Therapeutic points of intervention and clinical implications: role of desloratadine

Desloratadine, a potent, once-daily, orally active, nonsedating, histamine H₁-receptor antagonist, inhibits the release of histamine and other inflammatory mediators. Once-daily desloratadine therapy rapidly reduces the symptoms of perennial allergic rhinitis and seasonal allergic rhinitis (SAR), reduces the use of inhaled albuterol by patients with SAR and concomitant asthma, and improves symptoms and quality of life in patients with chronic idiopathic urticaria. An open-label, observational study in SAR patients revealed that desloratadine therapy significantly reduced nasal, ocular, dermal, asthma, and total symptoms, and enabled half of the patients with concomitant asthma to reduce their use of asthma medications. Globally, more than 91% of patients and physicians judged desloratadine to have excellent or good efficacy, and more than 98% judged it to have excellent or good tolerability. Furthermore, desloratadine therapy improved quality of life, decreasing by more than 10-fold the percentage of patients whose daily activities and/or sleep were moderately or severely affected by SAR. Allergic rhinitis, a major chronic airway disease that is a risk factor for asthma, warrants extended diagnostic procedures and well-tolerated therapy that encompasses the entire airway, addresses multiple steps in the allergic inflammatory cascade, and is effective on nasal, ocular, dermal, asthma, and total symptoms.     

Desloratadine activity in concurrent seasonal allergic rhinitis and asthma

Seasonal allergic rhinitis (SAR) and asthma, which are frequently comorbid, share some common allergic pathogenic bases. Clinical manifestations of these disorders might therefore be viewed as local manifestations of a systemic inflammatory state. Not only do the onsets of allergic-rhinitis (AR) and asthma symptoms often coincide (within 1 year), but also nasal challenges with SAR allergens can induce airways hyperreactivity (AHR). Eosinophils, which are key effector cells in both SAR and asthma, cause AHR, tissue damage, and neuronal effects through secretion of toxic granule proteins, enzymes, and other mediators. The novel, nonsedating, histamine H₁-receptor antagonist, desloratadine, which exerts various favorable effects on the allergic cascade, significantly decreased SAR symptoms (e.g., nasal congestion) and diminished daily β₂-agonist use and improved asthma symptoms, while maintaining pulmonary function, in patients with SAR-asthma who were treated with once-daily desloratadine regimens.     

The pharmacologic profile of desloratadine: a review

Desloratadine is a new agent for the treatment of diseases such as seasonal allergic rhinitis and chronic urticaria. The pharmacologic profile of desloratadine offers particular benefits in terms of histamine H₁-receptor binding potency and H₁ selectivity. Desloratadine has a half-life of 21–24 h, permitting once-daily dosing. No specific cautions are required with respect to administration in renal or hepatic failure, and food or grapefruit juice have no effect on the pharmacologic parameters. No clinically relevant racial or sex variations in the disposition of desloratadine have been noted. In combination with the cytochrome P450 inhibitors, ketoconazole and erythromycin, the AUC and C_max of desloratadine were increased to a small extent, but no clinically relevant drug accumulation occurred. With high-dose treatment (45 mg/day for 10 days), no significant adverse events were observed, despite the sustained elevation of plasma desloratadine levels. Specifically, desloratadine had no effects on the corrected QT interval (QTc) when administered alone, at high dose, or in combination with ketoconazole or erythromycin. Preclinical studies also show that desloratadine does not interfere with HERG channels or cardiac conduction parameters even at high dose. Desloratadine is nonsedating and free of antimuscarinic/anticholinergic effects in preclinical and clinical studies. Novel antiallergic and anti-inflammatory effects have also been noted with desloratadine, a fact which may be relevant to its clinical efficacy.     

