loratadine, Claritin
The pharmacokinetics of loratadine in normal geriatric volunteers.

Hilbert J, Moritzen V, Parks A, Radwanski E, Perentesis G, Symchowicz S, Zampaglione N.

Pharmaceutical Research Division, Schering Corporation, Bloomfield, New Jersey 07003.

The pharmacokinetics of loratadine, a non-sedating anti-histamine, were studied in 12 normal geriatric volunteers. In an open label fashion, each volunteer received one 40 mg loratadine capsule. Blood was collected prior to and at specified times (up to 120 h) after dosing. Plasma loratadine concentrations were determined by a specific radioimmunoassay and those of an active metabolite, descarboethoxyloratadine, by high performance liquid chromatography. Concentrations of loratadine in the disposition phase were fitted to a biexponential equation and those of descarboethoxyloratadine to either a monoexponential or biexponential equation for pharmacokinetic analysis. Loratadine was rapidly absorbed, reaching a maximum plasma concentration of 50.5 ng/ml at 1.5 h after dosing. The disposition half-lives of loratadine in the distribution and elimination phases were 1.5 and 18.2 h, respectively. The area under the plasma concentration-time curve, was 146.7 h.ng/ml. Descarboethoxyloratadine had a maximum plasma concentration of 28.0 ng/ml at 2.9 h post-dose and an area under the concentration-time curve of 394.9 h.ng/ml. Its disposition half-lives in the distribution and elimination phases were 2.8 and 17.4 h, respectively. Comparison of these data with those from a previous study of loratadine in young adults showed no clear differences in the disposition half-lives between the two groups. The clearance of loratadine tends to be lower in the elderly, but inter-individual variation within each age group appears greater than any age effect.

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loratadine, Claritin
Excretion of loratadine in human breast milk.

Hilbert J, Radwanski E, Affrime MB, Perentesis G, Symchowicz S, Zampaglione N.

Pharmaceutical Research Division, Schering Corporation, Bloomfield, New Jersey 07003.

The excretion of loratadine, a new nonsedating antihistamine, into human breast milk was studied in six lactating nonpregnant volunteers. Each volunteer received one 40-mg loratadine capsule. Milk and blood were collected before and at specified times (to 48 hours) after dosing. Plasma and milk loratadine concentrations were determined by a specific radioimmunoassay, and those of an active but minor metabolite, descarboethoxyloratadine, by high performance liquid chromatography (HPLC). Breast milk concentration-time curves of both loratadine and descarboethoxyloratadine paralleled the plasma concentration-time curves. For loratadine, the plasma Cmax was 30.5 ng/mL at 1.0 hour after dosing and the milk Cmax was 29.2 ng/mL in the 0 to 2 hour collection interval. Through 48 hours, the loratadine milk-plasma AUC ratio was 1.2 and 4.2 micrograms of loratadine was excreted in breast milk, which was 0.010% of the administered dose. For descarboethoxyloratadine, the plasma Cmax was 18.6 ng/mL at 2.2 hours after dosing, whereas the milk Cmax was 16.0 ng/mL, which was in the 4 to 8-hour collection interval. Through 48 hours, the mean milk-plasma descarboethoxyloratadine AUC ratio was 0.8 and a mean of 6.0 micrograms of descarboethoxyloratadine (7.5 micrograms loratadine equivalents) were excreted in the breast milk, or 0.019% of the administered loratadine dose. Thus, a total of 11.7 micrograms loratadine equivalents or 0.029% of the administered dose were excreted as loratadine and its active metabolite. A 4-kg infant ingesting the loratadine and descarboethoxyloratadine excreted would receive a dose equivalent to 0.46% of the loratadine dose received by the mother on a mg/kg basis.(ABSTRACT TRUNCATED AT 250 WORDS)

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loratadine, Claritin
Inhibition of IgE- and non-IgE-mediated histamine release from human basophil leukocytes in vitro by a histamine H1-antagonist, desethoxycarbonyl-loratadine.

Kleine-Tebbe J, Josties C, Frank G, Stalleicken D, Buschauer A, Schunack W, Kunkel G, Czarnetzki B.

Clinic of Dermatology, University Hospital Rudolf Virchow, Freie Universitat Berlin, Germany.

Loratadine, a new nonsedating histamine H1-antagonist, has been shown to inhibit immunologic release of inflammatory mediators in addition to its H1-receptor blocking properties. After oral administration, the agent is metabolized primarily to desethoxycarbonyl-loratadine (DCL). The basic piperidine, DCL, is readily soluble in water, whereas the nonbasic urethane, loratadine, is insufficiently soluble in water for some in vitro investigations. Therefore we used the metabolite, DCL, to study its influence on in vitro leukocyte histamine release (LHR) in 24 allergic and 22 nonallergic subjects. IgE-mediated and calcium ionophore A23187-induced LHR were inhibited by DCL in a dose-dependent fashion (values of drug concentration to induce 30% inhibition after stimulation with inhalant antigen, anti-IgE, concanavalin A, and calcium ionophore A23187 were 6, 8, 5, and 11 mumol/L, respectively). Higher concentrations of DCL caused mediator release in all subjects (n = 45, 30 mumol/L DC: 11% +/- 2% LHR, 100 mumol/L DCL: 35% +/- 1% LHR), abolishing any inhibitory effect of the drug. Rapid onset of inhibition by 10 mumol/L DCL was found in kinetic studies (n = 10). The inhibition of anti-IgE-induced histamine secretion was synergistically increased by simultaneous preincubation of DCL with the potent histamine H2-agonist, FRA-19. Additional data indicate that the inhibition of LHR by DCL might involve biochemical events that occur after cellular Ca++ influx because LHR induced by N-formyl-methionyl-leucyl-phenylalanine or the phorbol ester, 12-O-tetradecanoyl phorbol-12-acetate, was not significantly affected by DCL.

