piperidines and desloratadine

Bilastine is an orally administered, second-generation antihistamine used in the symptomatic treatment of seasonal or perennial allergic rhinoconjunctivitis and urticaria. In two well designed phase III trials, 14 days' treatment with bilastine was associated with a significantly lower area under the effect curve (AUEC) for the reflective total symptom score (TSS) than placebo in patients with symptomatic seasonal allergic rhinitis. Additionally, reflective nasal symptom scores were significantly lower in bilastine than placebo recipients in patients with a history of seasonal allergic rhinitis who were challenged with grass pollen allergen in a single-centre, phase II study. Neither bilastine nor cetirizine was effective in the treatment of perennial allergic rhinitis with regard to the mean AUEC for reflective TSS in another well designed phase III trial. However, results may have been altered by differences in some baseline characteristics and placebo responses between study countries. In another well designed phase III trial, compared with placebo, bilastine was associated with a significantly greater change from baseline to day 28 in the mean reflective daily urticaria symptom score in patients with chronic urticaria. There were no significant differences in primary endpoint results between bilastine and any of the active comparators used in these trials (i.e. cetirizine, levocetirizine and desloratadine). Bilastine was generally well tolerated, with a tolerability profile that was generally similar to that of the other second-generation antihistamines included in phase III clinical trials.

Topics: Area Under Curve; Benzimidazoles; Cetirizine; Histamine H1 Antagonists, Non-Sedating; Humans; Loratadine; Piperidines; Randomized Controlled Trials as Topic; Rhinitis, Allergic, Perennial; Urticaria

To compare the anti-inflammatory effects of fexofenadine with other H(1)-receptor antagonists in vitro.. Published literature.. Recent experimental studies on anti-inflammatory effects of H(1)-receptor antagonists. Databases searched: Medline, Medscape.. 1990-2003. Search terms: second-, third-generation antihistamines; sedating, nonsedating antihistamines; in vitro anti-inflammatory activity; cetirizine; ebastine; loratadine; fexofenadine; desloratadine.. Second- and third-generation H(1)-receptor antagonists may demonstrate significant in vitro anti-inflammatory activity at concentrations considered to be clinically relevant. In some instances, higher (supraclinical) concentrations are required to achieve comparable effects.. Experimental research suggests that second- and third-generation H(1)-receptor antagonists may achieve anti-inflammatory effects in a clinical context. Further studies are required to support this conclusion.

Topics: Animals; Anti-Inflammatory Agents; Butyrophenones; Cells, Cultured; Histamine H1 Antagonists; Loratadine; Piperidines; Terfenadine

To compare the peripheral antihistaminic activity of bilastine, rupatadine and desloratadine in inhibiting the histamine-induced wheal and flare (W&F) response.. Twenty-four healthy volunteers aged 18-40 years participated in this crossover, randomized, double-blind, placebo-controlled clinical study. Subjects received single doses of bilastine 20 mg, desloratadine 5 mg, rupatadine 10 mg and placebo. W&F responses induced by intradermal injection of histamine 5 μg were evaluated before treatment (basal value) and at 0.5, 1, 2, 4, 6, 9, 12 and 24 hours after treatment. Fifteen minutes after histamine injection, W&F surface areas (cm. The primary outcome measure was the percentage reduction in W&F areas after each active treatment compared with corresponding basal values.. Bilastine induced the greatest inhibition in wheal area and was significantly superior to desloratadine and rupatadine from 1 to 12 hours (both p < .001). Rupatadine and desloratadine were better than placebo without differences between them. Maximum wheal inhibition occurred at 6 hours (bilastine 83%, desloratadine 38%, rupatadine 37%). Onset of action was 1 hour for bilastine and 4 hours for desloratadine and rupatadine. Bilastine was significantly superior to desloratadine and rupatadine for flare inhibition from 1-24 hours (both p < .001) with an onset of action at 30 minutes. Bilastine was significantly better than desloratadine (2-12 hours; at least p < .05) and rupatadine (2-9 hours; at least p < .01) for reducing itching sensation. Neither desloratadine nor rupatadine significantly reduced itching compared to placebo. All active treatments were well tolerated.. Bilastine 20 mg induced significantly greater inhibition of the W&F response compared with desloratadine 5 mg and rupatadine 10 mg throughout the 24 hour study period, and had the fastest onset of action. Only bilastine significantly reduced itching sensation versus placebo.

