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Pharmaceuticals (Basel, Switzerland) Sep 2023is a highly infectious protozoan that causes giardiasis, a gastrointestinal disease with short-term and long-lasting symptoms. The currently available drugs for...
is a highly infectious protozoan that causes giardiasis, a gastrointestinal disease with short-term and long-lasting symptoms. The currently available drugs for giardiasis treatment have limitations such as side effects and drug resistance, requiring the search for new antigiardial compounds. Drug repurposing has emerged as a promising strategy to expedite the drug development process. In this study, we evaluated the cytotoxic effect of terfenadine on trophozoites. Our results showed that terfenadine inhibited the growth and cell viability of trophozoites in a time-dose-dependent manner. In addition, using scanning electron microscopy, we identified morphological damage; interestingly, an increased number of protrusions on membranes and tubulin dysregulation with concomitant dysregulation of were observed. Importantly, terfenadine showed low toxicity for Caco-2 cells, a human intestinal cell line. These findings highlight the potential of terfenadine as a repurposed drug for the treatment of giardiasis and warrant further investigation to elucidate its precise mechanism of action and evaluate its efficacy in future research.
PubMed: 37765140
DOI: 10.3390/ph16091332 -
Current Drug Metabolism 2019Common marmosets (Callithrix jacchus) are potentially useful nonhuman primate models for preclinical studies. Information for major drug-metabolizing cytochrome P450... (Review)
Review
BACKGROUND
Common marmosets (Callithrix jacchus) are potentially useful nonhuman primate models for preclinical studies. Information for major drug-metabolizing cytochrome P450 (P450) enzymes is now available that supports the use of this primate species as an animal model for drug development. Here, we collect and provide an overview of information on the activities of common marmoset hepatic and intestinal microsomes with respect to 28 typical human P450 probe oxidations.
RESULTS
Marmoset P450 2D6/8-dependent R-metoprolol O-demethylation activities in hepatic microsomes were significantly correlated with those of midazolam 1'- and 4-hydroxylations, testosterone 6β-hydroxylation, and progesterone 6β-hydroxylation, which are probe reactions for marmoset P450 3A4/5/90. In marmosets, the oxidation activities of hepatic microsomes and intestinal microsomes were roughly comparable for midazolam and terfenadine. Overall, multiple forms of marmoset P450 enzymes in livers and intestines had generally similar substrate recognition functionalities to those of human and/or cynomolgus monkey P450 enzymes.
CONCLUSION
The marmoset could be a model animal for humans with respect to the first-pass extraction of terfenadine and related substrates. These findings provide a foundation for understanding individual pharmacokinetic and toxicological results in nonhuman primates as preclinical models and will help to further support understanding of the molecular mechanisms of human P450 function.
Topics: Animals; Callithrix; Humans; Intestinal Mucosa; Liver; Microsomes; Models, Animal; Oxidation-Reduction; Pharmaceutical Preparations
PubMed: 30280664
DOI: 10.2174/1389200219666181003143312 -
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 -
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 -
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 -
Basic & Clinical Pharmacology &... Dec 2017Using moxifloxacin and terfenadine, which are known to induce benign and malignant QT interval prolongation, respectively, we analysed whether halothane-anaesthetized...
Using moxifloxacin and terfenadine, which are known to induce benign and malignant QT interval prolongation, respectively, we analysed whether halothane-anaesthetized microminipigs are an appropriate model for assessing the risk of drug-induced long QT syndrome. Moxifloxacin (0.03, 0.3 and 3 mg/kg) and terfenadine (0.03, 0.3 and 3 mg/kg) were intravenously infused over 10 min. with a pause of 20 min. to the halothane-anaesthetized microminipigs (n = 4 for each drug). Moxifloxacin decreased the heart rate, whereas it increased the blood pressure in a dose-related manner. It also prolonged the PR interval and QT/QTc in a dose-related manner without altering the QRS width. Terfenadine decreased the heart rate and blood pressure, whereas it prolonged the PR interval, QRS width and QT/QTc in a dose-related manner. Terfenadine significantly prolonged the beat-to-beat variability of QT interval reflecting its pro-arrhythmic potential, which was not observed with moxifloxacin. The peak plasma concentrations of moxifloxacin and terfenadine after doses of 3 mg/kg were 4.81 and 10.15 μg/mL, respectively, which were both 1.5 times less in microminipigs than those previously reported in dogs. These results indicate that halothane-anaesthetized microminipigs would be useful for detecting drug-induced cardiovascular responses as well as differentiating benign from malignant QT interval prolongation like dogs, although there may be some differences in pharmacokinetic profile between these animals.
