The anti-inflammatory effects of levocetirizine - are they clinically relevant or just an interesting additional effect?
Garry M Walsh
Abstract
Levocetirizine, the R-enantiomer of cetirizine dihydrochloride has pharmacodynamically and pharmacokinetically favourable characteristics, including rapid onset of action, high bioavailability, high affinity for and occupancy of the H1-receptor, limited distribution, minimal hepatic metabolism together with minimal untoward effects. Several wellconducted randomised clinical trials have demonstrated the effectiveness of levocetirizine for the treatment of allergic rhinitis and chronic idiopathic urticaria in adults and children. In addition to the treatment for the immediate shortterm manifestations of allergic disease, there appears to be a growing trend for the use of levocetirizine as long-term therapy. In addition to its being a potent antihistamine, levocetirizine has several documented anti-inflammatory effects that are observed at clinically relevant concentrations that may enhance its therapeutic benefit. This review will consider the potential or otherwise of the reported anti-inflammatory effects of levocetirizine to enhance its effectiveness in the treatment of allergic disease.
Introduction
The effects of histamine are exerted through three well defined classical G protein coupled histamine receptor subtypes termed H1R, H2R, and H3R and the more recently described H4R. Histamine signalling through H1R is responsible for the majority of the immediate manifestations of allergic disease. Levocetirizine (Xyzal) is the single R-isomer of the racemic mixture piperazine H1R-antagonist cetirizine dihydrochloride in a once-daily 5mg formulation. The parent compound cetirizine (Zyrtec), a once-daily 10 mg formulation, is also an effective treatment for allergic disease being the most-widely used second-generation antihistamine worldwide. Levocetirizine is a selective, potent, oral histamine H1R antagonist that is licensed in Europe as tablets and oral solution for use in adults and children over 2 years of age for the symptomatic treatment of allergic rhinitis (including persistent allergic rhinitis) and chronic idiopathic urticaria.
More recently, levocetirizine tablets under the trade name Xyzal have been approved by the Food and Drug Administration for use in adults and children over 6 years of age in the United States.
Efficacy and safety
Levocetirizine is a potent antihistamine as demonstrated by its ability to inhibit cutaneous histamine-induced itching and the wheal and flare reaction. The histamineinduced wheal and flare model in human skin is a widelyused reproducible and standardized methodology that gives an objective measure of the effectiveness of antihistamines in human subjects, together with any differences in onset and duration of action. The majority of these studies found levocetirizine to be the most potent of the antihistamines tested, including the parent compound cetirizine. Large, well designed controlled clinical trials have demonstrated the efficacy of levocetirizine in adults with allergic rhinitis and chronic idiopathic urticaria, while well conducted studies have demonstrated levocetirizine to be safe and effective in young children with atopic rhinitis or chronic urticaria.
Levocetirizine appears to have significant effects on nasal blockage. The positive effects on nasal congestion are important findings as many antihistamines are ineffective in this regard. Indeed, histamine is not thought to be the primary cause of nasal congestion but a consequence of other mast cell-derived mediators including prostaglandin D2 and leukotrienes acting in concert. The positive effect by levocetirizine on this important symptom of AR is likely due to its additional anti-inflammatory properties (see below).
In terms of its pharmacological profile levocetirizine exhibits rapid absorption and high bioavailability giving a fast onset and long duration of antihistaminic effect. These observed effects are mirrored by calculations of histamine H1 receptor occupancy that show a rapid and long-lasting presence of levocetirizine at its site of action. In terms of safety levocetirizine exhibits a low potential for drug interactions together with a lack of effect on cognition, psychomotor function and the cardiovascular system. Indeed a recent study examined the sedative potential of a comprehensive battery of first, second and newer generation antihistamines (levocetirizine, desloratadine and levocetirizine) by calculating a proportional impairment ratio for each drug based on studies that used standardised objective methodology and psychometric tests. Levocetirizine had the lowest proportional impairment ratio of all the antihistamines reviewed, followed by fexofenadine and desloratadine respectively.
