Human carboxylesterase 1 (CES1) is a serine esterase that hydrolyses various exogenous and endogenous compounds including oseltamivir, a prodrug used to treat influenza. A novel CES1 c.662A>G single ...nucleotide polymorphism (SNP) was predicted to decrease CES1 enzymatic activity in an in silico analysis. This study evaluated the effect of the c.662A>G SNP on the pharmacokinetics (PK) of oseltamivir in humans.
A single oral dose of oseltamivir at 75 mg was administered to 20 healthy subjects, 8 heterozygous c.662A>G carriers (c.662AG) and 12 non-carriers (c.662AA). The concentrations of oseltamivir and its active metabolite, oseltamivir carboxylate, were measured in plasma and urine using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. The PK parameters were calculated using a noncompartmental method. The geometric mean ratios (GMR, c.662AG to c.662AA) of the PK parameters and their 90% confidence intervals (CI) were calculated.
The systemic exposure to oseltamivir, as assessed by the AUC0-48h of oseltamivir, was increased by 10% in c.662AG subjects, whereas the AUC0-48h of oseltamivir carboxylate was 5% lower in c.662AG subjects. The GMR and 90% CI of the metabolic ratio (AUC0-48h, Oseltamivir carboxylate/AUC0-48h, Oseltamivir) was 0.87 (0.66-1.14). The amount of unchanged oseltamivir excreted in the urine was increased by 15% in subjects with the c.662AG genotype.
This result suggests that CES1 enzymatic activity may be decreased in these heterozygous allele carriers, although further studies are warranted to investigate the clinical implications of this genetic variation on CES1 substrate drugs.
ClinicalTtrials.gov NCT01902342.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Although metformin has been reported to affect the gut microbiome, the mechanism has not been fully determined. We explained the potential underlying mechanisms of metformin through a multiomics ...approach.
An open-label and single-arm clinical trial involving 20 healthy Korean was conducted. Serum glucose and insulin concentrations were measured, and stool samples were collected to analyze the microbiome. Untargeted metabolomic profiling of plasma, urine, and stool samples was performed by GC-TOF-MS. Network analysis was applied to infer the mechanism of the hypoglycemic effect of metformin.
The relative abundances of Escherichia, Romboutsia, Intestinibacter, and Clostridium were changed by metformin treatment. Additionally, the relative abundances of metabolites, including carbohydrates, amino acids, and fatty acids, were changed. These changes were correlated with energy metabolism, gluconeogenesis, and branched-chain amino acid metabolism, which are major metabolic pathways related to the hypoglycemic effect.
We observed that specific changes in metabolites may affect hypoglycemic effects through both pathways related to AMPK activation and microbial changes. Energy metabolism was mainly related to hypoglycemic effects. In particular, branched-chain amino acid metabolism and gluconeogenesis were related to microbial metabolites. Our results will help uncover the potential underlying mechanisms of metformin through AMPK and the microbiome.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The current study assessed the influence of the CYP2C19 genotype on the pharmacokinetics and tolerability of voriconazole after single and multiple oral doses in healthy volunteers. Six subjects for ...the CYP2C19 homozygous extensive metabolizer (EMs), 6 for heterozygous extensive metabolizer (HEMs), and 6 for poor metabolizer (PMs) were enrolled, and their CYP2C9, CYP3A5, and MDR1 genotypes were analyzed. After a single intravenous infusion or single and multiple oral doses of 200 mg of voriconazole, plasma concentrations of voriconazole were measured. Bioavailability was not significantly different among the CYP2C19 genotypes. Voriconazole exposure in PMs was approximately 3 times higher compared with EMs after a single intravenous or oral dose. At steady state, the plasma concentration just before the next dosing and area under the concentration-time curve from dosing to the time point of the next dosing for PMs were about 5 times and 3 times higher than EMs, respectively. These results suggest that the CYP2C19 genotype is the major determinant of the wide PK variability of voriconazole.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Futile reperfusion (poor functional status despite successful reperfusion) was observed in up to 67% of patients enrolled in recent endovascular treatment (EVT) clinical trials. We investigated the ...impact of baseline stroke severity on both futile reperfusion and therapeutic benefit of successful EVT.
Using a prospective multicenter stroke registry, we identified consecutive ischemic stroke patients with anterior circulation large artery occlusion, who were reperfused successfully by EVT (Thrombolysis in Cerebral Infarction grade 2b-3). The rate of futile reperfusion was assessed across the initial National Institutes of Health Stroke Scale (NIHSS) scores. The frequency of poor outcomes (modified Rankin scale mRS 3-6) according to NIHSS scores was compared between patients revascularized successfully by EVT and those who did not receive EVT, after standardizing for age.
