Comparison of inhibition of cutaneous histamine reaction of ebastine fast-dissolving tablet (20 mg) versus desloratadine capsule (5 mg): a randomized, double-blind, double-dummy, placebo-controlled, three-period crossover study in healthy, nonatopic adults.

BACKGROUND: 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. OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

A comparison of ebastine 10 mg fast-dissolving tablet with oral desloratadine and placebo in inhibiting the cutaneous reaction to histamine in healthy adults.

BACKGROUND AND OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: Ebastine 10 mg FDT demonstrated significantly superior antihistamine activity compared with desloratadine and placebo.

The prokinetic cinitapride has no clinically relevant pharmacokinetic interaction and effect on QT during coadministration with ketoconazole.

The present clinical trial was designed to evaluate the possible pharmacokinetic and electrocardiographic interactions of the gastroenteric prokinetic drug cinitapride with ketoconazole. The safety and tolerability of the study treatments were also evaluated. After a placebo-controlled, double-blind, crossover design, 16 healthy male (n = 8) and female (n = 8) volunteers were randomized into four treatment groups of four subjects (two males and two females): cinitapride (CTP; 1 mg t.i.d.) + ketoconazole (KET; 200 mg b.i.d.), CTP + placebo (PL), PL+KET, and PL+PL. Treatments were given for 7 days with a washout period of 14 days between crossover treatments. Cinitapride is rapidly absorbed after oral administration and is metabolized by the cytochrome P450 CYP3A4 and CYP2C8 isozymes. At steady state, coadministration with ketoconazole, a potent CYP3A4 inhibitor, increased mean C(max,ss) and AUC(tau) by 1.63- and 1.98-fold, respectively. Measurement of mean QTc interval or baseline-corrected QTc intervals on day 7 showed small increases that were due to the effects of ketoconazole alone. Comparing CTP+KET versus PL+KET, the differences between mean increases in the QTc parameters were always less than 2 ms. Finally, no outlier increase of the QTc interval versus baseline >60 ms was identified after any treatment. The study showed that cinitapride, either given alone or after coadministration with ketoconazole 200 mg b.i.d., had no effect on cardiac repolarization as measured by changes in the heart rate-corrected QT interval on the surface electrocardiogram.

Meta-analysis of the efficacy of ebastine 20 mg compared to loratadine 10 mg and placebo in the symptomatic treatment of seasonal allergic rhinitis.

BACKGROUND: Few randomized studies have compared the efficacy of ebastine and loratadine in the symptomatic treatment of seasonal allergic rhinitis (SAR). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Efficacy of ebastine, cetirizine, and loratadine in histamine cutaneous challenges.

BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.