate a cocktail approach to allow the simultaneous characterization of various CYP450-mediated oxidations by human heart microsomes for nine probe drug substrates, namely, 7-ethoxyresorufin, bupropion, repaglinide, tolbutamide, bufuralol, chlorzoxazone, ebastine, midazolam and dodecanoic acid. 2. The first validation step was conducted using recombinant human CYP450 isoenzymes by comparing activity measured for each probe drug as a function of (1) buffer used, (2) selectivity towards specific isoenzymes and (3) drug interactions between probes. Activity was all measured by validated LC-MSMS methods. 3. Two cocktails were then constituted with seven of the nine drugs and subjected to kinetic validation. Finally, all probe drugs were incubated with human heart microsomes prepared from ventricular tissues obtained from 12 patients undergoing cardiac transplantation. 4. Validated cocktail #1 including bupropion, chlorzoxazone, ebastine and midazolam was used to characterize CYP2B6-, 2E1-, 2J2- and 3A5-mediated metabolism in human hearts. 5. Cocktail #2 which includes bufuralol, 7-ethoxyresorufin and repaglinide failed the validation step. Substrates in cocktail #2 as well as tolbutamide and dodecanoic acid had to be incubated separately because of their physico-chemical characteristics (solubility and ionization) or drug interactions. 6. Activity in HHM was the highest towards ebastine, chlorzoxazone and tolbutamide.

Topics: Bupropion; Butyrophenones; Carbamates; Chlorzoxazone; Cytochrome P-450 Enzyme System; Drug Evaluation, Preclinical; Ethanolamines; Humans; Lauric Acids; Microsomes; Midazolam; Myocardium; Oxazines; Piperidines; Tolbutamide

Ebastine is a second-generation histamine H1 receptor antagonist that is used to attenuate allergic inflammation. Ebastine has also shown to affect hair loss; however, the immunoregulatory effect of ebastine cannot completely exclude the possibility of spontaneous hair regrowth in ebastine-treated mice. In this study, we examined the effects of ebastine on the growth of human follicle dermal papilla cells (HFDPC) using a WST-1 cell proliferation assay and a bromodeoxyuridine incorporation assay. Ebastine was shown to significantly increase the proliferation of HFDPC. The expression levels of cell-cycle regulatory proteins and an antiapoptotic protein were increased in ebastine-treated HFDPC. Furthermore, elevated expression levels of phospho-AKT and phospho-p44/42 extracellular signal-regulated kinase (ERK) were observed in ebastine-treated HFDPC. Ebastine-mediated HFDPC growth was completely reversed by blocking ERK kinase. The results from our present study suggest that the regulation of HFDPC proliferation by ebastine might be directly involved in hair regrowth through the ERK signaling pathway.

Topics: Alopecia; Apoptosis; Butyrophenones; Cell Line; Cell Proliferation; Dermis; Extracellular Signal-Regulated MAP Kinases; Gene Expression Regulation; Hair; Hair Follicle; Humans; Mitogen-Activated Protein Kinase 3; Piperidines; Proto-Oncogene Proteins c-akt

Broussonetia papyrifera (L.) Ventenat, a traditional medicinal herb, has been applied as a folk medicine to treat various diseases. Broussochalcone A (BCA), a chalcone compound isolated from the cortex of Broussonetia papyrifera (L.) Ventenat, exhibits several biological activities including potent anti-oxidant, antiplatelet, and cytotoxic effects.. The purpose of this study is to elucidate the inhibitory effect of BCA against CYP2J2 enzyme which is predominantly expressed in human tumor tissues and carcinoma cell lines.. The inhibitory effect of BCA on the activities of CYP2J2-mediated metabolism were investigated using human liver microsomes (HLMs), and its anti-cancer effect against human hepatoma HepG2 cells was also evaluated.. Two representative CYP2J2-specific probe substrates, astemizole and ebastine, were incubated in HLMs with BCA. After incubation, the samples were analyzed using liquid chromatography-tandem mass spectrometry. To investigate the binding model between BCA and CYP2J2, we carried out structure-based docking simulations by using software and scripts written in-house.. BCA inhibited CYP2J2-mediated astemizole O-demethylation and ebastine hydroxylase activities in a concentration dependent manner with K. Overall, this was the first report of the inhibitory effects of BCA on CYP2J2 in HLMs. The present data suggest that BCA is a potential candidate for further evaluation for its CYP2J2 targeting anti-cancer activities.

Topics: Antineoplastic Agents, Phytogenic; Astemizole; Butyrophenones; Cell Proliferation; Chalcones; Chromatography, Liquid; Cytochrome P-450 CYP2J2; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Forkhead Box Protein O3; Hep G2 Cells; Humans; Microsomes, Liver; Molecular Docking Simulation; Piperidines; Resorcinols; Tandem Mass Spectrometry

The influence of Arginine 117 of human cytochrome P450 2J2 in the recognition of ebastine and a series of terfenadone derivatives was studied by site-directed mutagenesis. R117K, R117E, and R117L mutants were produced, and the behavior of these mutants in the hydroxylation of ebastine and terfenadone derivatives was compared to that of wild-type CYP2J2. The data clearly showed the importance of the formation of a hydrogen bond between R117 and the keto group of these substrates. The data were interpreted on the basis of 3D homology models of the mutants and of dynamic docking of the substrates in their active site. These modeling studies also suggested the existence of a R117-E222 salt bridge between helices B' and F that would be important for maintaining the overall folding of CYP2J2.

Topics: Arginine; Butyrophenones; Catalytic Domain; Cytochrome P-450 CYP2J2; Cytochrome P-450 Enzyme System; Humans; Hydrogen Bonding; Hydroxylation; Molecular Docking Simulation; Molecular Structure; Mutation; Piperidines; Protein Conformation; Substrate Specificity

Ebastine (EBS) has been assayed in its laboratory-prepared co-formulated tablets with either pseudoephedrine hydrochloride (PSU) or phenylephrine hydrochloride (PHR) using isocratic reversed-phase chromatography. Separation was conducted using a 50 mm × 4.6 mm i.d., Chromolith® SpeedROD RP-18 end-capped column at ambient temperature. A mobile phase composed of water:acetonitrile in a ratio of 25:75 having a pH of 3.2, has been utilized at 1 mL/min with UV detection at 254 nm for both EBS and PSU and 274 nm for PHR which in turn increased the sensitivity of the proposed method significantly. Symmetric well-separated peaks resulted in a short chromatographic run; <5 min. The proposed method was subjected to detailed validation procedures and proved to be highly sensitive as shown from limit of quantification values which were 4.7, 39.4 and 10.2 μg/mL for EBS, PSU and PHR, respectively. The proposed method was used to analyze EBS in its laboratory-prepared co-formulated tablets; the obtained results were comparable to those resulting from the reference method.

Topics: Butyrophenones; Chromatography, Reverse-Phase; Limit of Detection; Linear Models; Piperidines; Reproducibility of Results; Sympathomimetics

Common marmosets (Callithrix jacchus) are attracting attention as animal models in preclinical studies for drug development. However, cytochrome P450s (P450s), major drug-metabolizing enzymes, have not been fully identified and characterized in marmosets. In this study, based on the four novel P450 4F genes found on the marmoset genome, we successfully isolated P450 4F2, 4F3B, 4F11, and 4F12 cDNAs in marmoset livers. Deduced amino acid sequences of the four marmoset P450 4F forms exhibited high sequence identities (87%-93%) to the human and cynomolgus monkey P450 4F homologs. Marmoset P450 4F3B and 4F11 mRNAs were predominantly expressed in livers, whereas marmoset P450 4F2 and 4F12 mRNAs were highly expressed in small intestines and livers. Four marmoset P450 4F proteins heterologously expressed in Escherichia coli catalyzed the ω-hydroxylation of leukotriene B4 In addition, marmoset P450 4F12 effectively catalyzed the hydroxylation of antiallergy drug ebastine, a human P450 2J/4F probe substrate. Ebastine hydroxylation activities by small intestine and liver microsomes from marmosets and cynomolgus monkeys showed greatly higher values than those of humans. Ebastine hydroxylation activities by marmoset and cynomolgus monkey small intestine microsomes were inhibited (approximately 60%) by anti-P450 4F antibodies, unlike human small intestine microsomes, suggesting that contribution of P450 4F enzymes for ebastine hydroxylation in the small intestine might be different between marmosets/cynomolgus monkeys and humans. These results indicated that marmoset P450 4F2, 4F3B, 4F11, and 4F12 were expressed in livers and/or small intestines and were functional in the metabolism of endogenous and exogenous compounds, similar to those of cynomolgus monkeys and humans.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amino Acid Sequence; Animals; Butyrophenones; Callithrix; Cytochrome P-450 Enzyme System; Female; Histamine Antagonists; Humans; Hydroxylation; Intestine, Small; Liver; Macaca fascicularis; Male; Microsomes, Liver; Middle Aged; Piperidines; Sequence Alignment; Species Specificity; Substrate Specificity; Young Adult

Forced degradation of Ebastine (1-(4-(1,1-dimethylethyl)phenyl)-4-(4-(diphenylmethoxy) piperidin-1-yl)butan-1-one) drug substance in ultraviolet light condition resulted into an unknown significant degradation product. This degradation product was analyzed using a newly developed reverse-phase HPLC, where it was eluted at 2.73 relative retention time to Ebastine peak. UV degradation product was isolated from reaction mass using preparative HPLC and its structure was elucidated using high resolution MS, multidimensional NMR and FTIR spectroscopic techniques. UV degradation product has been characterized as 2-(4-(benzhydryloxy)piperidin-1-yl)-1-(4-(tert-butyl)phenyl)-2-methylcyclopropanol. (1)H and (13)C NMR chemical shift values were generated using computational chemistry for possible two diastereomers (7R10S and 7R10R) and later 7R10R was confirmed (and its enantiomer) as final structure given it showed close agreement with experimental NMR data. Formation of UV degradation product as a recemic mixture was further verified by computational chemistry evaluation, chiral HPLC and polarimetery. To best of our knowledge, this is a novel degradation product which is not discussed at any form of publication yet.

