loratadine, Claritin
Desloratadine: A preclinical and clinical overview.

Norman P, Dihlmann A, Rabasseda X.

Norman Consulting, Burnham, England. xrabasseda prous.com

A new competitive histamine H(1)-receptor antagonist with superior binding affinity at this receptor as compared with other common antihistamines, desloratadine is the active metabolite of loratadine, the most extensively used agent of this class. Under development for the treatment of allergic rhinitis and urticaria and currently awaiting regulatory approval in the United States, desloratadine was recently approved and became commercially available in Europe for the treatment of allergic disease. Desloratadine is at least 50-fold more potent in vitro and appears to be 10-fold more potent in vivo than loratadine. The new antihistamine is metabolized to 3-hydroxydesloratadine, which retains biological activity. Absorption of orally administered desloratadine is dose proportional, and desloratadine achieves steady-state concentrations after approximately 5 doses with once-daily administration. This is consistent with mean half-life values of 24-27 h and a 24-h dosing interval. The absorption of desloratadine is not affected by food and there are no clinically relevant drug-drug interactions. In randomized, double-blind, placebo-controlled clinical trials, a single 5 mg dose of desloratadine conferred significant relief of seasonal allergic rhinitis (SAR) symptoms - including the complaint of nasal congestion - within hours of the first dose, and these effects were sustained both for the entire 24-h dosing interval and up to 2-4 weeks with once-daily treatment (5 mg/day). In addition, patients with seasonal exacerbations of mild to moderate asthma derived similar clinical benefits from desloratadine, with significant, first-dose relief of both SAR-related complaints such as nasal congestion as well as asthma symptoms. In addition, beta(2) agonist requirements for symptom management were significantly reduced from baseline in these asthma patients when treated with the 5 mg/day desloratadine regimen as compared with placebo. Also experiencing marked relief of symptoms upon treatment with desloratadine were patients with chronic idiopathic urticaria, who exhibited significant first-dose relief of pruritus and sustained reductions in this symptom, numbers of lesions (and size of largest hive) and sleep disturbances, with a marked improvement in their ability to carry out activities of daily living. The clinical benefits of desloratadine in the above clinical settings were accompanied by general improvements in quality of life. Desloratadine does not cross the blood-brain barrier, as demonstrated by both human studies using cognitive indices as well as work in animal models. Desloratadine is well tolerated, and no significant drug-related (or food-related) adverse effects were noted when the agent was administered together with cytochrome P450 inhibitors (e.g., ketoconazole, erythromycin). Administration of desloratadine has not been shown to cause any significant changes in cardiac activity at therapeutic doses, even at 9-fold higher doses, or in the presence of P450 inhibitors. Nor does administration of desloratadine lead to sedation, even in the presence of alcohol. (c) 2001 Prous Science. All rights reserved.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12768222&dopt=Abstract loratadine, Claritin



loratadine, Claritin
Histamine H1 receptor antagonism by cetirizine in isolated guinea pig tissues: influence of receptor reserve and dissociation kinetics.

Christophe B, Carlier B, Gillard M, Chatelain P, Peck M, Massingham R.

UCB Pharma, Allergo-Respiratory Pharmacology Department, Chemin du Foriest, Batiment R1, B-1420 Braine l'Alleud, Belgium. Bernard.Christophe UCB-Group.com

We characterised histamine H(1) receptor antagonism by cetirizine and its enantiomers on isolated guinea pig ileum and trachea. Competitive or mixed (competitive and apparent noncompetitive) antagonism profiles were observed. The order of potency was: chlorpheniramine> or =mepyramine>levocetirizine>cetirizine> or =terfenadine>loratadine>dextrocetirizine. The inhibitory effects of cetirizine, levocetirizine, terfenadine and loratadine were slowly reversible compared to those of dextrocetirizine or mepyramine. Cetirizine and its enantiomers were inactive on L-type Ca(2+) channels. Reduction of the histamine H(1) receptor reserve by dibenamine in the ileum (100-fold higher than in the trachea) showed a gradual change from the competitive profile of dextrocetirizine and mepyramine to a mixed profile. The present results show that cetirizine and levocetirizine are selective competitive but slowly reversible histamine H(1) receptor antagonists. Their mixed antagonism profile observed in the trachea can be explained by the small receptor reserve present in this tissue compared to the ileum and their very slow dissociation rate from the histamine H(1) receptor.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12787835&dopt=Abstract loratadine, Claritin



loratadine, Claritin
[Determination of donepezil in human plasma by HPLC-MS]

[Article in Chinese]

Lu YH, Wen HM, Li W, Chi YM, Zhang ZX.

Jiangsu Institute for Drug Control, Nanjing 210008, China.

AIM: To establish a sensitive and specific liquid chromatography-mass spectrometry (time-of-flight) [LC-MS (TOF)] method for the determination of donepezil in human plasma after an oral administration of 5 mg donepezil hydrochloride tablet. METHODS: Alkalized plasma was extracted with isopropanol-n-hexane (3:97) and loratadine was used as internal standard. Solutes were separated on a C18 column with a mobile phase of methanol-acetate buffer (pH 4.0) (80:20). Detection was performed on a time-of-flight mass spectrometry equipped with an ESI interface and operated in positive-ionization mode. Donepezil quantitation was realized by computing the peak area ratio (donepezil-loratadine) (donepezil m/z 380[M + H]+ and loratadine m/z 383[M + H]+) and comparing them with calibration curve (r = 0.9998). RESULTS: The linear calibration curve was obtained in the concentration range of 0.1-15 micrograms.L-1. The detection limit of donepezil was 0.1 microgram.L-1. The average recovery was more than 90%. The intra- and inter-run precision was measured to be below 15% of RSD. CONCLUSION: The method is sensitive, simple and rapid, so, it can meet the need of the studies on the pharmacokinetics and bioavailability of donepezil.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12830717&dopt=Abstract loratadine, Claritin



loratadine, Claritin
Desloratadine inhibits allergen-induced airway inflammation and bronchial hyperresponsiveness and alters T-cell responses in murine models of asthma.

