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Yakugaku Zasshi : Journal of the... 2015Drug transporters play an important role in the clinical pharmacokinetics of many therapeutic agents. Although it is estimated that about half of all therapeutic agents... (Review)
Review
Drug transporters play an important role in the clinical pharmacokinetics of many therapeutic agents. Although it is estimated that about half of all therapeutic agents are chiral, there has been little information on the stereoselective pharmacokinetics related to drug transporters. This review focuses on the drug transporters contributing to the stereoselective pharmacokinetics of fexofenadine enantiomers in humans. Fexofenadine is administered clinically as a racemic mixture, and the plasma concentration of (R)-fexofenadine is about 1.5-fold higher than that of the (S)-enantiomer. Because fexofenadine is poorly metabolized by cytochrome P450s, its pharmacokinetics depends on its drug-transporter activities. First, we examined whether drug-transporter polymorphisms influence fexofenadine enantiomer pharmacokinetics. The findings suggested that a combination of multiple transporters involving organic anion transporting polypeptide (OATP) 2B1, P-glycoprotein (P-gp), and multidrug resistance-associated protein 2 (MRP2) react to stereoselective fexofenadine exposure. Subsequently, we evaluated the roles of P-gp and OATPs in fexofenadine enantiomer pharmacokinetics using these inducer/inhibitors. Coadministration of P-gp inducer/inhibitors significantly altered the pharmacokinetics of fexofenadine enantiomers. In addition, the OATP inhibitors rifampicin and apple juice also affected fexofenadine enantiomer pharmacokinetics. Moreover, in in vitro studies, the uptake of both fexofenadine enantiomers into OATP2B1 cRNA-injected oocytes was significantly higher than that into water-injected oocytes, and this effect was greater for (R)-fexofenadine. Taken together, these studies indicated that multiple transporters including P-gp, OATPs, and MRP2 play important roles in fexofenadine enantiomer pharmacokinetics. Furthermore, OATP2B1 is a key determinant of the stereoselective pharmacokinetics of fexofenadine, and drug transporters may have chiral discrimination ability.
Topics: Animals; Biological Transport; Humans; Membrane Transport Proteins; Polymorphism, Genetic; Stereoisomerism; Terfenadine
PubMed: 25759055
DOI: 10.1248/yakushi.14-00218 -
Toxicology Jan 2021A human microfluidic four-cell liver acinus microphysiology system (LAMPS), was evaluated for reproducibility and robustness as a model for drug pharmacokinetics and...
A human microfluidic four-cell liver acinus microphysiology system (LAMPS), was evaluated for reproducibility and robustness as a model for drug pharmacokinetics and toxicology. The model was constructed using primary human hepatocytes or human induced pluripotent stem cell (iPSC)-derived hepatocytes and 3 human cell lines for the endothelial, Kupffer and stellate cells. The model was tested in two laboratories and demonstrated to be reproducible in terms of basal function of hepatocytes, Terfenadine metabolism, and effects of Tolcapone (88 μM), Troglitazone (150 μM), and caffeine (600 μM) over 9 days in culture. Additional experiments compared basal outputs of albumin, urea, lactate dehydrogenase (LDH) and tumor necrosis factor (TNF)α, as well as drug metabolism and toxicity in the LAMPS model, and in 2D cultures seeded with either primary hepatocytes or iPSC-hepatocytes. Further experiments to study the effects of Terfenadine (10 μM), Tolcapone (88 μM), Trovafloxacin (150 μM with or without 1 μg/mL lipopolysaccharide), Troglitazone (28 μM), Rosiglitazone (0.8 μM), Pioglitazone (3 μM), and caffeine (600 μM) were carried out over 10 days. We found that both primary human hepatocytes and iPSC-derived hepatocytes in 3D culture maintained excellent basal liver function and Terfenadine metabolism over 10 days compared the same cells in 2D cultures. In 2D, non-overlay monolayer cultures, both cell types lost hepatocyte phenotypes after 48 h. With respect to drug effects, both cell types demonstrated comparable and more human-relevant effects in LAMPS, as compared to 2D cultures. Overall, these studies show that LAMPS is a robust and reproducible in vitro liver model, comparable in performance when seeded with either primary human hepatocytes or iPSC-derived hepatocytes, and more physiologically and clinically relevant than 2D monolayer cultures.
