loratadine, Claritin
Cetirizine and loratadine-based antihistamines with 5-lipoxygenase inhibitory activity.

Lewis TA, Young MA, Arrington MP, Bayless L, Cai X, Collart P, Eckman JB, Ellis JL, Ene DG, Libertine L, Nicolas JM, Scannell RT, Wels BF, Wenberg K, Wypij DM.

UCB Research, 840 Memorial Drive, Cambridge, MA 02139, USA. timlewis1201 comcast.net

A series of compounds possessing both H(1) histamine receptor antagonist and 5-lipoxygenase (5-LO) inhibitory activities was synthesized. The H(1)-binding scaffolds of cetirizine, efletirizine, and loratadine were linked to a lipophilic N-hydroxyurea, the 5-LO inhibiting moiety of zileuton. Both activities were observed in vivo, as was increased CYP3A4 inhibition compared to their respective single-function drugs. Selected analogs in the series were shown to be orally active in guinea pig models.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15482930&dopt=Abstract loratadine, Claritin



loratadine, Claritin
Prophylactic management of children at risk for recurrent upper respiratory infections: the Preventia I Study.

Grimfeld A, Holgate ST, Canonica GW, Bonini S, Borres MP, Adam D, Canseco Gonzalez C, Lobaton P, Patel P, Szczeklik A, Danzig MR, Roman I, Bismut H, Czarlewski W.

Hopital Armand Trousseau, Paris, France. alain.grimfeld trs.ap-hop-paris.fr

BACKGROUND: Given the morbidity and mortality of asthma and the recent dramatic increase in its prevalence, pharmacologic prophylaxis of this disease in children at risk would represent a major medical advance. OBJECTIVES: The Preventia I Study was designed to evaluate the efficacy and long-term safety of loratadine in reducing the number of respiratory infections in children at 24 months. A secondary objective was to investigate the benefit of loratadine treatment in preventing the onset of respiratory exacerbations. METHODS: Preventia I was a randomized placebo-controlled study involving 22 countries worldwide. The children were 12-30 months of age at enrollment and had experienced at least five episodes of ENT infections, and no more than two episodes of wheezing during the previous 12 months. Phase I was a 12-month double-blind period during which the children were treated with loratadine 5 mg/day (2.5 mg/day for children</=24 months of age) or placebo. Phase II was a double-blind follow-up period without study medication. RESULTS: Of the 412 children enrolled, 342 and 310 completed Phase I and Phase II, respectively. The results showed a significant decrease in the number of infections in the whole population of children. However, no difference was observed between the loratadine and placebo group. When considering secondary end-points, loratadine was shown to reduce the number of respiratory exacerbations during the treatment phase. None of the 204 children who received loratadine discontinued the study because of drug-related events. Loratadine treatment was not more sedative than placebo and was not associated with cardiovascular events. CONCLUSION: The strong decrease in the rate of infections in the children at risk of recurrent infections, while not being influenced by loratadine treatment, should encourage future reflection in terms of prophylactic management. This study also confirms the long-term safety of loratadine and its metabolites in young children.

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loratadine, Claritin
Desloratadine inhibits constitutive and histamine-stimulated nuclear factor-kappaB activity consistent with inverse agonism at the histamine H1 Receptor.

Wu RL, Anthes JC, Kreutner W, Harris AG, West RE Jr.

Schering-Plough Research Institute, Schering-Plough Corporation, Kenilworth, NJ 07033, USA.

BACKGROUND: The human histamine H1 receptor is constitutively active and exhibits basal activation of nuclear factor-kappaB (NF-kappaB), an important modulator of allergic inflammation. Certain H1 antihistamines have recently been shown to inhibit basal NF-kappaB activity by stabilizing the H1 receptor in an inactive state, a phenomenon called 'inverse agonism'. METHODS: We evaluated the effect of the new H1 antihistamine, desloratadine, on basal and histamine-stimulated NF-kappaB activity and compared it with the activities of other H1 antihistamines. RESULTS: Transiently transfected COS-7 cells co-expressing NF-kappaB-luciferase and the H1 receptor exhibited constitutive NF-kappaB activity. H1 antihistamines reduced basal NF-kappaB activity (rank order of potency: desloratadine > pyrilamine > cetirizine > loratadine > fexofenadine). Histamine stimulated basal NF-kappaB activity 8-fold, which was blocked by H1 antihistamines (rank order of potency: desloratadine > cetirizine > pyrilamine > loratadine > fexofenadine). Neither histamine nor antihistamines had any effect on NF-kappaB activity in the absence of the H1 receptor. CONCLUSIONS: Desloratadine, acting through the histamine H1 receptor, inhibited basal NF-kappaB activity and can thus be classified as an inverse agonist. Inhibition of basal and histamine-stimulated NF-kappaB activity may help to explain previously reported inhibitory effects of desloratadine on allergic inflammatory mediators. 2004 S. Karger AG, Basel.

