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Intercellular adhesion molecules (ICAMs), in particular ICAM-1, appear to play a crucial role in the recruitment and migration of inflammatory cells to the site of an allergic reaction. Glucocorticoids and allergen-specific immunotherapy have been shown to exert effects on selected components of this system, both in vitro and in vivo, but further research is required to better understand the effects of these therapies. Nasal and conjunctival challenge models (including natural and experimental allergen exposure) represent useful and safe tools for studying the activity of antiallergy drugs in vivo. These tests allow the investigation of a wide variety of parameters including inflammatory infiltrate, ICAM-1 expression, and changes in the concentration of soluble inflammatory mediators. With these tools, anti-inflammatory activity related to the modulation of epithelial cell adhesion molecules has been demonstrated in vivo for several H(1)-receptor antagonists (azelastine, cetirizine, loratadine, levocabastine, oxatomide, and terfenadine). Fexofenadine is a nonsedating, long-acting antihistamine with highly selective H(1)-receptor antagonist activity and a particularly favorable safety profile. In addition, fexofenadine has proven anti-inflammatory activity and has been shown to inhibit a number of mediators at clinically relevant concentrations, including in vitro inhibition of ICAM-1 expression on conjunctival and nasal epithelial cells.

Antihistamines have been evaluated as potential therapies for asthma for more than 50 years. With first-generation compounds, side effects prevented effective dosing. By reviewing published studies of the effectiveness of terfenadine, cetirizine, and loratadine in clinical asthma, evidence for the relevant effect of the second-generation antihistamines on bronchial asthma can be found. Terfenadine, at doses of 120 or 180 mg twice a day, reduced symptoms and improved pulmonary function in mild and moderate allergic asthma but was ineffective in severe perennial asthma. Fexofenadine at doses used for allergic rhinitis had little effect on seasonal allergic asthma. Research is ongoing to determine the effects of higher doses of fexofenadine. In 5 studies, cetirizine at doses of 10 to 20 mg, once or twice daily, consistently improved asthma symptoms compared with placebo or terfenadine 60 mg twice a day in 2 cases, whereas in 2 studies, loratadine at doses of 10 to 20 mg daily has not produced significant improvement in asthma. However, loratadine 5 mg combined with 60 mg of pseudo-ephedrine twice a day significantly improved both asthma symptoms and peak expiratory flow. Similarly, the combination of loratadine 20 mg and the leukotriene-receptor antagonist montelukast improved asthma symptoms, peak expiratory flow, and beta-agonist use over montelukast alone. Therefore, there might be a role for second- and third-generation antihistamines in treating mild and moderate asthma, which might require administering doses greater than those commonly used to treat allergic rhinitis. If higher doses are sedative, the addition of decongestants or leukotriene-receptor antagonists might enhance the effects of lower doses of the antihistamines.

Background: Antihistamines are among the most frequently used medications in the United States. Despite dramatically higher cost, second-generation antihistamines are replacing diphenhydramine because of the perception that they are not constrained by its sedating effects. Objective: We sought to examine, through meta-analytic procedures, the collective evidence regarding the sedating and performance-impairing effects of diphenhydramine relative to placebo and second-generation antihistamines. Methods: A search that began with the MEDLINE database was limited to those studies that included patients with atopic disease and control subjects, were blinded and randomized clinical trials, objectively examined alertness and psychomotor performance, reported means and variances, and were written in English. Information was systematically abstracted from the resulting 18 articles, and effect size was calculated. Results: Diphenhydramine impaired performance relative to placebo control and second-generation antihistamines, including acrivastine, astemizole, cetirizine, fexofenadine, loratadine, and terfenadine. However, results were quite varied, the average sedating effect of diphenhydramine was modest, and in some instances results of tests of performance in the diphenhydramine group showed less sedation than in the control or second-generation antihistamine groups. A significant ( P

Background: Antihistamines have been evaluated for usefulness in the treatment of asthma for more than 50 years. Interest was limited until the introduction of newer compounds that were free of much of the dose-limiting sedation associated with the earlier drugs. Objective: In a murine model of allergen-induced airway inflammation and hyperresponsiveness, the efficacy of an H1 receptor antagonist to prevent allergic inflammation and altered airway function was evaluated. Methods: Mice were sensitized and challenged to an allergen, ovalbumin, which elicited marked airway and tissue eosino-philia and airway hyperresponsiveness. Fexofenadine was administered before challenge, and airway responsiveness to inhaled methacholine, airway and tissue eosinophilia, bronchoalveolar lavage fluid cytokine levels, and serum IgE levels were assayed. In a second group of experiments, sensitized and challenged mice were treated or not treated with fexofenadine before challenge. T cells were isolated from the lungs and adoptively transferred into naive recipients before exposure to limited airway allergen challenge, and lung function and inflammation were evaluated. Results: Fexofenadine treatment of sensitized mice prevented the development of airway hyperresponsiveness in both the primary sensitization and challenge, as well as in the adoptive transfer experiments. These changes were accompanied by decreases in bronchoalveolar lavage and tissue eosinophilia, lymphocyte numbers, and T H 2 cytokine production. Conclusion: The results demonstrate the efficacy of an H1 receptor antagonist in preventing allergen-induced alterations in pulmonary inflammation and airway function. The data support the evaluation of drugs such as fexofenadine in the treatment of allergic asthma. (J Allergy Clin Immunol 2002;110:85-95.)

