loratadine, Claritin
Stability indicating methods for the determination of loratadine in the presence of its degradation product.

El Ragehy NA, Badawey AM, Khateeb SZ.

Department of Analytical Chemistry, Faculty of Pharmacy, Cairo University, Kasr Elini Street, Cairo, Egypt. n.a.ragehy mailcity.com

Four stability-indicating procedures have been suggested for determination of the non sedating antihistaminic agent loratadine. Loratadine being an ester undergoes alkaline hydrolysis and the corresponding acid derivative is produced as a degradation product. Its identity was confirmed using IR and MS. The first procedure is based on determination of loratadine by HPLC with detection at wavelength, 250 nm. Mobile phase is acetonitrile:orthophosphoric acid (35:65) using benzophenone as an internal standard. Sensitivity range is 5.00-50.00 microg/ml. Second determination is a densitometric procedure based on determination of loratadine in the presence of its degradate at lambda 246 nm using the mobile phase; methanol:ammonia (10:0.15). Sensitivity range is 1.25-7.50 microg per spot. The third procedure is a spectrophotometric one where a mixture of loratadine and its degradate are resolved by first derivative ratio spectra. Sensitivity range is found to be 3.00-22.00 microg/ml, upon carrying out the measurements at wavelengths 236, 262.4 and 293.2 nm. The fourth procedure is based on second derivative spectrophotometry, where D(2) measurements are carried out at lambda 266 nm. The sensitivity range is 3.00-22.00 microg/ml. The validity of the described procedures was assessed by applying the standard addition technique. Statistical analysis of the results have been carried out revealing high accuracy and good precision. The suggested procedures could be used for determination of loratadine both in pure and dosage forms, as well as in the presence of its degradate.

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loratadine, Claritin
LC determination of loratadine and related impurities.

Ruperez FJ, Fernandez H, Barbas C.

Facultad de CC Experimentales y de la Salud, Universidad San Pablo-CEU Urbanizacion Monteprincipe, Ctra. Boadilla del Monte, km 5,3-28668 Madrid, Spain.

Loratadine, an antihistamine, could include in its raw material seven impurities that ought to be separated identified and quantified for drug development and quality control. A HPLC method employing a SymmetryShield RP8 column has been developed and validated for loratadine and related compounds measurement, the last ones under the 0.1% level. The mobile phase consisted of methanol-buffer A (65:35, v/v), being buffer A: H(3)PO(4) 10 mM (H(2)O) brought up to pH 7.00 with triethylamine. UV detection was performed at 244 nm. Validation parameters for linearity, accuracy and precision are in agreement with ICH guidelines for all the analytes and that permits to consider the method reliable and suitable for application to long-term stability and purity studies.

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loratadine, Claritin
Biochemical characterization of desloratadine, a potent antagonist of the human histamine H(1) receptor.

Anthes JC, Gilchrest H, Richard C, Eckel S, Hesk D, West RE Jr, Williams SM, Greenfeder S, Billah M, Kreutner W, Egan RE.

Schering-Plough Research Institute, K15-1-1600, 2015 Galloping Hill Rd., Kenilworth, NJ 07033, USA. john.anthes spcorp.com

