loratadine, Claritin
Loratadine blockade of K(+) channels in human heart: comparison with terfenadine under physiological conditions.

Crumb WJ Jr.

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

Recently, there has been considerable attention focused on drugs that prolong the QT interval of the electrocardiogram, with the H(1)-receptor antagonist class of drugs figuring prominently. Albeit rare, incidences of QT prolongation and ventricular arrhythmias, in particular torsade de pointes, have been reported with the antihistamines astemizole and terfenadine and more recently with loratadine. The most likely mechanism for these drug-related arrhythmias is blockage of one or more ion channels involved in cardiac repolarization. Several studies have demonstrated block of multiple cardiac K(+) channels by terfenadine, including I(to), I(sus), I(K1), and I(Kr) or human ether-a-go-go-related gene (HERG). In contrast to terfenadine, previous studies have shown the antihistamine loratadine to be virtually free of cardiac ion channel-blocking effects. This disparity in the lack of any significant cardiac ion channel-blocking effect and the existence of numerous adverse cardiac event reports for loratadine prompted the comparison of the human cardiac K(+) channel-blocking profile for loratadine and terfenadine under physiological conditions [37 degrees C, holding potential (V(hold)) = -75 mV] with the whole-cell patch-clamp method. Isolated human atrial myocytes were used to examine drug effects on I(to), I(sus), and I(K1), whereas HERG was studied in stably transfected HEK cells. In contrast to previous studies in nonhuman systems and/or under nonphysiological conditions, terfenadine (1 microM) had no effect on I(to), I(sus), or I(K1) at pacing rates up to 3 Hz. Similar results were found for 1 microM loratadine. However, both drugs potently blocked HERG current amplitude, with a mean IC(50) of 173 nM for loratadine and 204 nM for terfenadine (pacing rate, 0.1 Hz). Neither drug exhibited any significant use-dependent blockage of HERG (pacing rates = 0.1-3 Hz). These results point to a similarity in the human cardiac K(+) channel-blocking effects of loratadine and terfenadine and provide a possible mechanism for the arrhythmias associated with the use of either drug.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10604956&dopt=Abstract loratadine, Claritin



loratadine, Claritin
Causal prophylactic activity of antihistaminic agents against Plasmodium yoelii nigeriensis infection in Swiss mice.

Singh N, Puri SK.

Division of Microbiology, Central Drug Research Institute, Lucknow, India.

The causal prophylactic activity of five tricyclic anti-histaminic agents (histamine H1-receptor antagonists) cyproheptadine, ketotifen, loratadine, azatadine and terfenadine was evaluated in an experimental murine malaria model. Sporozoite induced infections with Plasmodium yoelii nigeriensis (N-67), a strain innately resistant to choloroquine, were employed for the efficacy test and pyrimethamine and primaquine were used as standard reference drugs. Treatment with cyproheptadine or ketotifen at 5 mg/kg and terfenadine at 50 mg/kg, orally for 3 days (-1, 0, +1) completely prevented the establishment of patent infection in mice inoculated with 1 x 10(5) sporozoites on day 0. Partial activity was recorded with lower doses of the above agents as well as with azatadine and loratadine at 10 mg/kg as indicated by marginal delay in the development of patent infection after sporozoite challenge. None of these agents showed blood schizontocidal activity at doses found effective in the causal prophylactic test, though initial suppression of parasitaemia was observed with cyproheptadine and ketotifen at higher doses. This study is the first report on efficacy of antihistaminic agents for growth inhibition of pre-erythrocytic stages of any malaria parasite.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9638277&dopt=Abstract loratadine, Claritin



loratadine, Claritin
Molecular basis for the lack of HERG K+ channel block-related cardiotoxicity by the H1 receptor blocker cetirizine compared with other second-generation antihistamines.

Taglialatela M, Pannaccione A, Castaldo P, Giorgio G, Zhou Z, January CT, Genovese A, Marone G, Annunziato L.

Section of Pharmacology, Department of Neuroscience, School of Medicine, University of Naples Federico II, 80131 Naples, Italy. mtaglial unina.it

In the current study, the potential blocking ability of K+ channels encoded by the human ether-a-go-go related gene (HERG) by the piperazine H1 receptor antagonist cetirizine has been examined and compared with that of other second-generation antihistamines (astemizole, terfenadine, and loratadine). Cetirizine was completely devoid of any inhibitory action on HERG K+ channels heterologously expressed in Xenopus laevis oocytes in concentrations up to 30 microM. On the other hand, terfenadine and astemizole effectively blocked HERG K+ channels with nanomolar affinities (the estimated IC50 values were 330 and 480 nM, respectively), whereas loratadine was approximately 300-fold less potent (IC50 approximately 100 microM). In addition, in contrast to terfenadine, cetirizine did not show use-dependent blockade. In SH-SY5Y cells, a human neuroblastoma clone that constitutively expresses K+ currents carried by HERG channels (IHERG), as well as in human embryonic kidney 293 cells stably transfected with HERG cDNA, extracellular perfusion with 3 microM cetirizine did not exert any inhibitory action on IHERG. Astemizole (3 microM), on the other hand, was highly effective. Terfenadine (3 microM) caused a marked (approximately 80%) inhibition of IHERG in SH-SY5Y cells, whereas loratadine, at the same concentration, caused a 40% blockade. Furthermore, the application of cetirizine (3 microM) on the intracellular side of the membrane of HERG-transfected human embryonic kidney 293 cells did not affect IHERG, whereas the same intracellular concentration of astemizole caused a complete block. The results of the current study suggest that second-generation antihistamines display marked differences in their ability to block HERG K+ channels. Cetirizine in particular, which possesses more polar and smaller substituent groups attached to the tertiary amine compared with other antihistamines, lacks HERG-blocking properties, possibly explaining the absence of torsade de pointes ventricular arrhythmias associated with its therapeutical use.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9658196&dopt=Abstract loratadine, Claritin