Topics: Adult; Benzimidazoles; Cross-Over Studies; Cyproheptadine; Double-Blind Method; Female; Healthy Volunteers; Histamine; Histamine Antagonists; Humans; Injections, Intradermal; Loratadine; Male; Piperidines; Skin

Bilastine is a novel, nonsedating H(1)-antihistamine developed for symptomatic treatment of Allergic Rhinitis and Chronic Idiopathic Urticaria. The objective of this study was to compare the efficacy and safety of bilastine 20 mg vs placebo and desloratadine 5 mg in subjects with seasonal allergic rhinitis (SAR).. This randomized, double blind, placebo-controlled, parallel-group multicentre study evaluated the effect of 2 weeks' treatment with bilastine 20 mg, desloratadine 5 mg or matched placebo once daily, in 12-70 years old symptomatic SAR patients. All subjects assessed the severity of nasal (obstruction, rhinorrhoea, itching, and sneezing) and nonnasal (ocular itching, tearing, ocular redness, itching of ears and/or palate) symptoms on a predetermined scale to provide a total symptom score (TSS), composed of nasal and nonnasal symptom scores (NSS and NNSS, respectively). The primary efficacy measure was the area under the curve (AUC) for the TSS over the entire treatment period.. Bilastine 20 mg significantly reduced the AUC of TSS to a greater degree from baseline compared to placebo (98.4 with bilastine vs 118.4 with placebo; P < 0.001), but not compared to desloratadine 5 mg (100.5). Bilastine 20 mg was not different from desloratadine 5 mg but significantly more effective than placebo in improving the NSS, NNSS, and rhinitis-associated discomfort scores (P < 0.05), and rhinoconjunctivitis quality of life questionnaire total (P < 0.005) and four out of seven individual domain (P < 0.05) scores. The incidence of treatment emergent adverse events was similar for bilastine (20.6%), desloratadine (19.8%), and placebo (18.8%).. Bilastine 20 mg once daily was efficacious, safe and not different from desloratadine 5 mg once daily in the treatment of SAR symptoms.

Topics: Adolescent; Adult; Aged; Area Under Curve; Benzimidazoles; Child; Double-Blind Method; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Loratadine; Male; Middle Aged; Piperidines; Quality of Life; Rhinitis, Allergic, Seasonal; Treatment Outcome; Young Adult

Ebastine is a long-acting, second-generation selective histamine H(1) receptor antagonist. The pharmacodynamics of a new 10mg fast-dissolving tablet (FDT) oral lyophilisate tablet formulation of ebastine were compared with those of desloratadine and placebo following histamine skin intradermal test challenge. The acceptability of the FDT was also assessed.. This was a double-blind, double-dummy, placebo-controlled, randomised, crossover, three-period study in 36 healthy adults. The histamine skin intradermal test (0.05 mL of 100 microg/mL solution) was administered into volunteers' forearms, and wheal area was measured 15 minutes later. Ebastine 10 mg FDT, desloratadine 5mg capsule or placebo were given on days 1-5. On day 1, a skin intradermal test was performed at baseline, then every 20 minutes for 2 hours after administration and at 24 hours. The final skin intradermal test was on day 6, 24 hours after the last drug dose. Subjective symptoms (itching, heat and pain) were assessed on day 1 for 2 hours following the first drug dose. There was a washout period of 7-10 days between treatments. At study end, the acceptability of the new ebastine formulation was evaluated using a questionnaire.. Ebastine 10mg inhibited the wheal response to histamine significantly more than desloratadine 5 mg or placebo 24 hours after 5 days' treatment (mean difference between treatments in wheal area reduction from baseline: 26.7%, p < 0.0001; 46.9%, p < 0.0001, respectively), and after 24 hours on day 1 (mean difference: 16.2%, p = 0.0082; 34.2%, p < 0.0001, respectively). The results with desloratadine were also significantly different from placebo on day 1 and after 5 days, but less than with ebastine after 5 days (difference, desloratadine vs placebo: 20.2%, p = 0.0001). No differences in itching, heat and pain were observed between the treatments. Most participants (70%) preferred the FDT, and all reported that it made adherence easier.. Ebastine 10 mg FDT demonstrated significantly superior antihistamine activity compared with desloratadine and placebo.

