-
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 -
Frontiers in Cellular and Infection... 2023The coronavirus disease 2019 (COVID-19) pandemic, stemming from the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has persistently threatened the global...
INTRODUCTION
The coronavirus disease 2019 (COVID-19) pandemic, stemming from the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has persistently threatened the global health system. Meanwhile, tuberculosis (TB) caused by () still continues to be endemic in various regions of the world. There is a certain degree of similarity between the clinical features of COVID-19 and TB, but the underlying common pathogenetic processes between COVID-19 and TB are not well understood.
METHODS
To elucidate the common pathogenetic processes between COVID-19 and TB, we implemented bioinformatics and systematic research to obtain shared pathways and molecular biomarkers. Here, the RNA-seq datasets (GSE196822 and GSE126614) are used to extract shared differentially expressed genes (DEGs) of COVID-19 and TB. The common DEGs were used to identify common pathways, hub genes, transcriptional regulatory networks, and potential drugs.
RESULTS
A total of 96 common DEGs were selected for subsequent analyses. Functional enrichment analyses showed that viral genome replication and immune-related pathways collectively contributed to the development and progression of TB and COVID-19. Based on the protein-protein interaction (PPI) network analysis, we identified 10 hub genes, including IFI44L, ISG15, MX1, IFI44, OASL, RSAD2, GBP1, OAS1, IFI6, and HERC5. Subsequently, the transcription factor (TF)-gene interaction and microRNA (miRNA)-gene coregulatory network identified 61 TFs and 29 miRNAs. Notably, we identified 10 potential drugs to treat TB and COVID-19, namely suloctidil, prenylamine, acetohexamide, terfenadine, prochlorperazine, 3'-azido-3'-deoxythymidine, chlorophyllin, etoposide, clioquinol, and propofol.
CONCLUSION
This research provides novel strategies and valuable references for the treatment of tuberculosis and COVID-19.
Topics: Humans; COVID-19; SARS-CoV-2; Computational Biology; Genes, Regulator; Tuberculosis; Mycobacterium tuberculosis; Gene Expression Profiling; MicroRNAs
PubMed: 38162574
DOI: 10.3389/fcimb.2023.1280223 -
Advanced Science (Weinheim,... Dec 2023Catalytic asymmetric hydroboration of fluoroalkyl-substituted alkenes is a straightforward approach to access chiral small molecules possessing both fluorine and boron...
Catalytic asymmetric hydroboration of fluoroalkyl-substituted alkenes is a straightforward approach to access chiral small molecules possessing both fluorine and boron atoms. However, enantioselective hydroboration of fluoroalkyl-substituted alkenes without fluorine elimination has been a long-standing challenge in this field. Herein, a copper-catalyzed hydroboration of difluoroalkyl-substituted internal alkenes with high levels of regio- and enantioselectivities is reported. The native carbonyl directing group, copper hydride system, and bisphosphine ligand play crucial roles in suppressing the undesired fluoride elimination. This atom-economic protocol provides a practical synthetic platform to obtain a wide scope of enantioenriched secondary boronates bearing the difluoromethylene moieties under mild conditions. Synthetic applications including functionalization of biorelevant molecules, versatile functional group interconversions, and preparation of difluoroalkylated Terfenadine derivative are also demonstrated.
PubMed: 37880870
DOI: 10.1002/advs.202304194 -
The Journal of Invasive Cardiology Dec 2023The Allegra-THV is a novel, self-expanding THV with supra-annular bovine leaflets. The valve is available in 3 different sizes and is delivered through an 18 French...
OBJECTIVES
The Allegra-THV is a novel, self-expanding THV with supra-annular bovine leaflets. The valve is available in 3 different sizes and is delivered through an 18 French sheath. To determine the safety and efficacy of the Allegra transcatheter heart valve (THV; Biosensors) for the treatment of severe aortic valve stenosis under real-world conditions.
METHODS
Consecutive patients undergoing transcatheter aortic valve replacement (TAVR) at the Heart-Centre Lucerne with the Allegra-THV were included. Echocardiographic data were collected at baseline, before discharge, and at 1-year follow-up; clinical outcomes were recorded for up to 3 years. Clinical endpoints were defined according to the definitions of the Valve-Academic-Research-Consortium.
RESULTS
One hundred-three patients (age 81 ± 7 years, 63% women) were enrolled. Median European System for Cardiac Operative Risk Evaluation II score was 4.1% (IQR 1.8%-4.2%). Mean aortic valve gradient was 6.9 ± 3.3 mm Hg and 7.7 ± 3.3 mm Hg, and an effective orifice area was 2.1 ± 0.5 cm2 and 2.0 ± 0.5 cm2 at 30 days and 1-year follow-up, respectively. More than mild paravalvular leak was observed in 2.0% of patients at 30 days and 3.3% at 1 year. At 1-year follow-up, 14.7% of patients required implantation of a new permanent pacemaker, 1 patient had endocarditis with an uneventful clinical course and good THV-function after antibiotic therapy, and no thrombosis, structural-valve-detoriation (SVD), or non-SVD had occurred. At 3-year follow-up, rates of all-cause and cardiovascular mortality were 31.4% and 18.8%, respectively.
