The pharmacokinetics and pharmacodynamics of terfenadine in children

The pharmacokinetics and pharmacodynamics of terfenadine were studied in 13 children with allergic rhinitis, mean age 7.45 +/- 0.54 SEM years. Serum concentrations of the active carboxylic acid metabolite of terfenadine (terfenadine metabolite I) were measured before and hourly for 8 hours after administration of a single dose of terfenadine suspension. The mean maximum serum concentration of terfenadine metabolite I, 242 +/- 28 ng/ml, occurred at 2.3 +/- 0.2 hours; the mean serum half-life value was 2.0 +/- 0.1 hours. Wheals and flares after epicutaneous tests with histamine phosphate, 1.0 mg/ml and 0.2 mg/ml, were significantly suppressed from 1 to 8 hours after the terfenadine dose compared to predose values. Maximum wheal suppression occurred at from 3 to 6 hours. Itching was completely suppressed for 8 hours. No serious adverse effects occurred. Terfenadine in children appears to be well absorbed, and its carboxylic acid metabolite has a short serum elimination half-life. The duration of its suppressive effect on the histamine-induced wheal and flare greatly exceeds that expected from consideration of serum terfenadine metabolite I concentrations.     

Pharmacokinetics and pharmacodynamics of terfenadine and chlorpheniramine in the elderly

In a double-blind, randomized, crossover study, the H1-receptor antagonists, terfenadine and chlorpheniramine, were investigated in eight healthy, fasting female subjects, aged 67.8 +/- SD 0.8 years, who ingested single doses of terfenadine, 1 mg/kg (mean dose, 69.6 +/- 11.2 mg), and chlorpheniramine, 0.12 mg/kg (mean dose, 8.4 +/- 1.3 mg). The mean serum-elimination half-life of terfenadine metabolite I was 8.7 +/- 3.7 hours. After terfenadine ingestion, significant wheal suppression occurred from 2 to 24 hours compared to predose wheal size, with maximum wheal suppression, 42 +/- 13% to 60 +/- 16% from 2 to 12 hours. Significant flare suppression occurred from 2 to 24 hours, with maximum flare suppression, 75 +/- 15% to 78 +/- 13% from 4 to 8 hours. The mean serum-elimination half-life of chlorpheniramine was 22.6 +/- 11.0 hours. After chlorpheniramine ingestion, significant wheal suppression occurred from 1 to 10 hours, inclusive, compared to predose wheal size, with maximum wheal suppression, 36 +/- 11% to 37 +/- 11% from 5 to 6 hours. Significant flare suppression occurred from 1 to 12 hours, with maximum flare suppression of 43 +/- 14% to 46 +/- 19% at 2, 5, and 6 hours (p less than 0.01). Adverse effects, chiefly sedation, occurred in five of eight patients after receiving terfenadine, and in all eight patients after receiving chlorpheniramine; but, since no placebo control was administered, these adverse effects could not be definitely attributed to H1-receptor-antagonist ingestion.     

Relative potency of fexofenadine HCl 180 mg, loratadine 10 mg, and placebo using a skin test model of wheal-and-flare suppression.

BACKGROUND: H1-receptor antagonists differ in their ability to produce peripheral H1-blockade. Suppression of histamine-induced flares and wheals is a useful objective test for measuring these differences. OBJECTIVE: To evaluate the relative potency of fexofenadine HCI 180 mg, loratadine 10 mg, and placebo (PBO) in suppressing histamine-induced flares and wheals and compare the onset, duration, and maximum suppression of histamine achieved with each agent. METHODS: Thirty healthy volunteers were enrolled in this randomized, double-blind, single-dose, crossover study. Flares and wheals induced by skin-prick testing with histamine 1.8 mg/mL were measured before treatment, every 20 minutes during the first hour after dosing, and thereafter hourly between 2 and 12 hours and between 23 and 25 hours postdose. RESULTS: Fexofenadine was significantly more effective than loratadine in suppressing the histamine-induced flare response at hours 2 through 7 and 10 through 12 and produced greater flare suppression than did PBO at hours 2 through 25. Onset of flare suppression occurred 2 hours after dosing with fexofenadine and 4 hours after dosing with loratadine. Likewise, fexofenadine was superior to loratadine in suppressing the wheal response from hours 1 through 12 and was more effective than PBO at hours 1 through 12, 24, and 25. Throughout the 25-hour measurement interval, the magnitude of difference in both wheal and flare suppression consistently favored fexofenadine over loratadine. CONCLUSIONS: In a skin test model of wheal-and-flare suppression, fexofenadine showed rapid distribution into the skin compartment with faster onset of action and greater potency vs loratadine.     