Topics: Butyrophenones; Chromatography, High Pressure Liquid; Mass Spectrometry; Piperidines; Spectroscopy, Fourier Transform Infrared; Ultraviolet Rays

A new method orthogonal projection to latent structures (O-PLS) combined with artificial neural networks is investigated for non-destructive determination of ebastine powder via near-infrared (NIR) spectroscopy. The modern NIR spectroscopy is efficient, simple and non-destructive technique, which has been used in chemical analysis in diverse fields. Being a preprocessing method, O-PLS provides a way to remove systematic variation from an input data set X not correlated to the response set Y, and does not disturb the correlation between X and Y. In this paper, O-PLS pretreated spectral data was applied to establish the ANN model of ebastine powder, in this model, the concentration of ebastine as the active component was determined. The degree of approximation was employed as the selective criterion of the optimum network parameters. In order to compare the OPLS-ANN model, the calibration models that use first-derivative and second-derivative preprocessing spectra were also designed. Experimental results showed that the OPLS-ANN model was the best.

Topics: Butyrophenones; Neural Networks, Computer; Piperidines; Powders; Spectrophotometry, Infrared

The radiation recall reaction (RRR) is an inflammatory reaction that occurs in previously irradiated areas. The phenomenon is probably due to an idiosyncratic hypersensitivity reaction, in which a second agent can recall the inflammatory reaction.. This case report documents a cold-weather-induced radiation recall dermatitis (RRD). We observed a severe RRD in a patient after chemoradiotherapy treatment with cisplatin for a nasopharyngeal carcinoma, precipitated by cold temperatures, which developed 9 days after completion of therapy. In the medical literature, RRD following extreme cold temperatures seems to be a peculiar event.. Until further information on the interaction is available, future studies on combined chemotherapy with cisplatin should be carefully monitored and any side effects clearly documented. This case suggests that environmental conditions may play a contributing role in the development of RRD. This case also implies that neither fraction size nor total radiation dose is a determining factor in the development of the dermatologic reaction.

Topics: Aged; Antineoplastic Agents; Butyrophenones; Carcinoma, Squamous Cell; Chemoradiotherapy; Cisplatin; Cold Temperature; Drug Therapy, Combination; Female; Humans; Methylprednisolone; Nasopharyngeal Neoplasms; Neoplasm Staging; Piperidines; Radiodermatitis

Topics: Adolescent; Adult; Antioxidants; Butyrophenones; Cysts; Drug Therapy, Combination; Female; Histamine H1 Antagonists; Humans; Male; Maxillary Sinus; Maxillary Sinusitis; Middle Aged; Picolines; Piperidines; Rhinitis, Allergic; Treatment Outcome; Young Adult

A stability-indicating ultra high performance liquid chromatographic (UHPLC) method has been developed for purity testing of ebastine and its pharmaceutical formulations. Successful chromatographic separation of the API from impurities was achieved on a Waters Acquity UPLC BEH C18, 50 mm × 2.1 mm, 1.7 μm particle size column with gradient elution of 10 mM acetate buffer pH 6.2 and a mixture of acetonitrile/2-propanol (1:1) as the mobile phase. Incorporating Quality by Design (QbD) principles to the method development approach by using the chromatography modeling software DryLab4 allows the visualization of a "Design Space", a region in which changes to method parameters will not significantly affect the results as defined in the ICH guideline Q8 (R2). A verification study demonstrated that the established model for Design Space is accurate with a relative error of prediction of only 0.6%. The method was fully validated for specificity, linearity, accuracy and precision, and robustness in compliance to the ICH guideline Q2 (R1). The method was found to be linear in the concentration range from the quantification limit (LOQ) to 125% of the specification limit for ebastine and each of the impurities with correlation coefficients of not less than 0.999. The recovery rate was between 98.15 and 100.30% for each impurity. The repeatability and intermediate precision (RSD) were less than 3.2% for ebastine and each of the impurities. The robustness of the developed method was studied by varying the six parameters: gradient time, temperature, ternary composition of the eluent, flow rate and start and end concentration of the gradient at 3 levels (+1, 0, -1). The resulting 729 experiments were performed in silico from the previously constructed model for Design Space and showed that the required resolution of 2.0 can be reached in all experiments. To prove the stability-indicating performance of the method, forced degradation (acid and base hydrolysis, oxidation, photolytic and thermal stress conditions) of ebastine was carried out. Baseline separation could be achieved for all peaks of the impurities, the degradation products and the API. Total run time was only 4 min, which is an impressive 40-fold increase in productivity in comparison to the method published in the Ph. Eur. monograph and allowed purity testing of more than 360 samples per day.

Topics: Butyrophenones; Chromatography, High Pressure Liquid; Histamine H1 Antagonists; Limit of Detection; Pharmaceutical Preparations; Piperidines; Reproducibility of Results

CYP2J2 epoxygenase is a membrane bound cytochrome P450 that converts omega-3 and omega-6 fatty acids into physiologically active epoxides. In this work, we present a comprehensive comparison of the effects of N-terminal modifications on the properties of CYP2J2 with respect to the activity of the protein in model lipid bilayers using Nanodiscs. We demonstrate that the complete truncation of the N-terminus changes the association of this protein with the E.coli membrane but does not disrupt incorporation in the lipid bilayers of Nanodiscs. Notably, the introduction of silent mutations at the N-terminus was used to express full length CYP2J2 in E. coli while maintaining wild-type functionality. We further show that lipid bilayers are essential for the productive use of NADPH for ebastine hydroxylation by CYP2J2. Taken together, it was determined that the presence of the N-terminus is not as critical as the presence of a membrane environment for efficient electron transfer from cytochrome P450 reductase to CYP2J2 for ebastine hydroxylation in Nanodiscs. This suggests that adopting the native-like conformation of CYP2J2 and cytochrome P450 reductase in lipid bilayers is essential for effective use of reducing equivalents from NADPH for ebastine hydroxylation.

Topics: Amino Acid Sequence; Butyrophenones; Cytochrome P-450 CYP2J2; Cytochrome P-450 Enzyme System; Escherichia coli; Humans; Hydroxylation; Lipid Bilayers; Models, Molecular; Molecular Sequence Data; Mutation; NADP; Nanostructures; Oxidation-Reduction; Piperidines; Protein Binding; Sequence Alignment

The histamine-1 receptor (H1R) antagonist ketotifen increased the threshold of discomfort in hypersensitive IBS patients. The use of peripherally restricted and more selective H1R antagonists may further improve treatment possibilities. We examined the use of fexofenadine and ebastine to reverse post-stress visceral hypersensitivity in maternally separated rats.. The visceromotor response to colonic distension was assessed in adult maternally separated and nonhandled rats pre- and 24 hours post water avoidance. Subsequently rats were treated with vehicle alone or different dosages of fexofenadine (1.8 and 18 mg/kg) or ebastine (0.1 and 1.0 mg/kg) and re-evaluated. Colonic tissue was collected to assess relative RMCP-2 and occludin expression levels by Western blot and histamine-1 receptor by RT-qPCR. β-hexosaminidase release by RBL-2H3 cells was used to establish possible mast cell stabilizing properties of the antagonists.. Water avoidance only induced enhanced response to distension in maternally separated rats. This response was reversed by 1.8 and 18 mg/kg fexofenadine. Reversal was also obtained by 1.0 but not 0.1 mg/kg ebastine. RMCP-2 expression levels were comparable in these two ebastine treatment groups but occludin was significantly higher in 1.0 mg/kg treated rats. There were no differences in histamine-1 receptor expression between nonhandled and maternally separated rats. Fexofenadine but not ebastine showed mast cell stabilizing quality.. Our results indicate that the peripherally restricted 2(nd) generation H1-receptor antagonists fexofenadine and ebastine are capable of reversing post stress visceral hypersensitivity in rat. These data justify future IBS patient trials with these well tolerated compounds.

Topics: Animals; Blotting, Western; Butyrophenones; Dose-Response Relationship, Drug; Histamine H1 Antagonists; Irritable Bowel Syndrome; Mast Cells; Maternal Deprivation; Occludin; Piperidines; Rats; Reverse Transcriptase Polymerase Chain Reaction; Stress, Psychological; Terfenadine

Maxillary sinus hypoplasia (MSH) is a radiologically detectable abnormality of the maxillary sinus that can be associated with sinusitis. Symptomatic MSH patients with a patent ostiomeatal complex (MSHPO) constitute a particular therapeutic challenge.. Ostiomeatal unit CT scans of 1293 patients with various sinonasal symptoms such as purulent discharge, postnasal drip, facial pain or headache were reviewed to determine the incidence, clinical symptoms and outcomes of MSHPO following medical treatment.. Seventy-five cases (5.8%) were found to have MSHPO. Excluding patients with nasal septal deviation and positive allergy test, 37 of those 75 patients (2.86% of the original cohort) had MSHPO as the only definable sinonasal abnormality. Radiographs showed all patients had antral mucosal thickening. Postnasal drip (43.2%) was the most common symptom, followed by nasal obstruction (40.5%), purulent rhinorrhea (32.4%), hyposmia or anosmia (32.4%), cough (21.6%) and headache (18.9%). Medical treatment consisted of clarithromycin and ebastine for all patients. Medical treatment resulted in complete symptom resolution in only 24.3% of patients.. Primary MSHPO was present in approximately 3% of patients with sinonasal symptoms. The response rate to medical treatment was poor. MSHPO should be considered a differential diagnosis in patients presenting with non-specific sinonasal complaints.

Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Butyrophenones; Clarithromycin; Cohort Studies; Drug Therapy, Combination; Female; Histamine H1 Antagonists; Humans; Male; Maxillary Sinus; Maxillary Sinusitis; Middle Aged; Nasal Mucosa; Piperidines; Tomography, X-Ray Computed; Young Adult

These findings suggest that the down-regulation of interleukin (IL)-5 gene expression in collaboration with the suppression of histamine H(1) receptor (H1R) gene expression in the nasal mucosa provides the basis for better therapeutic effects of preseasonal prophylactic treatment with antihistamines in patients with seasonal allergic rhinitis caused by Japanese cedar pollen.. The effects of prophylactic administration of antihistamines on the expression of IL-5 and IL-33 mRNA in the nasal mucosa of the patients with pollinosis were investigated.. Eight patients had already visited the hospital before the peak pollen period and started preseasonal prophylactic treatment with antihistamines. Seventeen patients who first visited the hospital during the peak pollen period were designated as the no treatment group. After local anesthesia, nasal mucosa was obtained by scraping the inferior concha with a small spatula during the peak pollen period.. During the peak pollen period, the expression of IL-5 mRNA, but not that of IL-33 mRNA, in the nasal mucosa of patients receiving preseasonal prophylactic treatment with antihistamines was significantly lower in comparison with that of patients without treatment. Moreover, there was a significant correlation between the expression of IL-5 mRNA and the nasal symptoms or the expression of H1R mRNA.