Topics: Adult; Butyrophenones; Chemistry, Pharmaceutical; Dermatitis, Contact; Double-Blind Method; Female; Histamine; Histamine H1 Antagonists; Humans; Loratadine; Male; Pain Measurement; Patient Acceptance of Health Care; Piperidines; Skin; Tablets; Treatment Outcome

Ebastine is a long-acting, second-generation, selective histamine H1-receptor antagonist. A fast-dissolving tablet formulation of ebastine has been developed at 10- and 20-mg doses, with the intention of facilitating administration to patients experiencing problems with swallowing, including those confined to bed and elderly people, as well as those who may need to use ebastine when they do not have easy access to water to aid swallowing a tablet.. This study was conducted to assess the pharmacodynamic effects (ie, inhibition of wheal response to cutaneous histamine challenge, and subjective assessments of itching, flare, and pain) and tolerability of the fast-dissolving 20-mg ebastine tablet formulation compared with desloratadine 5-mg capsule and placebo. Acceptability and convenience of the fast-dissolving tablet were also evaluated.. This double-blind, double-dummy, randomized, placebo-controlled, 3-period crossover study was conducted at the Drug Research Centre, Department of Clinical Pharmacology, the Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. Healthy, nonatopic, white adults aged 18 to 40 years were randomly assigned to 1 of 6 study sequences: ABC, ACB, BAC, BCA, CBA, or CAB, where A was the ebastine fast-dissolving 20-mg tablet, B was the desloratadine 5-mg capsule, and C was placebo. All study drugs were given orally once daily (8-9 AM) on days 1 to 5 of each study period. Study periods were separated by a washout period of 7 to 10 days. Histamine skin-prick test (SPT) challenge was performed before study drug administration on day 1 of each period (baseline), and then every 20 minutes for 2 hours after administration and again after 24 hours. The final SPT was 24 hours after the day-5 dose was administered. The primary end point was inhibition o f the histamine response, defined as the percentage reduction from baseline wheal area 24 hours after 5 days of administration. Subjective symptoms (itching, flare, and pain) were assessed by subjects using visual analog scales every 20 minutes for 2 hours after administration on day 1. At study end, acceptability (taste, convenience, and overall preference) of the fast-dissolving tablet and capsule formulations were assessed using a questionnaire completed by subjects. Tolerability was assessed using physical examination, laboratory analysis, physician questioning, and spontaneous reporting.. Thirty-six people were randomized (22 women, 14 men; mean [SD] age, 24.7 [4.1] years; mean [SD] weight, 63.2 [9.9] kg); 35 completed the study (1 subject was lost to follow-up after the second study period). Unadjusted mean (SD) wheal areas 24 hours after dose administration on day 5 were 72.9 (29.5), 115.0 (32.1), and 146.7 (32.2) mm(2), for ebastine, desloratadine, and placebo, respectively. Mean differences in reduction from baseline in wheal area were 29.0% for ebastine versus desloratadine and 43.7% for ebastine versus placebo (both, P < 0.001). Corresponding unadjusted mean (SD) wheal areas 24 hours after administration of the first dose on day 1 were 76.5 (22.5), 128.9 (24.0), and 140.5 (33.1) mm(2). Mean itching, flare, and pain ratings were not significantly different between study drugs. Results from the preference questionnaire indicated that the majority (80%) preferred the ebastine fast-dissolving tablet to the desloratadine capsule (and hypothetically also to tablets and oral solution, which were not tested in this study). Ninety-seven percent of subjects were of the opinion that compliance in the home setting would be facilitated by the fas-tdissolving tablet formulation. Fourteen adverse events (AEs) were reported in 9 (25%) volunteers; all AEs were of mild or moderate intensity. Five occurred with ebastine 20 mg (intermittent somnolence, back pain, pharyngolaryngeal pain, pyrexia, and oral pain [1 patient each]), 5 occurred with desloratadine 5 mg (asthenia [2 patients] and dry mouth, somnolence, and back pain [1 patient each]), and 4 occurred with placebo (diarrhea [2 patients] and somnolence and headache [1 patient each]). The relationship with the study drugs was considered unlikely in 6 cases and possible in the remaining 8 cases. An additional AE (back pain) occurred during a washout period.. In this small study in healthy, nonatopic white subjects, inhibition of the response to histamine injection was significantly greater with the ebastine 20-mg fast-dissolving tablet compared with desloratadine 5-mg capsule and placebo after 1 and 5 days of administration. Most participants expressed an overall preference for the fast-dissolving tablet formulation over capsules. All study drugs were well tolerated.