Among 21,591 patients with ischemic stroke, 972 (4.5%) received EVT within 12 h of onset, including 440 who met study eligibility criteria. Futile reperfusion was observed in 226 of the 440 study-eligible patients (51.4%) and was associated with stroke severity: 20.9% in NIHSS scores ≤5, 34.6% in 6-10, 58.9% in 11-20, and 63.8% in > 20 (p < 0.001). Nonetheless, the therapeutic benefit of EVT also increased with increasing stroke severity (p for interaction < 0.001): 0.1% in NIHSS ≤5, 18.6% in 6-10, 28.7% in 11-20, and 34.3% in > 20.
EVT is more beneficial with increasing stroke severity, although futile reperfusion also increases with higher stroke severity.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Aims
DWP16001 is a novel sodium–glucose cotransporter 2 inhibitor for the treatment of type 2 diabetes with selective and sustained sodium–glucose cotransporter 2 inhibition. We aimed to evaluate ...whether the coadministration of DWP16001 and metformin causes any changes in pharmacokinetics (PK) or pharmacodynamics (PD).
Methods
A randomized, open‐label, single‐ and multiple‐dose, 2‐sequence, crossover study was conducted in healthy male subjects. Subjects received the following treatments: a single oral dose of DWP16001 (DWP) 2 mg, metformin immediate release 1000 mg (MET) twice daily for 7 days and a single oral dose of DWP and MET at steady‐state for metformin (DWP+MET). Serial blood and interval urine were collected for PK and PD analyses. Safety and tolerability profiles were assessed throughout the study.
Results
DWP+MET displayed increased peak concentration and area under the concentration–time curve from time 0 to time of the last quantifiable concentration compared with DWP (per standard bioequivalence boundaries, 0.8–1.25); the geometric mean ratios (GMRs) and their 90% confidence intervals (CIs) were 1.22 (1.13–1.31) and 1.09 (1.05–1.14), respectively. DWP+MET and MET showed similar peak concentration and area under the concentration–time curve within a dosing interval at steady state for metformin; the GMRs and 90% CIs were 0.98 (0.90–1.06) and 1.05 (0.98–1.13), respectively. The amount of urinary glucose excretion from time 0 to 144 h was also comparable between DWP+MET and DWP (GMR and 90% CI; 0.99, 0.94–1.05).
Conclusion
The results suggest that DWP16001 and metformin could be coadministered without clinically relevant PK and PD interactions.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
• Atenolol is an antihypertensive drug, of which negligible amounts are metabolized.
• Fruit juices may decrease the oral absorption of drugs by inhibiting ...intestinal drug transporters, as demonstrated in vitro and in vivo.
WHAT THIS STUDY ADDS
• The pharmacokinetic characteristics of atenolol were determined according to the SLCO2B1 genotype after apple juice administration in healthy Korean volunteers.
• Apple juice ingestion markedly reduced the systemic exposure to atenolol, but genetic variations in SLCO2B1 were unlikely to contribute substantial variability to the pharmacokinetics of atenolol.
AIM Fruit juice reduces the plasma concentrations of several β‐adrenoceptor blockers, likely by inhibiting OATP2B1‐mediated intestinal absorption. The aim of this study was to investigate the effects of apple juice on the pharmacokinetics of atenolol.
METHODS Twelve healthy Korean volunteers with genotypes of SLCO2B1 c.1457C> T (*1/*1 (n= 6) and *3/*3 (n= 6)) were enrolled in this study. In a three‐phase, one‐sequence crossover study, the pharmacokinetics (PK) of atenolol was evaluated after administration of 50 mg atenolol. Subjects received atenolol with either 300 ml water, 1200 ml apple juice or 600 ml apple juice.
RESULTS Apple juice markedly reduced the systemic exposure to atenolol. The geometric mean ratios (95% confidence intervals) of apple juice : water were 0.18 (0.13, 0.25, 1200 ml) and 0.42 (0.30, 0.59, 600 ml) for the AUC(0,tlast). In this study, the PK parameters of atenolol responded in a dose‐dependent manner to apple juice.
CONCLUSIONS Apple juice markedly reduced systemic exposure to atenolol. The genetic variation of SLCO2B1 c.1457C>T had a minimal effect on the pharmacokinetics of atenolol when the drug was administered with water or apple juice.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
In Korea, gastric cancer screening, either esophagogastroduodenoscopy or upper gastrointestinal series (UGIS), is performed biennially for adults aged 40 years or older. Screening endoscopy has been ...shown to be associated with localized cancer detection and better than UGIS. However, the diagnostic sensitivity of detecting cancer is not satisfactory. The National Endoscopy Quality Improvement (QI) program was initiated in 2009 to enhance the quality of medical institutions and improve the effectiveness of the National Cancer Screening Program (NCSP). The Korean Society of Gastrointestinal Endoscopy developed quality standards through a broad systematic review of other endoscopic quality guidelines and discussions with experts. The standards comprise five domains: qualifications of endoscopists, endoscopic unit facilities and equipment, endoscopic procedure, endoscopy outcomes, and endoscopic reprocessing. After 5 years of the QI program, feedback surveys showed that the perception of QI and endoscopic practice improved substantially in all domains of quality, but the quality standards need to be revised. How to avoid missing cancer in endoscopic procedures in daily practice was reviewed, which can be applied to the mass screening endoscopy. To improve the quality and effectiveness of NCSP, key performance indicators, acceptable quality standards, regular audit, and appropriate reimbursement are necessary.