CONCLUSIONS
Transfemoral implantation of the Allegra-THV resulted in favorable clinical and echocardiographic outcomes at up to 3-year follow-up. Head-to-head randomized clinical trials are necessary to determine if the Allegra-THV valve performs as well as current generation valves.
Topics: Humans; Animals; Cattle; Female; Aged; Aged, 80 and over; Male; Heart Valves; Echocardiography; Terfenadine; Catheters
PubMed: 38108869
DOI: 10.25270/jic/23.00163 -
Chemical & Pharmaceutical Bulletin Jan 2024For taste masking of fexofenadine hydrochloride (FXD), ethylcellulose (EC) microparticles with FXD were developed. The amounts of EC, Tween 80, and polyvinyl alcohol...
For taste masking of fexofenadine hydrochloride (FXD), ethylcellulose (EC) microparticles with FXD were developed. The amounts of EC, Tween 80, and polyvinyl alcohol (PVA) in the composition had little effect on initial drug release properties. Based on the results of the drug recovery and the drug release properties, FXD(EC200) was the optimal FXD microparticle formulation. From the results of Fourier transform infrared spectroscopy spectra and X-ray diffraction patterns of FXD(EC200), FXD amorphization in the microparticles and interaction between FXD and other components were suggested, and the formation of a solid dispersion of FXD was suggested. Because the possibility of the complex of PVA and FXD on the particle surface was suggested, sodium lauryl sulfate (SLS) was added to the composition. The initial drug release from FXD microparticles with SLS was further suppressed compared with FXD(EC200). From these results, FXD microparticles with SLS can be prepared as a controlled-release formulation and are expected to be useful for masking the bitter tasting particulates.
Topics: Taste; Terfenadine; Cellulose; Spectroscopy, Fourier Transform Infrared; Particle Size; Solubility
PubMed: 38123341
DOI: 10.1248/cpb.c23-00754 -
Frontiers in Pharmacology 2023Genetic polymorphism of the cytochrome P450 (CYP) gene can significantly influence the metabolism of endogenous and xenobiotic compounds. However, few studies have...
Genetic polymorphism of the cytochrome P450 (CYP) gene can significantly influence the metabolism of endogenous and xenobiotic compounds. However, few studies have focused on the polymorphism of and its impact on drug catalytic activity, especially in the Chinese Han population. In this study, we sequenced the promoter and exon regions of in 1,163 unrelated healthy Chinese Han individuals using the multiplex PCR amplicon sequencing method. Then, the catalytic activities of the detected CYP2J2 variants were evaluated after recombinant expression in microsomes. As a result, , , 13 variations in the promoter region and 15 nonsynonymous variants were detected, of which V15A, G24R, V68A, L166F and A391T were novel missense variations. Immunoblotting results showed that 11 of 15 CYP2J2 variants exhibited lower protein expression than wild-type CYP2J2.1. functional analysis results revealed that the amino acid changes of 14 variants could significantly influence the drug metabolic activity of CYP2J2 toward ebastine or terfenadine. Specifically, 4 variants with relatively higher allele frequencies, CYP2J2.8, 173_173del, K267fs and R446W, exhibited extremely low protein expression and defective catalytic activities for both substrates. Our results indicated that a high genetic polymorphism of could be detected in the Chinese Han population, and most genetic variations in could influence the expression and catalytic activity of CYP2J2. Our data significantly enrich the knowledge of genetic polymorphisms in and provide new theoretical information for corresponding individualized medication in Chinese and other Asian populations.
PubMed: 37288113
DOI: 10.3389/fphar.2023.1186824 -
Clinical and Translational Science Jan 2024Intestinal P-glycoprotein (P-gp) activity plays a crucial role in modulating the oral bioavailability of its substrates. Fexofenadine has commonly been used as a P-gp...
Intestinal P-glycoprotein (P-gp) activity plays a crucial role in modulating the oral bioavailability of its substrates. Fexofenadine has commonly been used as a P-gp probe, although it is important to note the involvement of other drug transporters like, OATP1B1, OATP1B3, and OATP2B1. In vitro studies demonstrated an upregulation of P-gp protein in response to exposure to pregnancy-related hormones. The objective of this study was to investigate how intestinal P-gp activity is impacted by menopausal status. This study sampled fexofenadine plasma concentrations over 0-12 h after probe drug administration from two groups of patients with breast cancer: premenopausal (n = 20) and postmenopausal (n = 20). Fexofenadine plasma concentrations were quantified using liquid-chromatography tandem mass spectrometry. Area under the plasma concentration-time curve from zero to infinity (AUC ) was calculated through limited sampling strategies equation. Multiple linear regression was applied on AUC , maximum plasma concentration (C ), and time to C . Postmenopausal patients showed a significant increase in C (geometric mean and 95% confidence interval [CI] 143.54, 110.95-176.13 vs. 223.54 ng/mL, 161.02-286.06 and in AUC 685.55, 534.98-878.50 vs. 933.54 ng·h/mL 735.45-1184.99) compared to premenopausal patients. The carriers of the ABCB1 3435 allele T displayed higher C values of 166.59 (95% CI: 129.44-214.39) compared to the wild type at 147.47 ng/mL (95% CI: 111.91-194.34, p = 0.02). In postmenopausal individuals, the decrease in P-gp activity of ~40% may lead to an increased plasma exposure of orally administered P-gp substrates.