Topics: Butyrophenones; Cryptomeria; Female; Histamine Antagonists; Humans; Interleukin-33; Interleukin-5; Interleukins; Male; Middle Aged; Nasal Mucosa; Piperidines; Pollen; Rhinitis, Allergic, Seasonal; Terfenadine

Early success of kinase inhibitors has validated their use as drugs. However, discovery efforts have also suffered from high attrition rates due to lack of cellular activity. We reasoned that screening for such candidates in live cells would identify novel cell-permeable modulators for development. For this purpose, we have used our recently optimized epidermal growth factor receptor (EGFR) biosensor assay to screen for modulators of EGFR activity. Here, we report on its validation under high-throughput screening (HTS) conditions displaying a signal-to-noise ratio of 21 and a Z' value of 0.56-attributes of a robust cell-based assay. We performed a pilot screen against a library of 6912 compounds demonstrating good reproducibility and identifying 82 inhibitors and 66 activators with initial hit rates of 1.2% and 0.95%, respectively. Follow-up dose-response studies revealed that 12 of the 13 known EGFR inhibitors in the library were confirmed as hits. ZM-306416, a vascular endothelial growth factor receptor (VEGFR) antagonist, was identified as a potent inhibitor of EGFR function. Flurandrenolide, beclomethasone, and ebastine were confirmed as activators of EGFR function. Taken together, our results validate this novel approach and demonstrate its utility in the discovery of novel kinase modulators with potential use in the clinic.

Topics: Anti-Inflammatory Agents; Beclomethasone; Biosensing Techniques; Butyrophenones; Cell Line; Dose-Response Relationship, Drug; Drug Discovery; ErbB Receptors; Flurandrenolone; High-Throughput Screening Assays; Histamine H1 Antagonists; Humans; Permeability; Piperidines; Quinazolines; Receptors, Vascular Endothelial Growth Factor; Reproducibility of Results; Signal-To-Noise Ratio

Nicotine has been definitively shown to be critically involved in the neural bases of tobacco addiction. However, nicotine releases a wide variety of neurotransmitters. Nicotine-induced dopamine release has been shown to play a key role in facilitating nicotine self-administration. Other transmitter systems may also play important roles in the pharmacological effects of nicotine and may provide important leads for combating nicotine self-administration. Clozapine, an antipsychotic drug, which blocks a variety of different transmitter receptors including serotonin 5HT(2) and histamine H(1) receptors, has been found to decrease smoking. Previously we found that the serotonin 5HT(2) antagonist, ketanserin, significantly reduced nicotine self-administration. In the current study, we assessed histamine H(1) receptor interaction with nicotine self-administration. Young adult female Sprague-Dawley rats were fitted with IV catheters and trained to self-administer nicotine (0.03mg/kg/infusion). Acute doses of 40mg/kg of pyrilamine, a histamine H(1) antagonist, significantly reduced nicotine self-administration. We also found that repeated injections (20mg/kg) or chronic infusion via osmotic minipumps (50mg/kg/day) of pyrilamine also significantly decreased nicotine self-administration. The peripherally restricted H(1) antagonist ebastine was ineffective in reducing nicotine self-administration, pointing to central H(1) receptor blockade as key for the effectiveness of pyrilamine. H(1) antagonists may be a promising avenue to explore for new treatments to aid smoking cessation.

Topics: Animals; Butyrophenones; Drug Administration Schedule; Female; Follow-Up Studies; Food; Histamine; Histamine H1 Antagonists; Infusion Pumps; Injections; Motivation; Nicotine; Piperidines; Pyrilamine; Rats; Rats, Sprague-Dawley; Self Administration; Tobacco Use Disorder

P-glycoprotein (Pgp or ABCB1) is an ABC transporter protein involved in intestinal absorption, drug metabolism, and brain penetration, and its inhibition can seriously alter a drug's bioavailability and safety. In addition, inhibitors of Pgp can be used to overcome multidrug resistance. Given this dual purpose, reliable in silico procedures to predict Pgp inhibition are of great interest. A large and accurate literature collection yielded more than 1200 structures; a model was then constructed using various molecular interaction field-based technologies, considering pharmacophoric features and those physicochemical properties related to membrane partitioning. High accuracy was demonstrated internally with two different validation sets and, moreover, using a number of molecules, for which Pgp inhibition was not experimentally available but was evaluated in-house. All of the validations confirmed the robustness of the model and its suitability to help medicinal chemists in drug discovery. The information derived from the model was rationalized as a pharmacophore for competitive Pgp inhibition.

Topics: Animals; Aripiprazole; ATP Binding Cassette Transporter, Subfamily B, Member 1; Butyrophenones; Cell Line, Tumor; Cell Membrane Permeability; Drug Design; Humans; Hydrophobic and Hydrophilic Interactions; Ligands; Mice; Models, Molecular; Molecular Structure; Piperazines; Piperidines; Protein Binding; Quantitative Structure-Activity Relationship; Quinolones

H1-antihistamines are probably the most frequently used drugs in allergic diseases, with widely established efficacy, tolerance, and safety. We report a patient with urticaria due to ingestion of ebastine and fexofenadine. Skin prick tests, patch tests, and basophil activation tests with the implicated drugs and antihistamines from other families were negative. The oral challenges with the implicated antihistamines and other antihistamines tested were positive, but the patient tolerated an oral challenge with cetirizine. We present a patient with urticaria induced by different antihistamines in whom the diagnosis was established by oral challenge. The mechanism of sensitization remains unclear.

Topics: Administration, Oral; Butyrophenones; Diagnosis, Differential; Drug Hypersensitivity; Female; Histamine H1 Antagonists; Histamine H1 Antagonists, Non-Sedating; Humans; Middle Aged; Piperidines; Terfenadine; Urticaria

It is well established that cytochrome P450 2J (CYP2J) enzymes are expressed preferentially in the heart, and that ebastine is a substrate for CYP2J, but it is not known whether ebastine is metabolized in myocardium. Therefore, we investigated its pharmacokinetics in the rat isolated perfused heart.. Rat isolated hearts were perfused in the recirculating mode with ebastine for 130 min. The concentrations of ebastine and its metabolites, hydroxyebastine and carebastine, were measured using liquid chromatography with a tandem mass spectrometry. The data were analysed by a compartmental model. The time course of negative inotropic response was linked to ebastine concentration to determine the concentration-effect relationship.. Ebastine was metabolized to an intermediate compound, hydroxyebastine, which was subsequently further metabolized to carebastine. No desalkylebastine was found. The kinetics of the sequential metabolism of ebastine was well described by the compartmental model. The EC(50) of the negative inotropic effect of ebastine in rat isolated heart was much higher than free plasma concentrations in humans after clinical doses.. The kinetics of ebastine conversion to carebastine via hydroxyebastine resembled that observed in human liver microsomes. The results may be of interest for functional characterization of CYP2J activity in rat heart.

Topics: Animals; Butyrophenones; Cytochrome P-450 Enzyme System; Heart; Histamine H1 Antagonists; In Vitro Techniques; Male; Models, Chemical; Myocardium; Piperidines; Rats; Rats, Wistar

Topics: Adult; Alopecia Areata; Animals; Butyrophenones; Disease Models, Animal; Female; Histamine Antagonists; Humans; Immunotherapy; Mice; Mice, Inbred C3H; Piperidines; Remission Induction; Treatment Outcome

The clinical efficacy of antihistaminic preparation "Kestine" (Ebastine) in combined treatment of 50 patients suffering from photo-allergic dermatosis (15 - solar urticaria, 20 - solar erythema and 15 - solar eczema) are evaluated. Kestine in dosage of 10 mg a day was prescribed in duration of 10 days. Itch disappearance was observed in 87% of patients, reduction of itching - in 10% and in 3% of patients an itch was remain. Photo protector Avene-50 as sunburn preparation, assigned for different type of skins, has been used. This preparation fit for different demands (including prevention of both beginnings and exacerbation of photo allergic reactions) of patients. Water- and sweat-resistance of Avene-50 formula has been taken in account. Treatment caused increasing of some indices of non specific reactions (Kavetski skin test) that confirms recovery of conjunctive tissue elements' activity. Efficacy and safety of this combined method of photodermatosis treatment allow us to use it widely in dermatologic clinic.

Topics: Adolescent; Adult; Aged; Butyrophenones; Female; Histamine H1 Antagonists; Humans; Male; Middle Aged; Mineral Waters; Photosensitivity Disorders; Piperidines; Sunscreening Agents; Young Adult

Sedation is the most frequent side effect of H(1)-antihistamines, and, sometimes, it may be life-threatening for patients. Evaluation of the sedative properties of H(1)-antihistamines is important to improve the patients' quality of life (QOL). Therefore, we carried out a large-scale surveillance quantified through a questionnaire using visual analog scale (VAS) from 1,742 patients. The results showed that the degree of sleepiness caused by some nonsedative second-generation antihistamines, including fexofenadine, olopatadine and cetirizine, was disease dependent. In atopic dermatitis, an unexpectedly low VAS score of sleepiness was obtained for the first-generation antihistamine d-chlorpheniramine, which is similar to those obtained for bepotastine and epinastine. d-Chlorpheniramine also showed a high VAS score in efficacy. Meanwhile, fexofenadine showed a higher VAS score of sleepiness in atopic dermatitis than those obtained in the other allergic diseases including allergic rhinitis, urticaria and asthma. In asthma, a higher VAS score of sleepiness was found for olopatadine, ebastine and cetirizine, when compared with d-chlorpheniramine. On the other hand, bepotastine showed the lowest VAS score for sleepiness. Our findings suggest the existence of unknown factors influencing the sedative properties of H(1)-antihistamines. Therefore, appropriate H(1)-antihistamines may need to be selected, depending on allergic diseases, to improve patients' QOL.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Asthma; Butyrophenones; Cetirizine; Child; Chlorpheniramine; Dermatitis, Atopic; Dibenzazepines; Dibenzoxepins; Female; Histamine H1 Antagonists; Histamine H1 Antagonists, Non-Sedating; Humans; Imidazoles; Japan; Male; Middle Aged; Olopatadine Hydrochloride; Pain Measurement; Piperidines; Population Surveillance; Psychomotor Performance; Pyridines; Quality of Life; Rhinitis, Allergic, Perennial; Rhinitis, Allergic, Seasonal; Sleep Stages; Surveys and Questionnaires; Terfenadine; Urticaria

Allergies to iron salts are seldom reported. We studied a patient with iron-deficiency anemia who had suffered anaphylactic reactions caused by oral iron salts. An allergy study was performed using single-blind, placebo-controlled oral challenge and skin tests with various iron salts as well as excipients in commercial formulations. Oral challenges were positive for 2 of the commercial formulations of iron salts. Intradermal tests with ferrous sulphate and ferrous lactate also showed positive results. All of the cutaneous tests using the excipients were negative. A desensitization protocol was designed which enabled us to readminister ferrous sulphate, although antihistamines were necessary to guarantee good tolerance to iron salts. We report a patient with allergy to iron salts, positive skin tests, and positive controlled challenge. We highlight the desensitization protocol designed to complete the therapeutic management of the anemia.

