Impact of vancomycin-induced changes in the intestinal microbiota on the pharmacokinetics of simvastatin

The pharmacokinetic (PK) properties of drugs are affected in several ways by interactions with microbiota. The aim of this study was to investigate the effects of oral vancomycin on the gut microbiota and, consequently, on the PKs of simvastatin. An open-label, single arm, sequential crossover study was conducted in six healthy Korean male subjects. After 6 days on a control diet, simvastatin 40 mg was orally administered to the subjects before and after 1 week of oral vancomycin treatment. Blood samples for PK analysis and fecal samples for metagenomic and metabolomic analyses were collected. After vancomycin treatment, the richness of microbiota considerably decreased, and the composition was altered. In particular, the relative abundance of Bacteroidetes decreased, whereas that of proteobacteria increased. In addition, changes in fecal metabolites, including D-glucuronic acid, were observed. However, systemic exposure of simvastatin was not changed whereas that of hydroxysimvastatin showed a tendency to increase. The relationship between the change of PKs of simvastatin and the change of gut microbiota and fecal metabolites were not clearly observed

Evaluation of the pathogenicity of GJB3 and GJB6 variants associated with nonsyndromic hearing loss

AbstractA number of genes responsible for hearing loss are related to ion recycling and homeostasis in the inner ear. Connexins (Cx26 encoded by GJB2, Cx31 encoded by GJB3 and Cx30 encoded by GJB6) are core components of gap junctions in the inner ear. Gap junctions are intercellular communication channels and important factors that are associated with hearing loss. To date, a molecular genetics study of GJB3 and GJB6 as a causative gene for hearing loss has not been performed in Korea. This study was therefore performed to elucidate the genetic characteristics of Korean patients with nonsyndromic sensorineural hearing loss and to determine the pathological mechanism of hearing loss by analyzing the intercellular communication function of Cx30 and Cx31 variants. Sequencing analysis of the GJB3 and GJB6 genes in our population revealed a total of nine variants, including four novel variants in the two genes. Three of the novel variants (Cx31-p.V27M, Cx31-p.V43M and Cx-30-p.I248V) and two previously reported variants (Cx31-p.V84I and Cx30-p.A40V) were selected for functional studies using a pathogenicity prediction program and assessed for whether the mutations were located in a conserved region of the protein. The results of biochemical and ionic coupling tests showed that both the Cx31-p.V27M and Cx31-p.V84I variants did not function normally when each was expressed as a heterozygote with the wild-type Cx31. This study demonstrated that two variants of Cx31 were pathogenic mutations with deleterious effect. This information will be valuable in understanding the pathogenic role of GJB3 and GJB6 mutations associated with hearing loss

Changes in the gut microbiome influence the hypoglycemic effect of metformin through the altered metabolism of branched-chain and nonessential amino acids

AIMS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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

Population pharmacokinetics of artesunate and dihydroartemisinin following single- and multiple-dosing of oral artesunate in healthy subjects