The use of a visible light absorbing intermediate as a photosensitizer makes a chemical process simple and sustainable, obviating the need for the use of chemical additives. Herein, the formation of ...a photosensitizing disulfide in benzothiazole synthesis from 2-aminothiophenol and aldehydes was proposed and confirmed through in-depth mechanistic studies. A series of photophysical and electrochemical investigations revealed that an in situ-generated disulfide photosensitizes molecular oxygen to generate the key oxidants, singlet oxygen and superoxide anion, for the dehydrogenation step.
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IJS, KILJ, NUK, PNG, UL, UM
Mesenchymal stem cells (MSCs) play important roles in tissue homeostasis by providing a supportive microenvironmental niche for the hematopoietic system. Cigarette smoking induces systemic ...abnormalities, including an impeded recovery process after hematopoietic stem cell transplantation. However, the role of cigarette smoking-mediated alterations in MSC niche function have not been investigated.
In the present study, we investigated whether exposure to cigarette smoking extract (CSE) disrupts the hematopoietic niche function of MSCs, and pathways impacted. To investigate the effects on bone marrow (BM)-derived MSCs and support of hematopoietic stem and progenitor cells (HSPCs), mice were repeatedly infused with the CSE named 3R4F, and hematopoietic stem and progenitor cells (HSPCs) supporting function was determined. The impact of 3R4F on MSCs at cellular level were screened by bulk-RNA sequencing and subsequently validated through qRT-PCR. Specific inhibitors were treated to verify the ROS or NLRP3-specific effects, and the cells were then transplanted into the animal model or subjected to coculture with HSPCs.
Both direct ex vivo and systemic in vivo MSC exposure to 3R4F resulted in impaired engraftment in a humanized mouse model. Furthermore, transcriptomic profile analysis showed significantly upregulated signaling pathways related to reactive oxygen species (ROS), inflammation, and aging in 3R4F-treated MSCs. Notably, ingenuity pathway analysis revealed the activation of NLRP3 inflammasome signaling pathway in 3R4F-treated MSCs, and pretreatment with the NLRP3 inhibitor MCC950 rescued the HSPC-supporting ability of 3R4F-treated MSCs.
In conclusion, these findings indicate that exposure to CSE reduces HSPCs supportive function of MSCs by inducing robust ROS production and subsequent NLRP3 activation.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
During the development of a specific dipeptidyl peptidase 4 (DPP4) inhibitor to treat type 2 diabetes, a fluorogenic kinetic analysis for DPP4 enzymatic activity using Gly-Pro-Aminomethylcoumarin ...(AMC) as a substrate was optimized and validated for recombinant DPP4 and human plasma samples. The sensitivity, calibration curve, detection range, accuracy, precision, recovery efficiency, Km constant, short/long-term stability, and stability after freezing-thawing cycles were analyzed. DPP4 enzymatic activity (mU/min) was measured as the initial velocity (Vo) of the enzymatic reaction over time. The sensitivity of the Vo value was 14,488 mU/min for recombinant DPP4 and 17,995 mU/min for human plasma samples. The dynamic ranges of the calibration curve were linear and reliable between 1.11 × 104–1.86 × 106 mU/min of the mean Vo value and in the DPP4 concentration range of 23.4–3,000 ng/mL. The assay's accuracy and precision met acceptance criteria for all samples. Plasma DPP4 was stable under various storage temperatures, even after three freeze-thaw cycles. Our optimized, validated bioanalytic method for measuring DPP4 activity in plasma samples was successfully employed to evaluate the effect of evogliptin (DA-1229) tartrate, which irreversibly and dose-dependently inhibits DPP4 enzymatic activity, without the dilution effect of human plasma samples and irrespective of the co-treated metformin.
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•The activity of DPP4 was measured in 5 min by a newly optimized fluorogenic DPP4 enzymatic assay with 10 μl of human plasma using AMC substrate.•Our fluorogenic DPP4 enzymatic assay was optimized to detect the high levels of the DPP4 activity in human plasma samples without saturation.•Our fluorogenic DPP4 assay was validated to measure the DPP4 activities in plasma samples from patients with metabolic diseases.•Evogliptin (DA-1229) tartrate dose-dependently inhibited the DPP4 enzymatic activity with high potency.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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