Topics: Aged; Anaphylaxis; Butyrophenones; Chlorpheniramine; Desensitization, Immunologic; Drug Hypersensitivity; Female; Ferrous Compounds; Histamine H1 Antagonists; Humans; Lactates; Piperidines

Cytochrome P450 (P450) 2J2 catalyzes epoxidation of arachidonic acid to eicosatrienoic acids, which are related to a variety of diseases such as coronary artery disease, hypertension, and carcinogenesis. Recent experimental data also suggest that P450 2J2 could be a novel biomarker and a potential target for cancer therapy. However, the active site topology and substrate specificity of this enzyme remain unclear. In this study, a three-dimensional model of human P450 2J2 was first constructed on the basis of the crystal structure of human P450 2C9 in complex with a substrate using homology modeling method, and refined by molecular dynamics simulation. Flexible docking approaches were then employed to dock four ligands into the active site of P450 2J2 in order to probe the ligand-binding modes. By analyzing the results, active site architecture and certain key residues responsible for substrate specificity were identified on the enzyme, which might be very helpful for understanding the enzyme's biological role and providing insights for designing novel inhibitors of P450 2J2.

Topics: Amino Acid Sequence; Binding Sites; Butyrophenones; Computer Simulation; Cytochrome P-450 CYP2J2; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Drug Design; Humans; Ligands; Models, Molecular; Molecular Sequence Data; Oxygenases; Piperidines; Protein Interaction Domains and Motifs; Sequence Alignment; Structural Homology, Protein; Substrate Specificity; Terfenadine

Topics: Adrenal Cortex Hormones; Adult; Butyrophenones; Diagnosis, Differential; Female; Foot Dermatoses; Hand Dermatoses; Histamine H1 Antagonists; Humans; Piperidines; Pityriasis Rosea

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

CYP4F enzymes, including CYP4F2 and CYP4F3B, were recently shown to be the major enzymes catalyzing the initial oxidative O-demethylation of the antiparasitic prodrug pafuramidine (DB289) by human liver microsomes. As suggested by a low oral bioavailability, DB289 could undergo first-pass biotransformation in the intestine, as well as in the liver. Using human intestinal microsomes (HIM), we characterized the enteric enzymes that catalyze the initial O-demethylation of DB289 to the intermediate metabolite, M1. M1 formation in HIM was catalyzed by cytochrome P450 (P450) enzymes, as evidenced by potent inhibition by 1-aminobenzotriazole and the requirement for NADPH. Apparent K(m) and V(max) values ranged from 0.6 to 2.4 microM and from 0.02 to 0.89 nmol/min/mg protein, respectively (n = 9). Of the P450 chemical inhibitors evaluated, ketoconazole was the most potent, inhibiting M1 formation by 66%. Two inhibitors of P450-mediated arachidonic acid metabolism, HET0016 (N-hydroxy-N'-(4-n-butyl-2-methylphenyl)formamidine) and 17-octadecynoic acid, inhibited M1 formation in a concentration-dependent manner (up to 95%). Immunoinhibition with an antibody raised against CYP4F2 showed concentration-dependent inhibition of M1 formation (up to 92%), whereas antibodies against CYP3A4/5 and CYP2J2 had negligible to modest effects. M1 formation rates correlated strongly with arachidonic acid omega-hydroxylation rates (r(2) = 0.94, P < 0.0001, n = 12) in a panel of HIM that lacked detectable CYP4A11 protein expression. Quantitative Western blot analysis revealed appreciable CYP4F expression in these HIM, with a mean (range) of 7 (3-18) pmol/mg protein. We conclude that enteric CYP4F enzymes could play a role in the first-pass biotransformation of DB289 and other xenobiotics.

Topics: Amidines; Antibodies; Antiparasitic Agents; Arachidonic Acid; Benzamidines; Benzoflavones; Butyrophenones; Chromatography, High Pressure Liquid; Cytochrome P-450 CYP2J2; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP4A; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Cytochrome P450 Family 4; Enzyme Inhibitors; Fatty Acids, Unsaturated; Humans; Hydroxyeicosatetraenoic Acids; Intestinal Mucosa; Intestines; Kinetics; Methylation; Microsomes; Oxygenases; Piperidines; Prodrugs; Recombinant Proteins; Stereoisomerism

Topics: Adult; Butyrophenones; Female; Histamine H1 Antagonists; Humans; Male; Piperidines; Rhinitis, Allergic, Perennial

Topics: Butyrophenones; Chemical and Drug Induced Liver Injury; Female; Histamine H1 Antagonists; Humans; Middle Aged; Piperidines

Topics: Butyrophenones; Histamine; Histamine H1 Antagonists; Humans; Loratadine; Piperidines; Randomized Controlled Trials as Topic; Skin Tests

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 long QT syndrome is a rare disease. The prevalence is estimated at 1/5 000 to 1/20,000. Numerous drugs are contra-indicated because they can lengthen the QT interval. A case of pollen allergy in an adolescent with LQTS is described. The possibility to prescribe anti-H1 drugs is reviewed since cases of torsades de pointe and even deaths have been reported for terfenadine and astemizole. Diphenhydramine, orphenadrine and hydroxyzine are contra-indicated. No accidents and no effects on the QT interval have been published for ebastine, fexofenadine, desloratadine and levocetirizine. These anti-H1 drugs could be used with great care, without any association with drugs resulting in low serum potassium level. Azelastine eye drops have been authorized and a routine protection by inhaled corticosteroids during the pollinic period has been advised in this adolescent treated by betablockers.

Topics: Adolescent; Adrenergic beta-Antagonists; Anti-Asthmatic Agents; Butyrophenones; Cetirizine; Conjunctivitis, Allergic; Cromolyn Sodium; Diabetes Mellitus, Type 1; Heart; Histamine H1 Antagonists; Humans; Long QT Syndrome; Male; Piperazines; Piperidines; Rhinitis, Allergic, Seasonal; Terfenadine

Topics: Arrhythmias, Cardiac; Butyrophenones; Histamine H1 Antagonists; Humans; Piperidines; Rhinitis; Treatment Outcome; Urticaria

Topics: Animals; Arrhythmias, Cardiac; Automobile Driving; Butyrophenones; Electrocardiography; Histamine H1 Antagonists; Humans; Models, Animal; Piperidines; Potassium Channels; Time Factors

CYP2J2 plays important roles in the metabolism of therapeutic drugs, such as astemizole and ebastine, as well as endogenous fatty acids. This study aimed to identify CYP2J2 genetic variants in Koreans and to characterize their functional consequences. From direct sequencing of the CYP2J2 gene, 12 genetic variations, including the two novel nonsynonymous mutations G312R and P351L, were identified from 93 Korean subjects. The two novel CYP2J2 variants were co-expressed with NADPH-cytochrome P450 reductase in Sf9 cells and their catalytic activities were quantified. The recombinant CYP2J2 G312R variant showed almost complete loss of enzymatic activity, as determined by CYP2J2-catalysed astemizole O-demethylation and ebastine hydroxylation. The CYP2J2 P351L variant showed enzymatic activities that were comparable with the wild-type CYP2J2. The reduced CO spectra of the recombinant CYP2J2 proteins suggested no CO binding to the heme in CYP2J2 G312R. In addition, molecular modelling of the three-dimensional structure consistently predicted that there might be spatial hindrance between heme and the bulky side chain of the R312 residue in CYP2J2 G312R variant. The CYP2J2 G312R variant was not found in 192 Chinese, 99 African-Americans, 100 Caucasians and 159 Vietnamese subjects. Two of the 192 Chinese subjects (0.52%) were heterozygous for CYP2J2 P351L. Twelve CYP2J2 variants, including two novel nonsynonymous variants, were identified in a Korean population. The G312R variant is the first nonfunctional CYP2J2 allele to be identified, and is expected to influence the disposition of its substrate therapeutics, as well as endogenous compounds.