Topics: Anesthetics, Inhalation; Animals; Arrhythmias, Cardiac; Blood Pressure; Disease Models, Animal; Dose-Response Relationship, Drug; Fluoroquinolones; Halothane; Heart Rate; Long QT Syndrome; Male; Moxifloxacin; Reproducibility of Results; Risk Assessment; Sensitivity and Specificity; Swine; Swine, Miniature; Terfenadine
PubMed: 28654209
DOI: 10.1111/bcpt.12838 -
The Korean Journal of Internal Medicine Nov 2020Angiotensin II in the failing heart initially helps to maintain cardiac output and blood pressure, but ultimately accelerates its deterioration. In this study, we...
BACKGROUND/AIMS
Angiotensin II in the failing heart initially helps to maintain cardiac output and blood pressure, but ultimately accelerates its deterioration. In this study, we established a model of arrhythmia-induced heart failure (HF) in zebrafish and investigated the role of renin-angiotensin-aldosterone system (RAAS) modulation by using an angiotensin II type 1 receptor blocker, fimasartan, through the assessment of cellular and physiologic responses, morbidity, and mortality.
METHODS
HF was induced in zebrafish larvae by exposure to 20 μM terfenadine. Morphologic, physiologic, and functional parameters were assessed in the presence or absence of fimasartan treatment.
RESULTS
Zebrafish exposed to terfenadine showed marked dilatation of the ventricle and reduced systolic function. Treatment with terfenadine was associated with 10-fold higher expression of atrial natriuretic peptide (p < 0.001 vs. vehicle), increased p53 mRNA expression, and chromatin fragmentation in the TUNEL assay, all of which were significantly reduced by fimasartan treatment. Moreover, fimasartan improved fractional shortening (terfenadine + fimasartan 16.9% ± 3.1% vs. terfenadine + vehicle 11.4% ± 5.6%, p < 0.05) and blood flow (terfenadine + fimasartan 479.1 ± 124.1 nL/sec vs. terfenadine + vehicle 273.0 ± 109.0 nL/sec, p < 0.05). Finally, treatment with fimasartan remarkably reduced mortality (terfenadine + fimasartan 36.0% vs. terfenadine + vehicle 96.0%, p < 0.001).
CONCLUSION
Fimasartan effectively protected against the progression of HF in zebrafish by improving hemodynamic indices, which improved survival. A reduction in apoptotic cell death and an improvement in hemodynamics may be the mechanisms behind these effects. Further human studies are warranted to evaluate the possible role of fimasartan in the treatment of HF.
Topics: Angiotensin Receptor Antagonists; Animals; Biphenyl Compounds; Heart Failure; Humans; Pyrimidines; Tetrazoles; Zebrafish
PubMed: 32164398
DOI: 10.3904/kjim.2019.038 -
Fukuoka Igaku Zasshi = Hukuoka Acta... Jan 2016
Review
Topics: Administration, Inhalation; Cedrus; Desensitization, Immunologic; Disorders of Excessive Somnolence; Drug Combinations; Environmental Exposure; Glucocorticoids; Histamine H1 Antagonists, Non-Sedating; Humans; Nasal Obstruction; Nonprescription Drugs; Patient Satisfaction; Pollen; Practice Guidelines as Topic; Pseudoephedrine; Rhinitis, Allergic, Seasonal; Seasons; Surveys and Questionnaires; Terfenadine
PubMed: 27333653
DOI: No ID Found