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loratadine, Claritin
[Clinical examination of mizolastine in the seasonal allergic rhinitis]

[Article in Chinese]

Li H, Zhang H, Yin J, Wang R, Fang Q.

Department of Allergy, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, 100730, China.

OBJECTIVE: An open randomized comparative study versus loratadine was conducted in order to examine the efficacy and safety of mizolastine in the treatment of seasonal allergic rhinitis (SAR). METHOD: Six-seven adult patients completed mizolastine 10 mg (34/67) and loratadine 10 mg (33/67) once daily for 14 days. Other 5 patients withdrew or dropped out from the trial. RESULT: All symptom score decreased significantly after treatment in both groups. Efficacy assessment based on symptom score reducing index showed that the efficacy of Mizolastine was 82.4%, and the excellent rate was 20.6%, while the efficacy of Loratadine was 66.7%, and the excellent rate was 6.1%. No serious adverse events were reported in the two groups. The incidences of adverse drug reactions (ADRs) of Mizolastine and Loratadine were 38.2% and 33.3% respectively. The mild or moderate drowsiness and dry mouth in Mizolastine group were 26.5% and 8.8% respectively, and in Loratadine group they were 18.2% and 9.0%. There were no significant changes in laboratory examinations including blood and urine routine tests, liver and renal functions and ECG. CONCLUSION: Mizolastine is effective in relieving SAR symptoms. The efficacy and ADR of mizolastine is similar to Loratadine in the treatment of SAR.

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loratadine, Claritin
Comparative pharmacology of guinea pig cardiac myocyte and cloned hERG (I(Kr)) channel.

Davie C, Pierre-Valentin J, Pollard C, Standen N, Mitcheson J, Alexander P, Thong B.

Lead Generation & Discovery BioScience, AstraZeneca, R&D Charnwood, Loughborough, Leicestershire, United Kingdom.

INTRODUCTION: This study used whole-cell, patch clamp techniques on isolated guinea pig ventricular myocytes and HEK293 cells expressing cloned human ether-a-go-go-related gene (hERG) to examine the action of drugs causing QT interval prolongation and torsades de pointes (TdP) in man. Similarities and important differences in drug actions on cardiac myocytes and cloned hERG I(Kr) channels were established. Qualitative actions of the drugs on cardiac myocytes corresponded with results obtained from Purkinje fibers and measurement of QT interval prolongation in animal and human telemetry studies. METHODS AND RESULTS: Adult guinea pig ventricular myocytes were isolated by enzymatic digestion. Cells were continuously perfused with Tyrode's solution at 33-35 degrees C. Recordings were made using the whole-cell, patch clamp technique. Action potentials (APs) were elicited under current clamp. Voltage clamp was used to study the effect of drugs on I(Kr) (rapidly activating delayed rectifier potassium current), I(Na) (sodium current), and I(Ca) (L-type calcium current). Dofetilide increased the myocyte action potential duration (APD) in a concentration-dependent manner, with a pIC50 of 7.3. Dofetilide 1 microM elicited early afterdepolarizations (EADs) but had little affect on I(Ca) or I(Na). E-4031 increased APD in a concentration-dependent manner, with a pIC50 of 7.2. In contrast, 10 microM loratadine, desloratadine, and cetirizine had little effect on APD or I(Kr). Interestingly, cisapride displayed a biphasic effect on myocyte APD and inhibited I(Ca) at 1 microM. Even at this high concentration, cisapride did not elicit EADs. A number of AstraZeneca compounds were tested on cardiac myocytes, revealing a mixture of drug actions that were not observed in hERG currents in HEK293 cells. One compound, particularly AR-C0X, was a potent blocker of myocyte AP (pIC50 of 8.4). AR-C0X also elicited EADs in cardiac myocytes. The potencies of the same set of drugs on the cloned hERG channel also were assessed. The pIC50 values for dofetilide, E-4031, terfenadine, loratadine, desloratadine, and cetirizine were 6.8, 7.1, 7.3, 5.1, 5.2, and <4, respectively. Elevation of temperature from 22 to 35 degrees C significantly enhanced the current kinetics and amplitudes of hERG currents and resulted in approximately fivefold increase in E-4031 potency. CONCLUSION: Our study demonstrates the advantages of cardiac myocytes over heterologously expressed hERG channels in predicting QT interval prolongation and TdP in man. The potencies of some drugs in cardiac myocytes were similar to hERG, but only myocytes were able to detect important changes in APD characteristics and display EADs predictive of arrhythmia development. We observed similar qualitative drug profiles in cardiac myocytes, dog Purkinje fibers, and animal and human telemetry studies. Therefore, isolated native cardiac myocytes are a better predictor of drug-induced QT prolongation and TdP than heterologously expressed hERG channels. Isolated cardiac myocytes, when used with high-throughput patch clamp instruments, may have an important role in screening potential cardiotoxic compounds in the early phase of drug discovery. This would significantly reduce the attrition rate of drugs entering preclinical and/or clinical development. The current kinetics and amplitudes of the cloned hERG channel were profoundly affected by temperature, significantly altering the potency of one drug (E-4031). This finding cautions against routine drug testing at room temperature compared to physiologic temperature when using the cloned hERG channel.

