Levocetirizine

Introduction

Antihistamines are among the most commonly used medications by allergists and dermatologists worldwide. They are used to treat indications such as rhinitis, urticaria, seasonal allergies, and pruritus, and their potential role in treating the itch and rash of atopic dermatitis remains unclear. However, many antihistamines have the drawback of causing sedation. New antihistamines have been developed and released in recent years to overcome the limitations of older agents.

First generation antihistamines such as hydroxizine are effective but cause sedation. The initial second generation antihistamines, terfanadine and astemizole, were effective non-sedating medications but had drug interactions that caused cardiac problems and have been pulled from the market in the United States. Later second generation antihistamines, such as loratidine and cetirizine, have been found to be effective in the treatment of allergic rhinitis, and the latter to be effective in the treatment of chronic idiopathic urticaria. More recently, third generation antihistamines have been developed from existing agents (e.g. desloratadine is the active metabolite of loratidine, levocetirizine is the racemically active component of cetirizine, and fexofenadine is a derivative of terfanadine) to increase effectiveness and decrease side effects. Desloratadine has been released in the United States and Europe, while levocetirizine is currently only available in Europe. This article will review over 50 clinical studies and reviews regarding desloratadine and levocetirizine with an overview of their possible dermatological uses.

Levocetirizine

Introduction: Levocetirizine (R-cetirizine) is the active enantiomer of cetirizine, an antihistamine indicated in the treatment of allergic rhinitis and chronic idiopathic urticaria in Europe. Its onset of action is about 1 hour. It has not been approved for use in the United States. In Germany, it is sold under the trade names XYZAL[TM]/XUSAL[R].

Biochemical basis of levocetirizine

Like cetirizine, levocetirizine inhibits eotaxin-induced eosinophil TEM through both dermal and lung microvascular endothelial cells, suggesting that it has potential anti-inflammatory effects (1). This anti-inflammatory effect is underlined by the ability of levocetirizine's ability to inhibit eosinophil chemotaxis (2). It has a very high affinity for the H1 receptor (3). The carboxylic function of cetirizine and levocetirizine is important in this regard (4).

Uses to treat allergy

In one study of 470 patients, individual symptom severity scores for sneezing, rhinorrhea, itchy nose, and itchy eyes were significantly decreased for all doses of levocetirizine, with 5mg once daily possessing an optimal benefit/risk ratio in the treatment of seasonal allergic rhinitis (5). Both levocetirizine and cetirizine significantly attenuated the histamine-induced increase in nasal airway resistance by nearly 50% (6). Both cetirizine and levocetirizine caused a marked inhibition of histamine-induced wheal and flare, while levocetirizine 2.5mg has comparable anti-histaminic activity to cetirizine 5mg (7). Levocetirizine relieves symptoms associated with house-dust mite allergy (8).

Several large European uncontrolled studies have also suggested that levocetirizine is an effective agent. In one study, oral levocetirizine 5mg once daily for 32 days was reported effective in the treatment of patients with seasonal and perennial allergic rhinitis with or without concurrent asthma (n=14,319). Alleviation or improvement of symptoms (e.g., rhinorrhea, sneezing, conjunctivitis, asthmatic symptoms) was observed in over 80% of patients at the end of treatment. Global assessments also indicated very good or good efficacy in over 80%. Adverse effects were minimal (9).

Of note to dermatologists, a similar study showed that levocetirizine decreased the severity of eczema. In a large uncontrolled study, oral levocetirizine 5mg once daily for 32 days was reported effective in the treatment of patients with chronic urticaria (n=2707) or other dermatologic conditions (i.e., atopic dermatitis) (n=961). Collectively, alleviation or improvement of symptoms (e.g., pruritus, wheal/flare, eczema) occurred in at least 80% of patients at the end of treatment. Global assessments also indicated very good or good efficacy in over 80%. Adverse effects were minimal (10).

Levocetirizine compared to other agents

Levocetirizine's potency compares favorably with other agents. It was more potent at suppressing weal and flare than ebastine, fexofenadine, mizolastine, and loratadine (11). Levocetirizine (5 mg) is a potent inhibitor of the effects of histamine in human skin with an efficacy that exceeded that of loratadine (10 mg) when single doses of the drugs were administered 4 hours before the test (12).

