Article

Cetirizine

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Abstract

Cetirizine is a selective, second-generation histamine H 1 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 H 1 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 H 1 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 mile-stones 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.

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... Cetirizine, the active carboxylic acid metabolite of hydroxyzine, is a potent second-generation antihistamine possessing anti-inflammatory properties and high specific affinity for histamine H 1 receptors (2). Studies have shown cetirizine to be effective in treatment of skin inflammatory conditions by reducing histamine, bradykinin, and allergen-induced wheal and flare reactions; decreasing monocyte and T-lymphocyte chemotaxis; reducing eosinophil responses; and decreasing intercellular adhesion molecule-1 expression on epithelial cells (2,3). ...
... Cetirizine, the active carboxylic acid metabolite of hydroxyzine, is a potent second-generation antihistamine possessing anti-inflammatory properties and high specific affinity for histamine H 1 receptors (2). Studies have shown cetirizine to be effective in treatment of skin inflammatory conditions by reducing histamine, bradykinin, and allergen-induced wheal and flare reactions; decreasing monocyte and T-lymphocyte chemotaxis; reducing eosinophil responses; and decreasing intercellular adhesion molecule-1 expression on epithelial cells (2,3). The oral administration of cetirizine (used as cetirizine dihydrochloride, and referred to as cetirizine further) is commonly related to different side effects including sedation, ocular dryness, tiredness, and dry mouth (4). ...
Article
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Cetirizine is a piperazine-derived second-generation antihistaminic drug recommended for treatment of pruritus associated with atopic dermatitis. The present investigation encompasses development of a nanosized novel elastic vesicle-based topical formulation of cetirizine dihydrochloride using combination of Phospholipon® 90G and edge activators with an aim to have targeted peripheral H1 antihistaminic activity. The formulation was optimized with respect to phospholipid/drug/charge inducer ratio along with type and concentration of edge activator. The optimized formulation was found to be satisfactory with respect to stability, drug content, entrapment efficiency, pH, viscosity, vesicular size, spreadability, and morphological characteristics. The ex vivo permeation studies through mice skin were performed using Franz diffusion cell assembly. It was found that the mean cumulative percentage amount permeated in 8 h was almost twice (60.001 ± 0.332) as compared to conventional cream (33.268 ± 0.795) and aqueous solution of drug (32.616 ± 0.969), suggesting better penetration and permeation of cetirizine from the novel vesicular delivery system. Further, therapeutic efficacy of optimized formulation was assessed against oxazolone-induced atopic dermatitis in mice. It was observed that the developed formulation was highly efficacious in reducing the itching score (4.75 itches per 20 min) compared to conventional cream (9.75 itches per 20 min) with profound reduction in dermal eosinophil count and erythema score. To conclude, a novel vesicular, dermally safe, and nontoxic topical formulation of cetirizine was successfully developed and may be used to treat atopic dermatitis after clinical investigation.
Thesis
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As a consequence of the world population increase and the resulting water scarcity, water quality is the object of growing attention. In that context, organic anthropogenic molecules — often defined as micropollutants— represent a threat for water resources. Among them, pharmaceuticals are the object of particular concerns due to their permanent discharge, their increasing consumption and their effect-based structures. Pharmaceuticals are mainly introduced in the environment via wastewater treatment plants (WWTPs), along with their metabolites and the on-site formed transformation products (TPs). Once in the aquatic environment, they partition between the different environmental compartments in particular the aqueous phase, suspended particulate matter(SPM) and biota. In the last decades, pharmaceuticals have been widely investigated in the water phase. However, extreme polar pharmaceuticals have rarely been monitored due to the lack of robust analytical methods. Moreover, metabolites and TPs have seldom been included in routine analysis methods although their environmental relevance is proven. Furthermore, pharmaceuticals have been only sporadically investigated in SPM and biota and adequate multi-residue methods are lacking to obtain comprehensive results about their occurrence in these matrices. This thesis endeavors to cover these gaps of knowledge by the development of generic multi-residue methods for pharmaceuticals determination in the water phase, SPM and biota and to evaluate the occurrence and partition of pharmaceuticals into these compartments. For a complete overview, a particular focus was laid on extreme polar pharmaceuticals, pharmaceutical metabolites and TPs. In total, three innovative multi-residue methods were developed, they include analytes covering a broad range of physico-chemical properties. First, a reliable multi-residue method was developed for the analysis of extreme polar pharmaceuticals, metabolites and TPs dissolved in water. The selected analytes covered a significant range of elevated polarity and the method would be easily expendable to further analytes. This versatility could be achieved by the utilization of freeze-drying as sample preparation and zwitterionic hydrophilic interaction liquid chromatography (HILIC) in gradient elution mode. The suitability of HILIC chromatography to simultaneously quantify a large range of micropollutants in aqueous environmental samples was thoroughly studied. Several limitations were pointed out: a very complex and time-consuming method development, a very high sensitivity with regards to modification of the acetonitrile to water ratio in the eluent or the diluent and high positive matrix effects for certain analytes. However, these limitations can be overcome by the utilization of a precise protocol and appropriate labeled internal standards. They are overmatched by the benefits of HILIC which permits the chromatographic separation of extreme polar micropollutants. Investigation of environmental samples showed elevated concentrations of the analytes in the water phase. In particular, gabapentin, metformin, guanylurea and oxypurinol were measured at concentrations in the µg/L range in surface water. Subsequently, a reliable multi-residue method was established for the determination of 57 pharmaceuticals, 47 metabolites and TPs sorbed to SPM down to the low ng/g range. This method was conceived to cover a large range of polarity in particular with the inclusion of extreme polar pharmaceuticals. The extraction procedure was based on pressurized liquid extraction (PLE) followed by a clean-up via solvent exchange and detection via direct injection-reversed-phase LC-MS/MS and freeze-drying HILIC-MS/MS. Pharmaceutical sorption was examined using laboratory experiments. Derived distribution coefficients Kd varied by five orders of magnitude among the analytes and confirmed a high sorption potential for positively charged and nonpolar pharmaceuticals. The occurrence of pharmaceuticals in German rivers SPM was evaluated by the investigation of annual composite SPM samples taken at four sites at the river Rhine and one site at the river Saar between the years 2005 and 2015. It revealed the ubiquitous presence of pharmaceuticals sorbed to SPM in these rivers. In particular, positively charged analytes, even very polar and nonpolar pharmaceuticals showed appreciable concentrations. For many pharmaceuticals, a distinct correlation was observed between the annual quantities consumed in Germany and the concentrations measured in SPM. Studies of composite SPM spatial distribution permitted to get hints about specific industrial discharge by comparing the pollution pattern along the river. For the first time, these results showed the potential of SPM for the monitoring of positively charged and nonpolar pharmaceuticals in surface water. Finally, a reliable and generic multi residue method was developed to investigate 35 pharmaceuticals and 28 metabolites and TPs in fish plasma, fish liver and fish fillet. For this matrix, it was very challenging to develop an adequate clean-up allowing for the sufficient separation of the matrix disturbances from the analytes. In the final method, fish tissue extraction was performed by cell disruption followed by a non-discriminating clean-up based on silica gel solid-phase extraction(SPE) and restrictive access media (RAM) chromatography. Application of the developed method to the measurement of bream and carp tissues from German rivers revealed that even polar micropollutants such as pharmaceuticals are ubiquitously present in fish tissues. In total, 17 analytes were detected for the first time in fish tissues, including 10 metabolites/TPs. The importance of monitoring metabolites and TPs in fish tissues was confirmed with their detection at similar concentrations as their parents. Liver and fillet were shown to be appropriate for the monitoring of pharmaceuticals in fish, whereas plasma is more inconvenient due to very low concentrations and collection difficulties. Elevated concentrations of certain metabolites suggest possible formation of human metabolites in fish. Measured concentrations indicate a low bioaccumulation potential for pharmaceuticals in fish tissues.
Article
Acute generalized exanthematous pustulosis (AGEP) is an abrupt cutaneous adverse reaction usually in response to medications. It is generally a self-limiting disease if diagnosed promptly and the offending agent discontinued. Cetirizine, a commonly used anti-histamine medication for the treatment of allergic diseases has few reported side effects and is normally well-tolerated and effective. Herein, the first reported case of cetirizine induced AGEP is presented, followed by a discussion of the clinical and pathological aspects of this adverse cutaneous reaction to a widely used drug. Awareness of this reaction is vital owing to the extensive use of cetirizine and the importance of drug cessation once the reaction is identified. Lastly, other pustular cutaneous reactions may present similarly and therefore accurate identification of this disease can prevent unnecessary diagnostic testing.
Article
Cetirizine, a second-generation antihistamine, is an active metabolite of hydroxyzine and it is used in the treatment of allergies, but the data on fetal safety are inconclusive. Pregnant women who were counselled by the 'Motherisk Program' regarding cetirizine exposure were enrolled in a cohort study and compared with pregnant women counselled for non-teratogenic exposures. The objective was to measure the rate of adverse pregnancy outcomes. Subsequently, we also conducted meta-analysis of cohort studies that examined the pregnancy outcomes of women exposed to hydroxyzine or cetirizine during pregnancy. In the cohort study, there were no significant differences in the rates of major malformations between the cetirizine exposed and comparison group. In the meta-analysis, cetirizine was not associated with increased teratogenic risk. In contrast, a meta-analysis of cetirizine and hydroxyzine studies showed a marginal association with major malformations. Cetirizine is not associated with a clinically important increase in risk of adverse fetal outcomes.
Article
Urticaria is a distressing condition associated with diverse clinical presentations. Chronic spontaneous urticaria (CsU) is characterized by wheals and angioedema. Its treatment requires an algorithmic approach to identify the optimum medication. Cetirizine is commonly used in the treatment of urticaria. Rupatadine is a selective non-sedating H1 -antihistamine approved for the treatment of CsU. This trial was conducted to ascertain whether the properties of rupatadine offer advantages over cetirizine. Seventy patients with CsU were enrolled. Parameters assessed included: (i) mean number of wheals (MNW); (ii) pruritus; (iii) mean total symptom score (MTSS); (iv) size of wheal; (v) interference of wheals with sleep; and (vi) sedation. Patients with CsU were divided randomly into two groups. Routine investigations were performed at baseline and at the end of the study. Evaluations of MTSS, MNW, and pruritus revealed statistically significant differences at week 3 compared with baseline in the cetirizine group. However, greater reductions in these parameters were obtained with rupatadine. In patients receiving rupatadine, reductions in the MNW, size of wheals, and intensity of erythema were also significant at six weeks (P < 0.001) and were significantly greater than those in the cetirizine group (P < 0.05). Improvements in MTSS, MNW, size of wheals, intensity of erythema, and differential eosinophil count imply that rupatadine is a particularly attractive therapeutic modality compared with cetirizine for the treatment of CsU.
Article
Background: Cetirizine is among the first second-generation H1 antihistamines (SGAHs) developed to provide selective H1 receptor inhibition without central nervous system depression. Objective: The aim of this review is to summarize the amount of data collected over 25 years of clinical use of cetirizine and compare this with data available for other SGAHs in the management of patients with allergic rhinitis (AR). Methods: A comprehensive literature search for publications relating to cetirizine was performed using the Pubmed database, and relevant papers published in English were selected for detailed review. Results: Compared with the majority of other SGAHs, cetirizine was generally shown to have a more favourable pharmacological profile, to be well tolerated, be at least equally or more efficacious in attenuating/inhibiting nasal and ocular symptoms and to improve the quality of life in AR patients. The majority of clinical trials investigating the effect of SGAHs in AR patients further indicated that cetirizine was often employed as the main comparator active drug. Conclusion: Based on the evidence that cetirizine is a commonly employed active comparator drug in AR, it is tempting to suggest that cetirizine may be a suitable benchmark in the development of novel pharmacotherapies for AR.
Article
The enantioselective separation of levocetirizine via a hollow fiber supported liquid membrane was examined. O,O′-dibenzoyl-(2R,3R)-tartaric acid ((−)-DBTA) diluted in 1-decanol was used as a chiral selector extractant. The influence of concentrations of feed and stripping phases, and extractant concentration in the membrane phase, was also investigated. A mathematical model focusing on the extraction side of the liquid membrane system was presented to predict the concentration of levocetirizine at different times. The extraction and recovery of levocetirizine from feed phase were 75.00% and 72.00%, respectively. The mass transfer coefficients at aqueous feed boundary layer (kf ) and the organic liquid membrane phase (km ) were calculated as 2.41×102 and 1.89×102 cm/s, respectively. The validity of the developed model was evaluated through a comparison with experimental data, and good agreement was obtained.
