loratadine, Claritin
Antiallergic activity of loratadine: inhibition of leukotriene C4 release from human leucocytes.

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

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

The H1 antagonist loratadine has the capacity to inhibit histamine release from human basophils. The aim of this study was to investigate whether loratadine can also inhibit leukotriene C4 (LTC4) release from human leucocytes. Basophil-enriched mononuclear cell suspensions were prepared by centrifugation of peripheral venous blood (n = 10) on discontinuous Percoll gradients. Leucocytes were stimulated with anti-IgE, N-formylmethionyl-leucyl-phenylalanine (FMLP) and Ca2+ ionophore A23187; immunoreactive (i) LTC4 release in the cell supernatant was measured by a competitive radioimmunoassay and histamine release was evaluated by an automated fluorometric technique. Loratadine, in the concentration range of 1-50 microM, exerted a dose-dependent inhibitory effect on IgE-mediated and IgE-independent histamine and iLTC4 release. The concentrations inhibiting 50% of histamine release were 30 microM (anti-IgE), 27 microM (FMLP) and 19 microM (Ca2+ ionophore A23187). The concentrations inhibiting 50% of iLTC4 release were 2.3 microM (anti-IgE). 11 microM (FMLP) and 1.7 microM (Ca2+ ionophore A23187). The inhibitory activity on iLTC4 release was optimal after preincubation for 2 h at 37 degrees C, and was no longer evident when leucocytes were stimulated 2 h after cell washing. Increased extracellular Ca2+ concentrations reduced the inhibitory activity of loratadine. These results indicate that loratadine has the capacity to inhibit the release of preformed and newly generated mediators from human basophil-enriched mononuclear cell suspensions.

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loratadine, Claritin
Preclinical pharmacology of desloratadine, a selective and nonsedating histamine H1 receptor antagonist. 1st communication: receptor selectivity, antihistaminic activity, and antiallergenic effects.

Kreutner W, Hey JA, Anthes J, Barnett A, Young S, Tozzi S.

Schering-Plough Research Institute, Allergy, Kenilworth, New Jersey, USA.

Desloratadine (descarboethoxyloratadine, CAS 100643-71-8) is an active metabolite of loratadine (CAS 79794-75-5) that exhibits qualitatively similar pharmacodynamic activity with a relative oral potency in animals 2.5-4 times greater than loratadine. Its antihistaminic effect lasts 24 h. Desloratadine was shown to be a selective H1 antagonist with more potent antihistaminic activity in vitro than either loratadine or terfenadine (CAS 50679-08-8), as indicated by its displacement of 3H-mepyramine from H1 receptors in rat brain, guinea pig brain, and guinea pig lung, and by its antagonism of histamine-induced contractions of guinea pig ileum. Antihistaminic activity and anitallergic effects also were observed in vivo. After oral administration, desloratadine was 2.5 to 4 times more potent than loratadine in protecting against histamine-induced lethality in the guinea pig and paw edema in the mouse; after topical administration, it was almost 10 times more potent in antagonizing histamine-induced increases in nasal microvascular permeability in the guinea pig. Histamine-induced changes in pulmonary resistance and compliance were also prevented by oral administration of desloratadine and loratadine in the monkey. An oral antiallergic effect was demonstrated by important reductions of acute bronchospasm in the allergic monkey and potent inhibition of allergic cough in the guinea pig. These preclinical studies provide evidence that desloratadine is an antihistaminic agent with a greater potency than loratadine and, together with results from numerous published studies, suggest an antiallergic effect of desloratadine.

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loratadine, Claritin
In vivo and in vitro interaction of the novel selective histamine H1 receptor antagonist mizolastine with H1 receptors in the rodent.

Benavides J, Schoemaker H, Dana C, Claustre Y, Delahaye M, Prouteau M, Manoury P, Allen J, Scatton B, Langer SZ, et al.

Synthelabo Recherche, Central Nervous System Department, Bagneux, France.

The interaction of mizolastine (CAS 108612-45-9, SL 85.0324) with histamine H1 receptors has been evaluated in the rodent. Mizolastine inhibited with high affinity (IC50 = 47 nmol/l) the binding of [3H]pyrilamine to histamine H1 receptors in guinea pig cerebellar membranes and sections. The order of potency of mizolastine and various H1 antagonists in this binding assay was the following: cyproheptadine > pyrilamine > mequitazine > mizolastine > astemizole > terfenadine > cetirizine > loratadine. Mizolastine also potently antagonized the contractile effects of histamine in the guinea pig ileum (pA2 = 8.5) and histamine-induced stimulation of phosphoinositide turnover in rat cortical slices (IC50 = 0.35 mumol/l). In contrast, this compound displayed very low affinity for serotonergic, noradrenergic and muscarinic cholinergic receptors as evidenced in both binding assays and functional tests. In guinea pig cerebellar membranes, [3H]mizolastine labelled in a saturable and reversible manner a single population of binding sites with Kd and Bmax values of 1.1 nmol/l and 635 fmol/mg protein, respectively. [3H]Mizolastine binding in guinea pig cerebellar membranes was inhibited by histamine (IC50 = 30 mumol/l) and by drugs that possess affinity for the H1 receptor such as pyrilamine (IC50 = 1 nmol/1), DL-chlorphenyramine (IC50 = 6.4 nmol/l) terfenadine (IC50 = 6 nmol/l) and loratadine (IC50 = 50 nmol/l). At concentrations lower than 10 mumol/l, the H2 receptor ligands dimaprit and cimetidine and the H3 receptor ligands burimamide and 4-methyl-histamine failed to displace [3H]mizolastine binding.(ABSTRACT TRUNCATED AT 250 WORDS)

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loratadine, Claritin
Inhibitory activity of loratadine and descarboethoxyloratadine on expression of ICAM-1 and HLA-DR by nasal epithelial cells.