Similar rapid onset of action and magnitude of effect of fexofenadine and cetirizine as assessed by inhibition of histamine-induced wheal-and-flare reaction.

BACKGROUND: Histamine-induced wheal-and-flare studies are useful, objective tests for determining differences in the peripheral H1-receptor blockade activities of antihistamines. OBJECTIVE: To evaluate the time of occurrence of 95% inhibition of histamine-induced wheal and flare after administration of fexofenadine hydrochloride, 180 mg, or cetirizine, 10 mg. METHODS: Forty-two volunteers (aged 18-60 years) were included in a randomized, double-blind, crossover study. Skin prick tests were undertaken using histamine (100 mg/mL) before treatment and 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, and 4.0 hours after treatment. Wheal and flare areas were evaluated, and the time to occurrence of 95% inhibition and the frequency of subjects exhibiting 95% inhibition before median time to 95% inhibition were calculated. RESULTS: Mean +/- SD time to 95% wheal inhibition was 2.46 +/- 0.71 hours with fexofenadine and 2.55 +/- 0.57 hours with cetirizine. The estimated mean difference between fexofenadine and cetirizine (-7 minutes in favor of fexofenadine; 2-sided 95% confidence interval, -21 to +7 minutes) was not statistically significant (P = .34). For wheal, 29% of subjects receiving fexofenadine and 24% receiving cetirizine achieved 95% inhibition before the median time of inhibition (2.5 hours). An exact permutation test yielded a P = .37. For flare, 26% of subjects receiving fexofenadine and 10% receiving cetirizine achieved 95% inhibition before the median time of inhibition (3 hours; P = .12 by exact permutation test). CONCLUSIONS: Fexofenadine and cetirizine have comparable onset of action times and similar frequencies of inhibition, as evaluated by the occurrence of 95% inhibition of histamine-induced wheal and flare.     

Comparative activity of cetirizine and desloratadine on histamine-induced wheal-and-flare responses during 24 hours.

BACKGROUND: Cetirizine and desloratadine are antihistamines active in the treatment of symptoms associated with seasonal allergic rhinitis and chronic urticaria. OBJECTIVE: To compare the antihistamine activity of desloratadine, the active metabolite of loratadine, with that of cetirizine in the skin wheal-and-flare responses during 24 hours. METHODS: This was a double-blind, randomized, placebo-controlled, single oral dose, crossover study. Skin reaction to histamine (100 mg/mL), administered by prick tests, was measured by the wheal and flare surface areas for 24 hours (before treatment and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours). Eighteen healthy volunteers (mean age, 33.9 years; 13 women) participated in this study. The areas under the curves of the wheal-and-flare responses as a function of time (primary efficacy variables) were compared using analysis of variance. RESULTS: A highly significant overall treatment effect (P < .001) was detected for wheal and flare inhibition, with the activity of cetirizine and desloratadine significantly superior to that of placebo (P < .001). In addition, the activity of cetirizine was significantly superior to that of desloratadine (P < .001). With desloratadine, only 3 of the 18 subjects achieved a wheal inhibition of at least 70%, occurring between 2 and 4 hours, whereas all subjects using cetirizine reached a wheal inhibition of at least 70% between 0.5 and 3 hours (median time, 1.7 hours). The difference between the 2 active drugs was highly significant (P < .001). The median duration of wheal inhibition of at least 70% was zero with placebo and desloratadine and was 21.9 hours with cetirizine (P < .001). No serious adverse events were reported, and no subject withdrew from the study due to an adverse event. CONCLUSION: Cetirizine was associated with significantly greater suppression of skin reactivity to histamine compared with desloratadine during 24 hours after a single dose, with a consistent duration of action for cetirizine, as previously reported.     