Several studies have evaluated the effects of childhood use of corticosteroids on growth. In short-term studies, the budesonide (BUD) metered dose inhaler and methylprednisolone (injection) had significant effects on lower-leg growth, whereas terfenadine did not. When two doses of BUD (nasal inhaler, 200 or 400 μg once daily) were compared with placebo, only the 400-μg dose had a significant effect on short-term growth. Intranasal mometasone furoate (MF) (100 and 200 μg) had no significant effect on short-term lower-leg growth. In intermediate studies of 1-year duration, intranasal beclomethasone dipropionate (84 μg twice daily) significantly affected growth rate, whereas in a separate study, 100 μg intranasal MF once daily did not. Long-term growth data come from retrospective studies of children with asthma. In these studies, no significant effect on growth has been demonstrated in children taking inhaled beclomethasone dipropionate or BUD. The reason for the discrepancy between intermediate and long-term studies is unclear and warrants further study. Variables in childhood growth including seasonal variations may make growth difficult to assess. However, because growth suppression has been reported in children receiving inhaled or intranasal corticosteroids, the lowest effective dose of drug with a low systemic absorption ratio should always be used. Overall, there appears to be no growth suppression with 100 μg intranasal MF used once daily in children. (J Allergy Clin Immunol 2001;108:S40-4.)

Background: Antihistamine premedication has been used to increase safety of specific-allergen immunotherapy. Its influence on the efficacy of this treatment has not been studied so far. Objective: The goal was to analyze the influence of antihistamine premedication on long-term efficacy of specific-allergen immunotherapy. Method: Patients included in a double-blind, placebocontrolled trial who received premedication with terfenadine or placebo during initial rush immunotherapy with honeybee venom in 1988/1989 were assessed in a retrospective analysis for the long-term protective effect, as indicated by the tolerance of a bee sting challenge or field sting during immunotherapy. Results: Of the 52 patients who had participated in the 1988/1989 trial, 47 could be reassessed after an average of 3 years. Of these, 45 were still receiving bee venom immunotherapy. A total of 41 patients were stung by bees while receiving immunotherapy (20 of the terfenadine-premedicated group and 21 of the placebo-premedicated group), 17 with in-field stings and 24 with in-hospital sting challenge. Six (29%) of the patients receiving placebo had a mild-to-moderate systemic allergic reaction, whereas none of the patients receiving terfen-adine reacted to the bee sting ( P = .012). Conclusions: These results indicate that antihistamine premedication during the initial phase of specific-allergen immunotherapy may enhance the efficacy of this treatment. (J Allergy Clin Immunol 2001;107:81-6.)

Background: Terfenadine is a selective, nonsedative, H 1 -blocker antihistamine used for a variety of allergic conditions. The widespread popularity of terfenadine and its use by many women in their reproductive age raises concerns regarding its safety during pregnancy. Presently, no prospective controlled study has addressed its safety during gestation. Objective: We sought to determine whether terfenadine use during pregnancy is associated with an increased risk of major malformations, decreased birth weight, perinatal complications, or developmental delays. Methods: A multicenter, prospective controlled study was performed. Pregnant women exposed to terfenadine during gestation were matched with control subjects exposed to drugs not known to adversely affect pregnancy outcome. The primary end point was the incidence of major malformations. Secondary outcomes of interest were pregnancy outcome, rates of preterm delivery, birth weight, and developmental milestones. Results: One hundred eighteen women were exposed to terfenadine during pregnancy. Among those exposed during the first trimester (n = 65), rates of major malformations in the terfenadine group did not differ from rates in their matched control subjects (0% vs 2%; relative risk, 0.57; 95% confidence interval, 0.06-5.39; P = .53). The birth weight in the terfenadine-exposed newborns was significantly lower compared with that in their matched control subjects (3335 ± 582 vs 3499 ± 617 g; P = .04). However, the rates of birth weight below 2500 g and birth weight below the 10th percentile for gestational age were not different between the groups. Univariate and multiple regression analysis revealed that none of the terfenadine therapy–related factors (daily dose, duration of therapy, and trimester of exposure) had a significant predictive effect on birth weight. Gestational age at delivery, rates of preterm deliveries, and developmental milestones were comparable between the groups. Conclusions: On the basis of the limited sample size of this study, it appears that terfenadine is not associated with a 6-fold or greater increased incidence of major malformations. Terfenadine use during gestation was not associated with increased rates of prematurity or developmental delays. Further studies will be needed to confirm the finding of lower birth weight in newborns exposed to terfenadine. (J Allergy Clin Immunol 1999;104:953-6.)

Background: Fexofenadine hydrochloride (HCl) is a new H 1 antihistamine used twice daily in some countries. Objective: A multicenter, double-blind, parallel-group, placebo-controlled trial compared the efficacy and safety of fexofenadine HCl (120 and 180 mg administered once daily) and cetirizine (10 mg once daily) in the treatment of seasonal allergic rhinitis. Methods: After a 3- to 5-day run-in period, patients meeting entrance criteria were randomized to receive placebo, fexofenadine HCl 120 mg once daily, fexofenadine HCl 180 mg once daily, or cetirizine 10 mg once daily (active control) for 2 weeks. Eight hundred twenty-one patients comprised the intention-to-treat population and 722 patients completed the study. Symptom assessments were conducted 12 hours after the dose for the previous 12 hours and again at 24 hours after the dose for the previous 12 hours. In addition, assessment was made immediately before dosing in the morning for the previous 30 minutes. Total symptom score was calculated as the sum of scores for the 4 individual symptoms: (1) sneezing, (2) rhinorrhea, (3) itchy nose, palate, or throat, and (4) itchy, watery, or red eyes; the nasal congestion score was also recorded. Results: Both doses of fexofenadine HCl were superior to placebo in reducing the total symptom score. Efficacy was maintained for the entire dosing interval (ie, for 24 hours). There were no differences in efficacy between the 2 doses of fexofenadine HCl or between either dose of fexofenadine HCl and cetirizine. There was no major side effect, but the combined incidence of drowsiness or fatigue was greater with ce-tirizine (9%) than with placebo (4%) ( P = .07) or fexofenadine (4%) ( P = .02). Conclusions: Once-daily fexofenadine is thus a valuable addition to the nonsedating group of H 1 receptor antagonists currently available for the treatment of seasonal allergic rhinitis. (J Allergy Clin Immunol 1999;104:927-33.)