Topics: Alleles; Animals; Astemizole; Butyrophenones; Catalysis; Cell Line; Cytochrome P-450 CYP2J2; Cytochrome P-450 Enzyme System; DNA Primers; Dose-Response Relationship, Drug; Gene Frequency; Genetic Variation; Heterozygote; Histamine H1 Antagonists; Humans; Insecta; Kinetics; Korea; Methylation; Models, Molecular; Mutation; Oxygenases; Piperidines; Polymerase Chain Reaction; Polymorphism, Genetic; Polymorphism, Restriction Fragment Length; Recombinant Proteins; Recombination, Genetic; Sequence Analysis, DNA; Time Factors

Topics: Bendroflumethiazide; Butyrophenones; Cisapride; Diuretics; Electrocardiography; Female; Furosemide; Gastrointestinal Agents; Heart Arrest; Histamine H1 Antagonists; Humans; Middle Aged; Piperidines; Potassium Chloride; Sodium Chloride Symporter Inhibitors; Torsades de Pointes

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

We developed a method for determining ebastine, a new generation of antihistamines, and its three metabolites (hydroxyebastine, carebastine and desalkylebastine) in plasma simultaneously using LC/MS/MS. Four compounds and terfenadine, an internal standard, were extracted from plasma using a mixture of diethylether and dichloromethane in the presence of 1 M HCl. After drying the organic layer, the residue was reconstituted in mobile phase (acetonitrile:5 mM ammonium acetate, 50:50, v/v) and injected onto a reversed-phase C(18) column. The isocratic mobile phase was eluted at 0.2 ml/min. The ion transitions monitored in multiple reaction-monitoring mode were m/z 470.7-->167.1, 486.7-->167.1, 500.6-->167.1, 268.4-->167.1 and 472.7-->436.0 for ebastine, hydroxyebastine, carebastine, desalkylebastine and terfenadine, respectively. The coefficient of variation of the assay precision was less than 12.5%, and the accuracy exceeded 88%. The limit of detection was 0.5 ng/ml for desalkylebastine; 0.2 ng/ml for ebastine, hydroxyebastine and carebastine, respectively. This method was used to measure the plasma concentration of ebastine and its three metabolites from healthy subjects after a single 20 mg oral dose of ebastine. This analytic method is a very simple, sensitive, and accurate to determine the pharmacokinetic profiles of ebastine including its metabolites.

Topics: Butyrophenones; Chromatography, Liquid; Histamine H1 Antagonists; Humans; Mass Spectrometry; Piperidines; Sensitivity and Specificity

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.. 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.. 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.. 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.. 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.

Topics: Animals; Antitussive Agents; Butyrophenones; Cetirizine; Codeine; Dopamine; Dose-Response Relationship, Drug; Histamine H1 Antagonists; Limbic System; Male; Mice; Mice, Inbred ICR; Piperidines; Receptors, Dopamine D1; Reward

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.

Topics: Aerosols; Airway Resistance; Algorithms; Animals; Anti-Allergic Agents; Bronchial Spasm; Butyrophenones; Cetirizine; Guinea Pigs; Histamine; Histamine H1 Antagonists; Leukotriene C4; Loratadine; Male; Ovalbumin; Piperidines

Topics: Anti-Allergic Agents; Butyrophenones; Cetirizine; Double-Blind Method; Histamine H1 Antagonists; Histamine H1 Antagonists, Non-Sedating; Humans; Loratadine; Multicenter Studies as Topic; Piperidines; Randomized Controlled Trials as Topic; Rhinitis, Allergic, Perennial; Rhinitis, Allergic, Seasonal; Time Factors

Topics: Anti-Allergic Agents; Benzimidazoles; Butyrophenones; Cetirizine; Double-Blind Method; Histamine H1 Antagonists; Histamine H1 Antagonists, Non-Sedating; Humans; Loratadine; Meta-Analysis as Topic; Piperidines; Placebos; Randomized Controlled Trials as Topic; Rhinitis, Allergic, Perennial; Rhinitis, Allergic, Seasonal

Cytokine imbalance and cellular migration to inflammatory sites are critical components of allergic diseases. Redirecting cytokine imbalance and inhibiting cell migration therefore represent important therapeutic strategies for the treatment of these disorders.. To study the in vitro effect of ebastine, a novel non-sedating H1 receptor antagonist, on cytokine secretion and migration of activated T cells, as well as production of pro-inflammatory cytokines by macrophages.. Peripheral T cells obtained from healthy volunteers were cultured in wells coated with the combination of anti-CD3 monoclonal antibody (mAb) and anti-CD26 mAb, anti-CD3 mAb and anti-CD28 mAb, or anti-CD3 mAb with PMA, in the presence or absence of ebastine. T cell proliferation and the production of cytokines were measured by [3H]thymidine incorporation assay and ELISA, respectively. In addition, transendothelial migration of T cells and production of pro-inflammatory cytokines by macrophages were examined.. Ebastine inhibited T cell proliferation and the production of IL-4, IL-5, IL-6, and TNF-alpha by T cells under each co-stimulatory condition tested, whereas it exhibited no effect on the production of IL-2 or IFN-gamma. In addition, T cell migration and the production of such pro-inflammatory cytokines as TNF-alpha and IL-6 by macrophages were inhibited by ebastine.. These results indicate that ebastine has a specific inhibitory effect on Th2-type cytokine production. Moreover, ebastine inhibited T cell migration and pro-inflammatory cytokine production by T cells and macrophages, suggesting that ebastine might be useful for the treatment of T cell-mediated allergic inflammatory disorders, including asthma, atopic dermatitis, and Th2-type autoimmune diseases.

Topics: Antigens, CD; Butyrophenones; Cell Division; Cell Movement; Cells, Cultured; Cytokines; Dose-Response Relationship, Immunologic; Endothelium; Histamine H1 Antagonists, Non-Sedating; Humans; Ketotifen; Lymphocyte Activation; Macrophages; Piperidines; T-Lymphocyte Subsets; Th1 Cells; Th2 Cells

We report on a patient who suffered an anaphylactoid reaction because of moxifloxacin.

Topics: Adult; Anaphylaxis; Anti-Infective Agents; Aza Compounds; Butyrophenones; Female; Fluoroquinolones; Humans; Moxifloxacin; Otitis; Piperidines; Quinolines

Topics: Butyrophenones; Electrocardiography; Histamine H1 Antagonists; Humans; Piperidines; Rhinitis, Allergic, Seasonal; Urticaria

Orally administered astemizole is well absorbed but undergoes an extensive first-pass metabolism to O-desmethylastemizole. Desmethylastemizole is formed in the human microsomal systems of the small intestine as well as the liver, which suggests the role of cytochromes P450 (P450s) in the first-pass metabolism of astemizole. Human P450s involved in the O-demethylation of astemizole have, however, not been identified, and the involvement of twelve known drug-metabolizing P450s were denied. During the course of the P450 identification study, higher activities of the astemizole O-demethylation in the rabbit small intestine than in the liver (about 3-fold) were found. These data suggest the possible involvement of CYP2J, since P450 included in this subfamily is dominantly expressed in the small intestine of rabbits. Therefore, CYP2J2 cDNA has been isolated from the human cDNA library and expressed in COS-1 cells. A clear activity of astemizole O-demethylation was detected in recombinant CYP2J2 with K(m) = 0.65 microM and V(max) = 1129 pmol/nmol P450/min. Expression of the immunoreactive protein with CYP2J2 antibody was detected in the small intestine and liver. Expression levels of the immunoreactive protein with the CYP2J2 antibody in the small intestine were well correlated with the activities of the astemizole O-demethylation (r = 0.901, n = 5, p < 0.05). The CYP2J2 substrates, arachidonic acid and ebastine, strongly inhibited the microsomal astemizole O-demethylation in the human small intestines and recombinant CYP2J2. These results indicate the involvement of CYP2J2 in the presystemic elimination of astemizole in the human small intestine.

Topics: Animals; Antibodies, Blocking; Arachidonic Acid; Astemizole; Blotting, Western; Butyrophenones; Chlorocebus aethiops; Chromatography, High Pressure Liquid; Cloning, Molecular; COS Cells; Cytochrome P-450 CYP2J2; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Dealkylation; DNA, Complementary; Enzyme Inhibitors; Gene Library; Histamine H1 Antagonists; Humans; In Vitro Techniques; Intestinal Mucosa; Mass Spectrometry; Microsomes, Liver; Oxygenases; Piperidines; Rabbits; Recombinant Proteins

Topics: Butyrophenones; Electrocardiography; Heart Rate; Histamine H1 Antagonists; Humans; Piperidines; 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

The purpose of the study was to elucidate human intestinal cytochrome P450 isoform(s) involved in the metabolism of an antihistamine, ebastine, having two major pathways of hydroxylation and N-dealkylation. The ebastine dealkylase in human intestinal microsomes was CYP3A4, based on the inhibition studies with antibodies against CYP1A, CYP2A, CYP2C, CYP2D, CYP2E, and CYP3A isoforms and their selective inhibitors. However, ebastine hydroxylase could not be identified. We then examined the inhibitory effects of anti-CYP4F antibody and 17-octadecynoic acid, an inhibitor of the CYP4 family, on ebastine hydroxylation in intestinal microsomes, since CYP4F was recently found to be the predominant ebastine hydroxylase in monkey intestine; and a novel CYP4F isoform (CYP4F12), also capable of hydroxylating ebastine, was found to exist in human intestine. However, the inhibitory effects were only partial (about 20%) and thus it was thought that, although human CYP4F was involved in ebastine hydroxylation, another predominant enzyme exists. Further screening showed that the hydroxylation was inhibited by arachidonic acid. CYP2J2 was selected as a candidate expressed in the intestine and closely related to arachidonic acid metabolism. The catalytic activity of recombinant CYP2J2 was much higher than that of CYP4F12. Anti-CYP2J antibody inhibited the hydroxylation to about 70% in human intestinal microsomes. These results demonstrate that CYP2J2 is the predominant ebastine hydroxylase in human intestinal microsomes. Thus, the present paper for the first time indicates that, in human intestinal microsomes, both CYP2J and CYP4F subfamilies not only metabolize endogenous substrates but also are involved in the drug metabolism.

Topics: Antibodies, Blocking; Arachidonic Acid; Aryl Hydrocarbon Hydroxylases; Butyrophenones; Cloning, Molecular; Cytochrome P-450 CYP2J2; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Dealkylation; Enzyme Inhibitors; Histamine H1 Antagonists; Humans; In Vitro Techniques; Intestinal Mucosa; Intestines; Kinetics; Leukotriene B4; Microsomes; Mixed Function Oxygenases; Oxygenases; Piperidines; Recombinant Proteins

To compare antihistaminic and antiallergic activity of antihistaminic drugs of the latest generation (ebastin, cetirisine, fexofenadine, loratadine) and antihistaminic drugs of the first generation (clemastin) in the same patients with pollenosis.. Skin prick-titration with 10-dilution histamine and specific allergen, provocative nasal titration with 2-dilution histamine and allergen before and after a single intake of H1-antagonists were made in 30 patients in stable clinical remission of pollenosis during maximal antihistamine activity of the above drugs.. Systemic administration of the known H1-antagonists suppresses histamine sensitivity of both skin and nasal mucosa in the same degree. Drugs with more potent antihistaminic activity (fexofenadin and cetirisin) inhibited allergen-induced reactions more effectively. The order of the tested drugs by suppression of allergen-provoked skin and nasal reactions (by lowering antiallergic activity) is the following: fexofenadin and cetirisin > ebastin and loratadin > clemastin.. The above drugs of the latest generation seem to posses antiallergic activity not only due to antihistaminic effect but also due to other mechanisms. Different suppressive action of H1-antagonists reflects also individual sensitivity to different drugs. The factor of individual sensitivity of the patients to a pharmacological action of the drug may be crucial in the selection of the most effective medicine for each patient. This is confirmed by the data of individual sensitivity of the patient to antihistaminic and antiallergic action of H1-antagonists. The illustrated method may be helpful for individual selection of H1-antagonists for treatment of patients with allergic diseases.

