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Background: Clinical trials are widely used to approve the efficacy and discover adverse reactions of new drugs. However, there has been much concern about the unjustified exclusion of the older adults in clinical trials. The purpose of this study was to assess ageism in clinical trials and to find solution to any discovered discrimination. Methods: An online questionnaire was completed by 1,650 experts including doctors, pharmaceutical staff, and contract research organization members. An offline inquiry was conducted by 250 experienced professors from a single tertiary hospital and other allied professions. The questions covered the current state of elderly participation, possible reasons for under-representation, and plans for its solution. Results: Among 1,900 subjects, 246 (12.9%) individuals completed the survey. We excluded the six subjects who did not answer more than 10 questions, and analyzed the remaining 240 respondents. They agreed that there are tendencies to exclude the aged from clinical trials (69.2%), and that under-representation would cause difficulties for doctors and geriatric patients. Most people (84.6%) thought that treating older adults with the results from trials which exclude aged participants is inappropriate. Because respondents had difficulties explaining the trial process and obtaining informed consent, they thought establishing a geriatric clinical trial team would be highly effective. Experts also believed that financial inducements and legal regulations are required to increase elderly enrollment. Conclusion: Because the elderly have a unique physiology, the participation of older adults in clinical research is indispensable for verifying efficacy and determining potential adverse reactions. Consequently, clinical research professionals should be concerned about the participation of older subjects, and the authorities must begin to care about age discrimination in research fields. [ABSTRACT FROM AUTHOR]

Purpose: To compare surgical outcomes and complications after percutaneous nephrolithotomy (PCNL) under regional or general anesthesia. Materials and Methods: One hundred and one patients who underwent PCNL as a first-line treatment for kidney calculi between June 2004 and June 2013 were enrolled in this retrospective study. Patients were classified into two groups by anesthetic method: 77 were allocated to the regional anesthesia group and 24 to the general anesthesia group. Patient general characteristics, stone features, surgical outcomes, and complications were compared between the two groups. Results: The two groups were similar in terms of mean age and stone size, number, and type. Furthermore, they did not differ significantly in terms of general characteristics, treatment outcomes, or complications excluding postoperative fever. However, mean hospital stay was significantly shorter in the regional anesthesia group than in the general anesthesia group (8.9±3.2 days vs. 11.5±6.9 days, respectively, p=0.025). Also, the postoperative fever rate was significantly higher in the general anesthesia group (53.2% vs. 83.3%, respectively, p=0.007). Conclusions: Regional anesthesia is as effective as general anesthesia during percutaneous nephrolithotomy and is associated with shorter hospital stays and lower rates of postoperative fever. [ABSTRACT FROM AUTHOR]

Background Phenobarbital (PB), commonly used as the preferred treatment for neonatal seizure, is a drug that requires careful dose adjustments based on therapeutic drug monitoring. It has been reported that PB metabolism was affected by cytochrome P450 (CYP)2C19 polymorphisms in adults requiring dose adjustment. Aim This study aimed to evaluate the effects of CYP2C19 genetic polymorphisms on PB pharmacokinetics (PK) in neonates and infants with seizures. Methods CYP2C19 (wild type: CYP2C19*1/*1, heterozygous extensive metabolisers: CYP2C19*1/*2, *1/*3 and poor metabolisers: CYP2C19*2/*2, *2/*3) genetic polymorphisms in 52 neonates and infants with seizures were analysed. PK parameters were compared based on genotypes. The NONMEM program was used for population PK modelling. Results No significant difference in PB clearance (CL), volume of distribution (Vd) and concentrations were shown among the CYP2C19 genotype groups. The results of PK modelling were as follows: Vd=3590 ×(body weight (BWT)/4)0.766 ×(AGE/2)0.283 and CL=32.6×(BWT/4)1.21. Conclusions PB PK parameters of neonates and infants with seizures were not significantly different among the groups with different CYP2C19 genotypes. The addition of CYP2C19 genotyping to PK models did not improve the dosing strategies in neonates and infants. [ABSTRACT FROM AUTHOR]