Bryce PJ, Geha R, Oettgen HC.

Division of Immunology, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.

BACKGROUND: Histamine elicits many features of immediate hypersensitivity reactions. Recent evidence indicates that H1 receptors modulate immune responses to antigens. Desloratadine (DL), a new, long-acting, H1 receptor antagonist, has both a potent antihistaminic function and anti-inflammatory properties. OBJECTIVE: We sought to evaluate the effect of DL on allergic-airway responses in mice after inhalation of the naturally occurring aeroallergen Aspergillus fumigatus (Af ) and to examine the effects of DL on specific immune responses to a defined protein antigen with the use of an ovalbumin (OVA) model of asthma. METHODS: Mice were subjected either to repeated, intranasal application of Af extract or to intraperitoneal immunization with OVA, followed by inhalation challenge. DL or a control fluid was given daily throughout the sensitization process. Immunoglobulin E (IgE) levels, bronchoalveolar lavage-fluid cytokines and cytology, lung histology, and physiologic responses to methacholine were assessed in the allergen-treated mice. Anti-OVA IgE responses and OVA-driven T-cell cytokine production were examined. RESULTS: Treatment with DL did not impair IgE production but did inhibit bronchial inflammation and bronchial hyperresponsiveness in both Af- and OVA-treated mice. This inhibition required that DL be administered concurrently with allergen sensitization, indicating that the attenuation of bronchial hyperresponsiveness and inflammation was not caused by anticholinergic receptor effects. OVA-responsive T cells from DL-treated mice exhibited depressed production of IL-4, IL-5, and IL-13 and normal amounts of interferon-gamma. The amounts of IL-5 and IL-13 were also diminished in the bronchoalveolar lavage fluid. CONCLUSION: DL, given at the time of exposure to the allergen, inhibits T(H)2 responses, the induction of allergic pulmonary inflammation, and bronchial hyperresponsiveness. These results suggest that DL or similar agents given during times of antigen exposure might alter disease progression in patients with respiratory allergy.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12847492&dopt=Abstract loratadine, Claritin



loratadine, Claritin
Impurity profile study of loratadine.

Reddy KV, Babu JM, Kumar YR, Reddy SV, Kumar MK, Eswaraiah S, Reddy KR, Reddy MS, Bhaskar BV, Dubey PK, Vyas K.

Department of Analytical Research, Discovery Research Division, Dr Reddy's Laboratories Ltd., Bollaram Road, Miyapur, Hyderabad 500 050, India.

Three unknown impurities in loratadine bulk drug at levels below 0.1% (ranging from 0.05 to 0.1%) were detected by a simple isocratic reversed-phase high performance liquid chromatography (HPLC). These impurities were isolated from mother liquor sample of loratadine using reversed-phase preparative HPLC. Based on the spectral data (IR, NMR and MS) the structures of these impurities were characterized as 11-(N-carboethoxy-4-piperidylidene)-6,11-dihydro-5H-benzo(5,6) cyclopenta(1,2-b)-pyridine (I), 8-bromo-11-(N-carboethoxy-4-piperidylidene)-6,11-dihydro-5H-benzo(5,6) cyclopenta (1,2-b)-pyridine (II) and 8-chloro-11-(N-carboethoxy-4-piperidylidene)-5H-benzo(5,6) cyclopenta (1,2-b)-pyridine (III). The synthesis of these impurities was discussed.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12852446&dopt=Abstract loratadine, Claritin



loratadine, Claritin
A sensitive LC/MS/MS method using silica column and aqueous-organic mobile phase for the analysis of loratadine and descarboethoxy-loratadine in human plasma.

Naidong W, Addison T, Schneider T, Jiang X, Halls TD.

Covance Laboratories Inc., Department of Bioanalytical Chemistry, 3301 Kinsman Boulevard, Madison, WI 53704, USA. naidong.weng covance.com

A sensitive method using liquid chromatography with tandem mass spectrometric detection (LC/MS/MS) was developed and validated for the simultaneous analysis of antihistamine drug loratadine (LOR) and its active metabolite descarboethoxy-loratadine (DCL) in human plasma. Deuterated analytes, i.e. LOR-d(3) and DCL-d(3) were used as the internal standards (I.S.). Analytes were extracted from alkalized human plasma by liquid/liquid extraction using hexane. The extract was evaporated to dryness under nitrogen, reconstituted with 0.1% (v/v) of trifluoroacetic acid (TFA) in acetonitrile, and injected onto a 50 x 3.0 mm I.D. 5 microm, silica column with an aqueous-organic mobile phase consisted of acetonitrile, water, and TFA (90:10:0.1, v/v/v). The chromatographic run time was 3.0 min per injection and flow rate was 0.5 ml/min. The retention time was 1.2 and 2.0 min for LOR and DCL, respectively. The tandem mass spectrometric detection was by monitoring singly charged precursor-->product ion transitions: 383-->337 (m/z) for LOR, 311-->259 (m/z) for DCL, 388-->342 (m/z) for LOR-d(3), and 316-->262 (m/z) for DCL-d(3). The low limit of quantitation (LLOQ) was 10 pg/ml for LOR and 25 pg/ml for DCL. The inter-day precision of the quality control (QC) samples was 3.5-9.4% relative standard deviation (R.S.D.). The inter-day accuracy of the QC samples was 99.0-107.9% of the nominal values.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12899951&dopt=Abstract loratadine, Claritin