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loratadine, Claritin
In vitro inhibition, by loratadine and descarboxyethoxyloratadine, of histamine release from human basophils, and of histamine release and intracellular calcium fluxes in rat basophilic leukemia cells (RBL-2H3).

Berthon B, Taudou G, Combettes L, Czarlewski W, Carmi-Leroy A, Marchand F, Weyer A.

Unite de Physiologie et de Pharmacologie cellulaire, INSERM U 274, Universite Paris-Sud, France.

The effect of the H1-antihistamine drug loratadine and its active metabolite descarboxyethoxyloratadine upon histamine release was examined on anti-immunoglobulin E (IgE) triggered human basophils and 2,4-dinitrophenyl (DNP) triggered rat basophilic leukemia (RBL-2H3) cells. In both experimental systems, dose-dependent inhibition of histamine release was observed at descarboxyethoxyloratadine and loratadine doses above 2 and 7 microM, respectively. In the RBL-2H3 experimental system, inhibition by loratadine increased when the concentration of extracellular Ca2+ was reduced from 1.8 to 0.45 mM. We further investigated the effect of loratadine and descarboxyethoxyloratadine on the increase in cytosolic calcium concentration (Ca2+)i, an early step in biochemical events leading to exocytosis. The effect of these two drugs upon (Ca2+)i changes was measured using the fluorescent probe fura-2 loaded into RBL-2H3 cells passively sensitized with DNP-specific IgE. Both drugs inhibited, in a dose-dependent manner (2.5-25 microM), the (Ca2+)i rise induced by DNP-BSA challenge in sensitized RBL cells, a process observed in both the presence and absence of extracellular Ca2+. Loratadine also inhibited the Mn2+ influx into these cells, thus reflecting the Ca2+ influx. These results suggest that loratadine and descarboxyethoxyloratadine impair the increase in (Ca2+)i following cell activation by decreasing both the influx of extracellular Ca2+ and the release of Ca2+ from intracellular stores.

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loratadine, Claritin
Inhibitory effect of the H1 antagonist loratadine on histamine release from human basophils.

Miadonna A, Milazzo N, Lorini M, Marchesi E, Tedeschi A.

Department of Internal Medicine, University of Milan, Ospedale Maggiore Policlinico, Italy.

Loratadine is a powerful H1 antagonist commonly employed in the treatment of allergic disorders. The present study was performed to investigate whether loratadine, in addition to anti-H1 activity, is able to modulate histamine release from human basophils. Leukocyte suspensions were prepared by dextran sedimentation of peripheral venous blood drawn from 10 normal subjects. Leukocytes were stimulated with anti-IgE (1/5,000), N-formyl-methionyl-leucyl-phenylalanine (FMLP; 10 microM) and the Ca2+ ionophore A23187 (1 microM), and histamine release in the cell supernatants was measured by an automated fluorometric method. Loratadine, at concentrations ranging from 1 to 50 microM, exerted a dose-dependent inhibitory effect on IgE-mediated and IgE-independent histamine release. The concentrations inhibiting 50% of histamine release were 30 microM (anti-IgE), 29 microM (FMLP) and 24 microM (Ca2+ ionophore A23187). The inhibitory activity of loratadine was optimal after incubation for 2 h at 37 degrees C and the effect of the drug was no longer evident when leukocytes were stimulated 2 h after cell washing. Increased extracellular Ca2+ concentrations reduced the inhibitory activity of loratadine, indicating that external Ca2+ and loratadine have antagonistic effects on basophil histamine release. These results indicate that loratadine, in addition to H1 receptor blocking activity, has the capacity to inhibit histamine release from human basophils.

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loratadine, Claritin
Anti-oedematous action of some H1-receptor antagonists.

Blazso G, Gabor M.

Institute of Pharmacodynamics, Albert Szent-Gyorgyi, Medical University, Szeged, Hungary.

The oedema disk technique was used to study the effects of orally administered H1-receptor antagonists (cetirizine, chloropyramine, clemastine, cyproheptadine, dimethindene, loratadine, mequitazine and terfenadine) on the inflammation induced with capsaicin or croton oil in the mouse ear, and the effect of topically applied dimethindene maleate gel on the inflammation induced with croton oil in the mouse ear. In rats of the Wistar strain, oedema was induced in the hind paw by the subplantar injection of dextran or compound 48/80. Preliminary antihistamine treatment inhibited the development of oedema in the mouse ear, and of oedema in the rat paw, to statistically significant extents, in a dose-dependent manner. In all experiments, the most potent drugs were loratadine and cyproheptadine.

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