Non-sedating antihistamines in the treatment of chronic idiopathic urticaria using patient-reported outcomes

ABSTRACT

Background: Chronic idiopathic urticaria (CIU) greatly impairs quality of life (QoL). Thus, patient-reported outcome (PRO) measures, using validated scoring instruments, are probably the most accurate tools available for assessing the efficacy of medications that treat CIU, such as second-generation antihistamines.

Research methods: A structured search of the MEDLINE database was conducted to identify English-language papers published between 1 January 1991 and 30 September 2007 on the treatment of CIU with the second-generation antihistamines cetirizine, desloratadine, fexofenadine, and levocetirizine, and their effects on patient-reported QoL. We used the following search terms alone or in combination: ‘chronic idiopathic urticaria’; ‘pruritus’; ‘wheals’; ‘hives’; ‘second-generation antihistamines’; ‘cetirizine’; ‘desloratadine’; ‘fexofenadine’; ‘levocetirizine’; and ‘quality of life’.

Scope: We evaluated the effects of second-generation antihistamines on the QoL of subjects with CIU using desloratadine as a treatment model. Desloratadine was selected because it is the most frequently assessed non-sedating second-generation antihistamine in QoL studies in patients with CIU.

Findings: Desloratadine 5?mg QD improved QoL in numerous PRO studies. Treatment with desloratadine significantly (p?<?0.05) lowered (better) scores in three studies (n?=?364) that used validated dermatology-specific scoring instruments. Three 6-week double-blind, placebo-controlled trials (n?=?553) found that desloratadine significantly (p?<?0.05) improved patient-reported pruritus, sleep disruption, and interference with daily activities. Desloratadine was associated with a low incidence of adverse events and an overall tolerability profile similar to placebo.

Limitations: Limitations in this review include divergence in search practices that may lead to omission of relevant research, unintentional error in data transfer, inconsistency in quality of selected papers, and potential publication bias against papers that report results from small studies.

Conclusions: The favorable impact of second-generation antihistamines on the QoL of patients with CIU was demonstrated using desloratadine, the most frequently investigated drug in this field, as a treatment model.     

Levocetirizine: a review of its use in the management of allergic rhinitis and skin allergies

Levocetirizine (Xyzal) is a selective, potent, oral histamine H(1) receptor antagonist of the latest generation that is licensed for the symptomatic treatment of allergic rhinitis (including persistent allergic rhinitis [PER]) and chronic idiopathic urticaria (CIU). Large, well designed trials indicate that levocetirizine is effective and generally well tolerated in the treatment of allergic rhinitis and CIU. Its pharmacological profile offers many positive aspects: a rapid onset and long duration of antihistaminic effect; rapid absorption and high bioavailability; a low potential for drug interactions; a low volume of distribution; and a lack of effect on cognition, psychomotor function and the cardiovascular system. Allergen challenge chamber studies suggest that levocetirizine has better efficacy than desloratadine, loratadine or fexofenadine. Well controlled, long-term studies with other later-generation H(1) receptor antagonists are required to fully define its clinical profile relative to other agents in this class. Overall, levocetirizine is a valuable addition to the oral H(1) receptor antagonists available for the treatment of allergic rhinitis and as first-line therapy in patients with CIU.     

Antihistamines in late-phase clinical development for allergic disease

Allergic rhinitis (AR) is a global health concern and shares a high comorbidity with asthma. Recent research suggests that different allergic diseases, such as AR, asthma, allergic conjunctivitis and chronic idiopathic urticaria (CIU), are evoked by common pathological mechanisms characterised by the release of histamine and other inflammatory mediators. Although H(1) receptor antagonists are the mainstay of therapy for allergic disease, the unacceptably high incidence of anticholinergic and CNS-related side effects of first-generation H(1) antagonists led to the search for improved second-generation H(1) antagonists. While many of these agents were largely devoid of CNS side effects, their tendency for drug-drug interactions (e.g., terfenadine and astemizole) resulted in an increased incidence of cardiotoxicity. Furthermore, second-generation H(1) antagonists exhibited weak anti-inflammatory properties and had no effect on nasal congestion. These observations emphasised the need for newer anti-allergic agents with a broader spectrum of activity and an improved safety profile. Among the newer H(1) antagonists currently in clinical development, desloratadine and mizolastine are the most widely studied. Both have a rapid onset of action, and desloratadine has demonstrated clinical efficacy in AR, CIU and seasonal asthma. Desloratadine has several advantages over other H(1) antagonists in that it has proven decongestant activity, a sparing effect on the use of bronchodilators (beta(2)-agonists) and a low potential for drug interactions. The broad anti-inflammatory properties of desloratadine and mizolastine, which distinguish these agents from other H(1) antagonists in clinical development (e.g., norastemizole and levocetirizine), suggest they may have a more profound impact on the underlying disease in patients suffering from different forms of allergy. The lack of clinical efficacy and safety data on rupatadine and HSR-609, both novel H(1) antagonists, precludes an accurate assessment of their potential for treating allergic disease. Epinastine and efletirizine are being developed exclusively for topical application and are unlikely to play a significant role in the management of allergic diseases as a whole.     

