loratadine, Claritin
The role of ketoconazole in the QTc interval prolonging effects of H1-antihistamines in a guinea-pig model of arrhythmogenicity.

Gras J, Llenas J, Palacios JM, Roberts DJ.

Research Centre Almirall Laboratories, Cardener, Barcelona, Spain.

We have carried out experiments to re-evaluate the influence of ketoconazole (400 mg kg-1,p.o.) on the effects of ebastine, terfenadine and loratadine on the QTc interval in conscious guinea-pigs. Following a previously described protocol of oral drug administration, but using telemetric recording of the ECG, we have found that the prolongation of the QTc interval attributed to ebastine and terfenadine is in fact entirely due to ketoconazole, and that neither terfenadine, ebastine nor loratadine produce any additional effects on subsequent administration.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8886395&dopt=Abstract loratadine, Claritin



loratadine, Claritin
Characterization of AUCs from sparsely sampled populations in toxicology studies.

Pai SM, Fettner SH, Hajian G, Cayen MN, Batra VK.

Department of Drug Metabolism and Pharmacokinetics, Schering-Plough Research Institute, Kenilworth, New Jersy, USA.

PURPOSE: The objective of this work was to develop and validate blood sampling schemes for accurate AUC determination from a few samples (sparse sampling). This will enable AUC determination directly in toxicology studies, without the need to utilize a large number of animals. METHODS: Sparse sampling schemes were developed using plasma concentration-time (Cp-t) data in rats from toxicokinetic (TK) studies with the antiepileptic felbamate (F) and the antihistamine loratadine (L); Cp-t data at 13-16 time-points (N = 4 or 5 rats/time-point) were available for F, L and its active circulating metabolite descarboethoxyloratadine (DCL). AUCs were determined using the full profile and from 5 investigator designated time-points termed "critical" time-points. Using the bootstrap (re-sampling) technique, 1000 AUCs were computed by sampling (N = 2 rats/point, with replacement) from the 4 or 5 rats at each "critical" point. The data were subsequently modeled using PCNONLIN, and the parameters (ka, ke, and Vd) were perturbed by different degrees to simulate pharmacokinetic (PK) changes that may occur during a toxicology study due to enzyme induction/inhibition, etc. Finally Monte Carlo simulations were performed with random noise (10 to 40%) applied to Cp-t and/or PK parameters to examine its impact on AUCs from sparse sampling. RESULTS: The 5 time-points with 2 rats/point accurately and precisely estimated the AUC for F, L and DCL; the deviation from the full profile was approximately 10%, with a precision (%CV) of approximately 15%. Further, altered kinetics and random noise had minimal impact on AUCs from sparse sampling. CONCLUSIONS: Sparse sampling can accurately estimate AUCs and can be implemented in rodent toxicology studies to significantly reduce the number of animals for TK evaluations. The same principle is applicable to sparse sampling designs in other species used in safety assessments.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8893263&dopt=Abstract loratadine, Claritin



loratadine, Claritin
Antihistamines and production of granulocyte-macrophage colony-stimulating factor and interleukin-8 by human bronchial epithelial cells in vitro: evaluation of the effects of loratadine and cetirizine.

Amsellem C, Gormand F, Hosni R, Aloui R, Guibert B, Czarlewski W, Melac M, Lagarde M, Perrin-Fayolle M, Pacheco Y.

Service de Pneumologie, Centre Hospitalier Lyon-Sud, Pierre Benite, France.

1. In this study, we compared the effects of two antihistamine drugs on the production of granulocyte-macrophage colony-stimulating factor and interleukin-8 by human bronchial epithelial cells in vitro. 2. Cytokine production was assessed by the use of an enzyme-linked immunosorbent assay. 3. Epithelial cells spontaneously released both cytokines and tumor necrosis factor alone induced a significant increase in this production but loratadine and cetirizine had no effect at the various concentrations studied. 4. The antihistamines have no effect and this suggests that histamine plays no role in cytokine production under these conditions.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8919641&dopt=Abstract loratadine, Claritin



loratadine, Claritin
Influence of food on the oral bioavailability of loratadine and pseudoephedrine from extended-release tablets in healthy volunteers.

Nomeir AA, Mojaverian P, Kosoglou T, Affrime MB, Nezamis J, Rodwanski E, Lin CC, Cayen MN.

Department of Drug Metabolism, Schering-Plough Research Institute, Kenilworth, NJ 07033, USA.