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loratadine, Claritin
To evaluate and compare the effects of first generation anti-histamine (chlorpheniramine maleate) and second generation anti-histamine (loratadine) on isolated trachea of rabbit.

Jalbani GA, Aamir K, Shaikh AM, Unar MA, Ashraf R, Soomro FM.

Liaquat University Hospital, Hyderabad/Jamshoro.

OBJECTIVE: The incidence of respiratory allergy has increased gradually over the past several years and current estimates suggest that allergic rhinitis affects approximately 20% of the population. Large scales population surveys indicate that up to 38% of patients with rhinitis have asthma. The allergic response in the airways is an important pathogensis to cause bronchoconstriction owing to increased responsiveness of tracheo bronchial tree to various stimuli and also causes the release of histamine and other chemical mediators from mast cells. Histamine has been shown to be an important mediator of an allergic reaction in both the upper and lower respiratory airways. Chlorpheniramine maleate is a stable, most potent, sedative first generation anti-histamine and is effective in the treatment of allergic disorders. Loratadine is a highly potent, non-sedating, long acting tricyclic, second generation anti-histamine. It is indicated in allergic rhinits, chronic idiopathic urticaria and allergic bronchial asthma. The purpose of study was to evaluate the antagonistic effects of chlorpheniramine maleate and loratadine on histamine induced contractions in isolated trachea of rabbit and also to compare the effects of first generation anti-histamine (chlorpheniramine maleate and second generation anti-histamine loratadine). METHODS: In this study twenty-four experiments were performed on isolated trachea of rabbit, in the presence of selected standard concentration of histamine dihydrochloride, antagonistic effects of various concentrations of chlorpheniramine maleate (10-18 to 10(-3) gm/ml) and loratadine from concentrations 10(-18) to 10(-3) gm/ml were recorded by Polygraph Model 7B in terms of rate and amplitude. RESULTS: Chlorpheniramine maleate showed non-significant antagonistic effect from concentrations 10(-18) to 10(-3) gm/ml in case of rate and 10(-18) to 10(-8) gm/ml in case of amplitude. Significant response showed from concentrations 10(-8) to 10(-3) gm/ml in case of rate (P<0.001) and 10(-7) to 10(-3) gm/ml in case of amplitude (P<0.001) while, loratadine showed non-significant response from concentrations 10(-18) to 10(-12) gm/ml in case of rate and from concentration 10(-18) to 10(-14) gm/ml in case of amplitude. Significant response observed from concentrations 10(-11) to 10(-3) gm/ml in case of rate and 10(-13) to 10(-3) gm/ml in case of amplitude. CONCLUSION: It was concluded that chlorpheniramine maleate antagonized the histamine induced contractions 80.65% at concentration 10(-3) gm/ml in case of amplitude and 11.35% at concentration 10(-3) gm/ml in case of rate and loratadine 76.82% in case of amplitude and 10.59% in case of rate.

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