A treatment for allergic rhinitis: a view on the role of levocetirizine

BACKGROUND: Allergic rhinitis is a significant public health concern in many developed countries. However, despite evidence for a significant impact on patients' quality of life (QoL) including sleep disruption and reduced daytime performance, allergic rhinitis remains under-managed and hence poorly controlled. This is largely owing to lack of knowledge about, and poor adherence to, established treatment guidelines. SCOPE: The panel considered available evidence and focused on four published studies on the second-generation antihistamine, levocetirizine. Three of these studies explored the clinical impact of levocetirizine in a broad range of different clinical settings. FINDINGS: Levocetirizine demonstrated an increased benefit over other antihistamines in terms of a more durable antihistamine response: levocetirizine provided improved symptom relief at 24 hours compared to desloratadine or fexofenadine, two frequently prescribed second-generation antihistamines. Levocetirizine also maintained relief of the key symptoms of allergic rhinitis and improved patients' QoL over a treatment period of 6 months, in a real-life setting. The variable efficacy and durability of response of different antihistamines arise from differing modulatory effects on the H(1)-receptor. The speed of relief of symptoms with levocetirizine is supported by the pharmacokinetic data, which shows that steady state plasma concentrations are achieved in a shorter period of time than other second-generation histamines (additionally levocetirizine T(max) is reached in 0.9 h). CONCLUSION: These findings support both the short-term and long-term use of levocetirizine in the clinical management of allergic rhinitis. The World Health Organization (WHO) ARIA Guidelines (Allergic Rhinitis and its Impact on Asthma), recommend using a combination of a non-sedating antihistamine with a decongestant, or glucocorticosteroids for treating allergic rhinitis - with the order and combination of treatment depending on severity and duration of symptoms.     

Chronic urticaria: aetiology, management and current and future treatment options

Chronic urticaria is a common condition that can be very disabling when severe. A cause for chronic idiopathic urticaria (CIU) is only infrequently identified. Potential causes include reactions to food and drugs, infections (rarely) and, apart from an increased incidence of thyroid disease, uncomplicated urticaria is not usually associated with underlying systemic disease or malignancy. About one-third of patients with CIU have circulating functional autoantibodies against the high affinity IgE receptor or against IgE, although it is not known why such antibodies are produced, or how the presence of such antibodies alters the course of the disease or response to treatment. There are only a few publications relating to childhood urticaria, but it is probably similar to the adult form, except that adult urticaria is more common. The diagnosis is based on patient history and it is vital to spend time documenting this in detail. Extensive laboratory tests are not required in the vast majority of patients. Chronic urticaria resolves spontaneously in 30-55% of patients within 5 years, but it can persist for many years.Treatment is aimed firstly at avoiding underlying causative or exacerbating factors. Histamine H1 receptor antagonists remain the mainstay of oral treatment for all forms of urticaria. The newer low-sedating antihistamines desloratadine, fexofenadine, levocetirizine and mizolastine should be tried first. Sedating antihistamines have more adverse effects but are useful if symptoms are causing sleep disturbance. Low-dose dopexin is effective and especially suitable for patients with associated depression. There is controversy as to whether the addition of an histamine H2 receptor antagonist or a leukotriene antagonist is helpful. For CIU, second-line agents include ciclosporin (cyclosporine) [which is effective in approximately 75% of patients], short courses of oral corticosteroids, intravenous immunoglobulins and plasmapheresis, although the last two were found to be beneficial in small trials only. Treatments for CIU with only limited or anecdotal supportive evidence include sulphasalazine, methotrexate, stanazol, rofecoxib and cyclophosphamide. The efficacy of photo(chemo)therapy is controversial. Physical urticarias may respond to H1 receptor antagonists, although in delayed pressure urticaria, and cold, solar and aquagenic urticaria, the response may be disappointing. Second-line agents for physical urticarias vary depending on the urticaria and most have limited supportive evidence. The potential for spontaneous resolution, the variation in the disease activity and the unpredictable nature of the disease makes the efficacy of treatments difficult to assess.     