Topics: Acinar Cells; Cell Culture Techniques; Hepatocytes; Histamine H1 Antagonists, Non-Sedating; Humans; Liver; Microfluidics; Terfenadine
PubMed: 33307106
DOI: 10.1016/j.tox.2020.152651 -
British Journal of Clinical Pharmacology Jul 19781 Effect of four antihistamines, chlorpheniramine (4 mg), clemastine (1 mg), promethazine (10 mg) and terfenadine (60 mg), on visuo-motor coordination and on subjective... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
1 Effect of four antihistamines, chlorpheniramine (4 mg), clemastine (1 mg), promethazine (10 mg) and terfenadine (60 mg), on visuo-motor coordination and on subjective assessments of performance and well-being were compared with placebo in six healthy females from 0.5--7.0 h after morning ingestion of each drug. The study was double-blind, and the doses used were believed to be equally potent in their antihistaminic activity. 2 There was impaired performance 1.5 h (P less than 0.01) after chlorpheniramine, 3.0 h (P less than 0.05) and 5.0 h (P less than 0.01) after clemastine, and 3.0 h (P less than 0.01) and 5.0 h (P less than 0.001) after promethazine. It was not possible to establish effects on performance after ingestion of terfenadine. Subjective assessments of performance were not altered. 3 The subjects as a group reported improved alertness (P less than 0.05) and improved wakefulness (P less than 0.05) 0.5 h and 3.5 h respectively after ingestion of terfenadine, and were less energetic (P less than 0.05) 7.0 h after ingestion of chlorpheniramine. There were not other consistent changes in assessments of well-being.
Topics: Adult; Female; Histamine H1 Antagonists; Humans; Motor Skills; Placebos; Sleep; Wakefulness
PubMed: 27204
DOI: 10.1111/j.1365-2125.1978.tb01678.x -
Biomedicine & Pharmacotherapy =... Feb 2023Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are characterized by skin photosensitivity caused by accumulation of protoporphyrin IX. We aimed to... (Review)
Review
Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are characterized by skin photosensitivity caused by accumulation of protoporphyrin IX. We aimed to review the clinical evidence of efficacy and safety of skin photosensitivity treatments in individuals with EPP or XLP. We systematically searched MEDLINE, Embase, the Cochrane Library, and ClinicalTrials.gov. A total of 40 studies with data on 18 treatment modalities were included. Comprehensive treatment safety data were obtained from the European Medicines Agency and the United States Food and Drug Administration. The studies used different outcome measures to evaluate the sensitivity without a generally accepted method to assess treatment effect on skin photosensitivity. Of the included studies, 13 were controlled trials. Gathered, the trials showed moderate positive effect of inorganic sunscreen application and subcutaneous implant of afamelanotide and no effect of organic sunscreen application, or oral treatment with beta-carotene, cysteine, N-acetylcysteine, vitamin C, or warfarin. Studies without control groups suggested treatment effect of foundation cream, dihydroxyacetone/lawsone cream, narrow-band ultraviolet B phototherapy, erythrocyte transfusion, extracorporeal erythrocyte photodynamic therapy, or oral treatment with zinc sulphate, terfenadine, cimetidine, or canthaxanthin, but the real effect is uncertain. Assessment of treatment effect on photosensitivity in patients with EPP or XLP carries a high risk of bias since experienced photosensitivity varies with both weather conditions, exposure pattern, and pigmentation. Controlled trials of promising treatment options are important although challenging in this small patient population.
Topics: United States; Humans; Protoporphyria, Erythropoietic; Sunscreening Agents; Photosensitivity Disorders; Genetic Diseases, X-Linked; Protoporphyrins
PubMed: 36525819
DOI: 10.1016/j.biopha.2022.114132 -
Alimentary Pharmacology & Therapeutics Dec 1999Gastrointestinal prokinetics, such as metoclopramide, cisapride and levosulpiride, are widely used for the management of functional gut disorders. Recently, several... (Review)
Review
Gastrointestinal prokinetics, such as metoclopramide, cisapride and levosulpiride, are widely used for the management of functional gut disorders. Recently, several studies have shown that cisapride (a partial 5-HT4 receptor agonist) can induce dose-dependent cardiac adverse effects, including lengthening of the electrocardiographic QT interval, syncopal episodes and ventricular dysrhythmias. Until recently, it was not clear whether these effects were dependent on 5-HT4 receptor activation or related to peculiar characteristics in the molecular structure of single agents within the benzamide class. Experimental evidence now favours the second hypothesis: cisapride possesses Class III antiarrhythmic properties and prolongs the action potential duration through blockade of distinct voltage-dependent K+ channels, thus delaying cardiac repolarization and prolonging the QT interval. Patients at risk of cardiac adverse effects are children, subjects with idiopathic, congenital or acquired long QT syndrome and, in particular, those receiving concomitant medication with Class III antiarrhythmic agents, some H1-receptor antagonists (e.g. terfenadine), or drugs such as azole antifungals (e.g. ketoconazole, itraconazole, miconazole and fluconazole) and macrolide antibacterials (e.g. erythromycin, clarithrod-mycin and troleandomycin), which can inhibit cisapride metabolism by interfering with the CYP3A4 isoenzyme.