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Levocetirizine, the R-enantiomer of cetirizine dihydrochloride has pharmacodynamically and pharmacokinetically favourable characteristics, including rapid onset of action, high bioavailability, high affinity for and occupancy of the H1-receptor, limited distribution, minimal hepatic metabolism together with minimal untoward effects. Several wellconducted randomised clinical trials have demonstrated the effectiveness of levocetirizine for the treatment of allergic rhinitis and chronic idiopathic urticaria in adults and children. In addition to the treatment for the immediate shortterm manifestations of allergic disease, there appears to be a growing trend for the use of levocetirizine as long-term therapy. In addition to its being a potent antihistamine, levocetirizine has several documented anti-inflammatory effects that are observed at clinically relevant concentrations that may enhance its therapeutic benefit. This review will consider the potential or otherwise of the reported anti-inflammatory effects of levocetirizine to enhance its effectiveness in the treatment of allergic disease.
Introduction
The effects of histamine are exerted through three well defined classical G protein coupled histamine receptor subtypes termed H1R, H2R, and H3R and the more recently described H4R. Histamine signalling through H1R is responsible for the majority of the immediate manifestations of allergic disease. Levocetirizine (Xyzal) is the single R-isomer of the racemic mixture piperazine H1R-antagonist cetirizine dihydrochloride in a once-daily 5mg formulation. The parent compound cetirizine (Zyrtec), a once-daily 10 mg formulation, is also an effective treatment for allergic disease being the most-widely used second-generation antihistamine worldwide. Levocetirizine is a selective, potent, oral histamine H1R antagonist that is licensed in Europe as tablets and oral solution for use in adults and children over 2 years of age for the symptomatic treatment of allergic rhinitis (including persistent allergic rhinitis) and chronic idiopathic urticaria.
More recently, levocetirizine tablets under the trade name Xyzal have been approved by the Food and Drug Administration for use in adults and children over 6 years of age in the United States.
Efficacy and safety
Levocetirizine is a potent antihistamine as demonstrated by its ability to inhibit cutaneous histamine-induced itching and the wheal and flare reaction. The histamineinduced wheal and flare model in human skin is a widelyused reproducible and standardized methodology that gives an objective measure of the effectiveness of antihistamines in human subjects, together with any differences in onset and duration of action. The majority of these studies found levocetirizine to be the most potent of the antihistamines tested, including the parent compound cetirizine. Large, well designed controlled clinical trials have demonstrated the efficacy of levocetirizine in adults with allergic rhinitis and chronic idiopathic urticaria, while well conducted studies have demonstrated levocetirizine to be safe and effective in young children with atopic rhinitis or chronic urticaria.
Levocetirizine appears to have significant effects on nasal blockage. The positive effects on nasal congestion are important findings as many antihistamines are ineffective in this regard. Indeed, histamine is not thought to be the primary cause of nasal congestion but a consequence of other mast cell-derived mediators including prostaglandin D2 and leukotrienes acting in concert. The positive effect by levocetirizine on this important symptom of AR is likely due to its additional anti-inflammatory properties (see below).
In terms of its pharmacological profile levocetirizine exhibits rapid absorption and high bioavailability giving a fast onset and long duration of antihistaminic effect. These observed effects are mirrored by calculations of histamine H1 receptor occupancy that show a rapid and long-lasting presence of levocetirizine at its site of action. In terms of safety levocetirizine exhibits a low potential for drug interactions together with a lack of effect on cognition, psychomotor function and the cardiovascular system. Indeed a recent study examined the sedative potential of a comprehensive battery of first, second and newer generation antihistamines (levocetirizine, desloratadine and levocetirizine) by calculating a proportional impairment ratio for each drug based on studies that used standardised objective methodology and psychometric tests. Levocetirizine had the lowest proportional impairment ratio of all the antihistamines reviewed, followed by fexofenadine and desloratadine respectively.
DOWNLOAD COMPLETE PDF HERE
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