Safety of desloratadine syrup in children

BACKGROUND: Allergic rhinitis (AR) and acute urticaria are common childhood maladies. Typically, the firstline treatment options for both include non-sedating antihistamines. First-generation antihistamines, such as diphenhydramine and hydroxyzine, although useful, cause sedation. Desloratadine, an oral non-sedating antihistamine, has been shown in multiple studies to be safe and effective in relieving the symptoms of AR and chronic idiopathic urticaria (CIU) in adults and adolescents. OBJECTIVE AND METHODS: The current double-blind, placebo-controlled, parallel-group, single-center studies were undertaken to determine the safety and tolerability of desloratadine syrup in children aged 2 years-11 years with AR or CIU. Over 14 days, subjects aged 2 years-5 years were randomly assigned to receive once a day either 1.25 mg of desloratadine syrup (0.5 mg/mL) or matching placebo, and subjects aged 6 years-11 years were randomly assigned to receive once a day either 2.5 mg of desloratadine syrup or matching placebo. Safety evaluations included adverse event report collection, monitoring of vital signs, clinical laboratory measurements, and standard 12-lead electrocardiogram (ECG) measurements. RESULTS: In the study involving subjects aged 2 years-5 years (n = 111), the incidence of adverse events was 7/55 for the group treated with desloratadine and 6/56 for placebo. In the study involving subjects aged 6 years-11 years (n = 120), the incidence of adverse events was 1/60 for the group treated with desloratadine and 6/60 for placebo. No severe or serious adverse events occurred, and no clinically relevant changes were noted in median clinical laboratory test values or mean vital signs in either group. ECG results from both age groups demonstrated no significant changes (p = NS) in mean ventricular rate or PR, QRS, or QT. No subjects had a Fridericia QT(c) interval > 440 ms at day 8 or day 15. CONCLUSION: These studies demonstrate the safety of desloratadine syrup in children aged 2 years-11 years with AR or CIU.     

Antihistamines in late-phase clinical development for allergic disease

Allergic rhinitis (AR) is a global health concern and shares a high comorbidity with asthma. Recent research suggests that different allergic diseases, such as AR, asthma, allergic conjunctivitis and chronic idiopathic urticaria (CIU), are evoked by common pathological mechanisms characterised by the release of histamine and other inflammatory mediators. Although H₁ receptor antagonists are the mainstay of therapy for allergic disease, the unacceptably high incidence of anticholinergic and CNS-related side effects of first-generation H₁ antagonists led to the search for improved second-generation H₁ antagonists. While many of these agents were largely devoid of CNS side effects, their tendency for drug-drug interactions (e.g., terfenadine and astemizole) resulted in an increased incidence of cardiotoxicity. Furthermore, second-generation H₁ antagonists exhibited weak anti-inflammatory properties and had no effect on nasal congestion. These observations emphasised the need for newer anti-allergic agents with a broader spectrum of activity and an improved safety profile. Among the newer H₁ antagonists currently in clinical development, desloratadine and mizolastine are the most widely studied. Both have a rapid onset of action, and desloratadine has demonstrated clinical efficacy in AR, CIU and seasonal asthma. Desloratadine has several advantages over other H₁ antagonists in that it has proven decongestant activity, a sparing effect on the use of bronchodilators (β₂-agonists) and a low potential for drug interactions. The broad anti-inflammatory properties of desloratadine and mizolastine, which distinguish these agents from other H₁ antagonists in clinical development (e.g., norastemizole and levocetirizine), suggest they may have a more profound impact on the underlying disease in patients suffering from different forms of allergy. The lack of clinical efficacy and safety data on rupatadine and HSR-609, both novel H₁ antagonists, precludes an accurate assessment of their potential for treating allergic disease. Epinastine and efletirizine are being developed exclusively for topical application and are unlikely to play a significant role in the management of allergic diseases as a whole.     

A treatment for allergic rhinitis:a view on the role of levocetirizine

ABSTRACT

Background: Allergic rhinitis is a significant public health concern in many developed countries. However, despite evidence for a significant impact on patients’ quality of life (QoL) including sleep disruption and reduced daytime performance, allergic rhinitis remains under-managed and hence poorly controlled. This is largely owing to lack of knowledge about, and poor adherence to, established treatment guidelines.

Scope: The panel considered available evidence and focused on four published studies on the second-generation antihistamine, levocetirizine. Three of these studies explored the clinical impact of levocetirizine in a broad range of different clinical settings.

Findings: Levocetirizine demonstrated an increased benefit over other antihistamines in terms of a more durable antihistamine response: levocetirizine provided improved symptom relief at 24 hours compared to desloratadine or fexofenadine, two frequently prescribed second-generation antihistamines. Levocetirizine also maintained relief of the key symptoms of allergic rhinitis and improved patients’ QoL over a treatment period of 6 months, in a real-life setting. The variable efficacy and durability of response of different antihistamines arise from differing modulatory effects on the H₁‐receptor. The speed of relief of symptoms with levocetirizine is supported by the pharmacokinetic data, which shows that steady state plasma concentrations are achieved in a shorter period of time than other second-generation histamines (additionally levocetirizine T_max is reached in 0.9?h).