Topics: Adult; Anti-Allergic Agents; Butyrophenones; Cetirizine; Clemastine; Female; Histamine H1 Antagonists; Humans; Hypersensitivity; Loratadine; Male; Piperidines; Pollen; Terfenadine

A cDNA encoding a novel human CYP4F enzyme (designated CYP4F12) was cloned by PCR from a human small intestine cDNA library. RT-PCR analysis demonstrated that CYP4F12 is expressed in human small intestine and liver. This cDNA contains an entire coding region of a 524-amino-acid protein that is 81.7, 78.3, and 78.2% identical to CYP4F2, CYP4F3, and CYP4F8, respectively. When expressed in Saccharomyces cerevisiae, the P450 catalyzes leukotriene B(4) omega-hydroxylation and arachidonic acid omega-hydroxylation, typical reactions of CYP4F isoforms. Their activity levels are, however, much lower than those of CYP4F2. Interestingly, CYP4F12 catalyzes the hydroxylation of the antihistamine ebastine with significantly higher catalytic activity relative to CYP4F2 (385 vs 5 pmol/min/nmol P450). These results indicate that CYP4F12 has a different profile of substrate specificity from other CYP4F isoforms, enzymes responsible for metabolizing endogenous autacoids, therefore suggesting that it may play an important role in xenobiotic biotransformation in the human small intestine.

Topics: Amino Acid Sequence; Arachidonic Acid; Aryl Hydrocarbon Hydroxylases; Base Sequence; Butyrophenones; Catalysis; Cloning, Molecular; Cytochrome P-450 Enzyme System; Cytochrome P450 Family 4; DNA, Complementary; Gene Library; Humans; Intestine, Small; Leukotriene B4; Liver; Mixed Function Oxygenases; Molecular Sequence Data; Piperidines; Protein Isoforms; Reverse Transcriptase Polymerase Chain Reaction; Saccharomyces cerevisiae; Sequence Analysis, DNA; Sequence Homology, Amino Acid

We examined the role of a cytosolic phospholipase A2 (cPLA2) in antigen-induced eosinophil infiltration of airways and in airway hyperresponsiveness to methacholine. Inhibition of cPLA2, or blockade of the platelet-activating factor (PAF) receptor, blocked antigen-induced airway hyperresponsiveness and suppressed eosinophil infiltration. Neither cyclooxygenase nor 5-lipoxygenase inhibition had either effect. We show here that, in antigen-sensitized guinea pigs, cPLA2 inhibition prevents both eosinophilic infiltration and subsequent airway hyperresponsiveness after antigen challenge. We also show that this effect is mediated by first-step hydrolysis of membrane phospholipid into lysophospholipid rather than by prostanoid or leukotriene metabolites of arachidonate.

Topics: Animals; Antigens; Azepines; Benzoquinones; Bronchoconstriction; Butyrophenones; Eicosapentaenoic Acid; Enzyme Inhibitors; Eosinophils; Guinea Pigs; Indomethacin; Male; Methacholine Chloride; Phospholipases A; Phospholipases A2; Piperidines; Respiratory Hypersensitivity; Triazoles

Small intestinal microsomes of cynomolgus monkeys were found to catalyze hydroxylation and dealkylation of an H(1)-antihistamine prodrug, ebastine. To identify the main enzyme responsible for ebastine hydroxylation, which has been hitherto unknown, we purified two cytochrome P450 isoforms, named P450 MI-2 and P450 MI-3, from the intestinal microsomes on the basis of the hydroxylation activity. P450 MI-2 and P450 MI-3 showed the respective apparent molecular weights of 56,000 and 53,000 on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The internal amino acid sequence of P450 MI-2 had high similarity with those of human CYP4F2, CYP4F3, and CYP4F8. The first 27 amino acid residues of P450 MI-3 were highly homologous with those of monkey CYP3A8 and human CYP3A4/5/7. Furthermore, P450 MI-2 and P450 MI-3 were recognized by anti-CYP4F and anti-CYP3A antibodies, respectively, in immunoblot analysis and catalyzed leukotriene B(4) omega-hydroxylation and testosterone 6beta-hydroxylation, which are known to be mediated by CYP4F and CYP3A, respectively. Although both enzymes had ebastine hydroxylation activity, the V(max) value of P450 MI-2 was much higher than that of P450 MI-3 (37.0 versus 0.406 nmol/min/nmol of P450), and the former K(M) (5.1 microM) was smaller than the latter K(M) (10 microM). Anti-CYP4F antibody inhibited the hydroxylation in small intestinal microsomes strongly (70%), but anti-CYP3A antibody did not. These results indicate that P450 MI-2 belongs to the CYP4F subfamily and is mainly responsible for hydroxylation of ebastine in monkey small intestinal microsomes. This suggests that the small intestinal CYP4F enzyme, P450 MI-2, can play an important role in the metabolism of drugs given orally.

Topics: Amino Acid Sequence; Animals; Butyrophenones; Cytochrome P-450 Enzyme System; Electrophoresis, Polyacrylamide Gel; Histamine H1 Antagonists; Hydroxylation; Intestine, Small; Macaca fascicularis; Male; Microsomes; Molecular Sequence Data; Piperidines; Sequence Homology, Amino Acid

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

The transport characteristics of a selective peripheral H1 receptor antagonist, ebastine, a substrate for cytochrome P450 3A4, and its three major metabolites, i.e., the hydroxy metabolite of ebastine (M-OH), the pharmacologically active metabolite carebastine (Car), and the desbutyrophenone metabolite (des-BP), were studied in cultured human intestinal Caco-2 cells expressing a drug efflux pump, P-glycoprotein (P-gp), on the apical membrane. The polarized transport of [3H]cyclosporin A (CyA), mediated by P-gp in the basolateral to apical direction across the Caco-2 cell monolayers, was affected by the presence of ebastine in a concentration-dependent manner and significant inhibition was observed at high concentrations (>50 microM). M-OH (300 microM) also significantly inhibited whereas Car and des-BP did not. Although no marked polarized transport of [14C]ebastine in a secretory direction was observed in the Caco-2 systems, the flux in the basolateral to apical direction was slightly higher than that in the opposite direction at concentrations less than 30 microm. [14C]Ebastine (2 microM) uptake from the apical side was significantly increased in the presence of an excess of cold CyA, suggesting that the efflux process mediated by P-gp may be involved in the ebastine uptake by Caco-2 cells. Collectively, these results indicate that ebastine (and presumably M-OH) is transported via P-gp in Caco-2 cells, however, the affinity for P-gp is very low. It is unlikely that the secretory transport of ebastine mediated by P-gp will dramatically affect overall intestinal absorption in vivo because efficient passive diffusion of this drug should occur due to its high lipophilicity. However, it may be advantageous for its efficient first-pass metabolism.

Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Biological Transport, Active; Butyrophenones; Caco-2 Cells; Cyclosporine; Histamine H1 Antagonists; Humans; Immunosuppressive Agents; Piperidines

The present study was performed to compare the properties of ebastine--the long duration of antiallergic effect and less penetration to the CNS--with those of other H1-antihistamines. Passive cutaneous anaphylactic reaction was induced and the dye leakage from the skin measured after oral administration of the various H1-antihistamines in guinea pigs. The H1-antihistamines examined inhibited passive cutaneous anaphylactic reactions, with ED50 values of 1.55-5.77 mg/kg administered orally. Evaluation at doses close to the ED50 values determined that the rank order of the various H1-antihistamines for the duration of antiallergic effects, calculated from the AUC, was as follows: ebastine>cetirizine> or =oxatomide=loratadine=epinastine. The inhibition of [3H]-mepyramine binding to the cortical membrane was examined ex vivo after oral administration of the drugs in rats. Ketotifen as a positive control of sedative antihistamine, oxatomide, cetirizine, ebastine and epinastine dose-dependently inhibited the [3H]-mepyramine binding to rat cortical membranes. However, ebastine and epinastine did not show 50% [3H]-mepyramine binding inhibition even at 100 mg/kg orally In conclusion, ebastine was shown to be a potent and long-lasting H1-antihistamine with less effect to the CNS. Consequently, in conjunction the two experimental models used in this study--passive cutaneous anaphylactic reaction in guinea pigs and ex vivo [3H]-mepyramine binding to rat cortical membrane--may be important to estimate the duration of antiallergic effects of drugs and to detect their sedative effects, which are important indicators in the development of new antiallergic drugs.

Topics: Animals; Butyrophenones; Cerebral Cortex; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Guinea Pigs; Histamine H1 Antagonists; Intracellular Membranes; Male; Passive Cutaneous Anaphylaxis; Piperidines; Pyrilamine; Rats; Rats, Wistar; Receptors, Histamine H1; Skin

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

Topics: Astemizole; Butyrophenones; Heart Diseases; Histamine H1 Antagonists; Humans; Piperidines; Terfenadine

We examined and compared the inhibitory effects of three non-sedating antihistamines, terfenadine, ebastine, and epinastine, on delayed rectifier potassium current (IK) and transient outward potassium current (Ito) of rat isolated ventricular myocytes, using a patch clamp technique. Terfenadine, ebastine and epinastine were found to inhibit IK with IC50 values of 5.96, 15.3 and 145 microM, respectively. Ito was suppressed by epinastine with an IC50 value of 69.5 microM. The order of arrhythmogenicity, assessed by the inhibition of IK, was ranked as terfenadine > ebastine > epinastine, consistent with that of the potencies of each drug for QT prolongation reported in rats.