Background: Symptoms of chronic idiopathic urticaria (CIU) include relentless itching and painful wheals, which can be physically and psychologically debilitating. Half of all patients with urticaria have angioedema, which is often disfiguring. Objective: To evaluate the safety and efficacy of fexofenadine HCl for the treatment of CIU symptoms. Methods: In this 4-week, multicenter, placebo-controlled study, 439 patients with moderate to severe pruritus and urticaria received 1 of 4 oral doses of fexofenadine HCl (20, 60, 120, or 240 mg twice a day) or placebo. Patients reflectively assessed (over the previous 12 hours) the severity of pruritus, the number of wheals, and the interference with sleep (7 AM ) and normal activities (7 PM ) due to urticaria. Efficacy measures included a change from baseline of daily mean pruritus score (MPS), daily mean number of wheals (MNW) score, daily mean total symptom score (MTSS) (ie, the sum of the wheal and pruritus scores), and mean interference with sleep and daily activities due to urticaria. Results: All 4 doses of fexofenadine were statistically superior to placebo ( P ≤.0238) for MPS, MNW score, and MTSS. Patients receiving fexofenadine HCl also experienced significantly less interference with sleep and daily activities than patients receiving placebo ( P ≤.0001). Efficacy results were similar in the 60-, 120-, and 240-mg groups and were quantitatively better than those in the 20-mg group. Adverse events were mild and occurred with similar incidence in all treatment groups. Conclusions: Fexofenadine HCl is well tolerated and is statistically superior to placebo in reducing signs and symptoms of CIU and in ameliorating interference with sleep and daily activities due to urticaria. Doses of 60 mg twice a day or greater are most effective. (J Allergy Clin Immunol 1999;103:1071-8.)

Background: Fexofenadine, the hydrochloride salt of terfenadine active metabolite, is a nonsedative, noncardiotoxic antihistamine derivative for the treatment of allergic rhinitis. Objective: We sought to compare the effects of terfenadine and fexofenadine on nasal provocation tests with allergen. Methods: A preliminary provocation test (screening phase) was performed in 25 patients with a history of seasonal allergic rhinitis to grass pollen to determine the combined nasal reaction threshold, which was defined as 2 of the 3 following criteria: (1) at least a 40% decrease in peak nasal inspiratory flow and/or a 30% decrease in minimal cross-sectional area as measured by acoustic rhinometry, nasal secretions of 0.5 g, and 5 to 10 sneezes per minute. Patients were then included into a double-blind, randomized, 2-way crossover study to receive terfenadine or fexofenadine 120 mg 2 hours before provocation. Rhinorrhea, sneezing, peak nasal flow, and minimal nasal cross-sectional area, as well as symptom scores for nasal congestion and itchiness, were recorded at each allergen concentration up to the reaction threshold. The whole study was performed out of allergy season. Results: Fexofenadine was as potent as terfenadine in limiting pruritus and nasal congestion. Rhinorrhea and sneezing were better controlled by fexofenadine than by terfenadine. Overall, the allergen concentration necessary to reach the combined reaction threshold was increased after treatment with both drugs. Comparison between screening and each treatment phase indicated that the shift in allergen concentration to reach the reaction threshold was significantly greater after fexofenadine than after terfenadine ( P = .033). Conclusion: After oral administration, fexofenadine provided better protection than terfenadine against the immediate allergic reaction. (J Allergy Clin Immunol 1999;103:1025-30.)

With the prevalence of asthma and other allergic diseases increasing, the question of late-phase inflammatory response, a dynamic inflammatory response to a single exposure to antigen, has come to the forefront as one possible explanation for this increase in morbidity. If this explanation is acceptable, clinicians must examine their methods of management of allergic diseases and shift from crisis intervention with beta-agonists for asthma and first-generation antihistamines or decongestants for rhinitis to disease control with antiinflammatory agents. Topical application of corticosteroids to the upper airways blocks mediator release from the early and late phases after antigen challenges. In addition, recent studies using the skin-blister chamber model have shown that some of the newer, second-generation antihistamines may attenuate the infiltration and activation of eosinophils, neutrophils, and basophils during the late-phase response. Immunotherapy may have a selective effect, targeting inflammatory aspects of the late-phase response. It is clear that corticosteroids, second-generation antihistamines, and immunotherapy play a role in modifying the late-phase response and that each of these therapeutic modalities may operate by a different mechanism.

Drug selection for optimal treatment of common medical conditions may be difficult and involve many diverse factors.The efficacy, safety, quality of life, and cost of treatment of seasonal allergic rhinitis with cetirizine, chlorpheniramine, or terfenadine were compared in a prospective, two-phase, randomized, single-blind clinical trial conducted in a managed care setting.In phase I, which lasted 2 weeks, patients were randomized to receive one of the study drugs. In phase II, which lasted 4 weeks, the initial treatment was continued unless patients were dissatisfied, in which case they could be randomly assigned to receive another study drug. In both phases pseudoephedrine could be taken as needed. Patients kept daily diaries of symptoms and costs, and study drugs were evaluated at the end of each phase for efficacy, safety, and effect on quality of life by means of a validated questionnaire. A multiattribute outcomes assessment model for formulary decision making was used to rank the antihistamines.Physicians' and patients' assessments in phases I and II indicated that cetirizine and chlorpheniramine were significantly more effective than terfenadine (p0.05). Incidence of sedation in phase I and phase II was 40.5% and 16.7% for chlorpheniramine, 11.6% and 9.8% for cetirizine, and 6.7% and 5.1% for terfenadine, respectively. At the end of phase I, 28.9% of the patients treated with chlorpheniramine, 50% of the patients treated with terfenadine, and 69.4% of the patients treated with cetirizine were satisfied with their therapy and chose not to switch their medication. Quality of life scores improved most after treatment with cetirizine and least after treatment with terfenadine.The result of this trial indicate that antihistamine selection is best made with the use of a multiattribute evaluation that includes quality of life. In this study cetirizine was favored by patients and physicians most often, followed by chlorpheniramine and then terfenadine.