Conclusion: These findings support both the short-term and long-term use of levocetirizine in the clinical management of allergic rhinitis. The World Health Organization (WHO) ARIA Guidelines (Allergic Rhinitis and its Impact on Asthma), recommend using a combination of a non-sedating antihistamine with a decongestant, or glucocorticosteroids for treating allergic rhinitis – with the order and combination of treatment depending on severity and duration of symptoms.     

Non-interventional study comparing treatment satisfaction in patients treated with antihistamines

BACKGROUND AND OBJECTIVE: Allergic rhinitis and urticaria are common allergic disorders that may affect approximately 15% of people at some time in their lives. Antihistamines are the most widely used therapeutic interventions for these disorders but the newer generation agents have differing pharmacokinetic characteristics that may result in different patient satisfaction and preferences. The objective of this study was to investigate patients' and physicians' satisfaction with their current antihistamine treatment for allergic disease. METHODS: In an observational study, physicians in nine European countries completed questionnaires evaluating 7,274 patients treated with an oral antihistamine. The satisfaction of patients and physicians with the efficacy and tolerability of treatment was rated on a visual analogue scale. In addition, the proportion of patients satisfied with treatment (overall satisfaction) and willing to continue treatment with the same antihistamine were assessed. Safety and tolerability data were also gathered. RESULTS: The results of this study indicate that modern antihistamines are generally considered effective and well tolerated by patients. In general, levocetirizine scored significantly higher in terms of perception of efficacy, tolerability and overall satisfaction. In terms of tolerability, three-quarters of patients were 'very satisfied' and a further fifth were moderately satisfied with levocetirizine and almost all (95%) were happy to continue treatment. Overall, the most commonly reported adverse event in this study was somnolence, a well known effect of antihistamines. The rate of somnolence in the levocetirizine group (3.8%) was similar to that for fexofenadine (both doses) and desloratadine, two products which are considered to be nonsedating antihistamines, and significantly less than half the rate for cetirizine. CONCLUSION: Levocetirizine is considered an effective and well tolerated option for treating allergic disease by patients and physicians alike, particularly when the best available effectiveness and tolerability are required.     

Safety of desloratadine syrup in children

SUMMARY

Background: Allergic rhinitis (AR) and acute urticaria are common childhood maladies. Typically, the first-line treatment options for both include non-sedating antihistamines. First-generation antihistamines, such as diphenhydramine and hydroxyzine, although useful, cause sedation. Desloratadine, an oral non-sedating antihistamine, has been shown in multiple studies to be safe and effective in relieving the symptoms of AR and chronic idiopathic urticaria (CIU) in adults and adolescents.

Objective and methods: The current double-blind, placebo-controlled, parallel-group, single-center studies were undertaken to determine the safety and tolerability of desloratadine syrup in children aged 2?years–11?years with AR or CIU. Over 14 days, subjects aged 2?years–5?years were randomly assigned to receive once a day either 1.25?mg of desloratadine syrup (0.5?mg/mL) or matching placebo, and subjects aged 6?years–11?years were randomly assigned to receive once a day either 2.5?mg of desloratadine syrup or matching placebo. Safety evaluations included adverse event report collection, monitoring of vital signs, clinical laboratory measurements, and standard 12-lead electrocardiogram (ECG) measurements.

Results: In the study involving subjects aged 2?years–5?years (n = 111), the incidence of adverse events was 7/55 for the group treated with desloratadine and 6/56 for placebo. In the study involving subjects aged 6?years–11?years (n = 120), the incidence of adverse events was 1/60 for the group treated with desloratadine and 6/60 for placebo. No severe or serious adverse events occurred, and no clinically relevant changes were noted in median clinical laboratory test values or mean vital signs in either group. ECG results from both age groups demonstrated no significant changes (?p = NS) in mean ventricular rate or PR, QRS, or QT. No subjects had a Fridericia QT_c interval > 440?ms at day 8 or day 15.

Conclusion: These studies demonstrate the safety of desloratadine syrup in children aged 2?years–11?years with AR or CIU.     

Inhibition of allergen-induced wheal and flare reactions by levocetirizine and desloratadine

Aims

To evaluate the inhibitory activity of the new-generation antihistamines levocetirizine and desloratadine at their therapeutic doses on the allergen-induced wheal and flare reaction at 1.5 h, 4 h, 7 h, 12 h and 24 h postdose, and to measure their plasma and skin concentrations.