Topics: Adolescent; Adult; Butyrophenones; Cross-Over Studies; Double-Blind Method; Female; Histamine; Histamine H1 Antagonists; Humans; Loratadine; Male; Pain Measurement; Piperidines; Pruritus; Skin; Skin Tests

To investigate the pharmacokinetics of loratadine (LOR) and its active metabolite descarboethoxyloratadine (DCL) in healthy Chinese subjects.. Twenty healthy Chinese male subjects received a single oral dose of LOR 20 mg. A sensitive liquid chromatography-tandem mass spectrometry method (LC/MS/MS) was used for the determination of LOR and DCL in plasma.. Mean maximum concentration (C(max)) was found (17+/-14) microg/L for LOR at 1.2 h and (16+/-9) microg/L for DCL at 1.5 h. Mean area under the plasma concentration-time curve from zero to infinity (AUC(0-infinity)) was (47+/-49) microg x h x L(-1) for LOR and (181+/-122) microg x h x L(-1) for DCL, respectively. The apparent elimination half-life (T1/2) of LOR was (6+/-4) h, and that of DCL was (13.4+/-2.6) h. The ratios of AUC(DCL)/AUCLOR ranged from 0.36 to 54.5.. LOR was rapidly absorbed and transformed to DCL. AUC of the parent drug was extremely variable, while AUC of the active metabolite DCL was moderately variable after an oral dose of LOR to Chinese subjects.

Topics: Administration, Oral; Adult; Antipruritics; Area Under Curve; Asian People; Humans; Loratadine; Male; Piperidines; Pyridines

Due to Mexico's complicated socioeconomic environment, causing a high occurrence of >1 person sharing a single room, respiratory conditions are spread easily. Respiratory conditions are the main reason for consultation with a physician. The most frequent symptoms are throat soreness and cough; therefore, a new formulation combining loratadine and ambroxol hydrochloride was designed to treat these 2 major symptoms. The combination is expected to provide relief when coprescribed with more specific therapies, such as antibiotics.. This study determined the pharmacokinetic profile of single-dose loratadine-ambroxol hydrochloride combination therapy versus each component given separately. The analyses included descarboethoxyloratadine (DCL), the primary active metabolite of loratadine.. This was a 4-week, single-center, randomized, open-label, 3-period crossover study in adult male volunteers aged 18 to 50 years and in good general health. Subjects were randomized to receive single doses of treatment A (2 loratadine 5-mg tablets + ambroxol 30-mg tablets), B (2 ambroxol 30-mg tablets), or C (1 loratadine 10-mg tablet) in 1 of 3 sequences (ABC, BCA, or CAB) per period. A 14-day washout period separated each treatment period. Plasma concentration-time data curves for each subject and treatment were analyzed by noncompart-mental methods to obtain values for area under the curve (AUC), maximum plasma concentration (C(max)), and time to reach C(max) (T(max)).. Thirty subjects (mean [SD] age, 22.5 [2.6] years) were enrolled. All treatments were well tolerated. Formulations A and C produced similar loratadine and DCL AUC from time 0 to 24 hours (AUC(0-24)) values, but showed slightly high C(max). values for loratadine and slightly low C(max) values for DCL, indicating failure to demonstrate bioinequivalence. Formulations A and B produced similar ambroxol C(max), T(max), and AUC(0-24) values.. In this population of healthy mate volunteers, results showed the bioavailability of loratadine and ambroxol from the new formulation and did not show impairment of absorption when the drugs were formulated in a combination tablet.

Topics: Administration, Oral; Adolescent; Adult; Ambroxol; Area Under Curve; Cross-Over Studies; Drug Combinations; Expectorants; Histamine Antagonists; Humans; Loratadine; Male; Middle Aged; Piperidines; Pyridines; Tablets; Time Factors

Sedating and non-sedating histamine H(1) receptor (H1R) antagonists and H2R blockers are widely used drugs which are generally considered to be safe medications. However, recently, these drugs have been shown to possibly impair the outcome of perforating appendicitis in children.. It was the aim of this study to characterize the effects of histamine receptor blockade in severe bacterial infections in more detail.. To obtain information on the safety of histamine receptor blockade in more detail, we used pharmacological and genetic approaches targeting histamine receptors and performed cecal ligation and puncture (CLP), a mouse model of septic peritonitis. After induction of septic peritonitis, morbidity and mortality were monitored closely.. Here, we show that oral treatment with first-generation H1R antihistamine diphenhydramine, H2R blocker cimetidine and H3/4R blocker thioperamide impairs optimal innate immune responses in severe murine bacterial sepsis. However, these adverse effects are not mediated by H1R, as mice deficient for H1R show similar rates of morbidity and mortality after CLP as their wild-type controls. Similarly, the second-generation antihistamine desloratadine neither affects morbidity nor mortality after CLP.. Our findings indicate that sedating first-generation H1R antihistamines and H2R blockers might impair innate immune responses to bacteria and that these drugs should be used with caution in patients with severe bacterial infections.