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It has been reported that the histamine H(1) receptor (H1R) gene is up-regulated in patients with allergic rhinitis and H1R expression level strongly correlates with the severity of allergy symptoms. Accordingly compounds that suppress the H1R gene expression are promising as useful anti-allergic medications. Recently, we demonstrated that histamine or phorbol-12-myristate-13-acetate (PMA) stimulation induced the up-regulation of H1R gene expression through the protein kinase Cδ (PKCδ)/extracellular signal-regulated kinase/poly(ADP-ribose) polymerase-1 signaling pathway in HeLa cells expressing H1R endogenously. Quercetin is one of the well-characterized flavonoids and it possesses many biological activities including anti-allergic activity. However, effect of quercetin on H1R signaling is remained unknown. In the present study, we examined the effect of quercetin on histamine- and PMA-induced up-regulation of H1R gene expression in HeLa cells. We also investigated its in vivo effects on the toluene-2,4-diisocyanate (TDI)-sensitized allergy model rats. Quercetin suppressed histamine- and PMA-induced up-regulation of H1R gene expression. Quercetin also inhibited histamine- or PMA-induced phosphorylation of Tyr(311) of PKCδ and translocation of PKCδ to the Golgi. Pre-treatment with quercetin for 3weeks suppressed TDI-induced nasal allergy-like symptoms and elevation of H1R mRNA in the nasal mucosa of TDI-sensitized rats. These data suggest that quercetin suppresses H1R gene expression by the suppression of PKCδ activation through the inhibition of its translocation to the Golgi.
Article
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Novel strategies are evaluated for management of allergic rhinitis and asthma in patients co-afflicted with both disorders. It is hypothesized that the platelet activating factor receptor antagonist ginkgolide B (GB) and the carotenoid antioxidant astaxanthin (ASX) interact with antihistamines cetirizine dihydrochloride (CTZ) and azelastine (AZE) to potentiate their ability to downregulate potentially pathological immune activation. Peripheral blood mononuclear cells from asthmatics and healthy subjects, cultured 24 hours with 50 μg/ml phytohemaglutinin (PHA) or PHA plus each drug are analyzed by flow cytometry for expression of CD25+ or HLA-DR+ by CD3+ (T cells). Results are reported as stimulation indices for CD3+CD25+ (SICD3+CD25+) and CD3+HLA-DR+ (SICD3+HLADR+) cells in cultures treated with PHA alone, versus cultures treated with both PHA and drugs. Optimal suppression of activated cells was observed in cultures stimulated with ASX 10-6 M + CTZ 10-6 M (SICD3+CD25+, p = 0.016; SICD3+HLADR, p = 0.012); ASX 10-6 M + AZE 10-6 M (SICD3+CD25+, p = 0.012; SICD3+HLADR, p = 0.015); GB 10-6 M + CTZ 10-6 M (SICD3+CD25+, p = 0.024, SICD3+HLADR+, p = 0.019). Results demonstrate improved activity of antihistamines by 2 phytochemicals, suggesting dosing strategies for animal trials of ASX- or GB-augmented formulations for seasonal allergic rhinitis and asthma.
Article
Allergic rhinitis is a symptomatic disorder of the nose induced after allergen exposure by an IgE-mediated inflammation of the membranes lining the nose. It is a global health problem that causes major illness and disability worldwide. Over 600 million patients from all countries, all ethnic groups and of all ages suffer from allergic rhinitis. It affects social life, sleep, school and work and its economic impact is substantial. Risk factors for allergic rhinitis are well identified. Indoor and outdoor allergens as well as occupational agents cause rhinitis and other allergic diseases. The role of indoor and outdoor pollution is probably very important, but has yet to be fully understood both for the occurrence of the disease and its manifestations. In 1999, during the Allergic Rhinitis and its Impact on Asthma (ARIA) WHO workshop, the expert panel proposed a new classification for allergic rhinitis which was subdivided into 'intermittent' or 'persistent' disease. This classification is now validated. The diagnosis of allergic rhinitis is often quite easy, but in some cases it may cause problems and many patients are still under-diagnosed, often because they do not perceive the symptoms of rhinitis as a disease impairing their social life, school and work. The management of allergic rhinitis is well established and the ARIA expert panel based its recommendations on evidence using an extensive review of the literature available up to December 1999. The statements of evidence for the development of these guidelines followed WHO rules and were based on those of Shekelle et al. A large number of papers have been published since 2000 and are extensively reviewed in the 2008 Update using the same evidence-based system. Recommendations for the management of allergic rhinitis are similar in both the ARIA workshop report and the 2008 Update. In the future, the GRADE approach will be used, but is not yet available. Another important aspect of the ARIA guidelines was to consider co-morbidities. Both allergic rhinitis and asthma are systemic inflammatory conditions and often co-exist in the same patients. In the 2008 Update, these links have been confirmed. The ARIA document is not intended to be a standard-of-care document for individual countries. It is provided as a basis for physicians, health care professionals and organizations involved in the treatment of allergic rhinitis and asthma in various countries to facilitate the development of relevant local standard-of-care documents for patients.
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Abstract Cetirizine is indicated for the treatment of allergic conditions such as insect bites and stings, atopic and contact dermatitis, eczema, urticaria. This investigation deals with development of a novel ethosome-based topical formulation of cetirizine dihydrochloride for effective delivery. The optimised formulation consisting of drug, phospholipon 90 G™ and ethanol was characterised for drug content, entrapment efficiency, pH, vesicular size, spreadability and rheological behaviour. The ex vivo permeation studies through mice skin showed highest permeation flux (16.300 ± 0.300 µg/h/cm(2)) and skin retention (20.686 ± 0.517 µg/cm(2)) for cetirizine-loaded ethosomal vesicles as compared to conventional formulations. The in vivo pharmacodynamic evaluation of optimised formulation was assessed against oxazolone-induced atopic dermatitis (AD) in mice. The parameters evaluated were reduction in scratching score, erythema score, skin hyperplasia and dermal eosinophil count. Our results suggest that ethosomes are effective carriers for dermal delivery of antihistaminic drug, cetirizine, for the treatment of AD.
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Article
To control the release rate and mask the bitter taste, cetirizine dihydrochloride (CedH) was entrapped within chitosan nanoparticles (CS-NPs) using an ionotropic gelation process, followed by microencapsulation to produce CS matrix microparticles using a spray-drying method. The aqueous colloidal CS-NPs dispersions with a drug encapsulation efficiency (EE) of <15%, were then spray dried to produce a powdered nanoparticles-in-microparticles system with an EE of >70%. The resultant spherical CS microparticles had a smooth surface, were free of organic solvent residue and showed a diameter range of 0.5~5 μm. The in vitro drug release properties of CedH encapsulated microparticles showed an initial burst effect during the first 2 h. Drug release from the matrix CS microparticles could be retarded by the crosslinking agent pentasodium tripolyphosphate or the wall material. The technique of 'ionotropic gelation' combined with 'spray-drying' could be applicable for preparation of CS nanoparticlesin-microparticles drug delivery systems. CS-NPs based microparticles might provide a potential micro-carrier for oral administration of the freely water-soluble drug--CedH.
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The purpose of the current study was to mask the taste of cetirizine HCl and to incorporate the granules produced in oral disintegrating tablets (ODT). The bitter, active substance was coated by fluidized bed coating using Eudragit® RL30-D at levels between 15% and 40% w/w. The ODTs were developed by varying the ratio of superdisintegrants such as sodium croscarmellose, crospovidone grades and low substituted hydroxypropyl cellulose (L-HPC). A direct compression process was used to compress the ODTs under various compaction forces to optimize tablet robustness. The properties of the compressed tablets including porosity, hardness, friability and dissolution profiles were further investigated. The in vitro and in vivo evaluation of the tablet disintegration times showed almost identical rapid disintegration below 10 s at the optimal levels of each superdisintegrant. Finally, the taste and sensory evaluation in human volunteers demonstrated excellence in masking the bitter active and tablet palatability.
Article
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Article
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Article
The strength of sedation due to antihistamines can be evaluated using positron emission tomography (PET). The purpose of the present study is to measure histamine H(1) receptor (H(1)R) occupancy following oral administration of cetirizine (10 and 20 mg) in order to examine dose dependency. Fifteen healthy male volunteers (age range, 20-35 years) were divided into 3 subgroups and were studied following single oral administration of cetirizine at 10 mg (n = 5) and 20 mg (n = 5) or hydroxyzine at 30 mg (n = 5) using PET with 11C-doxepin. Each subject was scanned also following the administration of placebo. Binding potential and H(1)RO values were calculated in the prefrontal and anterior cingulate cortices. Subjective sleepiness was also measured, and the correlation to H(1)RO was examined for each antihistamine. The averaged H(1)ROs of cetirizine 10 mg, 20 mg, and hydroxyzine 30 mg in the prefrontal and cingulate cortices was 12.6%, 25.2%, and 67.6%, respectively. The H(1)RO of hydroxyzine 30 mg correlated well with subjective sleepiness (p < 0.001); however, those of cetirizine 10 and 20 mg showed no correlation with subjective sleepiness. It was demonstrated that the brain penetration of orally administered cetirizine was dose-dependent. Cetirizine 10 mg, with its low H(1)RO and thus minimal sedation, could be more safely used than cetirizine 20 mg for the treatment of various allergic disorders.
Article
(1)H NMR-pH titrations of cetirizine, the widely used antihistamine and four related compounds were carried out and the related 11 macroscopic protonation constants were determined. The interactivity parameter between the two piperazine amine groups was obtained from two symmetric piperazine derivatives. Combining these two types of datasets, all the 12 microconstants and derived tautomeric constants of cetirizine were calculated. Upon this basis, the conflicting literature data of cetirizine microspeciation were clarified, and the pharmacokinetic absorption-distribution properties could be interpreted. The pH-dependent distribution of the microspecies is provided.
Article
Levocetirizine inhibits the production of intercellular adhesion molecule (ICAM)-1 and secretion of interleukin (IL)-6 and IL-8, which may have beneficial effects on the pathophysiologic changes related to human rhinovirus (HRV) infection. We investigated the effects of levocetirizine on rhinovirus infection in primary human nasal epithelial cells (HNEC) and A549 cells. Cells were treated with different concentrations of levocetirizine, ranging from 0.5, 5 or 50nM, either starting at the time of infection and continuing thereafter, or beginning 24h before infection and continuing thereafter. Levocetirizine treatment inhibited the HRV-induced increase in ICAM-1 mRNA and protein levels, as well as the HRV-induced expression of IL-6 and IL-8 mRNA and protein levels. Viral titer, as measured by culture in MRC-5 cells, was reduced by levocetirizine. Levocetirizine treatment also reduced the increased nuclear factor-kappa B (NF-kappaB) expression seen with HRV infection. Levocetirizine inhibited the expression of Toll-like receptor (TLR)3 mRNA and protein levels. These findings indicate that, in HNEC and A549 cells, levocetirizine inhibits HRV replication and HRV-induced upregulation of ICAM-1, IL-6, and IL-8, TLR3 expression and NF-kappaB activation. The results of this study suggest that levocetirizine may have a possible clinical application in the treatment of airway inflammation caused by HRV infection.
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Dystonia is a movement disorder that causes involuntary contractions of the muscles. Dystonia can affect just 1 muscle, a group of muscles, or all of the muscles. The most common cause acquired dystonia in childhood is drugs. Cetirizine is widely used for allergic disorders in childhood. It is without central nervous system side effects at recommended dosages. There is only 1 case of cetirizine-induced dystonia in the literature. We report a second case of cetirizine-induced acute acquired dystonia whose symptoms completely resolved after the discontinuation of the drug.
Article
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.
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Abstract Cetirizine is a second-generation antihistamine, derived from the metabolism of hydroxyzine, highly specific for the H1 receptors, and with marked antiallergic properties. Although its history began more than 30 years ago, it remains one of the most used drugs in children with a leading role in the medical care of children with allergic diseases. Cetirizine use is licensed for paediatric patients for the treatment of allergic rhinitis, and chronic spontaneous urticaria, in Europe in children older than 2 years old and in the USA in children older than 6 months old. This review provides a practical update on the use of cetirizine in children and adolescents.
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Abstract Antihistamines are currently one of the most commonly administered categories of drugs. They are used to treat symptoms that are secondary to histamine release, which is typical of certain allergic conditions, including rhinitis, conjunctivitis, asthma, urticaria, and anaphylaxis. Cetirizine belongs to the second-generation family, so, it is very selective for peripheral H1 receptors, is potent and quickly relieves symptoms, exerts additional anti-allergic/anti-inflammatory effects, and is usually well-tolerated. It has been marketed 30 years ago. In these years, a remarkable body of evidence has been built. The current review provides a practical update on the use of cetirizine in clinical practice.
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Catalyst control over reactions that produce multiple stereoisomers is a challenge in synthesis. Control over reactions that involve stereogenic elements remote from one another is particularly uncommon. Additionally, catalytic reactions that address both stereogenic carbon and an element of axial chirality are also rare. Reported herein is a catalytic approach to each stereoisomer of a scaffold containing a stereogenic center remote from an axis of chirality. Newly developed peptidyl Cu‐complexes catalyze an unprecedented remote desymmetrization, involving enantioselective C‐N bond‐forming cross‐coupling. Then, chiral phosphoric acid catalysts set an axis of chirality, through an unprecedented atroposelective cyclodehydration to form a heterocycle with high diastereoselectivity. The application of chiral Cu‐complexes and phosphoric acids provides access to each stereoisomer of a framework with two different elements of stereogenicity.
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Catalyst control over reactions that produce multiple stereoisomers is a challenge in synthesis. Control over reactions that involve stereogenic elements remote from one another is particularly uncommon. Additionally, catalytic reactions that address both stereogenic carbon and an element of axial chirality are also rare. Reported herein is a catalytic approach to each stereoisomer of a scaffold containing a stereogenic center remote from an axis of chirality. Newly developed peptidyl Cu‐complexes catalyze an unprecedented remote desymmetrization, involving enantioselective C‐N bond‐forming cross‐coupling. Then, chiral phosphoric acid catalysts set an axis of chirality, through an unprecedented atroposelective cyclodehydration to form a heterocycle with high diastereoselectivity. The application of chiral Cu‐complexes and phosphoric acids provides access to each stereoisomer of a framework with two different elements of stereogenicity.