Topics: Benzamides; Cisapride; Clinical Trials as Topic; Dopamine Antagonists; Forecasting; Gastrointestinal Agents; Gastrointestinal Motility; Heart; Humans
PubMed: 10594392
DOI: 10.1046/j.1365-2036.1999.00655.x -
The American Journal of Cardiology Aug 1993Historically, QT prolongation, occurring with or without drug therapy, has been considered primarily as a clinical marker for risk of arrhythmia. However, as... (Review)
Review
Historically, QT prolongation, occurring with or without drug therapy, has been considered primarily as a clinical marker for risk of arrhythmia. However, as understanding of cardiac repolarization improves and ability to measure accurately small changes in QT interval increases, the QT interval will be used as a marker for drug action as well. In addition, QT prolongation may prove to be a valuable tool for detecting and quantifying risk of arrhythmia due to drugs. This has been emphasized recently by the experience with terfenadine. Use of the QT interval as a marker for toxicity and efficacy will require sensitive and specific methods that are currently being developed and validated. The current methodologies for detecting small changes in the QT interval and the significance of those changes are discussed.
Topics: Anti-Arrhythmia Agents; Dose-Response Relationship, Drug; Drug-Related Side Effects and Adverse Reactions; Electrocardiography; Humans; Torsades de Pointes
PubMed: 8256753
DOI: 10.1016/0002-9149(93)90039-f -
British Journal of Clinical Pharmacology Feb 2004To discuss the potential use of data mining and knowledge discovery in databases for detection of adverse drug events (ADE) in pharmacovigilance. (Review)
Review
AIMS
To discuss the potential use of data mining and knowledge discovery in databases for detection of adverse drug events (ADE) in pharmacovigilance.
METHODS
A literature search was conducted to identify articles, which contained details of data mining, signal generation or knowledge discovery in relation to adverse drug reactions or pharmacovigilance in medical databases.
RESULTS
ADEs are common and result in significant mortality, and despite existing systems drugs have been withdrawn due to ADEs many years after licensing. Knowledge discovery in databases (KDD) is a technique which may be used to detect potential ADEs more efficiently. KDD involves the selection of data variables and databases, data preprocessing, data mining and data interpretation and utilization. Data mining encompasses a number of statistical techniques including cluster analysis, link analysis, deviation detection and disproportionality assessment which can be utilized to determine the presence of and to assess the strength of ADE signals. Currently the only data mining methods to be used in pharmacovigilance are those of disproportionality, such as the Proportional Reporting Ratio and Information Component, which have been used to analyse the UK Yellow Card Scheme spontaneous reporting database and the WHO Uppsala Monitoring Centre database. The association of pericarditis with practolol but not with other beta-blockers, the association of captopril and other angiotensin-converting enzymes with cough, and the association of terfenadine with heart rate and rhythm disorders could be identified by mining the WHO database.
CONCLUSION
In view of the importance of ADEs and the development of massive data storage systems and powerful computer systems, the use of data mining techniques in knowledge discovery in medical databases is likely to be of increasing importance in the process of pharmacovigilance as they are likely to be able to detect signals earlier than using current methods.
Topics: Data Collection; Databases, Bibliographic; Databases, Factual; Drug-Related Side Effects and Adverse Reactions; Humans; Information Storage and Retrieval
PubMed: 14748811
DOI: 10.1046/j.1365-2125.2003.01968.x -
Experimental Hematology Oct 2010In mast cell (MC) neoplasms, clinical problems requiring therapy include local aggressive and sometimes devastating growth of MCs and mediator-related symptoms. A key...
OBJECTIVE
In mast cell (MC) neoplasms, clinical problems requiring therapy include local aggressive and sometimes devastating growth of MCs and mediator-related symptoms. A key mediator of MCs responsible for clinical symptoms is histamine. Therefore, use of histamine receptor (HR) antagonists is an established approach to block histamine effects in these patients.
MATERIALS AND METHODS
We screened for additional beneficial effects of HR antagonists and asked whether any of these agents would also exert growth-inhibitory effects on primary neoplastic MCs, the human MC line HMC-1, and on two canine MC lines, C2 and NI-1.
RESULTS
We found that the HR1 antagonists terfenadine and loratadine suppress spontaneous growth of HMC-1, C2, and NI-1 cells, as well as growth of primary neoplastic MCs in all donors tested (human patients, n = 5; canine patients, n = 8). The effects of both drugs were found to be dose-dependent (IC(50): terfenadine, 1-20 μM; loratadine, 10-50 μM). Both agents also produced apoptosis in neoplastic MCs and augmented apoptosis-inducing effects of two KIT-targeting drugs, PKC412 and dasatinib. The other HR1 antagonists (fexofenadine, diphenhydramine) and HR2 antagonists (famotidine, cimetidine, ranitidine) tested did not exert substantial growth-inhibitory effects on neoplastic MCs. None of the histamine receptor blockers were found to modulate cell-cycle progression in neoplastic MCs.