Methods

A double-blind, randomized, cross-over, placebo-controlled study in 18 allergic subjects was carried out. The time–response of the wheal and flare reaction areas under the curve (AUC) were compared by anova.

Results

Both antihistamines significantly (P < 0.001) inhibited the allergen-induced wheal and flare reactions compared with placebo. Levocetirizine was significantly more potent than desloratadine. Mean ± SEM wheal AUC(0–24 h) was 506.4 ± 81.0 with levocetirizine and 995.5 ± 81.0 mm² h with desloratadine as compared with placebo (1318.5 ± 361.0 mm² h). Flare AUC(0–24 h) was 5927.3 ± 1686.5 and 15838.2 ± 1686.5 mm² h, respectively [P < 0.001 for both compared with placebo (22508.2 ± 7437.1 mm² h)]. Levocetirizine showed significant inhibition of wheal and flare already at 1.5 h postdose compared with placebo (P ≤ 0.001); desloratadine achieved a significant effect only after 4 h. The mean total plasma concentration at 12 h and 24 h after intake was higher for levocetirizine (58.1 ± 13.4 and 20.0 ± 8.1 ng ml⁻¹, respectively) as compared with desloratadine (0.82 ± 0.24 and 0.45 ± 0.16 ng ml⁻¹). Similarly, higher mean unbound skin concentrations were observed for levocetirizine 24 h after intake (1.80 ng g⁻¹) than for desloratadine (0.07 ng g⁻¹). This was associated with greater receptor occupancy for levocetirizine (54%) than desloratadine (34%) at 24 h.

Conclusions

Levocetirizine suppressed the cutaneous allergic reactions with a higher potency than desloratadine, which correlated with its high receptor occupancy. Receptor occupancy rather than drug affinity or plasma half-life is more representative of antihistamine potency.

What is already known about this subject

• The reproducible and standardized histamine-induced wheal and flare model helps identify the objective effectiveness of antihistamines in humans, as well as their differences in onset and duration of action.
• Some of the newest antihistamines have already been compared in a head-to-head setting using this model. However, their objective action at inhibiting the allergen-induced wheal and flare response has not been reported yet.

What this study adds

• The time–response study presented here shows the objective activity of two of the newest generation of antihistamines, levocetirizine and desloratadine, at inhibiting the allergen-induced wheal and flare response in a randomized, cross over, placebo-controlled trial.
• This model is interesting to the clinical setting since allergic subjects are recruited, and the response to allergen involves mast cell degranulation and release of numerous vasoactive and pro-inflammatory mediators additionally to histamine.
• In addition, this study reports receptor occupancy for both antihistamines at therapeutic dosage, leading to analysis of potential differences in activity.
• This study clearly shows the potential anti-inflammatory properties of desloratadine and levocetirizine in their skin activity when allergen is the challenging agent as occurs in the clinical situation.

     

Pharmacokinetic evaluation of levocetirizine

INTRODUCTION: There have recently been guidelines developed for the diagnosis and treatment of rhinitis and urticaria. For both conditions, second-generation antihistamines remain as the first-line therapy. AREAS COVERED: The article presents the current pharmacology, chemical properties, pharmacokinetics and metabolism of levocetirizine. The article also reviews the clinical efficacy of levocetirizine for seasonal allergic and perennial rhinitis, as well as chronic urticaria. The article is formed through the review of all the published literature in English retrieved from the PubMed/MEDLINE database between 1966 and March 2011 using the search terms: levocetirizine, allergic rhinitis, chronic urticaria and antihistamine. Furthermore, the article also reviews data provided by the manufacturer in addition to reports from governmental agencies. EXPERT OPINION: Levocetirizine has several pharmacokinetic properties that are desirable for an antihistamine providing a combination of both potency and safety. Its clinical advantages are derived from its rapid and extensive absorption, limited distribution and its very low degree of metabolism. Furthermore, levocetirizine scores very highly in terms of clinical efficacy as well as in patient/physician satisfaction studies. Given the lack of large multi-center studies that compare the treatment options for urticaria, clinicians must rely on potency studies when choosing treatment and levocetirizine does score very highly. However, other potent skin antihistamines, such as desloratadine or fexofenadine, should be preferred for patients who have a strict contraindication to the sedative effects of the drug.     