Objective: The objective of this study was to compare the efficacy and side effects of sodium cromoglycate eye drops (Opticrom 2%) used regularly versus as needed in the treatment of seasonal (ragweed) allergic conjunctivitis. Methods: A randomized, unblinded, parallel group comparison was performed during the 6 weeks of the ragweed pollen season. Sixty-two adults with ragweed pollen–induced conjunctivitis were recruited for the study from previous ragweed studies and notices in the local media. Two drops of sodium cromoglycate were placed in each eye either four times daily (regular treatment group) or when needed, up to four times daily (prn group), from 1 week before and throughout the ragweed pollen season. Uncontrolled eye symptoms were treated with terfenadine 60 mg as needed, up to 120 mg daily. Subjects kept daily diaries for symptoms and medication requirements throughout the 6 weeks of treatment. The Rhinoconjunctivitis Quality of Life Questionnaire was administered and adverse experiences were reported after 1, 3, and 6 weeks of treatment. Results: Diary eye symptoms were similar in the two treatment groups, but quality of life was better in the regular treatment group. There was a trend for the prn group to require more terfenadine for uncontrolled eye symptoms. Conclusions: There may be some additional therapeutic benefit from using sodium cromoglycate eye drops regularly throughout the ragweed pollen season. (J ALLERGY CLIN IMMUNOL 1994;94:36-43.)

To investigate the role of H 1 receptor-mediated effects in allergic rhinitis, we challenged 12 allergic volunteers with allergen 2 hours after administration of either placebo or 60 mg of terfenadine. Filter paper discs were used for the unilateral administration of allergen and the collection of nasal secretions. Secretion weights, levels of histamine in recovered nasal secretions, and nasal airway resistance (NAR) were measured for each nostril separately, and the number of sneezes was counted. After placebo treatment, allergen challenge led to significant increases in ipsilateral and contralateral secretion weights, ipsilateral histamine levels, ipsilateral NAR, and sneezing. Contralateral histamine levels were not elevated. H 1 antagonism with terfenadine markedly reduced the number of sneezes and partially decreased ipsilateral and contralateral secretion weights, without affecting the increase in NAR. Terfenadine premedication also lowered the amount of histamine in ipsilateral secretions after allergen challenge. Performing identical nasal challenges with a 10-fold lower dose of antigen produced similar results. Previous studies showed that terfenadine had no effect on methacholine provocation and completely abolished ipsilateral and contralateral secretion weights after histamine challenge. We conclude that sneezing after allergen challenge is caused almost exclusively by a reflex initiated through H 1 receptors and that H 1 antagonism has no influence on allergen-induced increases in NAR. Unilateral allergen challenge leads to bilateral increases in secretion weights, which are only partially inhibited by terfenadine, suggesting the involvement of mediators other than histamine in the nasonasal reflex. As reported earlier, terfenadine also decreases allergen-induced histamine release after challenge with the highest dose of antigen. (J ALLERGY CLIN IMMUNOL 1994;93:594-605.)

Background: Kinins are potent vasoactive oligopeptides that may act as mediators in a variety of inflammatory diseases of the skin by interacting with specific receptors designated B 1 and B 2 In this study we have investigated the structure-activity relationship of intradermally injected bradykinin, kallidin (lysine-bradykinin), and [desArg 9 ]-bradykinin in atopic ( n = 8) and nonatopic ( n = 8) subjects. Methods: On two separate occasions, each separated by a week, subjects randomly underwent intradermal challenge with incremental doses (0.5, 5, and 50 nmol) of either the B 1 -agonist [desArg 9 ]-bradykinin, the B 2 -agonists bradykinin or kallidin, or vehicle placebo. In a separate randomized double-blind study we have also examined the effect of an orally administered antihistamine, terfenadine, on kinin-induced wheat and flare responses and their repeatability in a group of nine volunteers. The skin responses were monitored objectively by measurement of wheal and flare areas. Results: Both bradykinin and kallidin induced a dose-dependent increase in wheal and flare areas in all subjects studied. Although the effects of the two lowest doses (0.5 and 5 nmol) of [desArg 9 ]-bradykinin on skin responses were indistinguishable from those of placebo, this kinin at the highest dose administered (50 nmol) caused a significant increase in wheal and flare areas in all subjects studied. No difference could be identified in the skin responses to kinins between atopic and nonatopic subjects. In addition kinin-induced cutaneous responses were not altered by pretreatment with terfenadine. Conclusions: These in vivo structure activity studies suggest that in human beings the skin responses to kinins may be compatible with the stimulation of B 2 receptors, which is unrelated to histamine release from cutaneous mast cells.