Side Effects, Absorption and Pharmacokinetics

The side effect profile of levocetirizine is mild. Levocetirizine does not produce any deleterious effect on cognitive and psychometric functions compared with placebo in healthy male volunteers (13). Whereas promethazine affects cognitive function and psychomotor performance, levocetirizine does not (14). Skin rash (rarely), headache, and fatigue have been reported as side effects.

Levocetirizine is well absorbed (15). The metabolic pathways involved in levocetirizine's metabolism are oxidation (hydroxylation, O-dealkylation, N-oxidation and N-dealkylation), glucuroconjugation, taurine conjugation, and glutathione conjugation with formation of the mercapturic acids and is mostly excreted in the urine, but unpublished study results suggest the need for (lose adjustment in patients with moderate or severe renal insufficiency (16). Specific guidelines are unavailable. However, based on data for racemic cetirizine, a reduction in the dose of levocetirizine by 50% should be considered in patients with severe renal dysfunction (17).

Desloratadine

Introduction: Desloratadine is a biologically active metabolite of the second-generation antihistamine loratadine. Desloratadine is a highly selective peripheral H1 receptor antagonist that is about fifteen times more potent than loratadine with 2- to 3-hour onset of action. Its anti-inflammatory and antihistamine effects are independent (18). Oral desloratadine is non-sedating and free of antimuscarinic/anticholinergic effects taken in pre-clinical and clinical studies (19). Its clinical indications include chronic idiopathic urticaria and seasonal allergic rhinitis. It is sold in Europe under the brand names Aerius[TM] and Neoclarityn[TM] and in the US as Clarinex[TM]. Desloratadine is available in the United States as tablets and rapidly disintegrating tablets and in Europe as syrup as well.

Uses for the treatment of allergic disease

Desloratadine's clinical indications, as stated, are for seasonal allergic rhinitis and chronic idiopathic urticaria. It has a role in the treatment of systemic allergy (20), nasal congestion (21), and asthma (22). These roles have been documented in a number of studies (23). Desloratadine significantly reduced the severity of nasal obstruction and accompanying complaints of nasal congestion and other seasonal allergic rhinitis symptoms compared with the effects of placebo (24). Recent desloratadine studies have demonstrated that this highly potent H1 receptor antagonist consistently provides relief of nasal congestion and may provide benefits similar to montelukast in mild asthma patients (25). Desloratadine reduces nasal congestion in patients with intermittent allergic rhinitis as well (26). Recommended once daily doses of fexofenadine and desloratadine were equally effective in improving nasal peak flow and nasal symptoms in seasonal allergic rhinitis (27).

Desloratadine ameliorates chronic idiopathic urticaria (28). In a randomized, double-blind, placebo-controlled study of 190 patients aged 12-79 years, once-daily desloratadine improved the signs and symptoms of chronic idiopathic urticaria (29). This role makes it a promising agent for the treatment of this condition (30).

Side effects

Desloratadine has few drug interactions. There is little interaction of the CYP1A2, CYP2C9, CYP2C19, CYP2D6, or CYP3A4 isoenzymes of the P-450 system and desloratadine (31). Desloratadine has no clinically significant interaction with ketoconazole (32), flutoxine, or erythromycin (33). Similarly, although in one study there was a significant pharmacokinetic drug interaction between ketoconazole or cimetidine and loratadine, this effect was not accompanied by a change in the QTc interval in healthy adult volunteers (34). Small increases (<15%) in mean pharmacokinetics of desloratadine were observed with co-administration of azithromycin. In contrast, peak fexofenadine concentrations were increased by 69% and the AUC was increased by 67% in the presence of the azalide antibiotic (35).

Food does not affect its oral bioavailability (36). Grapefruit juice reduces the oral bioavailability of fexofenadine but not desloratadine (37). Desloratadine does not potentiate the adverse psychomotor effects of alcohol (38).

The absorption of many drugs is affected by their interaction with ATP-binding cassette (ABC) transporters. The most extensively studied of these ABC transporters is the protein product of MDR1 (multi-drug resistance) that encodes a 170-kDa integral plasma membrane phosphorylated glycoprotein known as P-glycoprotein (P-gp). Loratadine inhibited human P-gp much less than verapamil or cyclosporin A, and desloratadine inhibited human P-gp significantly less than loratadine (4 times). Because desloratadine minimally inhibits P-gp, it should not cause clinical drug interactions with agents that are P-gp substrates (39).