Changes in pH differently affect the binding properties of histamine H1 receptor antagonists

We investigated the effect of acidic pH, a condition that can be encountered during inflammation accompanying allergic reaction, on the binding properties of histamine H₁ receptor antagonists, including levocetirizine ((2-{4-[(R)-(4-chlorophenyl)(phenyl)methyl]piperazin-1-yl}ethoxy)acetic acid; Xyzal®), fexofenadine (rac-2-[4-[1-Hydroxy-4-[4-(hydroxydiphenylmethyl) piperidin-1-yl]butyl]phenyl]-2-methylpropionic acid hydrochloride; Allegra®) and desloratadine (8-Chloro-6,11-dihydro-11-(4-piperidylidene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridine; Clarinex®). Lowering the pH from 7.4 to 5.8 decreased the affinity of [³H]mepyramine for histamine H₁ receptors from 1.7 to 7.5 nM while the opposite was observed with [³H]levocetirizine, whose affinity increased from 4.1 to 1.5 nM. Competition curves with [³H]mepyramine indicated that decreasing the pH from 7.4 to 5.8 led to a 2- to 5-fold increase in the affinity of fexofenadine and levocetirizine, no change in affinity for desloratadine and a 5- to 10-fold decrease in affinity for mepyramine and histamine. Kinetic experiments showed that the increase in affinity of levocetirizine and, to a lesser extent, fexofenadine were totally attributable to a lower dissociation rate at acidic pH (t_1/2 increasing from 77 to 266 min and from 71 to 135 min, respectively). Although the affinity of desloratadine remained unchanged, lowering the pH caused a decrease in its dissociation rate (t_1/2 of 50 and 256 min at pH 7.5 and 5.8, respectively) accompanied by a concomitant 3.5-fold decrease in its association rate constant. The loss of affinity of mepyramine at acidic pH was driven by a decrease in its association rate constant. Interaction between the carboxylic moiety of levocetirizine and Lys¹⁹¹ is responsible for its slow dissociation rate from the receptor. We found that the magnitude of the pH effect on the dissociation rate of levocetirizine was maintained after mutating Lys¹⁹¹ into alanine, suggesting that a tighter interaction of levocetirizine with Lys¹⁹¹ at lower pH is not the cause of its even slower dissociation rate from the receptor. Although these changes may seem limited in amplitude, we show that they may have substantial effects on receptor occupancy in vivo.     

Cetirizine: a review of its use in allergic disorders

Cetirizine is a selective, second-generation histamine H1 receptor antagonist, with a rapid onset, a long duration of activity and low potential for interaction with drugs metabolised by the hepatic cytochrome P450 system. Cetirizine was generally more effective than other H1 receptor antagonists at inhibiting histamine-induced wheal and flare responses. Cetirizine is an effective and well tolerated agent for the treatment of symptoms of seasonal allergic rhinitis (SAR), perennial allergic rhinitis (PAR) and chronic idiopathic urticaria (CIU) in adult, adolescent and paediatric patients. In adults with these allergic disorders, cetirizine was as effective as conventional dosages of ebastine (SAR, PAR, CIU), fexofenadine (SAR), loratadine (SAR, CIU) or mizolastine (SAR). This agent was significantly more effective, and with a more rapid onset of action, than loratadine in 2-day studies in environmental exposure units (SAR). In paediatric patients, cetirizine was as at least as effective as chlorphenamine (chlorpheniramine) [SAR], loratadine (SAR, PAR) and oxatomide (CIU) in the short term, and more effective than oxatomide and ketotifen (PAR) in the long term. Cetirizine was effective in reducing symptoms of allergic asthma in adults and reduced the relative risk of developing asthma in infants with atopic dermatitis sensitised to grass pollen or house dust mite allergens. It had a corticosteroid-sparing effect in infants with severe atopic dermatitis and was effective in ameliorating reactions to mosquito bites in adults. Cetirizine was well tolerated in adults, adolescents and paediatric patients with allergic disorders. In adult, adolescent and paediatric patients aged 2-11 years, the incidence of somnolence with cetirizine was dose related and was generally similar to that with other second-generation H1 receptor antagonists. Although, its sedative effect was greater than that of fexofenadine in some clinical trials and that of loratadine or fexofenadine in a postmarketing surveillance study. In infants aged 6-24 months, the tolerability profile of cetirizine was similar to that of placebo. Cetirizine did not have any adverse effects on cognitive function in adults, or cognitive function, behaviour or achievement of psychomotor milestones in paediatric patients. Cetirizine was not associated with cardiotoxicity. CONCLUSION: Cetirizine is well established in the treatment of symptoms of SAR, PAR or CIU. It demonstrated a corticosteroid-sparing effect and reduced the relative risk of developing asthma in sensitised infants with atopic dermatitis. Cetirizine was effective in the treatment of allergic cough and mosquito bites; however, its precise role in these indications has yet to be clearly established. On the basis of its favourable efficacy and tolerability profile and rapid onset of action, cetirizine provides an important option for the treatment of a wide range of allergic disorders.     