<p>Abstract</p> <p>Background</p> <p>The population pharmacokinetics of artesunate (AS) and its active metabolite dihydroartemisinin (DHA) were studied in healthy subjects receiving single- or multiple-dosing of AS orally either in combination with pyronaridine (PYR) or as a monotherapy with or without food.</p> <p>Methods</p> <p>Data from 118 concentration-time profiles arising from 91 healthy Korean subjects were pooled from four Phase I clinical studies. Subjects received 2-5 mg/kg of single- and multiple-dosing of oral AS either in combination with PYR or as a monotherapy with or without food. Plasma AS and DHA were measured simultaneously using a validated liquid chromatography- mass spectrometric method with a lower limit of quantification of 1 ng/mL for both AS and DHA. Nonlinear mixed-effect modelling was used to obtain the pharmacokinetic and variability (inter-individual and residual variability) parameter estimates.</p> <p>Results</p> <p>A novel parent-metabolite pharmacokinetic model consisting of a dosing compartment, a central compartment for AS, a central compartment and a peripheral compartment for DHA was developed. AS and DHA data were modelled simultaneously assuming stoichiometric conversion to DHA. AS was rapidly absorbed with a population estimate of absorption rate constant (Ka) of 3.85 h^-1. The population estimates of apparent clearance (CL/F) and volume of distribution (V2/F) for AS were 1190 L/h with 36.2% inter-individual variability (IIV) and 1210 L with 57.4% IIV, respectively. For DHA, the population estimates of apparent clearance (CLM/F) and central volume of distribution (V3/F) were 93.7 L/h with 28% IIV and 97.1 L with 30% IIV, respectively. The population estimates of apparent inter-compartmental clearance (Q/F) and peripheral volume of distribution (V4/F) for DHA were 5.74 L/h and 18.5 L, respectively. Intake of high-fat and high-caloric meal prior to the drug administration resulted in 84% reduction in Ka. Body weight impacted CLM/F, such that a unit change in weight resulted in 1.9-unit change in CLM/F in the same direction.</p> <p>Conclusions</p> <p>A novel simultaneous parent-metabolite pharmacokinetic model with good predictive power was developed to study the population pharmacokinetics of AS and DHA in healthy subjects following single- and multiple-dosing of AS with or without the presence of food. Food intake and weight were significant covariates for Ka and CLM/F, respectively.</p

Nonaspirin nonsteroidal anti-inflammatory drugs and hemorrhagic stroke risk: the Acute Brain Bleeding Analysis study

BACKGROUND AND PURPOSE: The relationship between nonaspirin nonsteroidal anti-inflammatory drugs (NANSAIDs) and hemorrhagic stroke (HS) remains unclear. We examined the risk of HS associated with the use of NANSAIDs in Koreans. METHODS: We performed a nationwide, multicenter case-control study from 2002 to 2004. This study included 940 nontraumatic acute HS cases in patients aged 30 to 84 years, with an absence of a history of stroke or hemorrhage-prone brain lesions, alongside 940 community controls, matched to each case by age and sex. Pretrained interviewers obtained information on prescription drugs as well as over-the-counter drugs taken within 14 days before the onset of stroke. We adjusted potential confounders, including family histories of stroke, histories of hypertension, smoking, alcohol consumption, high salt intake, and laborious work hours. The adjusted ORs and their 95% CIs were calculated by conditional logistic regression. RESULTS: The proportion of NANSAIDs exposure within 14 days was 2.9% for HS patients and 2.0% for the controls. The adjusted odds ratios of stroke in NANSAIDs users compared with nonusers was 1.12 (95% CI, 0.77 to 1.65) for all HS, 1.03 (95% CI, 0.49 to 2.18) for subarachnoid hemorrhage, and 1.19 (95% CI, 0.76 to 1.87) for intracerebral hemorrhage. CONCLUSIONS: No increased risk of HS either subarachnoid hemorrhage or intracerebral hemorrhage was found among NANSAIDs users.This study was partially supported by the Korean Food and Drug Administration

Intramural gallbladder hematoma mimicking gallbladder neoplasm in a 55-year-old male patient

Hemorrhage in the gallbladder (GB) is usually associated with cholecystitis, GB neoplasm, trauma, hemobilia, and cystic artery aneurysm. Our patient had not experienced any previous abdominal trauma, and GB hemorrhage was unlikely to result from cholecystitis or bleeding diathesis. A 55-year-old male was admitted because of right upper quadrant pain. Both prothrombin time and partial thromboplastin time were normal. Abdominal computed tomography, endoscopic ultrasound and magnetic resonance cholangiopancreatography were performed. Image studies revealed GB wall thickening and an intraluminal mass. Laparoscopic cholecystectomy was performed. Upon opening the GB postoperatively, a large amount of fresh blood and old blood clot was noted. The incidence of GB hematoma is very rare. GB hematoma should always be considered in the differential diagnosis of GB tumor. In such a situation, surgical intervention is needed for further patient evaluation and management. We present a rare case of intramural GB hematoma, of which we were unable to make a definitive diagnosis preoperatively