loratadine, Claritin
A descriptive analysis of the use and cost of new-generation antihistamines in the treatment of allergic rhinitis: a retrospective database analysis.

Lee J, Cummins G, Okamoto L.

OBJECTIVE: This retrospective database analysis was conducted to evaluate the use and cost of new-generation antihistamines (i.e., those that are nonsedating) in the treatment of allergic rhinitis in a managed care population. STUDY DESIGN: The study is a retrospective database review of medical and pharmacy-related claims linked by episodes of care. METHODS: Patients who had been diagnosed as having allergic rhinitis and had at least 1 prescription claim were identified from a database containing patient-level medical and pharmacy-related claims. The treatment patterns of patients with allergic rhinitis who met the study criteria were documented for a 12-month period in which the use of nonsedating antihistamines was described and the associated costs of various medications were assessed. Subanalyses of patients categorized by comorbidity status were also performed. RESULTS: A total of 202,426 patients participated in the study. Nonsedating antihistamines were used by 71% of the patients; the most commonly prescribed drugs were loratadine and fexofenadine. The mean annual charges per patient for the treatment of allergic rhinitis in the study population were $465.21 (standard deviation [SD], 548). The greatest departmental cost was that of pharmacy-related charges (mean, $236.02; SD, 233); the next highest cost was that of outpatient charges (mean, $216.31; SD, 396). Comparisons of departmental charges indicated the use of loratadine was associated with significantly higher treatment costs than that of fexofenadine in a number of patient subgroups. CONCLUSION: In this analysis, loratadine was associated with significantly higher treatment charges than was fexofenadine. This result was observed consistently across different stratifications of patients, including the presence of comorbid respiratory infection, concomitant use of nasal steroids, and the presence of asthma and/or sinusitis. These results provided useful insights into the differential costs associated with the use of nonsedating antihistamines in the treatment of rhinitis.

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loratadine, Claritin
Determination of loratadine in human plasma by high-performance liquid chromatographic method with ultraviolet detection.

Kunicki PK.

Department of Clinical Biochemistry, National Institute of Cardiology, Warsaw, Poland. biblnauk ikard.waw.pl

A HPLC-UV determination of loratadine in human plasma is presented. After simple liquid-liquid extraction with 2-methylbutane-hexane (2:1) and evaporation of organic phase the compounds were re-dissolved in 0.01 M HCl, evaporated again and finally separated on a Supelcosil LC-18-DB column. The analyses were done at ambient temperature under isocratic conditions using the mobile phase: CH3CN-water-0.5 M KH2PO4-H3PO4 (440:480:80:1, v/v). UV detection was performed at 200 nm with a limit of quantification of 0.5 ng/ml. The precision was found to be satisfactory over the whole range tested (0.5-50 ng/ml) with relative standard deviations of 2.3-6.3 and 5.2-14.1% for intra- and inter-assays, respectively.

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loratadine, Claritin
Desloratadine.

McClellan K, Jarvis B.

Adis International Limited, Mairangi Bay, Auckland, New Zealand. demail adis.co.nz

Desloratadine is the orally active major metabolite of the nonsedating H1-antihistamine loratadine. The drug had no adverse cardiovascular effects in various animal models or when administered at 9 times the recommended adult dosage for 10 days in volunteers. Therapeutic dosages had no effects on wakefulness or psychomotor performance in healthy volunteers. No clinically significant interactions have been reported between desloratadine and drugs that inhibit the cytochrome P450 system, nor does the drug potentiate the adverse psychomotor effects of alcohol. Oral desloratadine 5 mg once daily for up to 4 weeks in patients with seasonal allergic rhinitis (SAR) significantly reduced nasal (including congestion) and non-nasal symptoms and improved health-related quality of life compared with placebo. Similar beneficial effects were observed in patients with SAR and coexisting asthma (in whom asthma symptoms and use of beta2-agonists were reduced). Desloratadine 5 mg once daily for 6 weeks significantly improved pruritus and reduced the number of hives compared with placebo in patients with chronic idiopathic urticaria (CIU). Sleep and daytime performance also improved. Desloratadine was well tolerated in clinical trials and had an adverse event profile similar to that of placebo in patients with SAR (with or without asthma) or CIU.

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loratadine, Claritin
Evaluation of the interaction of loratadine and desloratadine with P-glycoprotein.

Wang EJ, Casciano CN, Clement RP, Johnson WW.

Drug Metabolism and Pharmacokinetics, Schering-Plough Research Institute, 144 Route 94, Lafayette, New Jersey 07848, USA.