The effect of a high-fat breakfast on the bioavailability of the components of an extended-release tablet containing 10 mg loratadine in the immediate-release coating and 240 mg pseudoephedrine sulfate in the extended-release core was studied in 24 healthy male volunteers in a single-dose, two-way crossover study. The drug was administered after a 10-hour overnight fast or within 5 minutes of consuming a standardized high-fat breakfast. Serial blood samples were collected over a 48-hour period, and plasma was analyzed for loratadine and its active metabolite descarboethoxyloratadine (DCL), and pseudoephedrine. For pseudoephedrine, maximum concentration (Cmax) and area under the concentration-time curve extrapolated to infinity (AUCzero-infinity) were similar after both treatments, indicating no relevant food effect on the bioavailability of pseudoephedrine. Also, the absorption profiles of pseudoephedrine (from Wagner-Nelson analysis) were similar for the fed and fasted treatments, indicating no apparent differences in absorption. Plasma concentration-time profiles and values for Cmax and AUCzero-infinity of DCL were similar for the two treatments, indicating no relevant food effect on the pharmacokinetics of DCL. In contrast, for loratadine, administration with food resulted in a significantly increased mean Cmax (53%) and AUC from time zero to the final quantifiable sample (AUCif) (76%). However, the resultant Cmax and AUC of loratadine under fed conditions were well below those previously obtained at steady-state after multiple-dose administration of loratadine (40 mg/day) that were shown to be safe and well-tolerated in several clinical studies. The effect of food on the bioavailability and pharmacokinetic profiles of the components of a combination loratadine/pseudoephedrine extended-release tablet is not likely to be clinically significant.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8930779&dopt=Abstract loratadine, Claritin



loratadine, Claritin
Rate-dependent blockade of a potassium current in human atrium by the antihistamine loratadine.

Crumb WJ Jr.

Department of Pediatrics, Tulane University School of Medicine, New Orleans, Louisiana 70112-2699, USA. wcrumb tmcpop.tmc.tulane.edu

The antihistamine loratadine is widely prescribed for the treatment of symptoms associated with allergies. Although generally believed to be free of adverse cardiac effects, there are a number of recent reports suggesting that loratadine use may be associated with arrhythmias, in particular atrial arrhythmias. Nothing is known regarding the potassium channel blocking properties of loratadine in human cardiac cells. Using the whole-cell patch clamp technique, the effects of loratadine on the transient outward K current (Ito), sustained current (Isus), and current measured at -100 mV (IK1 and Ins), the major inward and outward potassium currents present in human atrial myocytes, were examined in order to provide a possible molecular mechanism for the observed atrial arrhythmias reported with loratadine use. Loratadine rate-dependently inhibited Ito at therapeutic concentrations with 10 nM loratadine reducing Ito amplitude at a pacing rate of 2 Hz by 34.9+/-6.0%. In contrast, loratadine had no effect on either Isus or current measured at -100 mV. These results may provide a possible mechanism for the incidences of supraventricular arrhythmias reported with the use of loratadine.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10188966&dopt=Abstract loratadine, Claritin



loratadine, Claritin
In vitro inhibitory effect of rupatadine on histamine and TNF-alpha release from dispersed canine skin mast cells and the human mast cell line HMC-1.

Queralt M, Brazis P, Merlos M, de Mora F, Puigdemont A.

Departament de Farmacologia i Terapeutica, Facultat de Veterinaria, Universitat Autonoma de Barcelona, Bellaterra, Spain.

OBJECTIVE AND DESIGN: To examine the inhibitory potential of rupatadine, a new H1-antihistamine and anti-PAF agent, on histamine and TNF-alpha release. Comparison with an H1-antihistamine (loratadine) and a PAF-antagonist (SR-27417A). MATERIAL: Dispersed canine skin mast cells were used to assess the effect of the drugs tested on FcepsilonRI-dependent and -independent histamine release; the human HMC-1 cell line was used to study TNF-alpha release. TREATMENT AND METHODS: Before stimulation mast cell populations were treated with increasing concentrations of rupatadine, loratadine and SR-27417A. Histamine and TNF-alpha release were measured following 15-30 min and 3 h activation, respectively. RESULTS: The IC50 for rupatadine in A23187, concanavalin A and anti-IgE induced histamine release was 0.7+/-0.4 microM, 3.2+/-0.7 microM and 1.5+/-0.4 microM, respectively whereas for loratadine the IC50 was 2.1+/-0.9 microM, 4.0+/-1.3 M and 1.7+/-0.5 microM. SR-27417A exhibited no inhibitory effect. Rupatadine, loratadine and SR-27417A inhibited TNF-alpha release with IC50 2.0+/-0.9 microM, 2.1+/-1.1 M and 4.3+/-0.6 microM, respectively. CONCLUSIONS: Rupatadine and loratadine showed similar inhibitory effect on histamine and TNF-alpha release, whereas SR-27417A only exhibited inhibitory effect against TNF-alpha.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10959557&dopt=Abstract loratadine, Claritin