Rupatadine: a review of its use in the management of allergic disorders

Rupatadine (Rupafin, Rinialer, Rupax, Alergoliber) is a selective oral histamine H(1)-receptor antagonist that has also been shown to have platelet-activating factor (PAF) antagonist activity in vitro. It is indicated for use in seasonal allergic rhinitis (SAR), perennial allergic rhinitis (PAR) and chronic idiopathic urticaria (CIU) in patients aged >/=12 years.Clinical trials show that rupatadine is an effective and generally well tolerated treatment for allergic rhinitis and CIU. It has a rapid onset of action and a prolonged duration of activity. Importantly, it has no significant effect on cognition, psychomotor function or the cardiovascular system. Once-daily rupatadine significantly improves allergic rhinitis symptoms in patients with SAR, PAR or persistent allergic rhinitis (PER) compared with placebo, and provides similar symptom control to that of loratadine, desloratadine, cetirizine or ebastine. In patients with CIU, longer-term use of rupatadine improves CIU symptoms to a greater extent than placebo. It is as well tolerated as other commonly used second-generation H(1)-receptor antagonists. Thus, the introduction of rupatadine extends the range of oral agents available for the treatment of allergic disorders, including allergic rhinitis and CIU.     

Desloratadine: an update of its efficacy in the management of allergic disorders

Desloratadine (Clarinex, Neoclarityn, Aerius, Azomyr, Opulis, Allex), the principal metabolite of loratadine, is itself an orally active, nonsedating, peripheral histamine H(1)-receptor antagonist. It is indicated in the US and Europe for the treatment of seasonal allergic rhinitis (SAR), perennial allergic rhinitis (PAR) and chronic idiopathic urticaria (CIU). It has a rapid onset of effect, efficacy throughout a 24-hour dosage interval, and sustained efficacy in these allergic conditions, as demonstrated in placebo-controlled trials of up to 6 weeks' duration in adult and adolescent patients. At present, there are no published direct comparisons of desloratadine and other H(1)-antihistamines; however, the principal, potential clinical advantages of desloratadine over late-generation H(1)-antihistamines are the drug's decongestant activity, which has been corroborated in several studies of patients with allergic rhinitis, and its anti-inflammatory effects. Indeed, the decongestant activity of desloratadine did not differ from that of pseudoephedrine in a trial in patients with SAR, and in patients with SAR and coexisting asthma, desloratadine reduced asthma symptoms and beta(2)-agonist use, and improved forced expiratory flow in 1 second. However, these issues warrant further study. Desloratadine is generally well tolerated. The overall incidence of adverse events in adults, adolescents and children was not significantly different to that with placebo, and similar proportions of desloratadine or placebo recipients reported events such as pharyngitis, dry mouth, myalgia, somnolence, dysmenorrhoea or fatigue. Desloratadine does not cause sedation or prolong the corrected QT (QTc) interval, can be administered without regard to concurrent intake of food and grapefruit juice, and appears to have negligible potential for drug interactions mediated by several metabolic systems. CONCLUSION: Although comparative studies with second-generation and other recently developed H(1)-antihistamines are needed to define the drug's clinical profile more clearly, desloratadine can be expected to claim a prominent place in the management of allergic disorders in general, and in the amelioration of specific symptoms of allergy (e.g. nasal congestion) in patients with such disorders.     

Levocetirizine: a new selective H1 receptor antagonist for use in allergic disorders

Levocetirizine is the active R-enantiomer of cetirizine and represents a new second-generation histamine H(1) antagonist. It has a high affinity and selectivity for H(1) receptors. Comparative studies have shown evidence of superior H(1) receptor binding affinity over its racemate, cetirizine. Levocetirizine has a favorable pharmacokinetic profile; it is rapidly and extensively absorbed, minimally metabolized, and has a lower volume of distribution (V(d)) than some other second-generation antihistamines. A number of studies using the histamine-induced wheal and flare model have repeatedly demonstrated marked suppressive effects for levocetirizine. Levocetirizine has also been found to be effective in relieving symptoms of seasonal and perennial allergic rhinitis, including nasal congestion, and its side effects are minor.     

Brain histamine H1 receptor occupancy measured by PET after oral administration of levocetirizine,a non-sedating antihistamine

Objective: Histamine H₁ receptor (H₁R) antagonists often have sedative side effects, which are caused by the blockade of the neural transmission of the histaminergic neurons. We examined the brain H₁R occupancy (H₁RO) and the subjective sleepiness of levocetirizine, a new second-generation antihistamine, comparing fexofenadine, another non-sedating antihistamine, as a negative active control.