Decongestant efficacy of desloratadine in patients with seasonal allergic rhinitis

Recent advances in experimental immunologic approaches to seasonal allergic rhinitis (SAR) have led to a shift in the concepts of its pathogenesis. The conventional view of SAR as a local response to inhaled allergens has largely given way to a new view of this disorder as a systemic condition with local tissue manifestations. This concept, together with an increasing recognition of specific mediators' distinct roles in driving the early- and late-phase allergic responses, has opened multiple lines of therapeutic attack within the allergic cascade. Potent inhibition of inflammatory mediator release at distinct points in this cascade is conferred by desloratadine. In addition to the familiar range of SAR symptoms amenable to antihistamine therapy, desloratadine uniquely attenuates patient ratings of nasal congestion. This novel, nonsedating histamine H₁-receptor antagonist is the only once-daily antiallergic product with a consistent decongestant effect that begins within hours of the first morning dose and is sustained for the entire treatment period.     

Is antihistamine (H1-receptor antagonist) therapy useful in clinical asthma?

Airway hyperresponsiveness to histamine is a hallmark of asthma, and histamine inhalation reproduces asthma symptoms. Plasma histamine concentrations are elevated during the early and late responses to inhaled allergens, and may also increase during spontaneous acute asthma episodes. Ordinary doses of currently available antihistamines (H₁-receptor antagonists) have minimal bronchodilator and bronchoprotective activity. In severe persistent asthma, H₁ antagonists have no significant clinical effect. In moderate persistent asthma, clinical benefits of H₁ antagonists are apparent, but may not be worth the potential risks of the higher-than-usual doses required. When mild seasonal asthma and allergic rhinitis coexist, however, relief of rhinitis symptoms with H₁ antagonists administered in ordinary dose is associated with significant improvement in asthma symptoms.     

Safety and efficacy of desloratadine 5 mg in asthma patients with seasonal allergic rhinitis and nasal congestion.

BACKGROUND: Antihistamines relieve most seasonal allergic rhinitis (SAR) symptoms, with the exception of nasal congestion, which is often the most troublesome symptom for patients. A nonsedating antihistamine that significantly decreases nasal congestion and improves symptoms of seasonal allergic asthma would be a significant advance in therapy. OBJECTIVES: To evaluate the safety and efficacy of desloratadine 5 mg in patients experiencing moderate SAR, nasal congestion, and symptoms of seasonal allergic asthma. METHODS: This 4-week, multicenter, parallel-group, double-blind study evaluated desloratadine treatment (5 mg once daily) versus placebo in 331 subjects with SAR and mild seasonal allergic asthma. Subjects evaluated SAR and asthma symptoms twice daily, recording 12-hour reflective and instantaneous severity evaluation scores. The primary efficacy parameter was the difference from baseline in AM/PM reflective total symptom scores. Changes in individual SAR and asthma symptoms were also analyzed. RESULTS: Compared with placebo, desloratadine significantly reduced mean AM/PM reflective total symptom scores for SAR, beginning with the first dose (P < 0.001) and continuing throughout days 1 to 15 (-4.90 vs -2.98; P < 0.001) and days 1 to 29 (-5.47 vs -3.73; P < 0.001). Desloratadine significantly decreased AM/PM reflective total asthma symptom scores for days 1 to 15 (P = 0.023) and AM/PM reflective nasal congestion scores over days 1 to 15 and days 1 to 29 (P = 0.006 and P = 0.014, respectively). Desloratadine was safe and well tolerated; adverse events were similar to placebo overall. CONCLUSIONS: Desloratadine provided significant relief from the signs and symptoms of SAR, including nasal congestion. In this patient population, symptoms of seasonal allergic asthma also improved.     

H1-receptor antagonists: effects on leukocytes, myth or reality?

H₁-receptor antagonists of the first and second generation have been used for many years to relieve symptoms arising from the action of histamine on the H₁ receptor. However, allergic inflammation is more than histamine release and action. Leukocyte infiltration during late allergic manifestations was demonstrated as being a hallmark of allergic inflammation. Second-generation H₁-receptor antagonists were studied in models of mast cell degranulation in vitro and of leukocyte infiltration in vivo . Analysis of the literature showed that a drug which is no more metabolized than cetirizine and fexofenadine allows a better relevance of in vitro models. Up to now, cetirizine was the only product in vivo able to reduce eosinphil infiltration in skin, nose, eyes and lungs during experimental allergenic challenges and late allergic inflammatory manifestations. Today, relevance of these properties can be seen in the recently published clinical results showing that cetirizine prevents the development of asthma in specifically sensitized infants with atopic dermatitis.     