The absorption of many drugs is affected by their interaction with ATP-binding cassette (ABC) transporters. The most extensively studied of these ABC transporters is the proein product of MDR1 (multidrug resistance) that encodes a 170-kDa integral plasma membrane phosphorylated glycoprotein known as P-glycoprotein (P-gp). The purpose of this study was to determine, using two different methods, whether the nonsedating antihistamine loratadine (L) and its active metabolite desloratadine (DL) interact with P-gp. MDR cells presenting human P-gp were incubated with the fluorescent P-gp substrate daunorubicin with or without L, DL, and several positive controls. The IC(50) of loratadine (approximately 11 microM) was approximately 160 times the maximum observed plasma concentration (C(max)) following a dose of 10 mg. The IC(50) of desloratadine (approximately 43 microM) was approximately 880 times the C(max) following a dose of 5 mg. The positive control, cyclosporin A, had an IC(50) of approximately 1 microM. ATP hydrolysis activity was measured in the membrane fraction prepared from MDR cells presenting P-gp, which were exposed to various concentrations of test compounds. Known substrates of P-gp demonstrated clear, repeatable, concentration-dependent increases in ATP hydrolysis activity. L caused an increase in ATPase activity above basal levels. L had a V(max) about 200% basal activity and K(m) of approximately 3 microM for P-gp. In contrast, DL had no significant effect on baseline ATP hydrolysis. L inhibited human P-gp much less than verapamil or cyclosporin A. DL inhibited human P-gp significantly less than L (4 times). DL therefore is not a significant inhibitor of P-gp and should not cause clinical drug interactions with agents that are P-gp substrates.

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loratadine, Claritin
Effect of desloratadine and loratadine on rhinovirus-induced intercellular adhesion molecule 1 upregulation and promoter activation in respiratory epithelial cells.

Papi A, Papadopoulos NG, Stanciu LA, Degitz K, Holgate ST, Johnston SL.

University Medicine, University of Southampton, Southampton, UK.

BACKGROUND: Rhinoviruses have been recently associated with the majority of asthma exacerbations for which current therapy is inadequate. Intercellular adhesion molecule 1 (ICAM-1) has a central role in airway inflammation in asthma, and it is the receptor for 90% of rhinoviruses. Rhinovirus infection of airway epithelium induces ICAM-1. Desloratadine and loratadine are compounds belonging to the new class of H(1)-receptor blockers. Anti-inflammatory properties of antihistamines have been recently documented, although the underlying molecular mechanisms are not completely defined. OBJECTIVE: We have investigated the effects of desloratadine and loratadine on rhinovirus-induced ICAM-1 expression, mRNA upregulation, and promoter activation. METHODS: Cultured primary bronchial or transformed (A549) respiratory epithelial cells were pretreated with desloratadine and loratadine for 16 hours and infected with rhinovirus type 16 for 8 hours. ICAM-1 surface expression was evaluated with flow cytometry, and ICAM-1 mRNA was evaluated with specific RT-PCR. In A549 cells promoter activation was evaluated with a chloramphenicol acetyltransferase assay, and binding activity of nuclear factor kappa B in nuclear extracts was evaluated with an electrophoretic mobility shift assay. RESULTS: Desloratadine and loratadine (0.1-10 micromol/L) inhibited rhinovirus-induced ICAM-1 upregulation in both primary bronchial or transformed (A549) respiratory epithelial cells. In A549 cells the 2 compounds showed a dose-dependent inhibition with similar efficacy (inhibitory concentration of 50%, 1 micromol/L). Desloratadine and loratadine also inhibited ICAM-1 mRNA induction caused by rhinovirus infection in a dose-dependent manner, and they completely inhibited rhinovirus-induced ICAM-1 promoter activation. Desloratadine also inhibited rhinovirus-induced nuclear factor kappa B activation. Desloratadine and loratadine had no direct effect on rhinovirus infectivity and replication in cultured epithelial cells. CONCLUSION: These effects are unlikely to be mediated by H(1)-receptor antagonism and suggest a novel mechanism of action that may be important for the therapeutic control of virus-induced asthma exacerbations.

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loratadine, Claritin
In vitro characterization of the inhibition profile of loratadine, desloratadine, and 3-OH-desloratadine for five human cytochrome P-450 enzymes.

Barecki ME, Casciano CN, Johnson WW, Clement RP.

Department of Drug Metabolism and Pharmacokinetics, Schering-Plough Research Institute, Lafayette, NJ 07848-0032, USA. mary.barecki spcorp.com

The purpose of this study was to evaluate loratadine, desloratadine, and 3-OH-desloratadine as inhibitors of certain human liver cytochrome P-450 enzymes. Pooled human liver microsomes were used to determine whether loratadine, desloratadine, and 3-OH-desloratadine were inhibitors of cytochrome P-450 (CYP) 1A2, 2C9, 2C19, 2D6, and 3A4. Loratadine did not inhibit CYP1A2 or CYP3A4 at concentrations up to 3829 ng/ml, which is approximately 815-fold greater than the expected maximal human plasma concentration (4.7 +/- 2.7 ng/ml) following the recommended dose of 10 mg/day. Loratadine inhibited CYP2C19 and CYP2D6 with IC(50) values of approximately 0.76 microM [291 ng/ml; K(i) congruent with 0.61 microM (234 ng/ml)] and 8.1 microM [3100 ng/ml; K(i) congruent with 2.7 microM (1034 ng/ml)], respectively, which are approximately 62 and 660 times the expected loratadine therapeutic exposure concentration. Neither desloratadine nor 3-OH-desloratadine inhibited CYP1A2, CYP2C9, CYP2C19, CYP2D6, or CYP3A4 greater than 25% at concentrations of 3108 or 3278 ng/ml, respectively. These results suggest that loratadine and the active metabolites desloratadine and 3-OH-desloratadine are unlikely to affect the pharmacokinetics of coadministered drugs which are metabolized by these five cytochrome P-450 enzymes.

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