Background: This study was designed to compare the efficacy and tolerability of a new topical (nasal spray and eye drops) H1-receptor antagonist, levocabastine, with that of orally administered terfenadine for the prophylaxis and treatment of seasonal allergic rhinoconjunctivitis. Methods: A total of 115 patients with documented birch pollen allergy were enrolled in this randomized, double-blind, double-dummy, parallel-group trial. Treatment was initiated immediately before the birch pollen season started and continued for a total of 8 weeks. Xylometrazoline (Otrivin) nasal spray was permitted as rescue medication. Results: The investigator's evaluation of symptoms showed similar effects for levocabastine and terfenadine. Both the patients' and the investigator's global evaluations of ocular and nasal symptoms disclosed a somewhat higher percentage of good or excellent results for levocabastine, but the differences were not statistically significant. Visual analog scale ratings from the patients' diaries showed better results for levocabastine. Levocabastine was significantly more effective than terfenadine in relieving sneezing, rhinorrhea, lacrimation, itch, and burning sensation (p < 0.05). For some symptoms, levocabastine was significantly more effective than terfenadine on days when the pollen count was high. There were no statistically significant differences in the use of rescue medication or in the incidence of adverse reactions reported in each treatment group. Conclusions: In the present study topical levocabastine was frequently more effective than orally administered terfenadine for the treatment of seasonal allergic rhinoconjunctivitis. Both drugs were well-tolerated.

Background: The development of potent H 1 -receptor antagonists that are free of adverse effects has renewed interest in their use in the treatment of asthma. Methods: We performed a study of the action of chlorpheniramine, terfenadine, brompheniramine, cetirizine, cyproheptadine, clemastine, and astemizole compared with placebo on histamine-induced skin wheals and bronchoconstriction in a single group of patients with asthma. Another group underwent methacholine bronchoprovocation. Results: Antihistamine pretreatment increased mean baseline measurements of forced expiratory volume in 1 second (FEV 1 ) between 2.58% and 9.28% compared with placebo, which was significant for all drugs except brompheniramine and clemastine. Compared with placebo, all antihistamines provided significant protection against histamine-induced bronchoconstriction when measured as the provocation concentration required to cause a 20% fall in FEV 1 ; terfenadine and cetirizine provided significantly greater protection than other antihistamines. Protection against histamine-induced skin wheals, measured as the slope of the log concentration-response curve, was only significant for the new drugs, terfenadine and cetirizine. There was a good correlation between the protective effect of the drugs in the skin and airways ( r = 0.85; p 1 values between treatments was found. Conclusions: The new H,-receptor antagonists terfenadine and cetirizine provided significantly better protection than the older antihistamines against the action of histamine in the skin and airways. None of the antihistamines showed evidence of anticholinetgie activity in the asthmatic airways at the doses studied.

Phenindamine, an H1-receptor antagonist that was developed almost 50 years ago, has been associated with both drowsiness and insomnia. Since its central nervous system profile has not been well characterized, we used a series of psychomotor tests to conduct two studies. In the first, 12 subjects received single oral doses of phenindamine (25 mg), diphenhydramine (50 mg), terfenadine (60 mg), or placebo in a four-way crossover study. Psychomotor tests included choice reaction time (CRT), tracking, and hand steadiness (HS). In the second trial, 15 subjects received single oral doses of phenindamine (25 mg), pseudoephedrine (60 mg), phenindamine and pseudoephedrine, diphenhydramine (50 mg), or placebo in a five-way crossover study. Psychomotor tests included CRT, HS, and a task that divided attention between tracking and reaction time. Introspective drowsiness was measured in both trials with use of a visual analog scale (VAS) and the Stanford Sleepiness Scale (SSS). All assessments were made before and 1, 3, and 5 hours after drug administration. In the first trial, diphenhydramine produced significant impairment relative to placebo (p < 0.05) in CRT, tracking, and HS tasks and higher SSS and VAS scores, with peak effect noted at 3 hours. Phenindamine did not significantly differ from placebo or terfenadine. In the second trial, diphenhydramine produced significant impairment relative to placebo (p < 0.05) in CRT, divided attention, HS, and VAS, and SSS, also peaking at 3 hours. Stanford Sleepiness Scale scores after phenindamine were greater than placebo at 3 hours (p < 0.05) but significantly less than diphenhydramine (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

A nasal lavage model and a new filter paper disk model have been used to measure biologic and physiologic responses to antigen challenge in patients with allergic rhinitis. Pretreatment of subjects with cetirizine reduced the number of sneezes induced by antigen challenge but did not significantly reduce levels of histamine or prostaglandin D2 in a double-blind, placebo-controlled trial with the lavage model. Pretreatment with 60 or 300 mg of terfenadine did significantly reduce levels of histamine, kinin, albumin, and TAME-esterase activity in a double-blind, placebo-controlled study with this model. Again with the nasal lavage model, a double-blind, placebo-controlled comparison of pretreatment with 60 mg of terfenadine or 10 mg of loratadine showed that both agents significantly reduced sneezing. Both drugs also lowered levels of antigen-induced histamine and TAME-esterase, but only terfenadine did so significantly. In a double-blind, placebo-controlled study, the new disk method showed that terfenadine reduced sneezing but not nasal congestion in eight patients with allergic rhinitis. Terfenadine significantly reduced the weight of nasal secretions on both sides of the nose and significantly reduced histamine on the ipsilateral side.

Some of the second-generation H1 antihistamines reduce the bronchoconstrictor response after exercise and antigen challenge. For example, terfenadine causes a slight but significant increase in forced expiratory volume after 1 second. At doses of 120 and 240 mg, terfenadine has a protective effect against asthma induced by ultrasonic nebulized distilled water and cold air hyperventilation challenge. Certain other newer antihistamines, such as ketotifen, azelastine, and cetirizine, have additional antiallergy properties. These effects include inhibition of eosinophil, basophil, and neutrophil migration and platelet-activating factor-induced eosinophil accumulation in skin. The ability of cetirizine (and perhaps other antihistamines) to inhibit these responses at usual therapeutic doses may be useful in investigating the late allergic reaction.