Comparative effects of desloratadine versus montelukast on asthma symptoms and use of beta 2-agonists in patients with seasonal allergic rhinitis and asthma

BACKGROUND: Asthma and seasonal allergic rhinitis (SAR) are recognized as manifestations of a single airway disease. Desloratadine has demonstrated efficacy in treating SAR symptoms, including nasal obstruction. METHODS: Safety and efficacy of desloratadine and montelukast each were assessed in a double-blind, placebo-controlled trial of patients with SAR and symptoms of asthma, who were assigned randomly to once-daily treatment with desloratadine 5 mg, montelukast 10 mg, or placebo for 4 weeks. Change from baseline of AM/PM reflective total asthma symptom severity scores (TASS), FEV(1), individual asthma symptom scores, and beta(2)-agonist usage were assessed. RESULTS: Desloratadine and montelukast each were associated with statistically significant reductions from baseline in the mean TASS averaged over the 4-week period (p < or =0.022 vs. placebo). Individual asthma symptom scores also improved significantly for both therapies (p < or = 0.05). Patients treated with desloratadine or montelukast demonstrated improvement from baseline in FEV(1) versus placebo; significant improvement was seen in a subset of patients with baseline FEV(1) <80% of predicted normal (both p < 0.05). Both active therapies significantly reduced beta(2)-agonist use (both p < 0.01). Improvements for both therapies were comparable for all efficacy parameters; they were tolerated well with adverse event profiles similar to placebo. CONCLUSIONS: Asthma symptoms and beta(2)-agonist were improved significantly in patients with concomitant SAR and asthma treated with desloratadine 5 mg as well as montelukast 10 mg once daily. Both therapies significantly improved FEV(1) in a subset of patients with FEV(1) <80% of predicted normal at entry. Improvements in asthma symptoms were comparable for both active treatment groups.     

Chronic urticaria: impact of allergic inflammation

Urticaria is defined by weals (hives), with or without angioedema, that appear and peak in minutes to hours, usually disappear within 24 h, and are accompanied by pruritus that worsens during the night. Urticaria is caused by cutaneous mast cell degranulation, attributed to immunological, nonimmunological, and idiopathic causes. Chronic idiopathic urticaria (CIU) is the diagnosis when the pathophysiological mechanism of persistent urticaria remains unclear; up to half of patients with CIU have functional autoantibodies directed against the high-affinity receptor for IgE ( Fcε RI) or against IgE itself, which appear to induce mast cell degranulation. Systemic histamine H₁-receptor antagonists, such as desloratadine, are central to the management of CIU. The efficacy and safety of desloratadine, 5 mg once daily, was studied in a double-blind, randomized, placebo-controlled, multicentre trial that included 190 patients, ages 12 and above, with at least a 6-week history of CIU and experiencing a flare of at least moderate severity. Desloratadine was superior to placebo in controlling pruritus and total symptoms after the first dose, and its superiority was maintained throughout the full 6 weeks of the study. Measures of sleep, daily activity, therapeutic response, and global CIU status were also significantly improved with desloratadine after the first dose and maintained throughout the study.     

Desloratadine in the treatment of chronic idiopathic urticaria

Chronic idiopathic urticaria (CIU) is a common dermatologic disorder that may severely impair quality of life. Patients may suffer symptoms such as pruritus and disfigurement due to wheals for years or decades. Advances have been made in the last 10 years with the identification of an autoimmune pathogenesis in a significant proportion of patients. Despite this, treatment remains symptomatic, and antihistamines are the first choice of therapy once the diagnosis of CIU has been established. The goal of treatment is rapid, long-lasting symptom relief, and currently available antihistamines fail to provide this in many cases. Desloratadine is a novel, potent H₁-receptor antagonist with additional inhibitory effects on inflammatory mediators such as cytokines and adhesion molecules. Newly published data on the efficacy and safety of desloratadine in CIU is highly encouraging, suggesting that the drug may improve symptom control above that currently available.     