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Background Antagonism of chemoattractant receptor-homologous molecule on T-helper type-2 cells (CRTH2), a G-protein coupled receptor for prostaglandin D2, could be beneficial for treating allergic disorders. We present findings on the efficacy and safety/tolerability of a CRTH2 antagonist (setipiprant) in participants with seasonal allergic rhinitis (AR) in a real-life setting over 2 weeks. MethodsA Phase 2 trial and a Phase 3 trial were conducted at seven centers in Texas, USA during the Mountain Cedar pollen season. Both were prospective, randomized, double-blind, placebo- and active-referenced (cetirizine) studies. The Phase 2 trial assessed setipiprant 100–1000 mg b.i.d. and 1000 mg o.d. versus placebo in adult and elderly participants. The Phase 3 trial assessed setipiprant 1000 mg b.i.d. in adolescent, adult, and elderly participants. Efficacy was assessed using daytime nasal symptom scores (DNSS), night-time nasal symptom scores (NNSS) and daytime eye symptom scores (DESS). Results579 participants were randomized in the Phase 2 trial (mean age 41.6–43.4 years); 630 were randomized in the Phase 3 trial (mean age 37.5–40.7 years). A statistically significant, dose-related improvement in mean change from baseline DNSS was observed over 2 weeks with setipiprant 1000 mg b.i.d. versus placebo in the Phase 2 trial (−0.15 [95% CI −0.29, −0.01]; p = 0.030). Setipiprant 1000 mg b.i.d. had no significant effect on this endpoint in the Phase 3 trial (−0.02 [95% CI −0.12, 0.07]; p = 0.652). Total and individual NNSS and DESS symptom scores were significantly improved with setipiprant 1000 mg b.i.d. versus placebo in the Phase 2 but not the Phase 3 trial. Setipiprant showed a favorable safety/tolerability profile. Conclusions The Phase 2 trial was the first large clinical study to assess a CRTH2 antagonist in seasonal AR in a real-life setting. Setipiprant dose-related efficacy in the Phase 2 trial was not confirmed during Phase 3. Setipiprant was well tolerated in both studies.Trial registration NCT01241214 and NCT01484119
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Common cold is an acute illness affecting pediatric population in particular. The use of antihistamines is a common practice, with cetirizine being a frequently used drug with a good safety profile. However, adverse events due to the use of antihistamines have been rarely reported, such as drug-induced dystonia with the use of cetirizine. In our present case, dystonia due to the intake of cetirizine was observed, which the patient responded well to the use of benzodiazapines, namely, clonazepam. We report this case to highlight the occurrence of this adverse event with the use of cetirizine.
Chapter
The term antihistamine refers to drugs that antagonize the actions of histamine. Histamine plays a pivotal role in allergic inflammation. It is released by the human immune system during allergic reactions, causing itching, swelling, and congestion, stimulating gastric secretion and constriction of bronchial smooth muscle, and dilating blood vessels, which causes a fall in blood pressure. It is involved also in the regulation of basic body functions, including energy and endocrine homeostasis, cognition and memory, and the sleep–wake cycle.
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Background: Ectodermal dysplasia is a clinically and genetically heterogeneous group of inherited disorders characterized by abnormal development of two or more of the following ectodermal-derived structures: hair, teeth, nails and sweat glands. The hair is the most frequently affected structure. Hair shaft abnormalities are of great concern to these patients, but no effective treatments are available. Methods: We describe three girls with congenital hypotrichosis (9, 5 and 6 years old) caused by ectodermal dysplasia treated with topical cetirizine solution (2 mL. once daily) and oral vitamin D supplementation (1000 IU daily). Results: After 6 months of treatment, the density of hair on the scalp increased in all patients. The vellus hair was replaced by terminal hair. Hair regrowth was evaluated both from the clinical and trichoscopic point of view. Conclusion: We propose a combination of topical cetirizine and oral vitamin D as a rational treatment of choice in congenital hypotrichosis caused by ectodermal dysplasia.
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An umpolung synthesis of diarylmethylamine derivatives is presented. This reaction entails a palladium-catalyzed arylation of 1,3-diaryl-2-azaallyl anions, in situ generated from N-benzyl aldimines. A Pd(NIXANTPHOS)-based catalyst together with hindered silylamide bases enabled the coupling of aldimines with aryl bromides in good to excellent yields without product isomerization. Moreover, regioselectivity in the arylation of unsymmetrical 1,3-diaryl-2-azaallyl anions was studied. This method is suitable for a gram scale synthesis of diarylmethylamine derivatives at room temperature without use of a glove box.
Article
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.
Article
Levocetirizine (Xyzal®) is a selective, potent, oral histamine Hi 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 antihis-taminic 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 H1 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 H1 receptor antagonists available for the treatment of allergic rhinitis and as first-line therapy in patients with CIU. Pharmacological Properties Levocetirizine, the R-enantiomer of racemic cetirizine, exhibits a higher in vitro affinity for the H1 receptor than racemic cetirizine or the S-enantiomer, dextroce-tirizine, with the antihistaminic properties of racemic cetirizine residing in the R- rather than the S-enantiomer. Levocetirizine has a more rapid onset and longer duration of action than other antihistamines, with maximal inhibition of histamine-induced wheal in healthy volunteers occurring 2–4 hours after drug administration. In several double-blind studies, histamine-induced wheal and/or flare responses were generally inhibited to a greater extent with single or multiple doses of levocetirizine 5mg than with therapeutic doses of other antihistamines (including loratadine, desloratadine, fexofenadine, ebastine and mizolastine) in healthy adult volunteers and atopic adult patients. Levocetirizine also exerts anti-inflammatory effects in patients with allergic disorders. The drug has no clinically relevant effect on cognitive function, psychomotor function or cardiovascular parameters. After single milligram-equivalent doses, the pharmacokinetic profile of levocetirizine did not differ regardless of whether it was given as the individual enantiomer or as a component of racemic cetirizine; however, levocetirizine exhibited a lower volume of distribution (suggesting a more limited distribution into tissues) and a lower renal clearance than dextrocetirizine. In healthy adult volunteers, levocetirizine is rapidly absorbed, with maximum plasma concentrations attained within 1 hour and steady-state concentrations after 2 days. The apparent volume of distribution of levocetirizine was low compared with that of other antihistamines (e.g. cetirizine, mizolastine, fexofenadine and desloratadine). The drug appears to have a high absolute oral bioavailability and exhibits a high level of plasma protein binding (≥87%). It undergoes minimal metabolism and is primarily excreted as unchanged drug in the urine, with 95% of the radiolabelled dose excreted over the first 48 hours. No conversion of radiolabelled levoce-tirizine to dextrocetirizine was detected. Pharmacokinetic parameters of levoce-tirizine 5mg in paediatric patients aged ≥6 years were similar to those in healthy adults. In patients with end-stage renal impairment, total body clearance of levocetirizine was ≈80% lower than that in subjects with normal renal function, with dosage adjustment recommended in patients with renal impairment. Levocetirizine appears to have a low potential for drug interactions, although no in vivo drug-interaction studies have been conducted to date. Therapeutic Efficacy Several well designed, placebo-controlled, short-term studies have shown oral levocetirizine 5mg once daily to be effective in alleviating symptoms in adult and/ or adolescent patients with seasonal allergic rhinitis (SAR), perennial allergic rhinitis (PAR), PER, CIU and other skin allergies, and in children (aged 6–12 years) with SAR and PAR. Levocetirizine also improved health-related quality of life in adults with PER and CIU and children with SAR and PAR. These data are supported by 2-day allergen challenge chamber studies and noncomparative, multicentre studies in the primary care setting, including a large noncomparative study in 17 638 patients with allergic disorders. Data from small (n < 50 patients), short-term studies and/or from 2-day allergen challenge chamber studies suggest that levocetirizine may be more effective than desloratadine, loratadine and fexofenadine in alleviating symptoms of SAR and has similar efficacy to cetirizine in CIU. In Addition, the longer-term efficacy of levocetirizine was demonstrated in adult patients with PER in XPERT (Xyzal® in Persistent Rhinitis Trial), a 6-month, double-blind, multicentre trial. Levocetirizine significantly improved health-related quality of life and the Total 5 Symptoms Score over the first 4 weeks of treatment in adult patients with PER (co-primary endpoints), with these benefits sustained over the 6-month treatment period. Furthermore, the proportion of patients who experienced an asthma event during the 6-month treatment period was significantly lower in the levocetirizine than in the placebo group, as was the mean number of asthma events requiring medication per patient. Tolerability Levocetirizine was generally well tolerated in adults, adolescents and children with allergic conditions participating in clinical trials and in the clinical practice setting, based on a pooled analysis of therapeutic trials, a large study in the primary care setting and a large postmarketing surveillance study. In the pooled analysis of therapeutic studies in adults and adolescents (12–71 years of age), 11.3% of 935 levocetirizine recipients experienced at least one adverse event, with the most common being somnolence (5.2%), dry mouth (2.6%) and fatigue (2.5%). The vast majority (91.6%) of these treatment-emergent adverse events were of mild to moderate severity, with very few levocetirizine recipients (1%) discontinuing treatment because of an adverse event. In the postmarketing surveillance study, <0.1% of patients discontinued levocetirizine treatment because of drowsiness/sedation.
Article
To evaluate the population pharmacokinetics of levocetirizine in young children receiving long-term treatment with cetirizine. Data were available from a randomized, double-blind, parallel group and placebo-controlled study of cetirizine in 343 young children between 12 and 24 months of age at entry, who were at high risk of developing asthma, but were not yet affected (ETAC® study). Infants received oral drops of cetirizine at 0.25 mg kg−1 twice daily for 18 months. Plasma concentration of the active enantiomer levocetirizine was determined in blood samples collected at months 3, 12 and 18 (1–3 samples per child). A one-compartment open model was fitted to the data using nonlinear mixed effects modelling (NONMEM). The influence of weight, age, gender, BSA and other covariates on CL/F and V/F was evaluated. CL/F increased linearly with weight by 0.044 l h−1 kg−1 over an intercept of 0.244 l h−1, and V/F increased linearly with weight by 0.639 l kg−1. Population estimates in children with weights of 8 and 20 kg were 0.60 and 1.13 l h−1 for CL/F, and 5.1 and 12.8 l for V/F, respectively, with interpatient variabilities of 24.4% and 14.7%. Weight-normalized estimates of CL/F and V/F were higher than in adults. The estimated relative bioavailability was 0.28 in 12% of instances of suspected noncompliance. Levocetirizine pharmacokinetics were not influenced by severe allergy or aeroallergen sensitization. Results on the effects of concomitant medications or diseases were inconclusive due to limited positive cases. AUCss, calculated in compliant subjects using posterior estimates of the final model, was 1952 (1227–3319) µg l−1 h (mean, min-max), a value similar to that in adults after intake of 5 mg oral solution (2036 (1414–2827) µg l−1 h. The model suggests that administration of levocetirizine 0.125 mg kg−1 twice daily in children 12–48 months of age or weighing 8–20 kg yields the same exposure as in adults taking the recommended dose of 5 mg once daily.
Article
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The efficacy, safety and side effects of Cetirizine and Astemizole were compared with Pheniramine maleate in sixty cases of allergic rhinitis. All medications were stopped one week prior to treatment. Cetirizine, Astemizole or Pheniramine maleate were given as a single daily dose for 15 days. On completion of treatment results were evaluated subjectively as well as objectively, Cetirizine and Astemizole were found to be more effective than Pheniramine maleate. The side effects were minimum with Cetirizine.
Article
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Objectives: To investigate the frequency with which sedation was reported in post-marketing surveillance studies of four second generation antihistamines: loratadine, cetirizine, fexofenadine, and acrivastine. Design: Prescription-event monitoring studies. Setting: Prescriptions were obtained for each cohort in the immediate post-marketing period. Subjects: Event data were obtained for a total of 43 363 patients. Main outcome measure: Reporting of sedation or drowsiness. Results: The odds ratios (adjusted for age and sex) for the incidence of sedation were 0.63 (95% confidence interval 0.36 to 1.11; P=0.1) for fexofenadine; 2.79 (1.69 to 4.58; P<0.0001) for acrivastine, and 3.53 (2.07 to 5.42; P<0.0001) for cetirizine compared with loratadine. No increased risk of accident or injury was evident with any of the four drugs. Conclusions: Although the risk of sedation was low with all four drugs, fexofenadine and loratadine may be more appropriate for people working in safety critical jobs.