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.     

Reliability of skin prick tests during terfenadine treatment in adults with pollen rhinitis

The variation in skin prick test (SPT) results was evaluated clinically during terfenadine treatment in 39 adult patients with pollen rhinitis. A change in the perceived state of the patient as regards sensitization to a specific pollen allergen or atopic constitution was judged to be clinically important. A randomized, double-blind, crossover design was used, comprising 2 weeks on terfenadine 120 mg once a day and 2 weeks on placebo. SPT for two pollen allergens and histamine (10mg/ml) were evaluated at the start of the study and at the end of each period. When SPT was used as a discovery test and liberal definitions were applied, predictive values for a positive test were 100%. 1-Sensitivity ranged between 10 and 54% with substantially lower values when a histamine wheal reaction was noted. The inhibitory effect of terfenadine was detectable 2 weeks after withdrawal as a reduction in the median of the mean diameter for the histamine-induced wheal response of 1 mm (0–1.5). The data implied that a positive SPT is reliable when liberal definitions are adopted for sensitization and atopy; a negative SPT is presumably reliable when the measurement artifact is considered and the wheal reaction to histamine is detectable.     

Histamine skin test reactivity following single and multiple doses of azelastine nasal spray in patients with seasonal allergic rhinitis.

OBJECTIVE: To determine whether azelastine nasal spray suppresses the dermal response to epicutaneous histamine in allergic patients and the duration of suppression after azelastine use is discontinued. METHODS: Seventy-eight patients with seasonal allergic rhinitis were entered into this randomized, double-blind, parallel-group, placebo-controlled study. Patients received either azelastine nasal spray (2 sprays per nostril twice daily) or placebo nasal spray for 14 days. Skin tests were performed 5 hours after the first dose of study drugs to determine the effect of a single dose of azelastine nasal spray on the wheal-and-flare response to histamine. At the end of the 14-day treatment period, skin tests were performed 5 hours after the last dose of study drugs and at 24-hour intervals thereafter, until each patient's wheal-and-flare response to histamine (1.0 and 5.0 mg/mL) returned to within 20% of baseline values. RESULTS: A single dose of azelastine nasal spray did not significantly alter the wheal-and-flare response to histamine. The wheal response was within 20% of the baseline value in 82% and 88% (1.0 and 5.0 mg/mL of histamine, respectively) of the patients 5 hours after discontinuing 14 days of treatment with azelastine nasal spray. Wheal responses were within 20% of baseline values 48 hours after treatment was discontinued, whereas flare responses returned to within 20% of baseline within 48 hours in 92% of the patients. CONCLUSIONS: Azelastine nasal spray should be discontinued for at least 48 hours before beginning allergy skin test procedures.     

A double-blind evaluation of skin test suppression produced by two doses of terfenadine

For some patients, terfenadine, in the currently recommended dose of 60 mg twice daily (bid), may be only modestly effective in the treatment of allergic rhinitis. In a double-blind placebo-controlled crossover study of 12 patients, a larger dose (300 mg bid) was evaluated for its suppression of titrated skin tests to histamine and compound 48/80 to determine whether this regimen might result in greater suppression while it maintained the freedom from side effects of the presently recommended dose. In seven patients, skin test suppression by these two doses of terfenadine each administered for 3 days, was compared to that produced in an earlier study by 3 days of treatment with chlorpheniramine (8 mg three times a day). The 300 mg bid terfenadine regimen produced significantly greater skin test suppression (p less than 0.05) than the currently recommended 60 mg bid dose. There was no significant difference in side effects between the two doses, and neither active treatment regimen produced more side effects than placebo treatment. Both doses of terfenadine suppressed cutaneous reactivity significantly more than had chlorpheniramine. It is concluded that the presently recommended dose of terfenadine produces submaximal skin test suppression and that further studies are needed to investigate the clinical efficacy and safety of larger doses of terfenadine in the treatment of allergic rhinitis.     