New findings in pharmacological effects induced by antihistamines: from PET studies to knock-out mice

Antihistamines are efficacious drugs to be used for the symptomatic relief of allergic diseases. The safety issue of antihistamines is of central importance because of their widespread use in current medical practice. To better understand the pharmacological effects of antihistamines on the central nervous system (CNS), we used two kinds of new methods, positron emission tomography (PET) and gene targeting regarding on histamine H₁ receptors. The histamine H₁ receptor occupancy was examined in young male volunteers with[¹¹C]-doxepin (a potent H₁ antagonist) after the oral or intravenous administration of antihistamines. In other studies, the cognitive performance was also measured tachistoscopically before and after taking antihistamines. The mutant mice lacking H₁ receptors were used in the behavioural and neurochemical experiments to re-evaluate the role of H₁ receptors. The H₁-receptor occupancy in the human frontal cortex caused by antihistamines is significantly correlated with the reported values of incidence of sleepiness in clinical trials, and the occupancy is well proportional to the impaired cognitive performance. The behavioural studies of the H₁-receptor knock-out mice confirmed the role of H₁ receptors in arousal, the sleep–wake cycle, locomotion, nociception and aggressive behaviour. The pharmacological effects induced by H₁ antagonism were re-evaluated by the PET and gene-targetting. Although any serious effects could not be observed in mice by the destruction of the H₁-receptor gene, the cognitive performance was impaired in humans after taking first generation antihistamines in recommended doses.     

Mizolastine: antihistaminic activity from preclinical data to clinical evaluation

Mizolastine, a new H₁-receptor antagonist, is highly selective for histamine H₁ receptors and has no anticholinergic, antiadrenergic, or antiserotonin activity. It is rapidly absorbed after oral ingestion, with peak plasma concentrations occurring at 1.5 h. The distribution and terminal elimination half-life values are 2 and 13 h, respectively, in healthy young adult volunteers. Half-life values are longer in the elderly and in subjects with chronic renal insufficiency; however, the differences are not large enough to be clinically relevant or to necessitate a dose adjustment in these populations.
  Mizolastine produces prompt, sustained, peripheral blockade of histamine H₁ receptors in the skin. Suppression of the histamine-induced wheal and flare begins 40–60 min after ingestion of a 10-mg dose, peaks at 3–4 h, lasts for at least 24 h, and does not decrease during regular once-daily dosing. The amount of wheal suppression is comparable to that produced by other leading new H₁-receptor antagonists.
  These pharmacokinetic and pharmacodynamic studies of mizolastine provide its clinical pharmacology 'signature'. They also provide the scientific rationale for recommending a once-daily 10-mg dose and suggest that the efficacy and effectiveness of mizolastine will be widely confirmed in allergic disorders, especially rhinitis and urticaria.     

Effect of desloratadine therapy on symptom scores and measures of nasal patency in seasonal allergic rhinitis: results of a single-center, placebo-controlled trial.

BACKGROUND: Desloratadine reduces symptoms and maintains nasal airflow in patients with seasonal allergic rhinitis (SAR) during experimental allergen exposure. OBJECTIVE: To compare the effects of desloratadine and placebo on symptom scores, quality of life (QOL), and nasal airway patency in patients with SAR during the allergy season. METHODS: Adults with symptomatic SAR were randomized in a double-blind manner to receive desloratadine, 5 mg, or placebo for 14 days. Patient-rated SAR symptoms were recorded twice daily (morning and evening). On days 1 and 15, SAR symptoms were scored jointly (investigator and patient), nasal airflow was measured using 4-phase rhinomanometry, and QOL and the overall condition of SAR were rated. Overall treatment response was scored on day 15. Adverse events were recorded. RESULTS: At day 15, total symptom (P = .03) and total nasal symptom (P = .02) scores and patient morning-rated individual nasal symptom scores (except nasal stuffiness) (P < or = .04) decreased significantly from baseline with desloratadine vs placebo. Flow in the descending expiratory nasal airflow phase was significantly greater (P = .046) and the percentage increase in total inspiratory nasal airway resistance was less (P = .03) in the desloratadine group vs the placebo group. The overall condition of SAR was less severe (P = .045), the therapeutic response was greater (P = .004), and the nasal symptom domain of the QOL score was significantly better (P = .03) in the desloratadine group. Adverse event rates were similar in both groups. CONCLUSION: Desloratadine treatment for 14 days improved nasal airflow and resistance as well as symptom and QOL scores in patients with symptomatic SAR during the allergy season.     