Methods: Eight healthy volunteers underwent positron emission tomography (PET) imaging with [¹¹C]doxepin, a PET tracer that specifically binds to H₁Rs, after a single oral administration of levocetirizine (5 mg), fexofenadine (60 mg) or placebo in a double-blind crossover study. Binding potential ratios and H₁ROs in the cerebral cortices regions were calculated using placebo. Subjective sleepiness was assessed with the Line Analogue Rating Scale and the Stanford Sleepiness Scale.

Results: There was no significant difference between the mean brain H₁RO after levocetirizine administration (8.1%; 95% CI: ?9.8 to 26.0%) and fexofenadine administration (?8.0%; 95% CI: ?26.7 to 10.6%). Similarly, subjective sleepiness was not significantly different between the two antihistamines and placebo. Neither subjective sleepiness nor plasma concentrations was significantly correlated with the brain H₁RO of the two antihistamines.

Conclusion: At therapeutic dose, levocetirizine does not bind significantly to the brain H₁Rs and does not induce significant sedation.     

Levocetirizine has a longer duration of action on improving total nasal symptoms score than fexofenadine after single administration

AIMS: To compare the onset and duration of action of the new antihistamine levocetirizine with that of the second-generation antihistamine fexofenadine using the Vienna Challenge Chamber (VCC). The latter is an environment where subjects can be exposed to specific aeroallergens in controlled and reproducible conditions allowing for precise comparisons of anti-allergic drugs. METHODS: Ninety-four subjects received a single dose of levocetirizine 5 mg, fexofenadine 120 mg or placebo in a random order using a three-way cross-over design. On day 1, subjects were exposed to grass pollens (1500 grains/m(3)) in the VCC over a period of 4 h. Treatment was given 2 h after the start of challenge. On day 2, 22 h after drug intake, subjects were again exposed to pollens for 6 h. Specified symptoms were assessed by the subjects every 15 min using 5-point scales. The main efficacy parameter was the change from baseline in the Major Symptom Complex Score (MSCS = sum of rhinorrhea, sneezing, itchy nose and eyes). RESULTS: Baseline characteristics, including symptoms scores, were similar in the three study groups. During the first 2 h after drug intake both antihistamines achieved clinically relevant and significant (P < 0.001) improvements in symptom scores. Twenty-two to 24 h after drug intake, mean (SEM) MSCS reductions were: 1.9 (0.3) after placebo (baseline of 9.7), 3.8 (0.3) after fexofenadine (baseline of 9.9), and 5.1 (0.3) after levocetirizine (baseline of 9.8). Levocetirizine was significantly (P < 0.001) more effective than fexofenadine with a score difference of 1.3 (95% CI 0.7, 1.9). This was maintained until the end of the study (up to 28 h). CONCLUSIONS: A rapid onset of action in alleviating seasonal allergic rhinitis (SAR) symptoms of subjects exposed to grass pollens in the VCC was observed after levocetirizine and fexofenadine. Levocetirizine was more effective than fexofenadine at and later than 22 h after drug intake, an indication of the longer-duration of action of levocetirizine.     

Desloratadine and levocetirizine improve nasal symptoms, airflow, and allergic inflammation in patients with perennial allergic rhinitis: a pilot study

BACKGROUND: Nasal obstruction is the main symptom in patients with perennial allergic rhinitis. Some new antihistamines have been demonstrated to be capable of improving this symptom. OBJECTIVE: The aim of this pilot study was to evaluate nasal symptoms, nasal airflow, eosinophils, and IL-4 in patients with perennial allergic rhinitis, before and after treatment with two new antihistamines: desloratadine and levocetirizine. METHODS: Thirty patients with perennial allergic rhinitis were evaluated, 26 males and 4 females (mean age 26+/-7.1 years). All of them received either desloratadine (5 mg/daily) or levocetirizine (5 mg/daily) or placebo for 4 weeks. The study was double-blind, parallel-group, placebo-controlled, and randomized. Total symptom score (including: rhinorrhea, nasal itching, sneezing, and nasal obstruction) was assessed before and after treatment. Rhinomanometry and decongestion test, nasal lavage, and nasal scraping were performed in all subjects before and after treatment. Eosinophils were counted by conventional staining; IL-4 was measured by immunoassay of fluids recovered from nasal lavage. RESULTS: Desloratadine and levocetirizine treatment induced significant symptom relief and significant reduction of IL-4. Both antihistamines significantly affected all parameters in comparison with placebo. CONCLUSIONS: This pilot study demonstrates the effectiveness of antihistaminic treatment in: i) relieving nasal symptoms, including obstruction, ii) improving nasal airflow, iii) exerting decongestant activity, iv) reducing eosinophil infiltration, and v) diminishing IL-4 levels.