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Safety of desloratadine syrup in children.

Bloom M, Staudinger H, Herron J.

Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA. melvyn.bloom spcorp.com

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

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15701213&dopt=Abstract desloratadine Clarinex



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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.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11398910&dopt=Abstract desloratadine Clarinex



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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.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11454724&dopt=Abstract desloratadine Clarinex



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Anticholinergic effects of desloratadine, the major metabolite of loratadine, in rabbit and guinea-pig iris smooth muscle.

Cardelus I, Anton F, Beleta J, Palacios JM.

Almirall Prodesfarma, Research Center, Pharmacology Department, Barcelona, Spain. icardelu almirallprodesfarma.com

Allergic conjunctivitis is the most common ocular allergic disease. Although very symptomatic it does not endanger vision, and topical antihistamines or chromones are the first choice treatment in clinical practice. Recently, equivalent nanomolar affinities for histamine H and muscarinic M 1 and M3 cloned human receptors have been reported for desloratadine, the active metabolite of loratadine, a widely prescribed antihistamine. This property might enhance its utility in the treatment of asthma, but could induce adverse anticholinergic effects after topical administration. In the present study, we compare the anticholinergic activity of desloratadine with other known muscarinic antagonists and antihistamines on rabbit and guinea-pig iris smooth muscle. Desloratadine was found to be a competitive antagonist (pA2 = 6.67+/-0.09) of carbachol-induced contractions in isolated rabbit iris smooth muscle. Atropine (pA2 = 9.44+/-0.02) and NPC-14695 (pA2 = 9.18+/-0.03) also behaved as competitive antagonists, whereas tiotropium bromide (pD'2 = 9.06+/-0.02) exhibited a non-competitive behaviour in this tissue. Carebastine (pA2 = 5.64+/-0.04) and fexofenadine (pA2 < 4.0) were also studied. After topical administration on the guinea-pig eye conjunctiva, desloratadine produced a potent (ED50 = 2.3 mg/ml) and long lasting mydriasis (> 120 min at the ED50) in conscious animals. Fexofenadine and carebastine were inactive even at the highest concentration tested (10 mg/ml). Atropine (ED50 = 30 microg/ml) and tiotropium bromide (ED50 = 10 microg/ml) were much more potent than desloratadine or pirenzepine (ED50 = 3 mg/ml) in this model. The competitive muscarinic antagonism of desloratadine in vitro, and its potency and duration of action in vivo, suggest that topical treatment of allergic conjunctivitis and rhinitis with desloratadine could produce undesirable peripheral anticholinergic side effects such as mydriasis and xerostomia.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10422766&dopt=Abstract desloratadine Clarinex