We have characterized desloratadine (5H-benzo[5,6]cyclohepta[1,2-b]pyridine, 8-chloro-6,11-dihydro-11-(4-piperidinylidene), CAS 100643-71-8) as a potent antagonist of the human histamine H(1) receptor. [3H]Desloratadine bound to membranes expressing the recombinant human histamine H(1) receptor in Chinese hamster ovary cells (CHO-H(1)) in a specific and saturable manner with a K(d) of 1.1+/-0.2 nM, a B(max) of 7.9+/-2.0 pmol/mg protein, and an association rate constant of 0.011 nM(-1) x min(-1). The K(d) calculated from the kinetic measurements was 1.5 nM. Dissociation of [3H]desloratadine from the human histamine H(1) receptor was slow, with only 37% of the binding reversed at 6 h in the presence of 5 microM unlabeled desloratadine. Seventeen histamine H(1)-receptor antagonists were evaluated in competition-binding studies. Desloratadine had a K(i) of 0.9+/-0.1 nM in these competition studies. In CHO-H(1) cells, histamine stimulation resulted in a concentration-dependent increase in [Ca(2+)](i) with an EC(50) of 170+/-30 nM. After a 90-min preincubation with desloratadine, the histamine-stimulated increase in [Ca(2+)](i) was shifted to the right, with a depression of the maximal response at higher concentrations of antagonist. The apparent K(b) value was 0.2+/-0.14 nM with a slope of 1.6+/-0.1. The slow dissociation from the receptor and noncompetitive antagonism suggests that desloratadine may be a pseudoirreversible antagonist of the human histamine H(1) receptor. The mechanism of desloratadine antagonism of the human histamine H(1) receptor may help to explain the high potency and 24-h duration of action observed in clinical studies.

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loratadine, Claritin
Increased risk of serious injury following an initial prescription for diphenhydramine.

Finkle WD, Adams JL, Greenland S, Melmon KL.

Consolidated Research, Inc, Los Angeles, California 90024, USA. bill consolidated-research.com

BACKGROUND: Diphenhydramine may be associated with excess risk of injury relative to nonsedating H1-receptor antagonists. OBJECTIVE: This study sought to compare the risk of injury in patients exposed to diphenhydramine with the risk of injury in patients exposed to loratadine. METHODS: A retrospective cohort study of injury was carried out in 12,106 patients whose initial antihistamine prescription was for diphenhydramine and in 24,968 patients whose initial antihistamine prescription was for loratadine. Data were taken from a health care claims database that included employees, dependents, and retirees who filed claims from January 1991 through December 1998. Rates of six serious injuries in the diphenhydramine cohort after and before the first prescription were compared with rates in the loratadine cohort after and before the first prescription. RESULTS: In the 30 days after the first antihistamine prescription, the rate of all injuries was 308 per 1,000 person-years in the diphenhydramine cohort versus 137 per 1,000 person-years in the loratadine cohort. The rate ratio estimate adjusted for age and gender using Poisson regression was 2.27 (95% confidence limits [CL] 1.93, 2.66). In the corresponding 30 days of the preceding year, the injury rates in the diphenhydramine and loratadine cohorts were 128 and 125 per 1,000 person-years, and the adjusted rate ratio was 1.02 (CL 0.83, 1.26). Thus, the cohorts appeared to have similar preprescription injury rates. The differences between the cohorts declined with time from prescription: For all injuries, the estimated percentage decline in the rate ratio was 4.1% per day (CL 3.3, 4.9), and the estimated time from the initial prescription until the diphenhydramine cohort returned to baseline risk was 32.3 days (CL 26.9, 37.6). CONCLUSIONS: If these associations are causal, the percentage of the injuries attributable to diphenhydramine was 55% (CL 41, 65), implying a substantial number of excess injuries and costs incurred as the result of diphenhydramine use. The high use rates of this drug and the high incidence of injury suggest that further study of the association between injury and type of antihistamine is needed.

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loratadine, Claritin
Effect of loratadine on nitrogen dioxide-induced changes in electrical resistance and release of inflammatory mediators from cultured human bronchial epithelial cells.

Bayram H, Devalia JL, Khair OA, Abdelaziz MM, Sapsford RJ, Czarlewski W, Campbell AM, Bousquet J, Davies RJ.

Academic Department of Respiratory Medicine, St Bartholomew's and the Royal London School of Medicine and Dentistry, The London Chest Hospital, London, United Kingdom.