Topics: Humans; Female; ATP Binding Cassette Transporter, Subfamily B, Member 1; Breast Neoplasms; Postmenopause; Terfenadine
PubMed: 38226443
DOI: 10.1111/cts.13713 -
BioRxiv : the Preprint Server For... Dec 2023Inducing apoptosis in different types of cancer cells is an effective therapeutic strategy. However, the success of existing chemotherapeutics can be compromised by...
Inducing apoptosis in different types of cancer cells is an effective therapeutic strategy. However, the success of existing chemotherapeutics can be compromised by tumor cell resistance and systemic off-target effects. Therefore, the discovery of pro-apoptotic compounds with minimal systemic side-effects is crucial. 14-3-3 proteins are molecular scaffolds that serve as important regulators of cell survival. Our previous study demonstrated that 14-3-3ζ can sequester BAD, a pro-apoptotic member of the BCL-2 protein family, in the cytoplasm and prevent its translocation to mitochondria to inhibit the induction of apoptosis. Despite being a critical mechanism of cell survival, it is unclear whether disrupting 14-3-3 protein:BAD interactions could be harnessed as a chemotherapeutic approach. Herein, we established a BRET-based high-throughput drug screening approach (Z'-score= 0.52) capable of identifying molecules that can disrupt 14-3-3ζ:BAD interactions. An FDA-approved drug library containing 1971 compounds was used for screening, and the capacity of identified hits to induce cell death was examined in NIH3T3-fibroblasts and colorectal cancer cell lines, HT-29 and Caco-2. Our results suggest that terfenadine, penfluridol, and lomitapide could be potentially repurposed for treating colorectal cancer. Moreover, our screening method demonstrates the feasibility of identifying pro-apoptotic agents that can be applied towards conditions where aberrant cell growth or function are key determinants of disease pathogenesis.
PubMed: 38168191
DOI: 10.1101/2023.12.14.571727 -
Clinical and Translational Science May 2024St. John's wort (SJW) extract, a herbal medicine with antidepressant effects, is a potent inducer of intestinal and/or hepatic cytochrome P450 (CYP) enzymes and...
St. John's wort (SJW) extract, a herbal medicine with antidepressant effects, is a potent inducer of intestinal and/or hepatic cytochrome P450 (CYP) enzymes and P-glycoprotein (P-gp), which can cause clinically relevant drug interactions. It is currently not known whether SJW can also induce P-gp activity at the human blood-brain barrier (BBB), which may potentially lead to decreased brain exposure and efficacy of certain central nervous system (CNS)-targeted P-gp substrate drugs. In this study, we used a combination of positron emission tomography (PET) imaging and cocktail phenotyping to gain a comprehensive picture on the effect of SJW on central and peripheral P-gp and CYP activities. Before and after treatment of healthy volunteers (n = 10) with SJW extract with a high hyperforin content (3-6%) for 12-19 days (1800 mg/day), the activity of P-gp at the BBB was assessed by means of PET imaging with the P-gp substrate [C]metoclopramide and the activity of peripheral P-gp and CYPs was assessed by administering a low-dose phenotyping cocktail (caffeine, omeprazole, dextromethorphan, and midazolam or fexofenadine). SJW significantly increased peripheral P-gp, CYP3A, and CYP2C19 activity. Conversely, no significant changes in the peripheral metabolism, brain distribution, and P-gp-mediated efflux of [C]metoclopramide across the BBB were observed following the treatment with SJW extract. Our data suggest that SJW does not lead to significant P-gp induction at the human BBB despite its ability to induce peripheral P-gp and CYPs. Simultaneous intake of SJW with CNS-targeted P-gp substrate drugs is not expected to lead to P-gp-mediated drug interactions at the BBB.
Topics: Humans; Hypericum; Blood-Brain Barrier; Phloroglucinol; Plant Extracts; Male; Adult; Positron-Emission Tomography; Terpenes; Female; Young Adult; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP Binding Cassette Transporter, Subfamily B; Bridged Bicyclo Compounds; Terfenadine; Cytochrome P-450 Enzyme System; Healthy Volunteers
PubMed: 38700454
DOI: 10.1111/cts.13804