Interaction with organ systems

Desloratadine has no effect on QRS and QTc intervals and does not cause arrhythmias. Desloratadine is not associated with any significant changes in gastrointestinal function. Pre-clinical studies showed that desloratadine has no central nervous system or cardiovascular effect (40). Subsequent study seems to show little risk for drug interactions or cardiotoxicity in the use of desloratadine (41). Studies in animals indicate that 5mg of desloratadine does not cross the blood-brain barrier and therefore does not cause sedation and does not impair cognition or psychomotor performance.

Dosing

Desloratadine does not require dose adjustment based on age group, race, or sex. No dosage adjustment of desloratadine is required in the elderly (42). In one study with doses of 7.5mg, 50% higher than the recommended 5mg clinical dose, desloratadine was well tolerated by healthy adults differing in sex and race, suggesting that no dosage adjustment is needed on the basis of sex or race (43). Desloratadine demonstrates dose proportionality in healthy adults after single doses (44). There were no statistically significant differences between 2.5, 5, 7.5, 10, or 20 mg of desloratadine in the treatment of seasonal allergic rhinitis, whereas the 2.5 mg of desloratadine was a less effective dose (45).

Duration of activity

The 27-hour half-life of desloratadine permits once daily administration. Its duration of effect of about 24 hours is due in part to its slow dissociation from the H1 receptor and noncompetitive antagonism thereof, which suggests that desloratadine may be a pseudo-irreversible antagonist of the human histamine H1 receptor (46).

Inflammatory mediators and desloratadine

Desloratadine down-regulates a variety of inflammatory mediators. It inhibits IL-4 and IL-13 generation and mediator release by human basophils (47). 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, platelet activating factor-induced eosinophil chemotaxis, TNF-alpha-induced eosinophil adhesion, and spontaneous and phorbol myristate acetate-induced superoxide generation in vitro (48). The broad anti-inflammatory properties of desloratadine, which appear to distinguish it from other H1 antagonists in clinical development (e.g., norastemizole), lead some to suggest that they may have a more profound impact on the underlying disease in patients suffering from different forms of allergy (49).

Antiviral powers

One study suggests that desloratadine has antiviral Powers (50). Desloratadine and loratadine seem to inhibit the propagation of rhinovirus. Desloratadine and loratadine (0.1-10 micromol/L) inhibited rhinovirus-induced ICAM-1 up-regulation in both primary bronchial and transformed (A549) respiratory epithelial cells. In A549 cells the two compounds showed a dose-dependent inhibition with similar efficacy (inhibitory concentration of 50%, 1 micro-mol/L). Desloratadine and loratadine also inhibited ICAM-1 mRNA induction caused by rhinovirus infection in a dose-dependent manner, and they completely inhibited rhinovirus-induced ICAM-1 promoter activation. Desloratadine also inhibited rhinovirus-induced nuclear factor kappa B activation. Desloratadine and loratadine had no direct effect on rhinovirus infectivity and replication in cultured epithelial cells. These effects are unlikely to be mediated by H1-receptor antagonism and suggest a novel mechanism of action that may be important for the therapeutic control of virus-induced asthma exacerbations.

Role as a topical agent

It appears that desloratadine does not have a role in topical therapy. The competitive muscarinic antagonism of desloratadine in vitro and its potency and duration of action in vivo suggest that topical treatment of allergic conjunctivitis and rhinitis with desloratadine could produce undesirable peripheral anticholinergic side effects such as mydriasis and xerostomia. (51)

Conclusion

Both levocetirizine and desloratadine are promising new medications. Their powerful effects against histamine and eosinophils appear to provide a basis for their putative anti-inflammatory powers that transcend their use simply as antihistamines. This power allows physicians to speculate that they might have a role in the treatment of atopic dermatitis, a role that trials already hint at. Because they have such mild side effect profiles, they can be used in patients old and young. It is interesting to speculate that they might be used in conjunction with other medications (e.g. montelukast) as parts of steroid sparing regimens. Their effectiveness in treating chronic urticaria is clear. More research needs to be done on their role in the treatment of atopic dermatitis and perhaps other dermatological diseases involving eosinophils and histamine.

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ADDRESS FOR CORRESPONDENCE:

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E-mail: Scheinfeld@rcn.com

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