Topics: Animals; Anti-Allergic Agents; Bacterial Infections; Diphenhydramine; Histamine Antagonists; Histamine H1 Antagonists; Histamine H1 Antagonists, Non-Sedating; Histamine H3 Antagonists; Humans; Immunity, Innate; Loratadine; Mice; Mice, Inbred C57BL; Peritonitis; Piperidines; Receptors, Histamine; Sepsis

A rapid, sensitive, and accurate liquid chromatography-tandem mass spectrometry assay for simultaneous determination of loratadine (L) and its active metabolite, descarboethoxyloratadine (DCL), in human plasma is developed using desipramine as internal standard (IS). The analytes and IS are separated on a Betabasic cyano (100 mm x 2.1 mm, 5 microm) column and detected by tandem mass spectrometry with a turbo ion spray interface operating in positive ion and multiple reaction monitoring acquisition mode. The total chromatographic runtime is 3.0 min with retention time for L, DCL, and IS at 0.82, 1.58, and 1.97 min, respectively. The method is validated over a dynamic linear range of 0.05-15.00 ng/mL for both L and DCL with a correlation coefficient of r(2) 0.9984 and 0.9979, respectively. The intra-batch and inter-batch precision (%CV) across five levels (LLOQ, LQC, MQC, HQC, and ULOQ) is less than 9%. The method is successfully applied to a bioequivalence study of 10 mg loratadine tablet formulation in 28 healthy Indian male subjects under fasted condition.

Topics: Chromatography, Liquid; Histamine H1 Antagonists, Non-Sedating; Humans; Loratadine; Male; Piperidines; Pyridines; Sensitivity and Specificity; Spectrometry, Mass, Electrospray Ionization; Tablets; Tandem Mass Spectrometry; Therapeutic Equivalency; Time Factors

Inter- and intra-individual variability of the loratadine (LOR) metabolism in Caucasian subjects was assessed during a bioequivalence study for two pharmaceutical formulations (solid oral dosage forms) containing 10 mg of the active substance. The analytical data were obtained by applying a reliable, low-cost and sensitive ion pair liquid chromatography/fluorescence (IPLC/FLD) method for determination of both loratadine and descarboethoxyloratadine (DCL) in human plasma samples. The sample preparation procedure is based on liquid-liquid extraction of the target analytes from alkalinized plasma using diethyl-ether. The separation of the analytes and 8-chloroazatadine as internal standard (IS) was achieved through an isocratic ion pair (IP) elution on a Purospher((R)) STAR RP-18 column. The mobile phase containing sodium dodecyl sulfate (SDS) as ion pairing agent was pumped at a flow rate of 1 mL/min. Fluorescence detection (FLD) was achieved at 280 nm (excitation) and 440 nm (emission) wavelengths. The increased sensitivity of the method is also based on a large sample injected volume (250 microL). Linear response was found over the 0.5-20 ng/mL concentration interval for both target compounds. Low limits of quantification (LLOQ) around 0.3 ng/mL were found for LOR and DCL. Method validation is presented.

Topics: Administration, Oral; Adolescent; Adult; Chromatography, High Pressure Liquid; Drug Stability; Female; Histamine H1 Antagonists, Non-Sedating; Humans; Loratadine; Male; Molecular Structure; Piperidines; Pyridines; Reference Standards; Reproducibility of Results; Sensitivity and Specificity; Spectrometry, Fluorescence; Therapeutic Equivalency

Topics: Butyrophenones; Histamine; Histamine H1 Antagonists; Humans; Loratadine; Piperidines; Randomized Controlled Trials as Topic; Skin Tests

Topics: Chromatography, Liquid; Humans; Loratadine; Omeprazole; Pharmaceutical Preparations; Piperidines; Protease Inhibitors; Pyridines; Reserpine; Spectrometry, Mass, Electrospray Ionization