Article
The use of antihistamines (AHs) has until recently been associated with a number of undesirable side effects, the most troublesome of which is sedation. There are two aspects to sedation. The first, an objectively determined measure based on the results of psychometric tests from controlled trials, and the second, the subject's response to the administration of a drug. Since AHs are largely used in ambulant patients, a complete evaluation of sedation should be performed through standardised objective and subjective tests, shown to be sensitive to the central effects of AHs. An extensive review of the literature identified 76 studies of H1 receptor antagonists in healthy volunteers, in which assessment of sedation was the primary objective. Results from studies published in peer‐reviewed journals which employed a placebo condition as well as a positive internal control using a crossover design were analysed to determine the extent to which a particular antihistamine produced impairments on a battery of psychometric tests. The impairment index for each antihistamine was calculated and subsequently compared with the impairment index obtained for all other AHs. The calculation of this proportional impairment ratio enabled the sedative potential of an individual antihistamine to be identified relative to all other AHs and thus allowed the ranking of AHs with respect to their ability to cause impairments of cognitive and psychomotor function. Findings from this review clearly demonstrate that there are distinct classes of AHs with respect to their ability to impair cognitive function and psychomotor performance. Copyright © 2000 John Wiley & Sons, Ltd.
Article
I. Acute urticaria/angioedema. A recent episode of urticaria/angioedema lasting less than 6 weeks is characterized as acute, while lesions recurring for more than six weeks are termed chronic. In acute urticaria/angioedema, the etiology may be readily apparent to both the patient and the physician. For example, the patient who presents with acute urticaria after drug administration, insect sting, or repetitive physical triggers will often note an association. The longer the urticaria persists the more difficult it is to determine a specific etiology. Urticaria should be considered when the patient presents with pruritic (and sometimes painful or burning), erythematous, circumscribed (or coalescent) wheals. Urticarial lesions commonly involve the extremities and trunk but may appear on any part of the body. In contrast to urticaria, angioedema presents as deeper subcutaneous swelling. Less circumscribed than the lesions of urticaria, angioedema has a predilection to areas of loose connective tissue such as the face or mucous membranes involving the lips or tongue. If angioedema involves the upper respiratory tract, life-threatening obstruction of the laryngeal airway may occur. Hereditary or acquired angioedema associated with C1 esterase inhibitor deficiency are particularly prone to this presentation, although other forms of angioedema can present either with laryngeal or glossopharyngeal edema causing hoarseness and difficulty in swallowing. The etiology of urticaria/angioedema can often be deduced by a detailed history. The patient should be asked about recent use of medications (including herbals and supplements), food exposures, physical triggers, viral infections, contactants, occupational and natural allergen exposures or systemic diseases which can manifest as acute urticaria. The physical examination should include the skin, lymph nodes, eyes, ears, throat, neck, joints, lungs, heart, and abdomen in an effort to detect an underlying causal condition. Findings ascertained by history or physical examination may direct attention towards an identifiable trigger or cause of urticaria/angioedema. Given the vast number of potential urticarial triggers and the difficulty in identifying them, any clues uncovered by history and physical may be extremely important. Evaluation of a suspected cause of acute urticaria/angioedema is often based on a clear temporal relationship between onset of symptoms and exposure to a specific food, insect sting or drug. If IgE-mediated penicillin-induced hives is suspected, predictive diagnostic skin tests are available. Allergy skin testing and/or in vitro tests may be useful in determining whether anaphylactogenic foods or inhalants are the cause of urticaria. Viral diagnostic studies may be helpful in confirming the association of hives with viral infections (eg, the Epstein-Barr virus). On the other hand, a complex evolving process may develop in patients with acute urticaria/angioedema. Initial evaluation may not provide definitive diagnosis and further management becomes empiric. In the absence of historical information or physical signs suggesting an underlying cause, therapeutic intervention should be implemented. The immediate treatment of acute urticaria/angioedema that occurs as a component of anaphylaxis necessarily takes precedence over diagnostic considerations. Patients may improve after removal of factors that augment or induce urticaria/angioedema (eg, aspirin, NSAIDs, or alcohol ingestion). The cornerstone of treatment for acute urticaria/angioedema not associated with anaphylaxis is the use of H1 antihistamines. Second generation H1 antihistamines are usually preferred. When these fail, first generation antihistamines, such as hydroxyzine or diphenhydramine may be effective, although caution about the sedating side effects of these agents should be emphasized. The use of glucocorticosteroids in the treatment of patients with acute urticaria/angioedema is rarely necessary. If they are required, short courses of oral glucocorticosteroids rather than depot parenteral preparations are preferred to lessen the duration of systemic effects. If known triggers or causes for urticaria/angioedema are not discovered within the first six weeks of the onset of symptoms, further evaluation and management of this chronic process becomes more complex. At this point, referral to an allergist/immunologist is appropriate, especially if the etiology has not been determined. II. CHRONIC URTICARIA. Urticarial lesions are defined as chronic if manifestations persist or recur beyond six weeks. Persistent symptoms may be daily or episodic. Diurnal patterns are often reported but these are highly variable from patient to patient. It is not possible to predict the duration of chronic urticaria/angioedema. Spontaneous remissions often occur within 12 months but many patients continue to have symptoms at least periodically for years. Conditions that can masquerade as urticaria include erythema multiforme minor, nonspecific maculopapular exanthemata, mast cell releasibility syndromes such as urticaria pigmentosa and urticarial vasculitis. The skin lesions of urticarial vasculitis differ from urticaria in that they are palpable, purpuric, and persist 24 hours or longer. Resolution of these lesions is prolonged and they often leave residual pigmented changes in the skin. If skin lesions have the appearance of urticarial vasculitis, a skin biopsy should be performed. Routine histopathology reveals the presence of leukocytoclastic vasculitis while immunofluorescence may demonstrate the presence of fibrinogen, various immunoglobulins, and complement within the vascular lesions. Systemic collagen vascular diseases should also be considered in the differential diagnosis of urticarial vasculitis. Treatment of this condition may require various anti-inflammatory agents such as glucocorticosteroids, colchicine, dapsone, hydrochloroquine, or other cytotoxic agents. Commonly, chronic urticaria and angioedema coexist; however, some patients may develop chronic angioedema without urticaria. Etiologic triggers of chronic angioedema without urticaria may be the same as those observed in acute urticaria and include medications, occupational exposures, insect sting, physical hypersensitivity disorders, delayed pressure angioedema, and C1 esterase inhibitor deficiencies. Drugs such as ACE inhibitors or aspirin/NSAIDs may induce or aggravate angioedema. If this relationship is suspected, the drug should be withdrawn as soon as possible. Of particular importance is the family history, because of the possibility of hereditary C1 esterase inhibitor deficiency. The episodes of swelling in patients with this disease are often precipitated by trauma. Screening C4 levels should be obtained in all patients with chronic angioedema without urticaria. C4 levels are usually decreased during and between attacks while C2 levels are reduced only during attacks. Fifteen percent of patients with hereditary C1 esterase inhibitor deficiency have normal quantitative levels of C1 esterase inhibitor protein that is dysfunctional. Chronic angioedema due to C1 esterase inhibitor deficiency may also be acquired as a manifestation of a systemic connective tissue disease, a lymphoproliferative disorder or as a de novo autoantibody to C1 esterase inhibitor protein. The treatment choices for recurrent, life-threatening attacks of C1 esterase inhibitor deficiency are limited and supportive. Plasma infusions or C1 esterase inhibitor concentrates (available only on an experimental basis) may offer short-term palliative benefit. Should these measures fail, intubation or tracheostomy may be necessary. To prevent recurrent episodes of angioedema due to C1 esterase inhibitor deficiency, prophylactic management with anabolic steroids may be helpful. It is very unusual to find an exogenous cause for chronic urticaria/angioedema. Nevertheless, every effort should be made to determine the etiology of these symptoms by redirecting attention to a detailed medical history and review of systems. Triggers such as foods, drugs, physical factors, insect bites, occupational exposures, and contactant exposures should have been ruled out during the initial workup of acute urticaria. The differential diagnosis of chronic urticaria/angioedema should include complement-mediated disorders, malignancies, cutaneous or systemic mastocytosis, mixed connective tissue diseases and cutaneous blistering disorders (eg, bullous pemphigoid and dermatitis herpetiformis). Only a few screening laboratory tests are possibly helpful in detecting etiology at this stage of the workup. These include a complete blood count with differential, erythrocyte sedimentation rate, urinalysis, and liver function tests. Since thyroid autoantibodies may be present in up to 28% of patients with urticaria/angioedema, particularly women with chronic urticaria/angioedema, some clinicians advocate that these tests be obtained regardless of the patient's thyroid status. Evaluation of the patient for autoantibodies to high affinity IgE receptor (FcεR1) should also be considered. If not previously obtained, a punch skin biopsy should also be performed in patients with difficult-to-manage chronic idiopathic urticaria. Two groups of patients with chronic urticaria have been identified based on the histopathology of the skin lesions: (1) perivascular lymphocyte-predominant urticaria and (2) perivascular polymorphonuclear-predominant urticaria.
Article
In this double-blind, randomized study, 46 patients with chronic idiopathic urticaria received loratadine 10 mg once daily (n=24) or cetirizine 10 mg once daily (n=22) for 2 weeks. At study end, the two agents showed comparable efficacy (loratadine 78% improvement, cetirizine 79% improvement) on physician-evaluated change in pruritus. Improvement was also similar for number and size of hives and erythema. By study end, 60% of loratadine recipients and 53% of cetirizine recipients had complete relief of symptoms. The greater reduction in wheals and flares seen with cetirizine was neither statistically significant nor clinically relevant. Both agents were well tolerated, except for cetirizine-associated sedation in 2 patients.
Article
In a 20-d, double-blind, randomized, parallel study, the efficacy of cetirizine and terfenadine was compared in 30 patients with chronic idiopathic urticaria. Subjects were randomly divided into two 15-patient groups. The first group was given cetirizine (10 mg once daily); the second terfenadine (60 mg twice daily). Cetirizine proved to be more effective than terfenadine in controlling urticaria symptoms. In fact, the score of the investigators' overall assessment was signifieantly lower in the cetirizine-treated group than in the terfenadine-treated group. Moreover, patient evaluation by a visual analog scale and symptoms assessed on a 4-point scale showed a better improvement in the cetirizine group. The number and severity of side-effects were similar in both treatment groups.
Pharmacokinetic studies and examination of safety on single and multiple oralintake of cetirizine, a new antiallergic drug, were performed in 37 healthy male adult Japanese volunteers (single dose: 15 subjects, multiple dose : 22 subjects, 4 of whomreceived placebo, age: 23-45 years).1) In the single-intake study (cetirizine: 2.5-30mg), the concentration of cetirizineplasma increased in a dose-dependent manner. When 10, 20 and 30mg of the drug wasgiven, the mean Cmax was 214.5, 438.1 and 679.2ng/ml with the mean Tmax of 1.44, 1.50and 2.20hr, respectively. The metabolite (ucb 026) in the plasma was detected in only afew cases and the level was very low, compared with the unchanged form. In the 10, 20and 30mg groups approximately 50% of the given doses was excreted in urine in theunchanged form by 24hr, but the metabolite was not detected in the urine.2) In the multiple-dose study, 20mg(once per day, 20mg×1 group: twice per day, 10mg×2group), 30mg(once per day, 30 mg×1group)or placebo was given for 7 days.On the first day and the 7th day, the mean Cmax was 547.8 and 624.5 ng/ml in the 20mg×1group, 272.7 and 424.2ng/ml in the 10mg×2group, and 852.7 and 832.7 ng/ml in the 30mg×1group, respectively. Simulation usin.g the parameters obtained on the first day ofthe multiple-dose study showed a constant plasma concentration of cetirizine from the2nd day after administration in the 20mg×1 and 30mg×1groups;this concentrationwas almost equivalent to the values obtained in the subsequent days. However, thesimulation did not correspond well with the actual values obtained in the 10mg×2group, this is probably due to the inability to measure the terminal phase. The metabolite inblood was detected on the 2nd day after administration and the level was nearly constanton 6 and 7th day. Urinary excretion of the unchanged form increased almost linearly to48-58% on the first day and 59-70% of the doses given on the 7th day in the three groups, but the metabolite was not detected in urine.3) There were no abnormal findings due to cetirizine in blood, biochemical andurinary examinations, nor physiological signs such as pulse, respiration, blood pressureor ECG in the single or multiple doses study. No subjective symptoms due to the drugwere observed in either study except for one subject who became slightly sleepy duringdays 1-3 after administration of 20mg.