Radiation-induced pneumonitis is closely associated with the interplay of various stress-activated signals and immune responses related to the progression of lung injury. Mitogen-activated protein (MAP) kinase pathways play critical roles in the progression of inflammation via a cellular damage. Here, we examined the regional distribution of phosphorylated MAP kinases (p-JNK, p-ERK, and p-p38) in the progression of pneumonitis after exposure of a single dose irradiation with 10 Gy for 0, 4, and 8 weeks in rats. Also, we identified positive cells for these kinases using specific cell-type markers related to inflammation and type II pneumocyte. p-JNK was present abundantly in activated macrophages, CD8+T-cells, peribronchiolar smooth muscle cells, and weakly type II pneumocytes at 4 weeks or 8 weeks after irradiation. p-p38 and p-ERK was predominantly expressed in macrophages, CD4+ T-cells, fibrotic cells as well as present in various lung parenchymal cells including alveolar epithelial cells and type II pneumocytes. In conclusion, it is considered that MAP kinase pathways play a pivotal role in early damage of residual cells as well as in the long-term regulation of distinct inflammatory cells during the progression of radiation-induced pneumonitis. [ABSTRACT FROM PUBLISHER]

Sibutramine is a pharmacologic intervention for the treatment of obesity. The effect of CYP2B6 genotypes on the pharmacokinetics of sibutramine and its active metabolites (desmethylsibutramine [M1] and didesmethylsibutramine [M2]) was evaluated in 57 healthy subjects. Each subject received a single oral dose of 10 or 15 mg sibutramine, and blood samples were collected up to 72 hours after dosing. The relationship between the genotypes and the pharmacokinetics of sibutramine, M1, and M2 was examined. A statistically significant difference in the elimination half-life (t 1/2) of sibutramine M1 was found among the 3 genotype groups (P = .0006), between the *1/*1 and *1/*6 groups (P = .0001), and between the *1/*4 and *1/*6 groups (P = .012). The mean value of M1 t1/2 in *1/*6 (33.3 ± 10.5 hours) was about 58% and 61% greater than that of the *1/*1 group (21.0 ± 7.4 hours) and the *1/*4 group (20.7 ± 9.8 hours), respectively. No significant differences in area under the concentration—time curve or maximum plasma drug concentration were observed between the groups. The CYP2B6*6 allele may be associated with a lower metabolic clearance of the M1 metabolite of sibutramine in human subjects. [ABSTRACT FROM PUBLISHER]

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • The phosphodiesterase (PDE) type 5 inhibitor is a widely used agent that facilitates penile erection. • Udenafil is newly developed as a PDE-5 inhibitor. WHAT THIS STUDY ADDS • This is the first study to determine the safety, tolerability and pharmacokinetics of udenafil in healthy subjects. • Udenafil was safe and well tolerated in healthy Korean subjects. • The AUC and Cmax of udenafil increased supraproportionally with increasing dose upon single administration, but there was no significant drug accumulation upon multiple administrations. AIM To evaluate the safety, tolerability and pharmacokinetics (PK) of udenafil, a novel phosphodiesterase type 5 inhibitor. METHODS A double-blind, randomized, placebo-controlled, dose-rising, parallel-group, single- and multiple-dose study was conducted in healthy Korean subjects. The subjects were allocated to single-dose groups of 25, 50, 100, 200 or 300 mg (eight subjects in each dose group, including two placebos), or to multiple-dose groups of 100 or 200 mg (once-daily dosing for 7 days; nine subjects in each dose group, including three placebos). Serial samples of blood and urine were collected after oral administration and the drug concentrations in plasma and urine were determined by high-performance liquid chromatography. Safety and tolerability were evaluated by monitoring clinical laboratory parameters and adverse events. RESULTS Udenafil reached peak plasma concentrations at 0.8–1.3 h, and then declined mono-exponentially with a terminal half-life of 7.3–12.1 h in the single-dose study. The area under the time–concentration curves (AUC) and maximum plasma concentrations ( Cmax) increased supraproportionally with increasing dose in the single-dose study. During multiple dosing, a steady state was reached at 5 days and little accumulation occurred after repeated dosing for 7 days. Udenafil was generally well tolerated in these healthy subjects, and no serious adverse events occurred. CONCLUSIONS Udenafil was safe and well tolerated in healthy volunteers. The AUC and Cmax of udenafil increased supraproportionally with increasing dose upon single administration, but there was no significant drug accumulation upon multiple administrations. [ABSTRACT FROM AUTHOR]