Triple quadrupole mass spectrometers, when operated in multiple reaction monitoring (MRM) mode, offer a unique combination of sensitivity, specificity, and dynamic range. Consequently, the triple quadrupole is the workhorse for high-throughput quantitation within the pharmaceutical industry. However, in the past, the unit mass resolution of quadrupole instruments has been a limitation when interference from matrix or metabolites cannot be eliminated. With recent advances in instrument design, triple quadrupole instruments now afford mass resolution of less than 0.1 Dalton (Da) full width at half maximum (FWHM). This paper describes the evaluation of an enhanced resolution triple quadrupole mass spectrometer for high-throughput bioanalysis with emphasis on comparison of selectivity, sensitivity, dynamic range, precision, accuracy, and stability under both unit mass (1 Da FWHM) and enhanced (

Topics: Calibration; Chromatography, High Pressure Liquid; Loratadine; Mometasone Furoate; Pharmaceutical Preparations; Piperidines; Pregnadienediols; Pyridines; Sensitivity and Specificity; Spectrometry, Mass, Electrospray Ionization

Topics: Anti-Inflammatory Agents; Butyrophenones; Cells, Cultured; Cetirizine; Chymases; Eosinophils; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoietic Cell Growth Factors; Histamine; Histamine H1 Antagonists; Humans; Hypersensitivity; Intercellular Adhesion Molecule-1; Interleukin-3; Interleukin-8; Loratadine; Mast Cells; Piperidines; Potassium Channel Blockers; Potassium Channels; Prostaglandin D2; Pyridines; Recombinant Fusion Proteins; Recombinant Proteins; Serine Endopeptidases; Terfenadine; Time Factors; Tryptases

Nonsedating H1-receptor antagonists appear to have wide and variable effects on the QT interval, mediated through modulation of cardiac K+ channels. By using the whole-cell patch-clamp technique, we examined the effects of terfenadine, loratadine, and descarboethoxyloratadine on a large family of K+ channels in ventricular myocytes and in Xenopus oocytes expressing the HERG delayed rectifier. The channels studied included the inward rectifier (I(Kl)) of rat and guinea pig, the transient outward K+ current (I(to)) of rat, the maintained K+ current (I(ped)) of rat, and the delayed rectifier K+ channels (I(Ks) and I(Kr)) of guinea pig myocytes. Loratadine and descarboethoxyloratadine, at therapeutic concentrations (30 to 100 nM), had no measurable effect on any one of the five types of K+ channels studied. At higher concentrations, 0.3 to 1.0 microM, only terfenadine had a significant suppressive effect on I(Kl) and delayed rectifier K+ channels, I(Kr) and I(Ks). At higher concentrations (1 to 2.5 microM), there were marked differences in the ability of the three drugs to suppress the five K+ channels. Generally, terfenadine was the most and loratadine, the least effective blocker of all K+ channels examined. The most susceptible K+ channels were the delayed rectifier channels (I(Ks) and I(Kr)) in guinea pig and I(ped) in rat myocytes. Comparative effects of loratadine and terfenadine examined on the I(Kr) channel (HERG) expressed in Xenopus oocytes suggest much higher affinity of this channel to terfenadine, such that 1 microM terfenadine completely suppressed the current, whereas loratadine had little or no effect. The preferential suppressive effect of terfenadine on the expressed HERG channel was consistent with data obtained on I(Kr) in isolated guinea pig ventricular myocytes. The strong suppressive effect of terfenadine, noted particularly on the I(Kr) and to a lesser extent on I(to), I(Kl), and I(Ks), may be the cause of the reported incidence of QT prolongation and arrhythmogenesis. The absence of significant effect of loratadine and descarboethoxyloratadine, especially on I(Kr), I(to), I(ped), and I(Kl), even at 100 x highest plasma concentrations achieved, may explain the absence of significant reports of QT prolongation and arrhythmogenesis by the latter drugs.

Topics: Animals; Cation Transport Proteins; Ether-A-Go-Go Potassium Channels; Gene Expression; Guinea Pigs; Heart Ventricles; Histamine H1 Antagonists; In Vitro Techniques; Loratadine; Male; Membrane Potentials; Myocardium; Oocytes; Patch-Clamp Techniques; Piperidines; Potassium Channel Blockers; Potassium Channels; Potassium Channels, Voltage-Gated; Pyridines; Rats; Rats, Wistar; Recombinant Proteins; Terfenadine; Xenopus laevis

The effects of descarboethoxyloratadine (DCL), the major metabolite of loratadine, were studied on a human cardiac K+ channel (hKv1.5) cloned from human ventricle and stably expressed in a mouse cell line by means of the patch-clamp technique. DCL (1-100 microM) inhibited hKv1.5 current in a concentration-dependent manner with an apparent affinity constant of 12.5+/-1.2 microM. The blockade increased steeply over the voltage range of channel opening, which indicated that DCL binds preferentially to the open state of the channel. At more depolarized potentials a weaker voltage-dependence was observed consistent with a binding reaction sensing approximately 20% of the transmembrane electrical field. DCL, 20 microM, increased the time constant of deactivation of tail currents, thus inducing a 'crossover' phenomenon. The present results demonstrated that DCL blocked hKv1.5 channels in a concentration-, voltage-, and time-dependent manner.