Article
Cetirizine, a selective histamine H1 receptor antagonist, is an effective oral treatment for patients with a number of atopic disorders. Studies conducted specifically in children aged between 2 and 14 years with allergic rhinitis show the drug to be beneficial in this population when administered once or twice daily as a tablet or solution. Therapeutic dosages of the drug have greater efficacy than placebo and similar rapid efficacy to chlorphenamine in children with seasonal allergic rhinitis. In particular, when compared with placebo, cetirizine is associated with significantly more days on which symptoms are absent or mild, irrespective of whether children are aged 2 to 6 years or 6 to 12 years. Generally, ocular pruritus, oral/nasal pruritus and, to a lesser extent, nasal blockage show the greatest improvements with cetirizine. In children with perennial allergic rhinitis, cetirizine is more effective than placebo. Administration of the drug results in a significantly greater percentage of days when the patient’s severest symptom is mild or absent than is achieved with placebo and a similar number of these days when compared with oxatomide. Cetirizine generally improves nasal obstruction, rhinorrhoea and sneezing more than placebo. Cetirizine has been shown to have some efficacy in children with atopic dermatitis. However, these data are not sufficient to allow the usefulness of cetirizine to be determined in children with atopic skin disorders. In addition, the drug may prevent the development of asthma in selected children with atopic diseases [those with elevated immunoglobulin (Ig)E or IgE antibody levels]. Adverse events occurring in children receiving cetirizine are generally mild or moderate and infrequently lead to treatment withdrawal irrespective of patient age (2 to 6 years or >6 years). Generally, cetirizine is well tolerated, with headache, pharyngitis, increased cough and abdominal pain being the most commonly reported events. Clinically important adverse cardiac events have not been reported with cetirizine in children. However, some sedation is reported with the drug. Conclusion: Cetirizine can be considered an option for treating children with allergic rhinitis. Although further clinical trials are needed to fully determine how cetirizine compares with other agents available, the drug has shown efficacy, good tolerability and a low potential for many of the unwanted effects associated with several other treatment options in this population. Overview of Pharmacology Cetirizine is the carboxylated metabolite of hydroxyzine. It is a selective histamine H1 receptor antagonist with higher polarity than hydroxyzine and therefore a reduced ability to cross the blood-brain barrier. In atopic and nonatopic volunteers, cetirizine produces long-lasting reductions in wheal and flare induced by histamine or inflammatory mediators with activity similar to or greater than that of a number of other histamine H1 receptor antagonists at therapeutic doses. In studies conducted specifically in children (aged 5 to 14 years with allergic rhinitis) and infants or toddlers (aged 7 to 25 months with respiratory tract infections or hypersensitivity-related diseases), cetirizine produced sustained reductions in skin reactions to histamine or allergen challenge when compared with baseline or placebo. In children, suppression of wheal and flare at 12 hours was maintained during 35 days’ administration of cetirizine 5 or 10 mg/day. Cetirizine may have a faster onset of action than loratadine or ebastine, although activity is not maintained for as long with cetirizine when compared with the latter agent. In atopic children aged 5 to 15 years, cetirizine reduces inflammatory cell counts and expression of intercellular adhesion molecule-1 (ICAM-1) on nasal epithelial cells. Decreases in eosinophil counts are similar in atopic children receiving cetirizine and loratadine or intranasal levocabastine. Although some histamine H1 receptor antagonists have been associated with adverse cardiac effects in patients, cetirizine has not been shown to cause these effects even at high dosages. No cardiorespiratory changes during sleep have been observed in infants (aged 6 to 13 months) with or without allergies receiving a single dose of cetirizine 0.25 mg/kg. The pharmacokinetics of cetirizine have been well described. Cetirizine is rapidly absorbed with maximum plasma concentrations usually being reached after 1 to 2 hours. Multiple dose administration (5 or 10mg daily in the evening for 35 days) indicates that, after week 1, the drug does not accumulate in children aged 5 to 12 years. Comparison of single dose pharmacokinetics of cetirizine in children (aged 2 to 4 years) and adults (aged 21 to 35 years) indicates that maximum plasma concentrations (Cmax) of cetirizine are lower, time to Cmax is longer, elimination half-life shorter and metabolic clearance higher in children. Cetirizine is predominantly excreted in the urine as unchanged drug; however, cumulative urinary excretion is lower in children aged 2 to 4 years than in adults, but similar in children aged 10 to 12 years and 6 to 24 months and adults. Volume of distribution does not differ between children (aged 2 to 4 years) and adults (aged 21 to 35 years) but appears decreased, and clearance increased, in infants and toddlers (6 to 24 months) when compared with values in older children (aged >2 years). Renal impairment (creatinine clearance ≥3.6 L/h) decreases renal and total body clearance and increases the Cmax of cetirizine so that patients with moderate to severe renal impairment may require lower dosages of cetirizine than other patients. Therapeutic Use Studies of cetirizine in allergic rhinitis generally included children aged 2 to 14 years who received the drug as a tablet or solution once or twice daily, usually at a dosage of 5 or 10 mg/day. In children with seasonal allergic rhinitis, therapeutic dosages of cetirizine are more effective than placebo and have similar rapid efficacy to chlorphenamine. The drug is associated with significantly more days during which symptoms are absent or mild than is placebo, irrespective of whether children are aged 2 to 6 years or 6 to 12 years. Similarly, reductions in total symptom scores over a 4-week treatment period are greater with cetirizine than with placebo. Global improvement is greater with cetirizine than placebo, with ocular pruritus, oral/nasal pruritus and, to a lesser extent, nasal blockage generally showing the greatest improvements. Cetirizine is also more effective than placebo in children with perennial allergic rhinitis. In the only placebo-controlled trial to assess this parameter, administration of cetirizine 10mg once daily resulted in a significantly greater percentage of days when the patient’s severest symptom was mild or absent than was achieved with placebo. When mean investigator-assessed symptom scores and global efficacy were considered in several trials, cetirizine 10 mg/day was significantly superior to placebo. Cetirizine generally improves nasal obstruction, rhinorrhoea and sneezing more than placebo. Cetirizine 5 mg/day and oxatomide 25 mg/day do not differ significantly as regards all efficacy parameters, including the percentage of days when the patient’s severest symptom is absent or mild, in children with perennial allergic rhinitis. Cetirizine also had similar efficacy to inhaled levocabastine in a small 15-day study reported as an abstract. Information presented in another abstract indicates that cetirizine 0.2 mg/kg/day as a solution was more effective than the same dosage of loratadine for controlling nasal symptoms according to daily symptom scores but produced similar control of ocular pruritus and had similar overall efficacy according to investigators in children with perennial allergic rhinitis. Cetirizine 5 or 10 mg/day (depending on weight) is not associated with worsening of asthma symptoms in children aged 6 to 11 years with allergic rhinitis. Indeed, asthma symptoms tend to improve with cetirizine. The drug also prevented the development of asthma in a subgroup of atopic infants (those with elevated IgE or IgE antibody levels), but had no significant effect in the overall study population, when administered prophylactically. Cetirizine has been evaluated for use in children with atopic dermatitis in 1 small double-blind study. Results indicated that although cetirizine recipients had significant reductions in disease severity scores after 4 and 8 weeks of treatment, when compared with investigator-assessed results for placebo-treated patients, the changes were not significant. Patient diaries indicated some significant advantages for cetirizine over placebo. Tolerability Irrespective of age (2 to 6 years or >6 years), adverse events occurring in children receiving cetirizine are generally mild or moderate and infrequently lead to treatment withdrawal. Generally, the adverse event profile of cetirizine does not differ significantly from that of placebo with respect to overall incidence, severity and/or type of events in children. Headache, pharyngitis, increased cough and abdominal pain are commonly reported events in both cetirizine and placebo recipients, although they occur more frequently with the active treatment. Somnolence appeared more common in cetirizine versus placebo recipients and this event appears to be dose related. In general, no significant differences in the incidence, severity or type of adverse events, including somnolence, occurred in children treated with cetirizine and the older histamine H1 receptor antagonists oxatomide or chlorphenamine. However, in single comparisons with other newer histamine H1 receptor antagonists, somnolence was reported in small numbers of cetirizine recipients, but not in patients receiving loratadine or levocabastine. However, results of larger trials conducted predominantly in adults indicate that cetirizine causes less sedation than older H1 receptor antagonists and may cause more sedation than other newer agents. Clinically important adverse cardiac events have not been reported with cetirizine in children or adults. Dosage and Administration Cetirizine should be administered once or twice daily at a dosage of 5 mg/day in children aged 2 to 6 years and 5 or 10 mg/day in those aged >6 years. In clinical trials, the drug was administered at a dosage of 5 mg/day in children weighing <30kg and 10 mg/day in those weighing >30kg. Patients with moderate or severe renal impairment may require smaller dosages of cetirizine than those with normal renal function.
Article
Synopsis Cetirizine, the carboxylated metabolite of hydroxyzine, is a specific and long-acting histamine H1-receptor antagonist. It has marked antiallergic properties and inhibits eosinophil chemotaxis during the allergic response. Clinical trial results indicate that cetirizine is an effective and well tolerated treatment for seasonal/perennial allergic rhinitis and chronic idiopathic urticaria in adults, and for seasonal/perennial allergic rhinitis in children. Cetirizine 10 mg/day appears to be as effective as conventional dosages of other established antihistamines such as astemizole, hydroxyzine, ketotifen, loratadine or terfenadine in relieving symptoms of these disorders, and is associated with a significantly lower incidence of sedation than hydroxyzine. However, when sedation was subjectively assessed, cetirizine appeared to be more sedating than placebo, loratadine or terfenadine in some clinical trials. This difference was not observed in several other double-blind studies. In contrast, when assessed objectively in pharmacodynamic comparisons, cetirizine was rarely more sedating than placebo or other second generation histamine H1-receptor antagonists. Cetirizine may also have a role in the treatment of certain forms of physical urticaria, atopic dermatitis and reactions to mosquito bites. In addition, it is being studied for the treatment of allergic asthma in adults and children. The pharmacokinetic profile and predominantly renal excretion of cetirizine suggest that this agent may have a reduced potential for adverse drug interactions involving hepatic enzyme systems compared with other histamine H1-receptor antagonists which are extensively metabolised. Thus, cetirizine, with its rapid onset and long duration of action, appears to provide a useful alternative to the antihistamine agents in clinical use. Overview of Pharmacology Cetirizine is a specific histamine H1-receptor antagonist which has greater antihistaminic activity than clemastine, hydroxyzine, mepyramine and terfenadine in animal models. In atopic and nonatopic volunteers, cetirizine 10mg, administered as a single dose or daily for 2 to 28 days, significantly suppressed histamine-, allergen- and antigen-induced weal and flare response compared with placebo. Following histamine challenge, this effect peaked 4 to 8 hours after administration of cetirizine and lasted up to 24 hours after a single dose. Against histamine-induced weal and flare, cetirizine 10mg had similar activity to diphenhydramine 50mg or hydroxyzine 25mg, and was at least as effective as standard doses of astemizole, azelastine, brompheniramine, chlorphenamine (chlorpheniramine), clemastine, cyproheptadine, ebastine, ketotifen, loratadine, mequitazine, oxatomide or terfenadine. In addition, it had a significantly more rapid onset of action than astemizole 10mg against histamine-induced weal and flare. In antiallergic assessments of weal and flare response, cetirizine 10mg was as active as astemizole 10mg, ketotifen 1mg or terfenadine 120mg, and was significantly more active than chlorphenamine 8mg or loratadine 10mg. A 20mg dose of cetirizine was also superior to clemastine 2mg in antiallergic studies. Cetirizine 5 to 20mg provided dose-dependent protection against inhaled histamine-induced bronchospasm in patients with asthma, and protected some patients from allergen-induced bron-chospasm. The immediate and late responses to allergen challenge in patients with allergic rhinitis were also attenuated by cetirizine 10 mg/day. The effect of cetirizine 10mg on histamine-induced bronchial response was significantly greater than that of astemizole 10mg, brompheniramine 4mg, chlorphenamine 4mg, clemastine lmg, cyproheptadine 4mg or terfenadine 60mg, while cetirizine 20mg was superior to hydroxyzine 25mg. Most in vitro investigations and studies in atopic or healthy volunteers showed that cetirizine had no effect on mast cells, but inhibited neutrophil and platelet responses following allergen challenge. Eosinophil chemotaxis following challenge with allergen, platelet activating factor or compound 48/80, but not histamine, was inhibited by cetirizine in a dose-dependent fashion. In addition, intercellular adhesion molecule-1 expression on epithelial cells was inhibited by cetirizine in vitro and in vivo, suggesting that cetirizine also has activity other than antagonism of histamine H1-receptors. In pharmacodynamic studies, subjective and objective measurements of drowsiness and cognitive performance were not usually significantly altered by cetirizine in single doses of ≤ 20mg. The incidence of sedation with cetirizine 10mg was similar to that of placebo, loratadine 10mg, or terfenadine 120mg, but was significantly less than that of oxatomide 30mg or ketotifen 1mg in pharmacodynamic studies conducted in nonatopic volunteers. In most assessments of psychomotor performance, cetirizine 5 to 20mg in single or repeated doses caused no impairment, whereas a single 10mg dose caused significant impairment of driving performance in 1 trial. Mean peak plasma concentrations (Cmax) of 257 and 580 μg/L were reached within 1 hour of the oral administration of cetirizine 10 and 20mg, respectively, to healthy adult volunteers. Food may delay the rate, but does not affect the extent, of cetirizine absorption. In adults, the terminal elimination half-life (t½β) is 6.5 to 10 hours. Over a 5-day period, about 70% of cetirizine 10mg is excreted in the urine (60% over 24 hours), predominantly as unchanged drug, and about 10% is excreted in the faeces. Cmax and t½β of cetirizine on a mg/kg basis are lower in very young children with symptoms of allergy than in adults, suggesting more rapid elimination in the former. In patients with renal impairment, the t½β of cetirizine is increased reflecting a reduction in renal and total body clearance. These parameters are similarly altered in the elderly, an effect that appears to be dependent on renal function rather than age per se. Therapeutic Efficacy The efficacy of cetirizine 5 to 20 mg/day in the treatment of seasonal and perennial allergic rhinitis, and chronic idiopathic urticaria has been established in a number of randomised blinded clinical studies. In addition, higher dosages of cetirizine tended to reduce some symptoms of mild allergic asthma (10 to 30 mg/day), were effective in the treatment of some physical urticarias (10 to 30 mg/day), and reduced symptoms in patients with moderate to severe atopic dermatitis (10 to 40 mg/day). Local reactions to mosquito bites have also been attenuated by treatment with cetirizine 10 mg/day. In comparisons with other antihistamines, cetirizine 5, 10 or 20 mg/day produced at least similar symptomatic control to astemizole 10 mg/day, loratadine 10 mg/day, or terfenadine 60mg twice daily or 120 mg/day in patients with seasonal allergic rhinitis; astemizole 10 mg/day, ketotifen 2 mg/day or terfenadine 120 mg/day in patients with perennial allergic rhinitis; astemizole 10 mg/day, hydroxyzine 25 to 75 mg/day or terfenadine 120 mg/day in those with chronic idiopathic urticaria; and terfenadine 60mg twice daily in patients with mild allergic asthma or atopic dermatitis. Cetirizine 5 or 10 mg/day was also effective in children (aged ≤ 12 years) with seasonal or perennial allergic rhinitis, while dosages of 5 to 15mg twice daily reduced the incidence of mild asthma in children and adolescents. Tolerability In a summary of placebo-controlled clinical trials, the most commonly reported adverse effects during cetirizine therapy were sedation, headache, dry mouth, fatigue and nausea. Comparative trials which included small numbers of patients and the results of earlier trials suggested that the incidence of sedation seen with cetirizine was similar to that of placebo, astemizole, loratadine or terfenadine. However, in some more recent comparisons cetirizine 10 mg/day tended to produce more sedation than loratadine 10 mg/day, terfenadine 120 mg/day or placebo. In contrast, cetirizine 5 to 20 mg/day produced significantly less sedation than hydroxyzine 25 to 75 mg/day. Spontaneously resolving liver function test abnormalities have been infrequently reported during cetirizine therapy. Dosage and Administration In adults and children aged > 12 years, the recommended initial cetirizine dosage is 10 mg/day (Europe) or 5 to 10 mg/day, up to a maximum of 20 mg/day (US and Canada). The recommended dosage for children aged 2 to 6 years is 5 mg/day, and for those aged up to 11 years it is 10 mg/day. In patients with moderate or severe renal impairment, the dosage of cetirizine should be reduced.