The aim of this study was to investigate the effect of terfenadine, an antihistamine, 180 mg orally, the anticholinergic drug, ipratropium bromide (IB), 0.5 mg nebulized aerosol, the combination of these two drugs, and placebo tablets and aerosol on histamine- and adenosine 5'-monophosphate (AMP)-induced bronchoconstriction in a randomized, double-blind fashion. Airway response was evaluated as FEV1. After placebo, the geometric mean (GM) provocative concentration causing a 20% in FEV1 from the postsaline baseline value (PC20) for histamine and AMP was 0.63 and 5 mg/ml, respectively. Terfenadine displaced the FEV1 concentration-response curves obtained with both histamine (GM PC20 values increasing to 26.92 mg/ml) and AMP (GM PC20 values increasing to 26.7 mg/ml) to the right. IB had a small, but significant, protective effect against the fall in FEV1 produced by histamine and AMP, the GM PC20 values increasing to 1.69 and to 12.6 mg/ml, respectively. Terfenadine and IB in combination produced protection against histamine and AMP that was more than the production produced by either drug alone, the GM PC20 values increasing to 54.76 and 47.7 mg/ml, respectively. There was no correlation between degree of bronchodilatation induced by active treatments and concentration ratios for AMP or histamine. These data suggest that histamine release and vagal reflexes both contribute to AMP-induced bronchoconstriction in clinical asthma in man.

H1-receptor antagonists are usually first-line treatment given for seasonal allergic rhinitis. However, many patients suffer with symptoms of allergic rhinitis rather than tolerate the sedative and anticholinergic side effects of the first-generation H1-receptor antagonists. Researchers have sought to replace these older H1-receptor antagonists with a new generation of H1-receptor antagonists that approach the optimal therapy: clinically effective, safe, free of side effects, and convenient for the patient. Among the new second-generation H1-receptor antagonists are terfenadine and astemizole (already marketed) and loratadine and cetirizine, which are expected to be approved soon. All four demonstrate efficacy, convenience, and minimal side effects on the central nervous system. In this review of the current treatment of seasonal allergic rhinitis, the clinical studies that compare these four new second-generation H1-receptor antagonists are discussed.

The second-generation H1-receptor antagonists terfenadine, astemizole, loratadine, and cetirizine are important first-line drugs for the relief of symptoms in patients with allergic rhinoconjunctivitis or chronic urticaria and may eventually supplant the potentially sedating first-generation H1-receptor antagonists in the treatment of these disorders. Terfenadine, astemizole, loratadine, and cetirizine produce an incidence of central nervous system and anticholinergic adverse effects similar to that produced by placebo. Our ability to use H1-receptor antagonists optimally has been greatly enhanced by recent pharmacokinetic and pharmacodynamic studies of these medications.

We objectively tested the relative antihistaminic effects of cetirizine, 10 mg; terfenadine, 120 mg; terfenadine, 60 mg; loratadine, 10 mg; astemizole, 10 mg; chlorpheniramine, 4 mg; and placebo in healthy, male volunteers, mean age 25±4 years, and mean weight, 73±9 kg. The wheal areas and flare areas produced by epicutaneous tests with histamine phosphate, 1 mg/ml, before ingestion of the H 1 -receptor antagonist or placebo, and afterward, at 0.3 and 0.7 hours, then hourly from 1 to 12 hours and at 24 hours, were traced at 10 minutes and measured with an IBM-PC digitizer and stereometric software. In this experimental model, the H 1 -receptor antagonists differed significantly with regard to time of onset of action, amount of suppression of the histamine-induced wheal and flare, and duration of action. The rank order was, from most effective to least effective, cetirizine, 10 mg; terfenadine, 120 mg; terfenadine, 60 mg; loratadine, 10 mg; astemizole, 10 mg; chlorpheniramine, 4 mg; and placebo.

For many years, H 1 , antihistamines have been the primary management option for urticaria. However, undesirable side effects, particularly daytime sedation, have limited the usefulness of these classic antihistamines. A new class of peripherally acting, nonsedating antihistamines (e.g., terfenadine, astemizole, loratadine, and cetirizine) has proved to have clinical efficacy comparable with the classic antihistamines. In comparative trials between the various nonsedating agents, no significant difference in efficacy has been noted. All these agents have good safety profiles, although astemizole use has been correlated with increased appetite and weight gain in some patients, and cetirizine has caused slightly increased sedative effects compared with placebo. Although H 1 /H 2 antihistamine combinations have been proposed as possible treatments for urticaria, studies have produced mixed results.

Unlike the classic antihistamines, the new H 1 -receptor antagonists do not block cholinergic or central H 1 receptors and thus do not produce the side effects, such as sedation, impaired psychomotor performance, and excessive mucosal drying, that are commonly associated with the older agents. Important pharmacokinetic and pharmacodynamic differences that exist among this class of antihistamines translate into varying pharmacologic effectiveness. Terfenadine, loratadine, and cetirizine are all rapidly absorbed in healthy and allergic volunteers (peak plasma levels, 2 to 5 hours); astemizole, however, has an initial distribution phase of 2 to 3 days. Further, astemizole has the longest time to relief of symptoms in this class: histamine wheal inhibition is not apparent until the second day of 10 mg dosing and does not peak for 9 to 12 days. In comparison, terfenadine's antihistaminic action peaks at 3 to 4 hours, loratadine's at 4 to 6 hours, and cetirizine's at 4 to 10 hours. However, whereas the recommended dose of loratadine (10 mg) confers 50% wheal inhibition, 60 mg terfenadine produces an 85% to 90% inhibition. In addition, loratadine and cetirizine have apparent dose-related sedative effects.