CONCLUSIONS
The HR1 antagonists terfenadine and loratadine, in addition to their antimediator activity, exert in vitro growth-inhibitory effects on neoplastic MCs. Whether these drugs (terfenadine) alone, or in combination with KIT inhibitors, can also affect in vivo neoplastic MC growth remains to be determined.
Topics: Animals; Apoptosis; Blotting, Western; Caspase 3; Cats; Cell Line, Tumor; Cell Proliferation; Dasatinib; Dogs; Dose-Response Relationship, Drug; Drug Synergism; Flow Cytometry; Histamine H1 Antagonists, Non-Sedating; Humans; Inhibitory Concentration 50; Loratadine; Mastocytoma; Mastocytosis, Systemic; Proto-Oncogene Proteins c-kit; Pyrimidines; Staurosporine; Terfenadine; Thiazoles; Tumor Cells, Cultured
PubMed: 20570632
DOI: 10.1016/j.exphem.2010.05.008 -
The Journal of the American Osteopathic... Jul 1999Azelastine hydrochloride is a nasally administered antihistamine that is effective and safe for the treatment of perennial and seasonal allergic rhinitis. In addition to... (Review)
Review
Azelastine hydrochloride is a nasally administered antihistamine that is effective and safe for the treatment of perennial and seasonal allergic rhinitis. In addition to acting as a histamine H1-receptor antagonist, azelastine also inhibits the production or release of many chemical mediators of the allergic response such as leukotrienes, free radicals, and cytokines. After nasal administration, azelastine is systemically absorbed with a bioavailability of about 40%. The side effects of azelastine are drowsiness, headache, and bitter taste. Azelastine has a rapid onset of action with a benefit in about 2 hours and a prolonged duration of activity (12 to 24 hours). Studies have shown azelastine to be more effective than placebo in terms of reduction of the major and total symptom complexes of allergic rhinitis. Comparison studies have demonstrated that azelastine is as effective as ebastine, loratadine, cetirizine hydrochloride, and terfenadine at symptom reduction, with varying results when compared with the corticosteroids budesonide and beclomethasone. Although there are conflicting studies, some have demonstrated that azelastine reduces the nasal congestion of allergic rhinitis. This feature that distinguishes it from oral antihistamines is of great interest because corticosteroids are known to be quite effective for the relief of nasal congestion, whereas the antihistamines are effective for the sneezing, itchy eyes, itchy nose, and watery eyes, but not the congestion. Azelastine nasal spray seems to be an efficacious treatment for allergic rhinitis with a rapid onset and long duration of activity, but without the systemic adverse effects of traditional sedating antihistamines.
Topics: Administration, Inhalation; Histamine H1 Antagonists; Humans; Phthalazines; Rhinitis, Allergic, Perennial; Rhinitis, Allergic, Seasonal
PubMed: 10478514
DOI: 10.7556/jaoa.1999.99.7.s7 -
ACS Infectious Diseases Jul 2021Schistosomiasis is a major neglected tropical disease with more than 200 million infections annually. Despite only one drug, praziquantel, being available, the drug...
Schistosomiasis is a major neglected tropical disease with more than 200 million infections annually. Despite only one drug, praziquantel, being available, the drug pipeline against schistosomiasis is empty, and drug screening tools have limitations. We evaluated the potential of human liver microtissues (hLiMTs) in antischistosomal drug discovery. Because hLiMTs express all human P450 enzymes, they are an excellent tool to evaluate compounds' bioinactivation, bioactivation, and toxicity. To validate the metabolic conversion capacity of hLiMTs, we first quantified ()- and ()-praziquantel and the main metabolite -OH-praziquantel following incubation with 0.032-50 μM (0.01-15.62 μg/mL) praziquantel for up to 72 h by a validated LC-MS/MS method. We cocultured hLiMTs with newly transformed schistosomula (NTS) and evaluated the antischistosomal activity and cytotoxicity of three prodrugs terfenadine, tamoxifen citrate, and flutamide. HLiMTs converted 300-350 ng ()-praziquantel within 24 h into -OH-praziquantel. We observed changes in the IC values for terfenadine, flutamide, and tamoxifen citrate in comparison to the standard NTS assay Cytotoxicity was observed at high concentrations of flutamide and tamoxifen citrate. An platform containing hLiMTs could serve as an advanced drug screening tool for , providing information on reduced or increased activity and toxicity.
Topics: Animals; Chromatography, Liquid; Drug Evaluation, Preclinical; Humans; Liver; Schistosoma mansoni; Schistosomiasis mansoni; Tandem Mass Spectrometry
PubMed: 33105989
DOI: 10.1021/acsinfecdis.0c00614