Article
Synopsis Cetirizine, a piperazine derivative and carboxylated metabolite of hydroxyzine, is a potent histamine H1-receptor antagonist with antiallergic properties. It has marked affinity for peripheral histamine H1-receptors and, at the standard dose of 10mg daily, lacks the CNS depressant effects of standard antihistamines. In addition, it inhibits histamine release and eosinophil chemotaxis during the secondary phase of the allergic response. Results from controlled clinical trials indicate that cetirizine is an effective and well tolerated treatment of seasonal and perennial allergic rhinitis and chronic idiopathic urticaria. Cetirizine appears to be as effective as conventional dosages ofterfenadine, chlorpheniramine and hydroxyzine in relieving symptoms associated with these disorders and produces a markedly lower incidence of sedation than chlorpheniramine, hydroxyzine and several other standard antihistamines. Thus, cetirizine appears to provide a useful alternative to other ‘nonsedating’ antihistamines; cetirizine may also have a future role in the treatment of allergic asthma and certain forms of physical urticaria. Pharmacodynamic Properties Cetirizine demonstrates similar affinity to terfenadine for in vitro binding to peripheral histamine H1-receptors. However, it is highly selective for histamine H1-receptors, possessing less affinity than terfenadine or hydroxyzine for calcium channel receptors, adrenergic α1-, dopamine D2-, serotonin 5-HT2 receptors and muscarinic receptors. Standard tests of antihistaminic activity in animals have shown cetirizine to have greater potency on a weight-to-weight basis than other antihistamines such as clemastine, mepyramine, terfenadine and hydroxyzine. In human studies, suppression of the weal esponse to intradermally injected histamine was greater with cetirizine 10mg than with placebo, peaking at 4 to 8 hours and lasting up to 24 hours. Cetirizine 10mg had a similar potency to diphenhydramine 50mg, hydroxyzine 25mg and terfenadine 180mg, but was more potent than terfenadine 60mg with a more rapid onset and longer duration of action, more potent than loratadine 10mg, chlorpheniramine 6mg or mequitazine 5mg, and more rapid in onset than astemizole 10mg. Cetirizine 5 to 20mg also provided a dose-dependent protective effect from bronchospasrn induced by inhaled histamine in asthmatics: a 20mg dose was superior in activity; o hydroxyzine 25mg. Antiallergic activity has been shown in models using allergens and other inflammatory agents. Cetirizine had little effect on mast cells and the release of mediators of immediate hypersensitivity. However, eosinophil chemotaxis in response to allergens was inhibited in atopic subjects. An inhibitory effect on the responses of neutrophils and platelets in allergy has also been demonstrated in experimental models and human volunteers. In psychomotor performance studies, cetirizine 10mg did not significantly affect subjective or objective assessments of drowsiness, or objective assessments of cognitive impairment in volunteers. Pharmacokinetic Properties Cetirizine is rapidly absorbed, reaching peak plasma concentrations of 257 μg/L within 1 hour of administration of 10mg oral doses to healthy volunteers (980 μg/L in children); AUC was 2.87 mg/L · h with this dose (6.37 mg/L · h in children). Plasma concentrations and AUC increase linearly with dose. Food does not affect the extent of absorption, but may slightly reduce the rate. The volume of distribution of cetirizine at steady-state is 30 to 40L. Animal studies indicate that peak concentrations in the brain are less than 10% of plasma concentrations. The terminal phase elimination half-life is 7 to 10 hours. Approximately 70% of a dose of cetirizine is excreted in the urine, mainly as unchanged drug, although small amounts of unidentified metabolites are found. Approximately 10% of the total dose is excreted in the faeces. The apparent total body clearance is 0.04 to 0.05 L/h/kg (0.06 to 0.07 L/h/kg in children). In patients with even mild impairment of renal function, the terminal elimination half-life of cetirizine is increased to approximately 20 hours. Half-life is also prolonged in elderly volunteers, an effect independent of age per se, but dependent on renal function. The elimination half-life is somewhat shorter in children, being 6 to 7 hours. Therapeutic Efficacy A number of randomised double-blind studies, most placebo controlled and many crossover in design, have established the efficacy of cetirizine 5mg to 20mg daily in the treatment of seasonal and perennial allergic rhinitis, and chronic idiopathic urticaria. In addition, several reports suggest a role for cetirizine 15 to 20mg daily, administered in 2 divided doses, in the treatment of pollen-associated asthma in atopic individuals. Comparisons with other histamine H1-receptor antagonists generally indicate similar symptomatic control, as well as patient and investigator acceptance, between cetirizine 5mg to 10mg daily, terfenadine 60mg twice daily and chlorpheniramine 8mg twice daily in seasonal allergic rhinitis; cetirizine 10mg daily and terfenadine 60mg twice daily in perennial allergic rhinitis; and cetirizine 5mg to 20mg daily, terfenadine 60mg twice daily and hydroxyzine 25mg once to 3 times daily in chronic idiopathic urticaria. A single brief report indicated that cetirizine 10mg twice daily alleviated asthmatic symptoms more successfully than did terfenadine 60mg twice daily in patients with pollen-associated asthma. Adverse Effects In the comparative studies discussed above, the incidence of sedation and/or somnolence was generally similar between cetirizine and terfenadine, and not significantly different from that reported with placebo. In contrast, the incidence reported with chlorpheniramine 8mg twice daily in patients with seasonal allergic rhinitis, and with hydroxyzine 25mg to 75mg daily in patients with chronic idiopathic urticaria, was significantly greater than that reported with placebo. Collated results from 1502 patients who received cetirizine 10mg in double-blind placebo-controlled clinical trials conducted in Europe indicate an incidence of sedation similar to that of other ‘nonsedating’ antihistamines, such as astemizole and terfenadine, and substantially less than that with ketotifen, clemastine, chlorpheniramine or mequitazine. In these collated results, there was no significant difference between cetirizine and placebo treatment in the incidence of headache, gastrointestinal disturbance, anticholinergic effects, dizziness or cardiovascular effects. Dosage and Administration The recommended dosage of cetirizine in adults and children over the age of 12 is one 10mg tablet daily (Europe) or one 5 or 10mg tablet daily, up to a maximum of 20mg once daily (USA and Canada). In the elderly and in patients with even a mild degree of renal impairment dosage should be reduced.
Article
At 1-week intervals, 12 healthy volunteers received oral cetirizine 10mg, oxatomide 30mg, ketotifen 1mg or placebo under randomised double-blind crossover conditions. Wheal and flare were induced by skin prick tests using histamine 100 and 500 g/L before, and 4, 8 and 24 hours after, drug ingestion. At each session volunteers recorded levels of pruritus and sedation on two 10cm visual analogue scales. Cetirizine was significantly more potent than oxatomide (p = 0.0001), ketotifen (p = 0.0002) or placebo (p = 0.0001) in the inhibition of wheals, with similar results for flare (p = 0.0007, 0.0001 and 0.0002, respectively). Relief from pruritus was significantly better with cetirizine than with oxatomide (p = 0.003) or ketotifen (p = 0.002). Cetirizine was slightly better than placebo in relieving pruritus, but this was not statistically significant. Oxatomide and ketotifen were clearly more sedative than cetirizine (p = 0.05 and p = 0.0006, respectively), which was not significantly different from placebo. In conclusion, cetirizine appeared to be better in reducing histamine-induced wheal, flare and pruritus compared with ketotifen and oxatomide, and had less sedative effect.
Article
This was a multicentre, double-blind study in 454 patients to compare the effectiveness and tolerability of fluticasone propionate nasal spray (FPANS) 200μg used once daily for 8 weeks on its own or in combination with oral cetirizine 10mg once daily in the treatment of seasonal allergic rhinitis. The results showed no significant difference between treatments in any of the symptoms or in the proportion of symptom-free days. Watery eyes were recorded as being the most troublesome symptom in the previous hayfever season, whilst during the study patients were, on average, free of eye symptoms for 56% of the time. Additionally, no difference was detected between the two groups with regard to the use of rescue medication. More than 75% of patients concluded at the end of the study that their symptoms had been adequately controlled and, similarly, investigators rated both treatments as being successful for the majority of patients. Overall, this study suggests that there is no significant difference in efficacy between FPANS 200μg, taken once daily in the morning, and FPANS 200μg once daily in combination with oral cetirizine 10mg, in the prophylactic treatment of seasonal allergic rhinitis.
Article
Cetirizine 2.5mg or 5mg twice daily was compared with placebo over a 2-week period in a multicentre double-blind parallel group study in 138 (3 groups of 46) children aged 2 to 14 years with perennial allergic rhinitis. The principal symptoms of allergic rhinitis including nasal obstruction, nonpurulent rhinorrhoea, nasal pruritus, sneezing and pharyngeal drip were chosen for the evaluation of efficacy. In addition, sore throat, conjunctival erythema, lacrimation and ocular pruritus were also evaluated. Each symptom was assessed by investigators using a scale from 0 = ‘none’ to 4 = ‘Very severe’ and requiring additional medication for control. Parents and patients were asked to record symptom severity on a scale of 0 (none) to 3 (severe) and any adverse events on a daily basis. Tolerability was assessed by means of reported adverse events, together with the results of routine clinical laboratory tests performed before and after treatment. Patients receiving cetirizine 10mg daily had a significantly greater improvement in symptoms of perennial allergic rhinitis than patients on placebo as assessed by average symptom scores and investigators’ global evaluation of efficacy. In addition, cetirizine 10 mg/day produced a significantly greater improvement in the symptoms of nasal obstruction and rhinorrhoea than either cetirizine 5 mg/day or placebo. Parents’ evaluations also favoured cetirizine 10 mg/day ahead of both cetirizine 5 mg/day and placebo. Cetirizine was well tolerated. No patient withdrew from treatment because of an adverse event; furthermore, mild sedation was only occasionally reported.
Article
The rapidity of action, efficacy and tolerability of cetirizine and astemizole, 2 second generation H1-receptor antagonists, were investigated in patients in a 1-month double-blind parallel randomised study. 59 patients known to be perennial rhinitis sufferers completed the study; 30 patients received a regimen of cetirizine 10mg and 29 received astemizole 10mg. Symptoms were assessed at days 1, 14 and 28 by the investigator, and were scored daily by the patients. In addition, the H1 antagonist activity was measured using several allergens, intradermal skin tests and a nasal histamine sensitivity test (NHST). The time to relief of symptoms was recorded by the patients in minutes, hours or days. A 10cm visual analogue scale was used for the assessment of the patients’ general condition. The results showed a faster relief of symptoms and a better effect on rhinorrhoea with cetirizine (p < 0.03). NHST was significantly improved with both astemizole and cetirizine compared with baseline data, but there was no significant difference between astemizole and cetirizine. Patients’ reports also indicated that cetirizine relieved the symptoms faster than astemizole, at mean times of 0.58 and 13.6 hours, respectively (p < 0.01). Both products were similarly well tolerated, with mild and transient drowsiness affecting 4 of 30 patients taking cetirizine and 4 of 29 patients taking astemizole.