We compared the effects of pretreatment of 800 micrograms of inhaled Smith KlineFrench (SKF) 104353, a leukotriene receptor antagonist, and 120 mg of oral terfenadine on the bronchial responses to inhaled histamine in 12 subjects with asthma. The study took place on 3 different days and was conducted according to a double-blind, crossover, double-dummy, randomized, and placebo-controlled design. There was no difference in baseline and prechallenge FEV1 after placebo, SKF 104353, and terfenadine administration. The median ratio of the provocative dose causing a 20% fall in FEV1 from baseline (PD20) with terfenadine over PD20 with placebo was 12.36 (range, 3.2 to 30.3; p less than 0.01) and that of PD20 with SKF 104353 over PD20 with placebo was 1.51 (range, 0.8 to 5.9; not significant). Analysis of individual results demonstrated a shift toward the right of the dose-response curves to histamine with SKF 104353 compared to that with placebo in three subjects, whereas the active compound did not exhibit any protective effect against histamine in the remaining nine subjects. We conclude that there is a leukotriene component to the bronchial responses to histamine in some, but not all, subjects. This component remains, however, small and does not appear to be clinically important in the population of subjects with asthma that was studied.

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.

Background Nasal H 3 receptors might have a role in mediating the effects of histamine in patients with allergic rhinitis. Objective This study explored the effect of the potent oral H 3 receptor antagonist PF-03654746 in combination with an oral H 1 receptor antagonist on the objective (acoustic rhinometry) and subjective (symptoms) responses to nasal allergen challenge. Methods Twenty patients with out-of-season allergic rhinitis displaying a 30% or greater decrease in minimum nasal cross-sectional area (A min ) after bolus (ragweed) complete nasal allergen challenge at screening were studied by using a randomized, double-blind, single-dose, 4-way crossover design. Treatments included 10 mg of PF-03654746 plus 60 mg of fexofenadine (group 1), 1 mg of PF-03654746 plus 60 mg of fexofenadine (group 2), 60 mg of fexofenadine/120 mg of pseudoephedrine (group 3), and placebo (group 4). After dosing, subjects underwent complete nasal allergen challenge. Nasal symptom scores (no. of sneezes and 0- to 5-point scores for severity of congestion, itching, and rhinorrhea), A min (in square centimeters), and nasal volume (in cubic centimeters) were recorded 15, 30, 45, and 60 minutes after allergen. There was a minimum 10-day washout between periods. Results The following symptom scores were significantly ( P ≤ .05) reduced by active treatments versus placebo: group 1, congestion of −0.7 (SE, 0.3), itching of −1.0 (SE, 0.3), rhinorrhea of −1.3 (SE, 0.3), and sneeze of −8.8 (SE, 1.5); group 2, itching of −0.6 (SE, 0.3), rhinorrhea of −0.8 (SE, 0.3), and sneeze of −9.1 (SE, 1.5); and group 3, rhinorrhea of −0.7 (SE, 0.3) and sneeze of −7.0 (SE, 1.5). There was no significant effect of any treatment on mean A min proportion or nasal volume proportion after nasal allergen challenge. Conclusions In combination with fexofenadine, single doses of PF-03654746 caused a reduction in allergen-induced nasal symptoms. H 3 receptor antagonism might be a novel therapeutic strategy to further explore in patients with allergic rhinitis.

The recent advances in therapy for allergic diseases, including allergic rhinitis, asthma, and urticaria, have posed new challenges to physicians who must carefully assess the risks and benefits to the patient of new treatment. Appreciation of the drug interaction between certain second-generation antihistamines, including terfenadine and astemizole, with selective macrolide antibiotics and imidazole antifungal agents leading to QTc interval prolongation, and the potential for fatal cardiac arrhythmias is an example of the need to assess risks of therapy. Risk management in allergic disease includes minimizing disease morbidity by emphasizing allergen avoidance in asthma and by minimizing the therapeutic morbidity and mortality that can occur when allergen immunotherapy is administered either improperly, such as in an unsupervised setting, or inappropriately, such as to unstable asthmatics. Physicians must carefully weigh the benefits of therapies designed to decrease costs, including regimens combining second- and first-generation antihistamines, considering both the potential risk ensued related to sedation and impaired cognitive performance when using first-generation antihistamines and the unproven efficacy of such regimens. Clearly, risk management in asthma and allergic disease will become more complex with greater understanding of mechanisms of allergic disease, of provocative factors exacerbating allergic disease, of the potential adverse consequences of therapy, and of the potential interaction among therapeutic modalities. It is essential that physicians treating the nearly 20% of Americans who have allergic disease thoroughly appreciate the risks and benefits of their therapeutic decisions. (J Allergy Clin Immunol 1996;98:S289-90.)

Rationale To date, the primary pharmacological target of antiallergic drugs (antihistamines) has been regarded as the histamine H 1 -receptor. However, previous studies have shown that terfenadine may suppress IL-4–modulated gene expression of T-cell cytokines, indicating that this agent may have immunomodulatory properties. Therefore, in the present study we assessed whether other currently available antihistamines also possess immunomodulatory properties. Methods T-cells were isolated from peripheral blood samples, pre-incubated with various doses of Cetirizine, Loratadine, Olopatadine or Fexofenadine for 30 minutes and then stimulated with interleukin (IL)-12 or IL-4 to skew the immune response towards Th1 or Th2. Six hours later RNA was extracted and semi-quantitative RT-PCR was performed using primers for IL-4, IL-5 or interferon (IFN)-γ. Supernatants were collected 24 hours after stimulation and ELISA assays were performed to determine the production of cytokines. Results RT-PCR revealed that IL-12–induced expression of IFN-γ was partially suppressed by Loratadine or Fexofenadine, while all agents markedly inhibited IL-4–induced expression of IL-4 and IL-5. ELISA assays demonstrated that IL-12–induced IFN-γ production was moderately, but significantly suppressed by Cetirizine or Fexofenadine ( p Conclusions Our study demonstrates that antihistamines may exert modulatory effects on IL-4– or IL-12–induced T-cell activation. Since the local cytokine milieu of allergic disease may be biased to Th1 or Th2, depending on the disease state or conditions, these findings may provide a further understanding of the impact of antihistamines in allergic conditions.