Topics: Animals; Butyrophenones; Dibenzazepines; Electrophysiology; Heart Ventricles; Histamine H1 Antagonists; Imidazoles; Male; Patch-Clamp Techniques; Piperidines; Potassium Channels; Rats; Rats, Sprague-Dawley; Terfenadine

Ebastine and terfenadine are both marketed nonsedating H1 histamine receptor antagonists. Although apparently similar in chemical structure, the compounds have different pharmacological profiles, particularly with respect to cardiac effects. These effects are consistently observed in a wide range of experimental models with terfenadine, but not with ebastine, despite the fact that the latter is more potent as an antihistamine. The objective of this study was to provide a structural basis to explain such differences.. A complete computer-assisted conformational and electronic characterisation was made for both drugs.. The preferred 3-dimensional spatial orientations were found to be different, as were the molecular locations of the highest occupied and lowest unoccupied molecular orbitals. Furthermore, for terfenadine, additional points of interaction as a hydrogen bond donor were found, which were not evident in ebastine or other noncardiotoxic antihistamines. These extra points of interaction were also found in other compounds that have shown cardiac effects similar to those of terfenadine.

Topics: Butyrophenones; Histamine H1 Antagonists; Models, Molecular; Molecular Conformation; Piperidines; Signal Processing, Computer-Assisted; Terfenadine

Topics: Butyrophenones; Dermatitis, Allergic Contact; Drug Evaluation; Histamine H1 Antagonists; Humans; Moscow; Piperidines; Prevalence

Ebastine [4'-tert-butyl-4-[4-(diphenylmethoxy)piperidino]butyro phe- none] is a new-generation, nonsedative, H1 antihistamine. The present study was performed to characterize the cytochrome P450 (CYP) isoforms responsible for ebastine N-dealkylation and hydroxylation. Human liver microsomes metabolized ebastine to two major metabolites, i.e. a desbutyrophenone metabolite (des-BP) and hydroxyebastine (M-OH), and the ratio of Vmax values was 3:1. N-Dealkylation yielded des-BP, whereas M-OH, an hydroxylation product, could be further oxidized to the pharmacologically active carebastine. In a panel of 14 human liver microsomal preparations, the rate of dealkylation showed a highly significant correlation with CYP3A-mediated testosterone 6beta-hydroxylation but not with reactions of seven other CYP isoforms. However, there was no correlation between the two pathways for ebastine (dealkylation and hydroxylation). Differential chemical inhibition in liver microsomes, in which dealkylation was more sensitive than hydroxylation, was demonstrated with ketoconazole, troleandomycin, cyclosporin A, and midazolam. Anti-CYP3A antibodies markedly reduced the dealkylation rate (>95%) in liver microsomes but exhibited insignificant effects on hydroxylation (<5%). Among 12 cDNA-expressed human CYP isoforms, which account for up to 70% of the total CYP enzyme content in human liver, CYP3A4 alone metabolized ebastine; the ratio of des-BP to M-OH formation was 12:1. This ratio for metabolism by the pure enzyme was much larger than the ratio (3:1) observed for the microsomal reaction mixture. This change in ratio, which is attributed to a decrease in M-OH formation, indicates that, although ebastine is metabolized to two major metabolites, N-dealkylation to des-BP is mediated by CYP3A, whereas hydroxylation to M-OH appears to be mediated mainly by unidentified enzymes other than CYP3A.

Topics: Butyrophenones; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Dealkylation; Histamine H1 Antagonists; Humans; Hydroxylation; Microsomes, Liver; Piperidines

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

To test the efficiency and tolerance of the second generation antihistamine drug ebastin (kestine) in patients with seasonal allergic rhinitis (SAR).. Kestin was given for 3 weeks in doses 10 and 20 mg/day to 226 patients with SAR running for 6.8 +/- 6.1 years. SAR symptoms relief, subjective effects, side effects were studied.. The total index of rhinitis symptoms diminished from 11.6 to 1.2 scores. Subjective response was registered in 82% of the patients, objective in 77%. Neither treatment aggravations nor serious side effects occurred. 2 patients had drowsiness, head aches, dizziness and discontinued treatment.. Kestin is effective in SAR, had no serious side effects, is well tolerated.

Topics: Administration, Oral; Adolescent; Adult; Aged; Butyrophenones; Child; Female; Follow-Up Studies; Histamine H1 Antagonists; Humans; Male; Middle Aged; Piperidines; Rhinitis, Allergic, Seasonal; Treatment Outcome

Topics: Animals; Butyrophenones; Cell Membrane; Chromones; Cyproheptadine; Guinea Pigs; Histamine H1 Antagonists; Ileum; Leukotriene Antagonists; Leukotriene D4; Lung; Membrane Proteins; Muscle Contraction; Phthalazines; Piperidines; Receptors, Leukotriene

Nonsedating H1 receptor (H1-R) antagonists exert variable effects on QT interval, most likely mediated through modulation of cardiac K+ channels. We examined the effects of a novel H1-R antagonist, ebastine, on a family of K+ currents in isolated rat and guinea pig ventricular cardiomyocytes as well as on HERG-induced rapidly delayed rectifier K+ current (I(Kr)) in Xenopus laevis oocytes. The effect of ebastine was compared with that of two other H1-R antagonists, terfenadine and loratadine, with and without reported cardiotoxicity, respectively. In guinea pig ventricular myocytes, ebastine at concentrations approximating those found in plasma under certain conditions suppressed in a voltage-independent manner the I(Kr) (Kd = 0.14 microM, maximum block 74%) more effectively than the slowly delayed rectifier K+ current (I(Ks)) (Kd = 0.8 microM, maximum block 60%). Ebastine also suppressed I(Kr) in HERG-expressing X. laevis oocytes with the Kd value of 0.3 microM and a maximal block of 46% at 3 microM. The block of the rapidly activating delayed rectifier channel in rat myocytes (Iped) (Kd = 1.7 microM, maximum block 58%) had a small voltage dependence. Ebastine only minimally suppressed rat transient K+ current (Ito) (Kd = 1.1 microM, maximum block 10%). The drug was also not a very potent blocker of the inwardly rectifier K+ current (I(K1)) of rat and guinea pig (15 +/- 3% block at 3 microM). At concentrations of <100 nM, ebastine produced negligible effect on all K+ currents. We conclude that ebastine blocks various cardiac K+ channels with different potencies. The group of delayed rectifier K+ currents appeared to be most susceptible to ebastine with the order of sensitivity of I(Kr) > I(Ks) > Iped. Ebastine-induced inhibition of all K+ current types was always weaker than that observed with similar concentrations of terfenadine.

Topics: Animals; Butyrophenones; Electrocardiography; Guinea Pigs; Heart; Histamine H1 Antagonists; Male; Piperidines; Potassium Channel Blockers; Potassium Channels; Rats; Rats, Wistar; Xenopus laevis

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 metabolic conversion of ebastine (CAS 90729-43-4, LAS-90), an antiallergic agent, to its active principle carebastine (CAS 90729-42-3) in the rat intestine and liver was investigated using intravenous-intraportal infusion techniques and jejunum loop preparations. The steady state blood concentrations of ebastine and carebastine were determined during continuous intravenous or intraportal infusion of ebastine to evaluate their respective activity to metabolize ebastine in the intestine and liver. Total body clearance of ebastine was calculated to be approximately 22-26 ml/ min. The intestinal and hepatic clearances were 6.7 ml/min and 15.4 ml/min, respectively, accounting for about 32% and 60% of the total clearance, respectively. The ratio of the concentrations of carebastine in portal blood to that in arterial blood was 1.41 during intravenous infusion, suggesting the single-pass metabolic conversion of ebastine to carebastine in the intestine. The ratio of the arterial blood concentration of carebastine during intraportal infusion to that during intravenous infusion was 1.88, suggesting the single-pass metabolic conversion in the liver. The contribution of the intestine to form carebastine from ebastine present in the systemic circulation was thus about 1/2 (0.41/0.88) of that of the liver under these conditions. When [14C]ebastine was administered in the jejunal loop, carebastine was detected in the mesenteric plasma circulated from the loop, as the major component accounting for approximately 56% of the plasma radioactivity, while the unchanged ebastine was only about 13%. Therefore, the jejunal tissue converted > 1/2 of the permeated fraction of ebastine to carebastine under these conditions. The results in the infusion studies suggested that metabolic potential to convert ebastine to carebastine was higher in the liver than in the intestine. However, since after oral administration all of the drug appeared in the systemic circulation firstly permeated the mucosa of small intestine and then passed through the liver, the contribution of the small intestine in the metabolic conversion of ebastine given orally would be greater than that of the liver, as suggested by the above in situ jejunum loop study.