Article
Second-generation histamine H1 receptor antagonists are recognized as being highly effective treatments for allergic-based disease and are among the most frequently prescribed drugs in the world. The newer antihistamines represent a heterogeneous group of compounds with markedly different chemical structures, a spectrum of antihistaminic properties, adverse effects, half-life, tissue distribution, metabolism and varying degrees of anti-inflammatory effects. Histamine is an important mast cell- and basophil-derived mediator that has been implicated in the pathogenesis of asthma, resulting in smooth muscle contraction, mucus hypersecretion, and increased vascular permeability leading to mucosal edema. Antihistamines should never be used as monotherapy for asthma but there is evidence that these drugs give a measure of protection in histamine-induced bronchoconstriction. Furthermore, several studies have demonstrated that the use of second-generation antihistamines, as adjunct therapy, may benefit those patients whose allergic asthma co-exists with allergic rhinitis. Indeed, many patients present with both allergic rhinitis and asthma. The link between the upper and lower respiratory airways is now well established and there is increasing evidence that allergic rhinitis is a risk factor for the development of asthma. More recently, a number of novel antihistamines have been developed which are either metabolites of active drugs or enantiomers and there is emerging evidence that at least one of these drugs, desloratadine, may give significant symptomatic benefit in some types of asthma. It is of interest to note that cetirizine provides a primary pharmacological intervention strategy to prevent the development of asthma in specifically-sensitized high risk groups of infants. Moreover, the documented anti-inflammatory activities of antihistamines may provide a novel mechanism of action for the therapeutic control of virus-induced asthma exacerbations by inhibiting the expression of intercellular adhesion molecule-1 (ICAM-1) by airway epithelial cells. Finally, several well-conducted studies suggest that combination therapy with antihistamines and anti-leukotrienes may be as effective as corticosteroid use in patients with allergic asthma and seasonal allergic rhinitis.
Article
Background: In the present work, we studied the effect of cetirizine on the cytokine-stimulated immune response of human umbilical vein endothelial cells (HUVECs). Methods: Our research was directed to analyze the effect of preincubation of HUVECs with cetirizine (1 μg/ml) on (1) the TNFα-, IL-4- and IFNγ-induced surface expression of ICAM-1 and VCAM-1, (2) the secretion of IL-6 and IL-8, (3) the recruitment of NFκB and AP-1 and (4) the adhesion of histiocytic monocytes (U937) to activated endothelial monolayers. Results and Conclusion: Cetirizine exerts a stimulus-dependent pattern of regulatory action on various parameters of endothelial cell activation. In detail, cetirizine significantly reduces the expression of ICAM-1 and VCAM-1 paralleled by a reduced monocytic adhesion in particular to TNFα-activated HUVECs. With regard to the cytokine release, dual effects are obtained by cetirizine: IL-6 and IL-8 secretion is suppressed by cetirizine in TNFα and IL-4-activated cells, whereas the IFNγ-induced suppression of IL-8 is nearly abrogated. In this context, the TNFα-induced signal transduction with regard to NFκB and AP-1 was also suppressed by cetirizine.
Article
ICAM-1, a transmembrane glycoprotein promoting adhesion in immunologic and inflammatory reactions, was found to be increased on nasal epithelial cells of patients with allergic rhinitis. Loratadinae, an H1-Mocker, was found to reduce in vitro the expression of ICAM-1 on nasal epithelial cells. A double-blind, parallel-group study was carried out during the pollen season to compare the effect of two H1-blockers, cetiraizine (10 mg OD) and loratadine (10 mg OD), on the release of soluble ICAM-1 in nasal secretions. A group of untreated patients was used as a control group. sICAM-1 was measured by enzyme immunoassay before and after 2 weeks of treatment. Symptoms were significantly decreased in the actively treated groups. sICAM-1 levels were unchanged in the control group but were significantly reduced in the two treated groups (P
Article
In a double-blind, randomized, parallel-group study, 29 adult patients suffering from chronic urticaria were treated with either cetirizine 10 mg od (n = 10), mequitazine 5 mg bid (n = 10), or placebo (n = 9) for 3 weeks. Three symptoms (weals, erythema, pruritus) were rated according to severity (none, mild, moderate, severe) by the investigator at each of the four visits (days 1, 3, 14, 21). At each visit the investigator and patients also assessed the patients' general condition using a 5-point scoring system (very bad, bad, moderate, good, very good). On day 21 the global evaluation of efficacy and tolerance was assessed by the investigator and patients on a 4-point scale (excellent, good, moderate, bad). Also, a histamine skin-prick test was performed on days 3, 14, and 21. Evaluation of safety was based on the frequency of patients reporting adverse events as well as the clinical laboratory results. The cetirizine, mequitazine, and placebo groups of patients were comparable at inclusion. Overall compliance with the trial schedule was excellent for all groups. After 3 days of treatment a significant improvement in control of all urticaria symptoms was observed in the cetirizine group. Cetirizine elicited a statistically significant better control of pruritus (P = 0.006) and erythema (P = 0.018) than mequitazine on day 21. A trend in favor of cetirizine vs. mequitazine was also observed regarding control of weals (P = 0.114). Cetirizine clearly and rapidly improved the general condition of the patient as evaluated by both patients and investigator compared to the baseline results. The differences vs. mequitazine as well as vs. placebo were statistically significant on every visit, starting from day 3. After three weeks of treatment, the clinical efficacy results in the cetirizine group were rated by both patients and investigator as excellent or good, which was statistically significantly better than the results obtained in the mequitazine and placebo group (P > 0.05). The histamine skin-prick test results revealed a marked difference for the group treated with cetirizine compared to the two other groups in favor of CTZ. On day 3, cetirizine produced a statistically significant suppression of the weals (98%) and flares (74%), compared to 24% and 3%, respectively, by mequitazine. With respect to the tolerance results, no statistically significant differences were observed between the three groups. The safety profile was similar for all groups. No serious adverse event has been reported during the present study, nor did the treatments induce any clinically significant abnormal changes in the laboratory tests. It can be concluded from the present study that the effect of cetirizine was statistically and clinically significantly superior to that of mequitazine. On the other hand, of all parameters studied there were no marked differences between the patients of the mequitazine group and the patients of the placebo group. Drug Dev. Res. 43:185–192, 1998.
Article
Background: Mizolastine is a potent and selective H-1-receptor antagonist with additional anti-allergic properties. Objective: The aim of this European multicenter, randomized, double-blind study was to compare the efficacy of mizolastine 10 mg (n = 122), cetirizine 10 mg (n = 125), and placebo (n = 128) once daily for 28 days in patients with seasonal allergic rhinoconjunctivitis (SAR), with focus on the onset of action. Methods: Symptoms were evaluated by the investigator using a total symptom score (TS) and by the patient (first week). Responders (R) were patients with a TS decrease of at least 50%. Safety was assessed according to the spontaneous reporting of adverse events. Results: Both mizolastine and cetirizine were effective in relieving the symptoms of SAR. After 7 days of treatment, the improvement in TS and responder's rate were significantly (P <.05) greater in patients treated with mizolastine (TS change versus baseline, mean +/- SD: -6.40 +/- 5.71; R: 55%) and cetirizine (TS change versus baseline: -6.24 +/- 5.24; R: 53%) than with placebo (TS change versus baseline: -4.11 +/- 5.91; R: 40%). Both drugs acted rapidly, within 2 hours of the first intake. During the first 3 days, mizolastine relieved symptoms more effectively than cetirizine, the difference being significant on the second (P =.027) and third (P =.050) day. Both mizolastine and cetirizine were well tolerated. Conclusion: Mizolastine 10 mg once daily is at least as effective as cetirizine in relieving symptoms of SAR, onset of action is rapid with clinical effect evident within 2 hours.
Article
Histamine is an important neurotransmitter. Old (first-generation) H1- receptor antagonists such as chlorpheniramine, diphenhydramine, or triprolidine produce histamine blockade at H1-receptors in the central nervous system (CNS) and frequently cause somnolence or other CNS adverse effects. New (second generation) H1-antagonists such as cetirizine, fexofenadine, and loratadine represent an advance in therapeutics; in manufacturers' recommended doses, they enter the CNS in smaller amounts, produce relatively little somnolence or other CNS adverse effects, and do not exacerbate the adverse CNS effects of alcohol or other CNS-active chemicals. Two H1-antagonists, astemizole and terfenadine, have been found to prolong the QTc interval and, rarely, to cause cardiac dysrhythmias after overdose or under other specific conditions. This has led to withdrawal of regulatory approval for them. An H1-antagonist absolutely free from adverse effects under all circumstances is not yet available for use.
Article
This guideline was compiled by members of a standing committee of the American Academy of Otolaryngic Allergy. The intent of this guideline is to provide practitioners, referring physicians, patients, third-party payers, and cognizant government authorities with the fundamental principles involved in the diagnosis and treatment of the patient with allergic rhinitis. Although developed solely through the American Academy of Otolaryngic Allergy, the statements and recommendations are drawn from the entire spectrum of English-speaking literature from the United States and Europe. Articles were independently reviewed by members of the Committee, many of whom sit on editorial review boards for major professional publications. A grading system was used to categorize individual articles to demonstrate the format used to arrive at conclusions. The grade is recorded at the end of each article reference. The grading scale follows: Grade A: A study involving prospective or well-selected retrospective patient populations. The conclusions drawn are well supported by the scientific work. Little controversy relating to these conclusions would be expected. Grade B: A scientific study executed without major flaws. Limitations may exist such that the conclusions drawn remain subject to controversy. Grade C: An anecdotal or case report study.
Article
Background: Eotaxin plays a central role in the development of allergic diseases such as atopic dermatitis (AD), asthma, and nasal allergy because it acts as a chemoattractant for eosinophils in allergic inflammation. The inflammatory cytokines interleukin (IL)-4, tumor necrosis factor-alpha, and IL-13 have been reported to enhance eotaxin production synergistically in normal human fibroblasts. Histamine is known to be an important mediator of allergic inflammation.Objective: In this study, we investigated the expression of eotaxin in the skin in AD, whether histamine induces eotaxin production by cultured human fibroblasts, and the effect of various doses of the histamine H1-receptor antagonist cetirizine on histamine-induced eotaxin production during a 72-hour period.Methods: After histamine stimulation of cultured fibroblasts, supernatants were collected to measure eotaxin by enzyme-linked immunosorbent assay and the cells were lysed for detection of eotaxin mRNA. Eotaxin expression was studied using immunohistochemical methods and the reverse transcription-polymerase chain reaction (RT-PCR).Results: Histamine enhanced eotaxin production and its mRNA expression in a dose-dependent manner. The histamine-receptor antagonist diphen-hydramine inhibited eotaxin production and mRNA expression. Similarly, cetirizine also blocked histamine and IL-4-induced eotaxin production and mRNA expression.Conclusions: These observations suggest that eotaxin may have an important role in allergic inflammation and that cetirizine may inhibit histamine-induced eotaxin production and its mRNA expression in human fibroblasts.
Article
Background: In very young children, H1-receptor antagonists have not been adequately studied, although they are widely used and assumed to be safe. Objective: Our objective was to test the hypothesis that cetirizine would be as safe as placebo for long-term use in this population. Methods: In the prospective, double-blind, parallel-group, 18-month-long Early Treatment of the Atopic Child (ETAC) study, 817 children with atopic dermatitis who were 12 to 24 months old at study entry were randomized to receive either cetirizine 0.25 mg/kg or placebo twice daily. Safety was assessed by using the reports of all adverse events, diary cards, physical examinations, developmental assessments, electrocardiograms, blood hematology and chemistry tests, and urinalyses. Results: The population evaluated for safety consisted of 399 children receiving cetirizine and 396 children receiving placebo. Drop-outs and serious events, including hospitalizations, occurred infrequently and were less common in the children receiving cetirizine than in those children receiving placebo, although the differences were not statistically significant. Most reported symptoms and events were mild and were attributed to intercurrent respiratory or gastrointestinal infections, exacerbations of allergic disorders, or age-related concerns rather than to medication-related adverse effects. There were no clinically relevant differences between the groups for neurologic or cardiovascular symptoms or events, growth, behavioral or developmental assessments, laboratory test results, or electrocardiograms, and no child receiving cetirizine therapy had prolongation of the QTc interval. Conclusions: The safety of cetirizine has been confirmed in this prospective study, the largest and longest randomized, double-blind, placebo-controlled safety investigation of any H1-antagonist ever conducted in children and the longest prospective safety study of any H1-antagonist ever conducted in any age group.
Article
The efficacy and tolerability of fluticasone aqueous nasal spray, 200µg once daily for 21 days, was compared with cetirizine, 10mg once daily for 21 days, in a multicentre, randomised, double-blind, double-dummy, parallel group study. 237 evaluable patients aged 12 years and above, with seasonal allergic rhinitis (defined as having a positive skin test and a total symptom score of ≥ 6/15), received either fluticasone aqueous nasal spray (n = 119) or cetirizine (n = 118). Improvement in total symptom score was observed in patients from both treatment groups, with the improvement in the fluticasone treatment group being significantly greater (decrease in total symptom score from 9.23 to 2.13) than in the cetirizine treatment group (decrease in total symptom score from 9.36 to 4.31; p < 0.001). There was also a significantly greater improvement in the number of symptom-free days for all symptoms in favour of fluticasone aqueous nasal spray compared with cetirizine (p < 0.001). Furthermore, the percentage of days when patients did not require terfenadine as rescue therapy was significantly greater in the fluticasone group (87%) than in the cetirizine group (80%; p < 0.05). Five adverse events were reported during intranasal fluticasone treatment and 10 adverse events were reported during cetirizine therapy. There were no treatment-related withdrawals from therapy in the fluticasone group, but 5 treatment-related withdrawals were reported in the cetirizine group. This study demonstrated that fluticasone aqueous nasal spray, 200µg once daily, was significantly more effective than cetirizine, 10mg once daily, and had comparable (if not better) tolerability, in the treatment of seasonal allergic rhinitis.