Eleven healthy male volunteers ingested terfenadine, 60 mg, every 12 hours for 56 days. Compliance was monitored strictly throughout the study. Before the first terfenadine dose on day 0, and 12 hours after the evening terfenadine dose every seventh day and on randomly selected "unscheduled" days, wheal-and-flare areas were measured after intradermal injections of 0.01 ml of histamine phosphate (1.0 mg/ml and 0.1 mg/ml). On days 0, 28, and 56, six volunteers had skin tests hourly for 12 hours after the morning terfenadine dose. On all study days, serum terfenadine metabolite I concentrations were measured each time histamine skin tests were performed. On days 7, 14, 21, 28; 35, 42, 49, and 56, the mean areas of the histamine-induced wheals did not differ significantly from each other but were significantly decreased compared to the mean wheal area on day 0 ( p p p p p p = 0.01). On day 56 in the subgroup, the mean wheal areas did not differ significantly from before the dose to 12 hours after the dose, nor did the mean flare areas differ significantly at any time ( p = 0.01). The mean serum concentration of terfenadine metabolite 112 hours after the evening dose did , not differ significantly on days 7, 14,21, 28, 35, 42, 49,adn 56 ( p = 0.01). Unscheduled serum terfenadine metabolite I concentrations measured 12 hours after the dose provided additional confirmation of compliance. In the subgroup, the mean serum elimination half-life value and the mean area under the serum concentration versus time curve of terfenadine metabolite I did not differ significantly on day 0, day 28, or day 56 ( p = 0.01). We conclude that subsensitivity to the antihistaminic effect of terfenadine did not develop during 56 days in compliant subjects, as evidenced by continued suppression of the histamine-induced wheals and flares. Also, the pharmacokinetics of terfenadine metabolite 1 remained unchanged after 56 days of terfenadine treatment.

The efficacy of terfenadine, a nonsedating H1 antihistamine, in the management of chronic idiopathic urticaria was compared with chlorpheniramine and placebo in a parallel multicenter trial. Subjects with symptoms of hives for 3 days per week for at least 6 weeks were initially screened and admitted if no identifiable cause for symptoms could be determined. Patients entered a single-blind placebo period, and if hives of moderate severity were present for at least 3 days during the week, they were randomly assigned in a double-blind fashion to take terfenadine, 60 mg twice daily, chlorpheniramine, 4 mg three times a day, or placebo for 6 weeks. Data were analyzed for 122 patients. Those patients receiving both active treatments noted significant improvement in symptoms: pruritus, redness, number of hives, and waking hours during which hives were present, at the end of the first day of therapy. Symptom control by terfenadine was statistically superior to placebo during all 6 weeks, as rated by both patients and investigators. However, statistical significance was not achieved for chlorpheniramine at all observation points. Diphenhydramine was permitted as a relief medication for refractory symptoms and was taken by 52% of subjects receiving placebo, 26% taking chlorpheniramine, and only 9% of patients who were receiving terfenadine. In addition to providing superior symptom control, terfenadine caused less drowsiness and fatigue than chlorpheniramine. Terfenadine is a useful therapeutic agent for primary management of chronic idiopathic urticaria.

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.

Loratadine, a new nonsedating antihistamine, was evaluated for efficacy and safety in 228 patients with perennial allergic rhinitis. Taken at a dose of 10 mg once daily, loratadine was significantly more effective than placebo and comparable to terfenadine, 60 mg taken twice daily, in reducing combined symptom scores in this patient population. Efficacy was maintained throughout the 28-day course of treatment. The overall incidence of side effects with loratadine was low (14%) with few occurrences of sedation (3%) and dry mouth (4%).

Most oral drugs used for the treatment of allergic rhinitis are classified as H1-receptor antagonists, and although they represent major sales throughout the world, their mechanism of action is still poorly known. In an attempt to understand better the in vivo therapeutic effects of these drugs, a double-blind, crossover study was carried out. The study compared the effects of terfenadine and loratadine, nonsedative H1-receptor antagonists, on the immediate allergic response of the upper airways to challenge with orchard-grass pollens in 14 highly allergic subjects. Increasing numbers of pollen grains were insufflated into the nostrils, and the response of the subjects was assessed by examining symptoms and measuring the release of histamine and prostaglandin D2 in nasal secretions. Each drug was administered for a week before challenge. This study demonstrated the clinical efficacy of both drugs by comparison to that of a control day, since symptoms were observed for a significantly (p = 0.014) greater number of pollen grains. Only one patient had a significant release of histamine when they were treated with loratadine versus 10 during control day (p < 0.0023) and six when they were treated with terfenadine (p < 0.01). Prostaglandin D2 release occurred with a higher allergen dose when patients were treated with both drugs. This study indicates that some H1 antagonists also possess antiallergic activities.

The H1-histamine antagonist, terfenadine, has been proposed to have reduced cognitive side effects. In the present study, the relative cognitive effects of terfenadine, 60 mg, chlorpheniramine maleate, 8 mg, and placebo were tested with a double-blind, randomized, three-period crossover design in 24 healthy adult subjects. The dependent variable was latency of the P3-evoked potential. The P3 is a cognitively evoked electroencephalographic response that is an objective and sensitive measure of sustained attention and cerebral processing speed. Disease and drug states that adversely affect the central nervous system can slow P3 latency. For example, the centrally active anticholinergic scopolamine slows cognitive processing speed and prolongs P3 latency. P3 latency (millisecond) means (+/- mean standard error) were pretreatment, 310 (+/- 1.7; placebo, 313 (+/- 3); terfenadine, 320 (+/- 3); and chlorpheniramine, 333 (+/- 3). The findings suggest that terfenadine may be particularly advantageous in patients who require alertness and intact cognitive abilities.