Suppressive effects of histamine skin reactivity by a nonsedating antihistamine-mequitazine.

The suppressive activity of mequitazine (MQZ) on histamine skin reactivity was evaluated in 29 healthy subjects (age 22-25 years) in a single-blind study. Fifteen subjects received MQZ, at a dosage of 5 mg BID, for 7 days while 14 served as controls. A prick skin test with saline or histamine hydrochloride (1 mg/ml and 10 mg/ml) was performed in duplicate, on both forearms, starting from the baseline day and continuing for 4 days after medication had been discontinued (total of 11 days). The skin-test subject and the reader was unaware of the randomization process. Mean diameters of wheal and flare as well as the skin index scores (after Voorhost) were used in the analysis. Maximal flare suppression (as compared to the baseline values) was observed on day 6 (97% suppression for 1 mg/ml and 54% suppression for 10 mg/ml, p less than 0.01). Suppression of wheal size was significant (19% for 1 mg/ml and 28% for 10 mg/ml) but was not clinically relevant. Suppression of skin index scores was maximal on day 6 (71% for 1 mg/ml and 43% for 10 mg/ml, p less than 0.01). After MQZ had been discontinued, all measurements gradually returned to baseline values and were not different therefrom within 3 days. However, final measurements of wheal and flare were smaller than baseline values (60-94% of baselines). We conclude that MQZ, at the manufacturers's recommended dose of 5 mg BID, significantly suppressed flare size of histamine skin tests and recommend that MQZ be discontinued for at least 3 days prior to performing allergy skin tests.     

Comparison of the suppressive effect of astemizole, terfenadine, and hydroxyzine on histamine-induced wheals and flares in humans

Thirty-two healthy volunteers completed a 14-day, double-blind, noncrossover study comparing the efficacy and adverse effects of astemizole, terfenadine, and hydroxyzine. The subjects received either astemizole (load), 30 mg once daily for 1 week and then 10 mg once daily for 1 week, or astemizole (no load), 10 mg once daily for 2 weeks, or terfenadine, 60 mg twice daily for 2 weeks, or hydroxyzine, 50 mg once daily for 2 weeks. Before and on days 7 and 14 of treatment, five intradermal tests with various amounts of histamine phosphate (range 0.3 to 40 micrograms) were performed. Wheal-and-flare responses were traced, and the areas were computed by use of a graphics tablet. All four H1-receptor antagonist treatment regimens were equally effective in reducing the flare response to histamine. Astemizole (load) and hydroxyzine were significantly more effective than terfenadine and astemizole (no load) in reducing wheal size. The incidence of adverse effects, including sedation, was low overall and lowest in the astemizole (no load) and terfenadine groups, although this difference was not statistically significant.     

Twenty-four hours of activity of cetirizine and fexofenadine in the skin.