BACKGROUND: Recent studies have demonstrated that some antihistamines can attenuate histamine-induced release of inflammatory mediators from bronchial epithelial cells. OBJECTIVE: The purpose of study was to test the hypothesis that loratadine may influence pollution-induced inflammation of the airways by modulating epithelial membrane integrity and the synthesis and/or release of inflammatory mediators from airway epithelial cells. METHODS: We have cultured human bronchial epithelial cell (HBEC) cultures from surgical explants and investigated the effect of loratadine on NO2-induced changes in both electrical resistance of HBEC cultures and release of IL-8, RANTES, and soluble intercellular adhesion molecule-1 (sICAM-1) from these cells after exposure for 6 hours to either air or 400 ppb NO2. RESULTS: Exposure for 6 hours to NO2 significantly decreased the electrical resistance of HBEC cultures by 18.1% from baseline (P <.05). Incubation with 0.25 to 25 micromol/L loratadine did not alter the NO2-induced decrease in the electrical resistance of HBEC cultures. NO2 also significantly increased the release of IL-8 from a control value of 52.5 pg/microgram cellular protein to 81.9 pg/microgram cellular protein (P <.05), RANTES from a control value of 0.023 pg/microgram cellular protein to 0.062 pg/microgram cellular protein (P <.05), and sICAM-1 from a control value of 7.7 pg/microgram cellular protein to 16.3 pg/microgram cellular protein (P <.05). The NO2-induced release of all 3 mediators was significantly attenuated by incubation of HBECs with 25 micromol/L loratadine. Incubation with 2.5 micromol/L loratadine also significantly attenuated the NO2-induced release of RANTES and sICAM-1, but not IL-8. CONCLUSIONS: These results suggest that loratadine has the potential to reduce airway inflammation by modulating the release of inflammatory cytokines from airway epithelial cells.

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loratadine, Claritin
P-glycoprotein limits the brain penetration of nonsedating but not sedating H1-antagonists.

Chen C, Hanson E, Watson JW, Lee JS.

Pfizer Global Research and Development, Pfizer Inc., Groton, Connecticut 06340, USA. cuiping_chen groton.pfizer.com

The present study evaluates the impact of P-glycoprotein (P-gp) on plasma-brain disposition and transepithelial transport of sedating versus nonsedating H1-antagonists using multidrug-resistant (mdr) gene 1a and 1b (mdr1a/b) knockout (KO) mice and human MDR1-transfected Madin-Darby canine kidney (MDCK) cells. Three nonsedating (cetirizine, loratadine, and desloratadine) and three sedating (diphenhydramine, hydroxyzine, and triprolidine) H1-antagonists were tested. Each compound was administered to KO and wild-type (WT) mice intravenously at 5 mg/kg. Plasma and brain drug concentrations were determined by liquid chromatography-mass spectrometry analysis. Mean pharmacokinetic parameters (CL, V(ss), and t(1/2)) were obtained using WinNonlin. In addition, certirizine, desloratadine, diphenhydramine, and triprolidine (2 microM) were tested as substrates for MDR1 using MDR1-MDCK cells. The bidirectional apparent permeability was determined by measuring the amount of compound at the receiving side at 5 h. The brain-to-plasma area under the curve (AUC) ratio was 4-, 2-, and >14-fold higher in KO compared with WT mice for cetirizine, loratadine, and desloratadine, respectively. In contrast, the brain-to-plasma AUC ratio between KO and WT was comparable for hydroxyzine, diphenhydramine, and triprolidine. Likewise, the efflux ratio between basolateral to apical and apical to basolateral was 4.6- and 6.6-fold higher in MDR1-MDCK than the parental MDCK for certirizine and desloratadine, respectively, whereas it was approximately 1 for diphenhydramine and triprolidine. Our results demonstrate that sedating H1-antagonists hydroxyzine, diphenhydramine, and triprolidine are not P-gp substrates. In contrast, nonsedating H1-antagonists cetirizine, loratadine, and desloratadine are P-gp substrates. Affinity for P-gp at BBB may explain the lack of central nervous system side effects of modern H1-antagonists.

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