loratadine, Claritin
Inhibitory effect of loratadine on leukotriene B4 production by neutrophils either alone or during interaction with human airway epithelial cells.

Amsellem C, Czarlewski W, Lagarde M, Pacheco Y.

Centre Hospitalier Lyon-Sud, Laboratoire d'Immuno-Allergologie Respiratoire, Pierre-Benite, France.

Leukotriene B4 (LTB4), an inflammatory mediator, is a potent chemoattractant for neutrophils (PMN) that plays an important role in the late reaction in asthma. Human airway epithelial cells (HAEC) can interact with PMN to increase LTB4 production. The aim of this study was to determine the influence of loratadine, an antihistaminic drug, on the production of LTB4 by PMN either alone or during interaction with transformed HAEC. The effect of tumour necrosis factor-alpha (TNF-alpha) was also examined. LTB4 production was measured by RP-HPLC after cell stimulation with calcium ionophore. Loratadine (0.25-25 microM) induced a significant and dose-dependent decrease of LTB4 production by PMN alone whereas it was up-regulated by TNF-alpha. As reported by others, we confirmed the increase of LTB4 release when PMN were cocultured with HAEC as compared to PMN alone. Addition of loratadine to HAEC before co-culture with PMN induced a significant decrease of LTB4 formation by cell interaction. This effect was noted when HAEC were washed following incubation with loratadine, demonstrating a direct action of the drug on this cell type. Moreover, the TNF-alpha-induced stimulation of LTB4 release that we demonstrated in PMN-HAEC interaction was also inhibited by loratadine. These results indicate that loratadine might reduce inflammatory reaction by a direct effect on PMN LTB4 production but also through an influence on HAEC during interaction with PMN.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10101740&dopt=Abstract loratadine, Claritin



loratadine, Claritin
[Effect of loratadine--selective antagonist of histamine (H1) receptor--on allergen-induced bronchoconstriction in atopic asthmatics]

[Article in Polish]

Cieslewicz G, Gondorowicz K, Grzelewska-Rzymowska I, Rozniecki J, Wojciechowska B.

Kliniki Pneumonologii i Alergologii IMW AM, Lodzi.

The aim of this study was to evaluate the effect of loratadine on allergen-induced bronchoconstriction. The study was performed in 7 asthmatic patients with sensitivity to Dermatophagoides pteronyssinus, 4 women and 3 men. aged from 19 to 37 years. The allergen inhalatory--challenge test was performed according to Chai et al. Early phase of Dermatophagoides pteronyssinus--induced bronchoconstriction appeared in all examined patients, but late phase of bronchial obstruction was observed only in 3 persons. 30 mg orally administered of loratadine have no protect effect on early phase of allergen--induced bronchoconstriction. After loratadine ingestion the late phase of this bronchial obstruction disappeared.

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loratadine, Claritin
Effects of antihistamines on cutaneous reactions and influx of eosinophils after local injection of PAF, kallikrein, compound 48/80 and histamine in patients with chronic urticaria and healthy subjects.

Juhlin L, Pihl-Lundin I.

Department of Dermatology, University Hospital, Uppsala, Sweden.

The effects of one week's daily treatment with dexchlorpheniramine (3 + 3 mg x 2) and loratadine (10 mg x 2) on the cutaneous reactions to putative mediators of urticarial reactions were studied in healthy subjects and in patients with chronic urticaria. Biopsy specimens were taken from skin with delayed reactions and studied immunohistochemically for the presence of eosinophilic cationic protein (ECP). In healthy subjects both antihistamines significantly decreased the weal and flare induced by histamine and the histamine releaser compound 48/80. They also reduced the flare seen after injection of PAF (platelet activating factor) and kallikrein. In patients with chronic urticaria the delayed reactions to PAF and kallikrein were larger than in healthy subjects. The immediate flare seen after injection of histamine, 48/80 and PAF, and the delayed reaction to 48/80, were significantly decreased by treatment with loratadine. No correlation was found between the clinical response and test reactions. In the group of healthy subjects, eosinophils were increased in the skin of all subjects after intradermal injection of 100 micrograms of PAF and in 50% after 1 microgram of PAF, but no eosinophils were seen after injection of 1 ng of PAF. In patients with chronic urticaria the eosinophils were increased at all sites where 1 ng of PAF had been injected and also at a limited number of sites of injection of histamine, 48/80, kallikrein and saline. Treatment with the antihistamines had no effect on the influx of eosinophils in the skin.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1357858&dopt=Abstract loratadine, Claritin