BACKGROUND: Cetirizine and fexofenadine, the active metabolite of terfenadine, are powerful and well-tolerated H1 receptor antagonists effective in the treatment of skin and nose atopic diseases. OBJECTIVE: We have compared the pharmacodynamic activity of the two antihistamines at therapeutic dosages, cetirizine at 10 mg and fexofenadine at 120 mg and 180 mg, on histamine-induced skin reactivity during a 24-hour period after single intake. METHODS: Twenty-six healthy volunteers participated in a randomized, double-blind, crossover, placebo-controlled study. The areas of wheal and flare induced by histamine (100 mg/mL) administered by prick test were measured at 0, 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hours postdose. Statistical analysis of the areas under the time-response curves was performed by a Friedman's ANOVA followed by a Wilcoxon test and Bonferroni's correction. RESULTS: The three active treatments clearly inhibited the wheal and flare areas throughout the 24-hour period compared with placebo. Maximal inhibition occurred at 4 hours postdose. Between 4 and 24 hours postdose, the time course of inhibition by cetirizine differed significantly (P < 0.001) from that by fexofenadine at either dose, which did not differ from each other. At 24 hours, fexofenadine inhibited <40% of the skin reaction, whereas cetirizine reduced 60% of the wheal. The duration of effect, considered as the time for wheal to be inhibited by at least 70%, also significantly favored cetirizine (19 hours) compared with fexofenadine (9.3 and 8.5 hours for 180 and 120 mg, respectively; P < 0.001). Consistency of activity was evaluated by the frequency of total inhibition of the wheal (> or =95%). Consistency was observed in 26 of 26 participants for cetirizine, 21 of 26 for fexofenadine, 180 mg, and 10 of 26 for fexofenadine, 120 mg (P < 0.001), suggesting better consistency for cetirizine. There was no serious adverse event. CONCLUSIONS: Our study clearly shows better duration of action and consistency of the antihistaminic activity of cetirizine compared with fexofenadine (120 and 180 mg) in the histamine-induced skin reaction during a 24-hour period.     

The effect of ranitidine, alone and in combination with clemastine, on allergen-induced cutaneous wheal-and-flare reactions in human skin

The effect of intradermal ranitidine (administered alone and in combination with clemastine) on allergen-mediated wheal-and-flare reactions has been evaluated in a double-blind study on 10 healthy atopic volunteers. Ranitidine alone, administered in doses over a 10(4)-fold concentration range, had no effect on the size either of allergen-induced wheal or flare reactions. Clemastine alone evoked a dose-related inhibition of both wheal and flare. Compared to the inhibition achieved by clemastine alone, the combination of ranitidine with clemastine produced a small but significant increase in inhibition of allergen-induced flare at ranitidine concentrations of 10(-5) mol/L (p less than 0.001) and 10(-6) mol/L (p less than 0.01), and of allergen-induced wheal at ranitidine concentration 10(-5) mol/L (p less than 0.01). Our results provide further evidence for the presence of cutaneous histamine H2 receptors and their participation in the formation of allergen-mediated skin reactions but indicate that the contribution of cutaneous histamine H2-receptor stimulation to the production of immediate wheal-and-flare reactions evoked by allergen is only modest.     

A double‐blind, single‐dose, crossover comparison of cetirizine, ebastine, epinastine, fexofenadine, terfenadine, and loratadine versus placebo: suppression of histamine‐induced wheal and flare response for 24 h in healthy male subjects

BACKGROUND: New H1-antagonists have become available, but there has been no comparison of their potency for inhibiting histamine in the skin. METHODS: 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. RESULTS: 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. CONCLUSIONS: The inhibition of histamine effects in the skin may be useful in predicting the clinical utility of newly introduced antihistamines in treating allergic disorders.     

Suppression of epicutaneous reactivity by terfenadine and loratadine.

We compared the relative antihistaminic effects of loratadine (10 mg), terfenadine (120 mg), and placebo in patients with tree pollen-induced allergic rhinitis. Wheals were produced by epicutaneous tests with serial dilutions of histamine phosphate, tree and grass pollen extracts before ingestion of medication. Repeat tests were performed after seven days of treatment. Terfenadine was more effective than both loratadine (P less than .01) and placebo (P less than .001) at suppressing histamine induced wheals. Terfenadine was more effective than placebo (P less than .01), but not loratadine at inhibiting both tree-induced and grass-induced epicutaneous reactions. In this study, terfenadine was more potent than loratadine in inhibiting both histamine-induced and allergen-induced epicutaneous wheals.     