Topics: Animals; Biological Availability; Biotransformation; Butyrophenones; Chromatography, Thin Layer; Femoral Vein; Half-Life; Histamine H1 Antagonists; Infusions, Intravenous; Intestinal Absorption; Intestine, Small; Liver; Male; Piperidines; Portal Vein; Rats; Rats, Wistar

Topics: Adult; Butyrophenones; Cetirizine; Histamine H1 Antagonists; Humans; Piperidines; Rhinitis, Allergic, Seasonal

Topics: Animals; Astemizole; Butyrophenones; Electrocardiography; Guinea Pigs; Histamine H1 Antagonists; Models, Biological; Piperidines; Terfenadine

Second generation antihistamines are widely used because of their efficacy in treating allergic disorders without significant sedative side effects. Recent clinical evidence shows that some of the early prototypes in this class, namely terfenadine and astemizole, have the potential for producing torsade de pointes, a rare form of ventricular arrhythmia that is life-threatening. Important questions have been raised as to whether this is a property shared by newer, recently-introduced second generation antihistamines. The objective of this study was to characterize and compare the ECG and cardiovascular effects of terfenadine (CAS 50679-08-8) and ebastine (CAS 90729-43-4), a new second generation antihistamine, in an experimental animal model predictive of the cardiotoxic proclivity of these agents. Also, the drug interaction effect of the antifungal drug ketoconazole (CAS 65277-42-1) was evaluated, which blocks hepatic first-pass biotransformation of ebastine and terfenadine leading to increased cardiotoxity of terfenadine in man, on the ECG effects of terfenadine and ebastine in this animal model. Terfenadine (10 mg/kg) and ebastine (50 mg/kg) were administered intravenously to anesthetized guinea pigs. Electrocardiographic (ECG) and cardiovascular parameters (blood pressure and heart rate) were measured during the course of the experiment. The ECG wave form was analyzed to determine QTc interval, PR interval, QRS interval and heart rate. In separate studies in conscious guinea pigs, the effect of oral ketoconazole (200 mg) on the ECG effects of oral terfenadine (60 mg) and ebastine (10 mg) was studied. Terfenadine (10 mg/kg) and ebastine (50 mg/kg) produced significant prolongation of the QTc interval and disruption of the ECG signal when given intravenously to anesthetized guinea pigs. The ECG effects were characterized by large amplitude, morphologically aberrant T-waves, and instances of arrhythmogenic activity. Both drugs produced pronounced bradycardia and hypotension. In conscious animals, pretreatment with oral ketoconazole significantly enhanced the QTc interval prolongation effects of terfenadine and ebastine. Oral terfenadine and ebastine, when given alone at the doses tested, were devoid of adverse QTc interval prolongation effects in the conscious guinea pig. In separate studies in conscious guinea pigs, oral loratadine (10 mg; CAS 79794-75-5) given alone or in animals pretreated with ketoconazole did not affect ECG parameters. The present st

Topics: Animals; Butyrophenones; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Drug Interactions; Electrocardiography; Guinea Pigs; Heart Diseases; Histamine H1 Antagonists; Ketoconazole; Liver; Male; Mixed Function Oxygenases; Piperidines; Terfenadine; Torsades de Pointes

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 study of the analytical error function has been applied to evaluate the pharmacokinetics of ebastine active acid metabolite after a single oral dose of 10 mg of metabolite in 6 healthy volunteers. Plasma concentrations were measured using an automated solid phase extraction method. The analytical method was fully validated and the function of the analytical error subsequently determined. The parametric approach was performed by nonlinear regression analysis comparing the results obtained after the application of different weighted least square 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 function of the analytical error. The results obtained in the study showed no influence of the different weighting methods used on the estimation of the pharmacokinetic parameters of ebastine acid metabolite.

Topics: Administration, Oral; Adolescent; Adult; Area Under Curve; Butyrophenones; Half-Life; Histamine H1 Antagonists; Humans; Male; Metabolic Clearance Rate; Piperidines; Regression Analysis

Topics: Animals; Antifungal Agents; Butyrophenones; Disease Models, Animal; Drug Interactions; Electrocardiography; Guinea Pigs; Histamine H1 Antagonists; Injections, Intravenous; Ketoconazole; Piperidines; Terfenadine; Torsades de Pointes

Topics: Animals; Antifungal Agents; Butyrophenones; Cats; Disease Models, Animal; Drug Interactions; Guinea Pigs; Histamine H1 Antagonists; Humans; Ketoconazole; Piperidines; Terfenadine; Torsades de Pointes

Topics: Animals; Butyrophenones; Drug Design; Guinea Pigs; Histamine H1 Antagonists; In Vitro Techniques; Molecular Structure; Muscarinic Antagonists; Piperidines; Stereoisomerism; Structure-Activity Relationship

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

A series of optically active analogues of the H1-antihistamine ebastine, with chiral center(s) at the benzhydryl and/or phenylbutyl part of the molecule, have been synthesized. Their in vitro antihistaminic and antimuscarinic activities were investigated, along with a molecular modelling study. It was found that introduction of the benzhydryl chiral center yielded significant stereoselectivity for both antihistaminic and antimuscarinic activities. The steric preferences of the benzhydryl chiral center for antihistaminic and antimuscarinic actions were mirror images of each other. The (-)-isomer of 4-methylebastine (6d) showed more than 10-fold higher in vitro antihistaminic potency than ebastine. Meanwhile the selectivity of 6d for histamine H1-receptors was also increased by more than 20 times in comparison with ebastine. The chirality at the phenylbutyl part of the molecule does not significantly alter the antihistaminic or antimuscarinic activity of the compounds although the (S)-isomers showed slightly but unanimously higher antihistaminic activity than the (R)-isomers. These results have been discussed with existing stereoselectivity data of antihistamines and an asymmetric pharmacophore model for H1-antagonists has been described.

Topics: Animals; Butyrophenones; Guinea Pigs; Histamine; Histamine H1 Antagonists; Ileum; In Vitro Techniques; Models, Molecular; Muscarinic Antagonists; Piperidines; Receptors, Histamine H1; Receptors, Muscarinic; Stereoisomerism

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

Absorption, distribution, metabolism and excretion of ebastine (4'-tert-butyl-4-[4-(diphenylmethoxy)piperidino]butyrophenone, LAS-90, CAS 90729-43-4), a new potent histamine H1-receptor antagonist, were studied with 14C-labeled compound in male rats during and after 21 consecutive daily oral administrations at a dose of 2 mg/kg/d. Plasma levels at 2 h after each administration were virtually constant in the range of 81-166 ng eq./ml for 21 days. The plasma levels at 24 h following each administration were lower than the reliable limit of radioactivity measurements during the course of the experiment. Plasma level reached the maximum (Cmax) of 109 ng eq./ml at 2 h after the 21st administration and decreased monophasically with a half-life (t1/2) of 2.5 h, which was similar to the results in the previous single dose study. [14C]Ebastine radioactivity was distributed to the liver, kidney, submaxillary gland, hypophysis, adrenal, lung and pancreas twice as high or more, and to others including brain similarly as or lower than in plasma, at 1 h after the last administration. At 168 h, radioactivity was detected at low levels in several tissues such as liver, kidney, submaxillary gland, etc. and not in other examined tissues. About 2-3% and more than 90% of the daily dose were excreted in urine and feces, respectively, within 24 h after each administration and radioactivity was virtually completely excreted within 120 h after the last administration. The analysis by thin-layer chromatography revealed that the composition of radioactive metabolites in plasma, urine and feces after repeated administration was similar to that in the single dose study.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Oral; Animals; Autoradiography; Behavior, Animal; Biotransformation; Butyrophenones; Chromatography, Thin Layer; Eating; Histamine H1 Antagonists; Intestinal Absorption; Male; Piperidines; Rats; Rats, Wistar; Tissue Distribution; Weight Gain

The identification of rat faecal metabolites of a new antihistaminic agent, ebastine, 4'-tert-butyl-4-[4-(diphenylmethoxy)piperidino]butyrophenone, is presented. After oral administration of (14C)ebastine (20 mg kg-1) to rats, 84% of the radioactive dose was excreted in the 24 h faeces. Unchanged drug and five metabolites were isolated from the faeces by thin-layer chromatography and solid-phase extraction, and their structures were identified by liquid secondary ion mass spectrometry using the B/E linked scanning technique. The main metabolic pathways were oxidation of a terminal methyl group to give the hydroxymethyl and carboxyl derivatives, and hydroxylation of a phenyl ring in the diphenylmethoxy moiety. In addition to the oxidative mechanism, metabolism of ebastine involved sulphate conjugation. It is noteworthy that M-4, having both phenolic and alcoholic hydroxyl groups, was sulphated selectively in the latter position.

Topics: Animals; Biotransformation; Butyrophenones; Chromatography, Thin Layer; Feces; Histamine H1 Antagonists; Hydrolysis; Hydroxylation; Magnetic Resonance Spectroscopy; Male; Mass Spectrometry; Oxidation-Reduction; Piperidines; Rats; Rats, Wistar; Sulfates

Partial least-squares calibration was used for the spectrophotometric determination of the active compound and preservative in a syrup also containing several light absorbing excipients. The calibration matrix was constructed from laboratory-made mixtures of the analytes and excipients and was used to quantify three samples from different batches. The most suitable conditions for quantitation were determined and the results obtained are compared with those provided by HPLC.

Topics: Butyrophenones; Excipients; Histamine H1 Antagonists; Indicators and Reagents; Least-Squares Analysis; Nephelometry and Turbidimetry; Parabens; Piperidines; Spectrophotometry, Ultraviolet

The pharmacokinetics and pharmacodynamics of ebastine at single oral doses of 10 and 20 mg were studied in six healthy beagle dogs. Plasma concentrations of the active metabolite of ebastine were measured at predetermined times after the dose. At these times an intradermal injection of 0.01 mL of a 0.2 mg mL-1 histamine diphosphate solution was given, and wheal areas were computed. The plasma elimination half-life of ebastine was 4.38 +/- 1.01 h after 10 mg ebastine and 4.09 +/- 0.74 h after 20 mg ebastine; the distribution volume was 3.99 +/- 0.88 and 3.65 +/- 0.75 L kg-1 after 10 and 20 mg of ebastine, respectively; the clearance after the 10 mg dose of ebastine was 0.67 +/- 0.24 L h-1 kg-1 and after 20 mg ebastine was 0.63 +/- 0.17 L h-1 kg-1. The mean histamine-induced wheal areas were significantly suppressed from 1 to 25 h after the 10 mg dose ebastine and from 1 to 32 h after the 20 mg dose ebastine, compared with the mean predose wheal areas (P < 0.001). Maximum suppression of the wheals was 75 and 82% from 10 and 20 mg ebastine, respectively. A combined pharmacokinetic-pharmacodynamic model was used to analyse the relationship between inhibition of wheal skin reaction and changes in the active metabolite of plasma concentration after ebastine administration. A significant delay of 3-4 h was present between the maximum effect and the peak plasma concentration. Calculated from mean data, the rate constant for equilibration of the drug between plasma and effect site was 0.17 and 0.22 h-1 after 10 and 20 mg ebastine with a half-life of 4.13 and 3.56 h, respectively, and the steady-state plasma concentration resulting in 50% of maximal effect was 18.9 +/- 4.8 ng mL-1 after 10 mg and 18.2 +/- 5.7 ng mL-1 after 20 mg ebastine.

Topics: Administration, Oral; Analysis of Variance; Animals; Biological Availability; Butyrophenones; Chromatography, High Pressure Liquid; Dogs; Half-Life; Histamine H1 Antagonists; Injections, Intradermal; Male; Piperidines; Skin