Desloratadine: A new, nonsedating, oral antihistamine

Desloratadine is a new, selective, H(1)-receptor antagonist that also has anti-inflammatory activity. In vitro studies have shown that desloratadine inhibits the release or generation of multiple inflammatory mediators, including IL-4, IL-6, IL-8, IL-13, PGD(2), leukotriene C(4), tryptase, histamine, and the TNF-alpha-induced chemokine RANTES. Desloratadine also inhibits the induction of cell adhesion molecules, plateletactivating factor-induced eosinophil chemotaxis, TNF-alpha-induced eosinophil adhesion, and spontaneous and phorbol myristate acetate-induced superoxide generation in vitro. In animals desloratadine had no effect on the central nervous, cardiovascular, renal, or gastrointestinal systems. Desloratadine is rapidly absorbed, has dose-proportional pharmacokinetics, and has a half-life of 27 hours. The absorption of desloratadine is not affected by food, and the metabolism and elimination are not significantly affected by the subject's age, race, or sex. There are no clinically relevant interactions between desloratadine and erythromycin, ketoconazole, or grapefruit juice. Desloratadine is not a significant substrate of the P-glycoprotein transport system. Once daily administration of desloratadine rapidly reduces the nasal and nonnasal symptoms of seasonal allergic rhinitis, including congestion. In patients with seasonal allergic rhinitis and concomitant asthma, desloratadine treatment was also associated with significant reductions in total asthma symptom score and use of inhaled beta(2)-agonists. Use of desloratadine in patients with chronic idiopathic urticaria was associated with significant reductions in pruritus, number of hives, size of the largest hive, and interference with sleep and daily activities. Clinical experience in over 2300 patients has shown that the adverse event profile of desloratadine is similar to that of placebo; desloratadine has no clinically relevant effects on electrocardiographic parameters, does not impair wakefulness or psychomotor performance, and does not exacerbate the psychomotor impairment associated with alcohol use.     

Experimental models in asthma

Histamine is an important mediator released from activated mast cells in acute bronchoconstriction provoked by allergen, exercise, hypertonic stimuli and inhaled adenosine. Histamine may also contribute to the allergen-induced late asthmatic response probably following the recruitment and activation of basophils. H₁-receptor antagonists partially attenuate these responses but greater inhibition when these drugs are combined with cysteinyl LT₁-receptor antagonists indicative of an interaction between mast cell-derived mediators. The combination of two or more selective mediator antagonists in the treatment of allergic disorders such as asthma offers a new therapeutic approach worthy of careful appraisal.     

Current status of intranasal glucocorticosteroids in the management of allergic rhinitis

Glucocorticosteroids are the most effective drugs for controlling inflammation of allergic rhinitis (AR). Because of their strong pharmacological action, which can be a so-called 'double-edged sword', glucocorticosteroids are usually taken intranasally so as to reduce their potential for eliciting adverse effects. Accumulating evidence suggests that intranasal glucocorticosteroids control not only nasal symptoms but also ocular symptoms. In contrast to sedating H₁-receptor antagonists, intranasal glucocorticosteroids can improve impaired performance such as daytime sleepiness associated with AR. In Japanese cedar pollinosis, treatment begun immediately after initiation of pollen release or onset of initial symptoms, known as prophylactic (initial) treatment, is recommended. The current version of the practical guideline for management of allergic rhinitis in Japan recommends the use of chemical mediator release inhibitors, second-generation H₁-receptor antagonists, or leukotriene receptor antagonists for prophylactic treatment. However, recent evidence suggests that intranasal glucocorticosteroids might also be useful as first-line drugs for prophylactic treatment. The molecular mechanism of anti-inflammatory action of glucocorticosteroids supports this contention. Moreover, a meta-analysis of studies of intranasal glucocorticosteroids given as monotherapy has revealed that these agents are superior to oral H₁-receptor antagonists and leukotriene antagonists for controlling major symptoms of AR. These findings suggest that glucocorticosteroids, especially intranasal glucocorticosteroids, might be positioned as first-line drugs for the treatment of both perennial and seasonal AR.     