Topics: Animals; Cell Line; Dose-Response Relationship, Drug; Heart Ventricles; Humans; Ion Channel Gating; Kv1.5 Potassium Channel; Loratadine; Membrane Potentials; Mice; Patch-Clamp Techniques; Piperidines; Potassium Channel Blockers; Potassium Channels; Potassium Channels, Voltage-Gated; Pyridines

[3H]Loratadine was incubated with human liver microsomes to determine which cytochrome P450 (CYP) enzymes are responsible for its oxidative metabolism. Specific enzymes were identified by correlation analysis, by inhibition studies (chemical and immunoinhibition), and by incubation with various cDNA-expressed human P450 enzymes. Descarboethoxyloratadine (DCL) was the major metabolite of loratadine detected following incubation with pooled human liver microsomes. Although DCL can theoretically form by hydrolysis, the conversion of loratadine to DCL by human liver microsomes was not inhibited by the esterase inhibitor phenylmethylsulfonyl fluoride (PMSF), and was dependent on NADPH. A high correlation (r2 = 0.96, N = 10) was noted between the rate of formation of DCL and testosterone 6 beta-hydroxylation, a CYP3A-mediated reaction. With the addition of ketoconazole (CYP3A4 inhibitor) to the incubation mixtures, the residual rate of formation of DCL correlated (r2 = 0.81) with that for dextromethorphan O-demethylation, a CYP2D6 reaction. Rabbit polyclonal antibodies raised against the rat CYP3A1 enzyme (5 mg IgG/nmol P450) and troleandomycin (0.5 microM), a specific inhibitor of CYP3A4, decreased the formation of DCL by 53 and 75%, respectively, when added to 1.42 microM loratadine microsomal incubations. Quinidine (5 microm), a CYP2D6 inhibitor, inhibited the formation of DCL approximately 20% when added to microsomal incubations of loratadine at concentrations of 7-35 microM. Incubation of loratadine with cDNA-expressed CYP3A4 and CYP2D6 microsomes catalysed the formation of DCL with formation rates of 135 and 633 pmol/min/nmol P450, respectively. The results indicated that loratadine was metabolized to DCL primarily by the CYP3A4 and CYP2D6 enzymes in human liver microsomes. In the presence of a CYP3A4 inhibitor, loratadine was metabolized to DCL by the CYP2D6 enzyme. Conformational and electrostatic analysis of loratadine indicated that its structure is consistent with substrate models for the CYP2D6 enzyme.

Topics: Anti-Bacterial Agents; Antifungal Agents; Antimalarials; Binding Sites; Biotransformation; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Histamine H1 Antagonists; Humans; In Vitro Techniques; Ketoconazole; Loratadine; Microsomes, Liver; Mixed Function Oxygenases; Models, Molecular; Oxidation-Reduction; Piperidines; Pyridines; Quinidine; Recombinant Proteins; Substrate Specificity; Troleandomycin

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.

Topics: Adult; Histamine; Histamine H1 Antagonists; HLA-DR Antigens; Humans; In Vitro Techniques; Intercellular Adhesion Molecule-1; Loratadine; Middle Aged; Nasal Mucosa; Nasal Polyps; Piperidines; Pyridines; Turbinates

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.

Topics: Chromatography, High Pressure Liquid; Humans; Loratadine; Piperidines; Pyridines; Spectrometry, Fluorescence

A sensitive gas-liquid chromatographic (GLC) method was developed for the determination of loratadine, a long-acting tricyclic antihistamine, and its active metabolite, descarboethoxyloratadine, in human plasma. The method involved extraction with organic solvent at neutral and alkaline pH. The organic layer from the neutral pH extraction was evaporated to dryness, reconstituted and injected into the GLC system. On the other hand, to the organic layer from the alkaline pH extraction trifluoroacetic anhydride was added. Following addition of H2O, the mixture was centrifuged and the organic layer was evaporated to dryness, reconstituted and injected onto the GLC system that was equipped with a nitrogen specific detector and a fused-silica capillary column. The linearity for both loratadine and descarboxyloratadine were demonstrated with r > or = 0.998 at concentrations ranging from 0.1 to 30 ng/ml. The results showed that the GLC method was accurate (bias < or = 12%) and precise (coefficient of variation, C.V., < or = 12%) for loratadine and descarboethoxyloratadine. The limit of quantitation was 0.1 ng/ml for loratadine with a C.V. of 9.2% and for descarboethoxyloratadine with a C.V. of 5.3%. The GLC method described has been demonstrated to be useful for the determination of loratadine and descarboethoxyloratadine in plasma samples of pediatric volunteers following oral administration of a single dose of 10 mg of loratadine syrup.