Vignola AM, Crampette L, Mondain M, Sauvere G, Czarlewski W, Bousquet J, Campbell AM.

Clinique des Maladies Respiratoires, Hopital Arnaud de Villeneuve, Montpellier, France.

Nasal epithelial cells represent the first barrier against noxious agents and allergens. In allergic rhinitis, these cells are activated and histamine may be involved in this activation. Loratadine and one of its active metabolites, descarboethoxyloratadine, were studied for their ability to reduce the activation of nasal epithelial cells by histamine. Nasal turbinates or polyps were removed during surgery from 19 subjects, and nasal epithelial cells were recovered after enzymatic digestion. The in vitro activation of epithelial cells with histamine using an optimal dose (1 microM) and an optimal time (24 h) of incubation was studied, and the effect of loratadine or descarboethoxyloratadine (10 microM) was investigated. The expression of membrane markers (intercellular adhesion molecule-1 (ICAM-1) and a human leukocyte class II antigen (HLA-DR) was assessed by immunocytochemical analysis using an alkaline-antialkaline phosphatase (APAAP) system. The spontaneous expression of both markers was not significantly different in cells recovered from nasal turbinates or polyps, and there was a highly significant increase in the numbers of cells expressing ICAM-1 and HLA-DR following incubation with histamine. Loratadine or descarboethoxyloratadine significantly blocked these effects. This study shows a new possible antiallergic effect of H1-blockers and suggests that their effects on epithelial cells may be relevant in vivo.

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loratadine, Claritin
The effect of H1 receptor antagonists on peripheral blood mononuclear cells, adenoid cells and primary cell lines.

Holen E, Elsayed S, Nyfors A.

Institute of Clinical Biology, University Hospital, Bergen, Norway.

This study describes the in vitro effect of three H1 receptor antagonists (dexchlorpheniramine, terfenadine and loratadine) on human peripheral blood mononuclear cells (PBMC, n = 30) from allergic patients and healthy individuals. The three H1 receptor antagonists significantly inhibited antigen/mitogen-induced PBMC proliferation in a concentration-dependent manner. Allergen-specific T-cell responses in allergic individuals were similarly inhibited. The effect of the three drugs was also tested in cultures of mononuclear cells derived from adenoid tissue. The growth kinetics were investigated using spontaneously proliferating cell lines to examine whether the inhibition was caused by general toxicity. Three cell lines, HCT 8 (an ileocaecal adenocarcinoma) RPMI 8866 (B-cell line) and 166 A2 (T hybridoma) were tested. Loratadine (< 0.03 microM) and dexchlorpheniramine (< 0.62 microM) altered the kinetics of HCT 8 and RPMI 8866, respectively. When testing RPMI 8866 and 166 A2, the growth-inhibitory effect of terfenadine and loratadine could be neutralized by addition of cell culture filtrate from RPMI 8866 or 166 A2. These culture filtrates are rich in soluble low-affinity IgE receptor (sCD23) and IgE-binding factor (IgEBF), respectively. Our findings show that the antihistamines investigated display some non-convential in vitro anti-allergic properties possibly not related to their interaction with the H1 receptor. In addition, our results suggest: a) The H1 receptor antagonists used differ in their pattern of cell inhibition; b) The inhibitory effect is completely reversible at low drug concentrations.

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loratadine, Claritin
[HPLC-determination of loratadine and its active metabolite descarboethoxyloratadine in human plasma]

[Article in German]

Zhong D, Blume H.

Zentrallaboratorium Deutscher Apotheker, Eschborn.

The quantitative determination of loratadine (1) and its active metabolite descarboethoxyloratadine (2) is described. Because of the high difference in polarity between 1 and 2, the two analytes were determined in two HPLC-systems separately. As internal standards propyl-4-(8-chloro-5,6-dihydro-11H-benzo-[5,6]-cyclohepta-[1,2-b]- pyridin-11-ylidin)-1-piperidincarboxylate (3) and 1-ethyl-4-(8-chloro-5,6-dihydro-11H-benzo-[5,6]-cyclohepta- [1,2-b]-pyridine-11-ylidin)-piperidine (4) were used for 1 and 2, respectively. After extraction with organic solvents from 1 ml plasma, 1 and 2 were reextracted with diluted phosphoric acid from the organic phase. Chromatographic separation on a RP-18 column and fluorescence detection allowed a sufficiently sensitive determination of 1 and 2 in plasma with a lower limit of quantitation of 0.5 ng/ml for both analyts. The method was successfully applied to human plasma samples from 16 subjects after oral administration of 20 mg 1.

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