Comparison of the effects of desloratadine 5-mg daily and placebo on nasal airflow and seasonal allergic rhinitis symptoms induced by grass pollen exposure

BACKGROUND: Nasal congestion is a chronic symptom of seasonal allergic rhinitis (SAR) that is often difficult to treat with antihistamines. Desloratadine, a new, potent, H1-receptor antagonist has been shown to decrease nasal congestion in clinical trials and to maintain nasal airflow in response to grass pollen exposure. We compared the effects of desloratadine 5 mg and placebo on nasal airflow, nasal secretion weights and SAR symptoms, including nasal congestion, in patients exposed to grass pollen in an environmental exposure unit. METHODS: Forty-six grass pollen allergic SAR patients received desloratadine or placebo for 7 days, followed by a 10-day washout, and then crossed over to the other treatment for 7 days. A 6-h allergen exposure was performed at the end of each treatment period. RESULTS: Desloratadine was significantly superior to placebo in maintaining nasal airflow (P 相似文献   

Inhibitory effect of levocabastine on allergen-induced increase of nasal reactivity to histamine and cell influx

For evaluation of the effect of levocabastine pretreatment on allergen-induced rhinitis symptoms, changes in nasal washings, and nasal responsiveness to histamine, 12 asymptomatic patients with documented allergic rhinitis participated in a single-blind, placebo-controlled study. Eight-day treatment with levocabastine (twice in each nostril, four times a day) caused significant reduction in nasal symptoms and inflammatory cell influx after allergen challenge, as compared with placebo administration. Levocabastine inhibited increased nasal reactivity to histamine induced by allergen provocation, as controlled by rhinitis symptoms and albumin level in nasal washings. These data reveal a high effectiveness of levocabastine in the prevention of allergen-induced rhinitis symptoms. Moreover, its inhibitory effect on inflammatory cell influx and hyperresponsiveness to histamine suggest that levocabastine is more than a simple H₁-receptor antagonist.     

Desloratadine for allergic rhinitis

Seasonal allergic rhinitis (SAR) and perennial allergic rhinitis (PAR) affect up to 40% of the population (depending on geographical area), and are associated with significant morbidity, socioeconomic costs and reductions in quality of life. Antihistamines are a first-line therapy, with newer nonsedating agents having superseded sedating first-generation drugs. Desloratadine is a nonsedating, nonimpairing antihistamine that is effective in relieving nasal and non-nasal symptoms of SAR and PAR, including nasal congestion. Desloratadine has a 24-h duration of action, enabling once-daily dosing and providing relief of morning symptoms. Clinical trials have demonstrated that it has no performance impairment, cardiovascular effects or clinically relevant interactions with other tested medications. This article reviews the use of desloratadine in the treatment of SAR and PAR.     

The systemic safety of fexofenadine HCl

Fexofenadine is a highly specific, H₁-receptor antagonist with a safety profile similar to placebo. In placebo-controlled trials of seasonal allergic rhinitis (SAR) and chronic idiopathic urticaria (CIU), the type and incidence of adverse events were comparable in fexofenadine and placebo recipients. Fexofenadine does not impair performance in tests of driving or psychomotor performance and has been shown to improve quality of life in patients with SAR. Fexofenadine has a high margin of safety and is also well tolerated in subjects with renal or hepatic impairment, in children and the elderly. No clinically significant drug interactions have been identified. Fexofenadine is not associated with cardiotoxicity. Unlike some other antihistamines, such as loratidine or cetirizine [ 1 , 2 ], fexofenadine is truly non-sedating, showing no dose-related increase in sedation, even at high doses [ 3 , 4 ]. Fexofenadine is formulated and marketed as the hydrochloride salt. The recommended dose of fexofenadine HC1 is 120 mg daily for SAR (either as 120 mg once daily or 60 mg twice daily) or 180 mg once daily for CIU.