Skin responses to intradermal histamine and leukotrienes C4, D4, and E4 in patients with chronic idiopathic urticaria and in normal subjects

Mast cell inflammatory mediators, such as histamine, and newly formed compounds, such as the leukotrienes, cause wheal and flare when they are injected intradermally into normal subjects and may therefore play a role in the formation of urticaria. The effects of intradermal injections (50 microliters) of six different concentrations of histamine (range, 3.3 x 10(-4) to 3.3 x 10(-9) mol/L) and the leukotrienes C4, D4, and E4 (range, 2 x 10(-4) to 2 x 10(-9) mol/L) have been compared in 10 normal subjects and in 10 patients with chronic idiopathic urticaria. Wheal-and-flare sizes were measured at timed intervals up to 4 hours, and area under the curve for each response over time was calculated. There were no significant differences in leukotriene-induced responses between groups. Maximum sizes of histamine-induced wheal and flare were similar in each group of subjects. There were, however, significant increases in mean areas under the response curve of histamine wheal and flare in the patients with urticaria (wheal, p less than 0.001; flare, p less than 0.001; analysis of variance). These findings demonstrate a prolongation of skin responses to histamine in patients with urticaria and suggest an impaired clearance of histamine (or other vasoactive agents released by histamine) from the skin of these patients.     

Attenuation of hyperventilation-induced bronchospasm by terfenadine: a new antihistamine

The effect of terfenadine, a selective H1-receptor antagonist devoid of central nervous system side effects, was evaluated on hyperventilation-induced bronchospasm in 11 adult subjects with asthma in a double-blind, placebo-controlled, crossover study. Increases in specific airway resistance (SRaw) were induced by isocapnic hyperventilation with dry air on two occasions, 7 days apart. Before the tests, the subjects received oral terfenadine (120 mg, twice daily) or placebo for 3 days with the last dose administered 3 hours before the test. Baseline SRaw and spirometric values (vital capacity and FEV1) were similar for the two tests. Terfenadine yielded a significant (p less than 0.001) parallel shift to the right of the stimulus (hyperventilation)-response (SRaw) curve; 100% increases in SRaw occurred at ventilation rates of 44 L/min after placebo treatment and 64 L/min after terfenadine treatment. These data suggest that histamine release plays a role in hyperventilation-induced bronchospasm despite the fact that increase in plasma histamine has not been found in this situation, in contrast to exercise-induced bronchospasm.     

A double-blind, randomized, single-dose, crossover comparison of levocetirizine with ebastine, fexofenadine, loratadine, mizolastine, and placebo: suppression of histamine-induced wheal-and-flare response during 24 hours in healthy male subjects.

BACKGROUND: Levocetirizine is the active enantiomer of cetirizine, a potent drug with little metabolism widely used for allergic rhinitis and urticaria. OBJECTIVE: This study compares the potency, consistency, onset, and duration of action of levocetirizine with other popular antihistamines. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.     

Effects of loratadine (SCH 29851) in suppression of histamine-induced skin wheals

The efficacy and safety of single oral doses (10, 20, 40, and 80 mg) of loratadine (SCH 29851) in suppressing formation of histamine-induced wheals were assessed in a crossover study in 29 healthy male subjects. One hour prior to dosing and 1, 2, 3, 4, 6, 8, 12, 16, 24, 28, 32, 36, 40, and 48 hours after dosing, histamine and saline were injected intradermally into opposite arms. Measurements of resulting wheal areas showed loratadine suppressed wheal formation significantly better than placebo; suppression was dose related. The mean suppression over 48 hours was 16% in placebo-treated subjects and 35%, 45%, 51%, and 67% in the 10, 20, 40, and 80 mg loratadine-treated subjects, respectively. The onset of action occurred within the first hour. Duration of suppression was dose related, ranging from 12 hours with the lowest dose (10 mg) to 48 hours with the higher doses (40 and 80 mg). Incidence of sedation and other side effects were comparable among all doses of loratadine and placebo.     

A study comparing the inhibitory effects of single and repeated oral doses of ebastine and fexofenadine against histamine-induced skin reactivity

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.