This study was designed to compare the efficacy and safety of cetirizine and oxatomide in young children who have perennial allergic rhinitis. During this 10-day multicenter, double-blinded, randomized, parallel-group study, 102 children aged 2-6 years received orally administered cetirizine (5 mg once daily) or oxatomide (12.5 mg twice daily), Sneezing, rhinorrea, nasal obstruction, nasal itching, and ocular itching were evaluated by means of symptom scores by investigators and, on daily record cards, by parents, Tolerability was assessed on the basis of adverse events and on the results of routine laboratory tests performed before and after treatment, Compared to baseline both cetirizine and oxatomide improved symptoms significantly, No significant difference in efficacy was found between the two drugs, Both products were well tolerated, Mild sedation was only occasionally reported and no patient withdrew from treatment because of an adverse event, In clinical practice cetirizine may be preferable because of its long action and convenient single daily dose, (Pediatr Asthma Allergy Immunol 1997;11 [2]:119-128.)
Article
Twelve adult volunteers were enrolled in a four-session, double-blind, crossover, randomized study. On each session, two capsules were administered in the morning and contained the pulverised products of either placebo (P) + P, terfenadine (T) 60 (mg) +P, T 60 + T 60, or cetirizine (C) 10 + P. On the evening of each experimental day, two capsules were taken at 0800 pm either as P + P or as T 60 + P or as P + P, or as P + P. We thus have four groups called, respectively, placebo, terfenadine 60 bid, terfenadine 120, and cetirizine 10. Pricks (100 mg/ml histamine) were performed before drug intake and 5, 12, 17, and 24 hr after drug intake. Ten minutes after each prick, wheal areas were underlined and transfered onto a transparency to be measured later. One volunteer gave up the trial due to the appearance of a serious disease not related to the trial. Regarding initial wheals, cetirizine 10, terfenadine 60 bid, and terfenadine 120 significantly (P < 0.01) reduced the wheal at H5, H12, H17, and H24 (except NS at H17 for T120). At H5, H12, and H17, cetirizine 10, terfenadine 60 bid, and terfenadine 120 were significantly more potent than P (P < 0.03). At H24, only cetirizine 10 and terfenadine 60 bid were significantly more potent than placebo. Pairwise global comparison shows a significant difference (P = 0.03) in favour of cetirizine regarding terfenadine 120. Side effects under active drugs were not different from those under placebo.
Background: In previous clinical trials, cetirizine has been shown to be efficacious in the treatment of seasonal allergic rhinitis (SAR), perennial allergic rhinitis, and chronic idiopathic urticaria when given once daily. As significant QT prolongation and cardiac arrhythmias have been reported with some of the newer antihistamines, the electrocardiographic effects of cetirizine were evaluated. A previous study in normal, healthy, adult volunteers had demonstrated that cetirizine does not prolong the QT interval at up to six times the maximum clinical dose. Objective: The intent of this study was to evaluate the electrocardiographic effects of cetirizine in children. Methods and Patients: As part of a randomized, 4-week, controlled clinical trial, electrocardiograms (ECGs) were obtained for 119 children aged 6 to 11 years with SAR. Participants in this trial received either a placebo (N = 40), 10 mg of cetirizine (N = 44), or 5 mg of cetirizine (N = 35). The QT interval was measured on a 12-lead ECG at the baseline visit (day 1) and at visit 2 (days 11-17). The QT interval was determined by a digitizing method and corrected for heart rate by the Hedges' formula for corrected QT interval (QT,). Results: Five and 10 mg of cetirizine did not result in changes in the QT, interval that were significantly different statistically from those of a placebo. Furthermore, the number of patients with a 10% to 20% increase in QT, interval was comparable across all treatment groups. Finally, no patients had a QT, interval increase of greater than 20% from baseline. Conclusions: The study demonstrates that cetirizine, up to 10 mg once daily, did not prolong the QT, interval in pediatric patients with SAR.
Cetirizine, a selective Hi-antagonist, has been found efficacious in the treatment of seasonal allergic rhinitis (SAR) when given once daily. In the present multicenter, randomized, parallel-group study the efficacy and safety of cetirizine (5-10 mg in a single dose or 2 divided doses) and of an active control, chlorpheniramine (2 mg tid), were compared in children aged 6-11 years with SAR at 4 centers. Patients rated symptoms twice daily on diary cards on a 4-point scale, for sneezing, nasal discharge, itchy eyes, itchy nose or mouth, conjunctivitis, and nasal congestion. A total symptom severity (TSS) score was derived from all symptoms except nasal congestion. TSS score at entry was 5.8 for each treatment group and was markedly reduced after 2 weeks' treatment: cetirizine once daily, -2.5; cetirizine twice daily, -2.6; chlorpheniramine -2.6; there were no statistically significant differences between groups (p = 0.91). Individual symptoms and investigator ratings followed this pattern. Reduction in TSS occurred after the first dose within the first 12 h [-1.6, -2.1, and -1.2, respectively (p < 0.03)] confirming a rapid onset of action. There was no exacerbation of asthma among the 117 patients entering with mild-to-moderate asthma. Most of the patients who experienced adverse events reported only mild-to-moderate severity. Cetirizine, given once daily or in divided doses twice daily and chlorpheniramine given 3 times daily for SAR in children aged 6-11 years, had a rapid onset of action. Neither drug was associated with worsening of asthma.
Article
The pharmacokinetics of the second-generation H1-receptor antagonist cetirizine were studied in 15 infants and toddlers (mean SD age, 12.3 5.4 months) who were treated with a single 0.25 mg/kg dose of cetirizine solution. The infants and toddlers were hospitalized for recurrent respiratory infections or other hypersensitivity-related diseases. Blood samples were collected at ½, 1, 1½, 2, 4, 6, 8, 12, and 24 hours, and a 24-hour urine sample was obtained. A peak plasma level of 390 135 ng/ml was observed after 2.0 1.3 hours. The elimination half-life was 3.1 1.8 hours, the apparent oral body clearance was 2.13 1.15 ml/min/kg, and the apparent volume of distribution was 0.44 0.19 L/kg. The excretion of unchanged cetirizine in six complete urinary collections was 62.7% 13.2% of the administered dose. An additional pharmacodynamic study (inhibition of the histamine-induced wheal and flare) was performed in 10 of these infants and toddlers, after the intake of 0.25 mg/kg cetirizine twice a day for at least 4 days. A 90% 12% inhibition of the wheal and a 87% 17% inhibition of the flare were still observed 12 hours after the last intake. The duration of the H1-inhibition by cetirizine at the cutaneous level is thus longer in infants and toddlers than could be inferred from its pharmacokinetics; the level of inhibition at 12 hours was the same as in older age groups.
Article
Twelve healthy subjects with atopy received single doses of hydroxyzine, 25 mg, its metabolite cetirizine, 10 and 20 mg, and placebo in a four-way crossover study randomized by Latin square design. Skin wheal response to histamine, psychomotor effects, and serum concentrations of each drug were measured for 36 hours after each dose. Central nervous system (CNS) effects were measured with critical flicker frequency, Stroop word testing, and visual analog scales. All three active treatments (cetirizine, 10 mg, cetirizine, 20 mg, and hydroxyzine) produced an equivalent suppression of skin wheal response to histamine that was significantly greater than placebo (P < 0.01). Hydroxyzine produced a significant change compared with placebo in all three CNS parameters. Neither cetirizine, 10 mg, nor cetirizine, 20 mg, produced any significant change in CNS parameters. Both the intensity and time course of CNS effects were related significantly (P < 0.05) to hydroxyzine concentrations. The CNS changes measured after oral hydroxyzine are the result of the parent drug, whereas its metabolite cetirizine when administered alone produced significant antihistaminic effects without CNS changes.
Article
Background. Assessment methods for atopic dermatitis (AD) are not standardized, and therapeutic studies are difficult to interpret. Aims. To obtain a consensus on assessment methods in AD and to use a statistical method to develop a composite severity index.Methods. Consensus definitions were given for items used in the scoring system (extent, intensity, subjective) and illustrated for intensity items. Slides were reviewed to address within and between-observer variability by a group of 10 trained clinicians, and data were statistically evaluated with a two way analysis of variance. Two variants of an assessment system were compared in 88 patients at 5 different institutions. Data were analyzed using principal-component analysis. Results. For 5 intensity items studied (erythema, edema/papulation, oozing/crusts, excoriations, lichenification), within- and between-observer variability was good overall, except for edema/papulation which was difficult to assess with slides. In the series of 88 patients, principal-component analysis allowed to extract two unrelated components: the first one accounting for 33% of total variance was interpreted as a ‘severity’ component; the second one, accounting for 18% of variance, was interpreted as a ‘profile’ component distinguishing patients with mostly erythema and subjective symptoms and those with mostly lichenification and dryness and lower subjective symptoms. Of the two evaluation systems used, the one using the rule of nine to assess extent was found more workable than the one using a distribution × intensity product. A scoring index (SCORAD) combining extent, severity and subjective symptoms was mathematically derived from the first system and showed a normal distribution of the population studied. Conclusion. The final choice for the evaluation system was mostly made based on simplicity and easy routine use in outpatient clinics. Based on mathematical appreciation of weights of the items used in the assessment of AD, extent and subjective symptoms account for around 20% each of the total score, intensity items representing 60%. The so-designed composite index SCORAD needs to be further tested in clinical trials.
Article
Cetirizine, a human metabolite of hydroxyzine, is a selective H1-receptor antagonist currently approved for the treatment of seasonal allergic rhinitis, perennial allergic rhinitis, and chronic urticaria. In U.S. clinical trials, transient reversible hepatic transaminase elevations were observed in <2% of patients during cetirizine therapy. We report a case of cetirizine-induced cholestasis in a 28-year-old man with no previous hepatobiliary disease after a 2-year period of taking cetirizine on a daily basis. The treatment of this patient included the use of ursodeoxycholic acid, as well as hydroxyzine, for symptomatic relief of pruritus. In light of the patient's clinical and biochemical improvement while using hydroxyzine, it appears that the hepatic metabolism of hydroxyzine to metabolites, including cetirizine, is not involved in the pathogenesis of this particular case of drug-induced hepatotoxicity. Cetirizine should be considered as a potential cause of drug-induced cholestasis.
Article
In a multicenter, randomized, doubleblind parallel trial, the efficacy and safety of Ioratadine and cetirizine were compared in 118 adults with atopic dermatitis. Symptomatic improvements and efficacy, as rated by physicians and patients, were generally similar for the two treatments. Both drugs were well tolerated; 25% of the patients who received loratadine and 27% of those treated with cetirizine reported at least one adverse event. However, the incidence of somnolence was 9% with cetirizine and only 3% with loratadine. In the management of symptoms of atopic dermatitis, loratadine is as effective as cetirizine and is less sedating.
Article
Chronic urticaria is defined as the daily or almost daily occurrence of wheals for at least 6 weeks. This disorder affects 0.1% of the general population and is more common in females. Recently a subgroup of patients with chronic urticaria has been found to have circulating autoantibodies directed against the high-affinity IgE receptor (Fc∍RI) or against IgE antibodies. These “autoantibodies” are felt to play a role in mast cell histamine release. Urticaria patients with these circulating antibodies also have a higher prevalence of other autoimmune diseases. The management of patients with chronic urticaria is to identify and eliminate the underlying cause, however, an etiology for chronic urticaria is rarely identified. Thus the approach to treatment usually centers on the use of antihistamines initially with the addition of other immune modulating agents as necessary.
Article
The primary objective of the present study was to compare the absorption and disposition of levocetirizine, the eutomer of cetirizine, when administered alone (10 mg) or in presence of the distomer. An additional objective was also to investigate the configurational stability of levocetirizine in vivo in humans. The study was performed in a randomized, two-way cross-over, single-dose design with a wash-out phase of 7 days between the two periods. A total of 12 healthy male and 12 healthy female volunteers were included in the study. Bioequivalence can be concluded from the analysis of the pharmacokinetic parameters of levocetirizine when administered alone or as the racemate cetirizine. No chiral inversion occurs in humans when levocetirizine is administered, i.e. there is no formation of the distomer. When comparing the pharmacokinetic characteristics of levocetirizine and the distomer, the apparent volume of distribution of the eutomer is significantly smaller than that of the distomer (0.41 and 0.60 L/kg, respectively). For an H1-antagonist a small distribution volume can be considered as a positive aspect, both in terms of efficacy and safety. Moreover the non-renal clearance of levocetirizine is also significantly lower than that of the distomer (9.70 and 28.70 mL/min, respectively), which constitutes an additional positive aspect particularly as far as metabolism-based drug interactions are concerned. The information collected in the present study on the pharmacokinetics of levocetirizine and the distomer provide additional reasons for eliminating the distomer and developing levocetirizine as an improvement on cetirizine.