Topics: Child; Chromatography, Gas; Female; Humans; Hydrogen-Ion Concentration; Loratadine; Male; Nitrogen; Phosphorus; Piperidines; Pyridines; Sensitivity and Specificity

The disposition of loratadine, a new orally active histamine H1 receptor antagonist and its primary metabolite descarboethoxyloratadine were characterized in adult volunteers with normal renal function (group I), patients with chronic renal failure, i.e., creatinine clearance less than 30 mL/min (group II), as well as chronic hemodialysis patients (group III). The effect of hemodialysis on the disposition of loratadine and descarboethoxyloratadine was also assessed. Subjects in groups I and II were given a single oral 40 mg dose of loratadine while the patients in Group III received two single 40 mg doses of loratadine (during an interdialytic period and just prior to hemodialysis). Loratadine was rapidly absorbed and the decline of plasma concentrations after attainment of the Cmax was biexponential in all subjects. No significant differences in t1/2 beta were observed between the three groups (8.7 +/- 5.9, 7.6 +/- 6.9, 8.6 +/- 1.6 hrs: in groups I, II, and III, respectively). The apparent total body clearance and apparent volume of distribution of loratadine also did not differ significantly among the three groups. No significant differences in the Cmax or tmax of the metabolite were observed. The metabolite AUC infinity 0 however was significantly greater in group II subjects: (212.4 +/- 37.8, 469.5 +/- 95.4, 325.2 +/- 114.6 ng.hr/mL; groups I, II, and III, respectively). No significant relationship was observed between the terminal elimination half-life of loratadine or descarboethoxyloratadine and creatinine clearance. Hemodialysis augmented endogenous clearance by less than 1%. The disposition of loratadine is not significantly altered in patients with severe renal insufficiency nor is hemodialysis an effective means of removing loratadine or descarboethoxyloratadine from the body.

Topics: Adult; Cyproheptadine; Female; Humans; Kidney Failure, Chronic; Loratadine; Male; Middle Aged; Piperidines; Pyridines; Renal Dialysis; Time Factors

The excretion of loratadine, a new nonsedating antihistamine, into human breast milk was studied in six lactating nonpregnant volunteers. Each volunteer received one 40-mg loratadine capsule. Milk and blood were collected before and at specified times (to 48 hours) after dosing. Plasma and milk loratadine concentrations were determined by a specific radioimmunoassay, and those of an active but minor metabolite, descarboethoxyloratadine, by high performance liquid chromatography (HPLC). Breast milk concentration-time curves of both loratadine and descarboethoxyloratadine paralleled the plasma concentration-time curves. For loratadine, the plasma Cmax was 30.5 ng/mL at 1.0 hour after dosing and the milk Cmax was 29.2 ng/mL in the 0 to 2 hour collection interval. Through 48 hours, the loratadine milk-plasma AUC ratio was 1.2 and 4.2 micrograms of loratadine was excreted in breast milk, which was 0.010% of the administered dose. For descarboethoxyloratadine, the plasma Cmax was 18.6 ng/mL at 2.2 hours after dosing, whereas the milk Cmax was 16.0 ng/mL, which was in the 4 to 8-hour collection interval. Through 48 hours, the mean milk-plasma descarboethoxyloratadine AUC ratio was 0.8 and a mean of 6.0 micrograms of descarboethoxyloratadine (7.5 micrograms loratadine equivalents) were excreted in the breast milk, or 0.019% of the administered loratadine dose. Thus, a total of 11.7 micrograms loratadine equivalents or 0.029% of the administered dose were excreted as loratadine and its active metabolite. A 4-kg infant ingesting the loratadine and descarboethoxyloratadine excreted would receive a dose equivalent to 0.46% of the loratadine dose received by the mother on a mg/kg basis.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Cyproheptadine; Female; Histamine Antagonists; Humans; Loratadine; Milk, Human; Piperidines; Pyridines