Abstract??The wound healing process is a highly orchestrated process, which includes inflammation, re-epithelialization, granulation tissue formation, matrix formation and re-modeling. In this paper, we attempt to determine if bio-active ceramic resource powder particles had an effect on cutaneous wound healing. Furthermore, we investigated its related mechanism and the expression of Smads of cutaneous wound healing, which can be accelerated by bio-active ceramic ointment. Topically applied lesions of 5%, 10% and 15% bio-active ceramic ointment (AO) showed accelerated wound closure, re-epithelialization, and the related immediate down stream of TGF-? (p-Smad2/3 and Smad3) was suppressed. In particular, 10% and 15% AO lesions became closed faster at Days 3 and 4 of post-wound and p-Smad2/3 was also suppressed. All AO lesions showed accelerated mild wound closure at Day 6, but there were no significant difference. Several papers reported that Smad3 may mediate the signaling pathways that is inhibitory to wound healing, as the deletion of Smad3 leads to enhanced re-epithelialization and contraction of the wound area. This study showed that topical, bio-active ceramic ointment applications accelerated wound closure, re-epithelialization and the suppression of Smad proteins (p-Smad2/3, Smad3). The data revealed that the suppression of Smad3, which was induced by bio-active ceramic resources powder particles affected re-epithelialization and cutaneous wound closure. At the end of this paper, we concluded that bio-active ceramic resources affect cutaneous wound healing by accelerating the re-epithelialization of keratinocytes and that is mediated by the suppression of related protein, Smad3. [ABSTRACT FROM AUTHOR]

Abstract??Glutamate is the major excitatory neurotransmitter in the central nervous system, and evidence for peripheral glutamatergic fibers in mammals is still lacking. However, glutamate receptors have been identified in peripheral organs, including taste buds, myenteric plexus, and pancreatic islet cell. Protection against anoxic damage could also be explained by mechanisms mediated by postsynaptic mGluR2 or mGluR3, such as the inhibition of membrane excitability resulting from a reduction of cAMP formation by a G-protein-dependent modulation of ion channels. In addition, activation of mGluR3 present in glial cells may contribute to neuroprotection by enhancing the production of death. Thus, mGluR2/3 behaves potentially as a major defensive mechanism anoxia-tolerant species. There are a few reports for the regional pattern of hypoxic damage, which was inversely related to the expression of mGluR2/3. The aim of this study was to characterize the expression of mGluR3 in hypoxic liver in experimental model of rat liver. Proteomic analysis of protein extracts from CCl4?induced cirrhotic liver revealed the presence?of the mGluR3. The presence of mGluR3 in the cirrhotic liver was confirmed by immunohistochemical analysis. There were a number of macrophages expressing mGluR3 mainly in the fibrous septa. After 2?weeks recovery, however, most of mGluR3 positive macrophages disappeared with collagen fibers. These results demonstrate that mGluR3 involved in the liver in response to persistent hypoxic status such as fibrotic/cirrhotic condition, and suggest that the expression of mGluR3 may be a key role functional metabolism and viability in the liver by interacting with the glutamate receptors in vivo. [ABSTRACT FROM AUTHOR]

To evaluate the pharmacokinetic and pharmacodynamic characteristics of YH1885, a novelproton pump inhibitor, a single-blind, randomized, placebo-controlled, dose-rising, parallel-group study was conducted in 46 healthy volunteers. The volunteers were randomly allocated to single dose groups of 60 mg, 100 mg, 150 mg, 200 mg, and 300 mg (6 subjects per dose, including 2 placebos) or to multiple-dose groups of 150 mg and 300 mg (once-daily dosing for 7 days; 8 subjects per dose, including 2 placebos). The multiple-dose study was conducted separately after the single-dose study. YH1885 was administered orally after overnight fasting. Serial blood samples, urine samples, and pharmacodynamic measurements were taken. Drug concentrations in plasma and urine were determined by liquid chromatography/mass spectrometry (LC/MS). Pharmacodynamic changes were evaluated by ambulatory intragastric pH monitoring and by serialmeas urements of serum gastrin concentrations. Assessments of safety and tolerability also were made. Plasma concentrations of YH1885 reached peak levels 1.3 to 2.5 hours after single-dose administration and then declined monoexponentially with a terminal half-life (t1/2) of 2.2 to 2.4 hours in dosage groups up to 200 mg in the single-dose study. YH1885 showed linear pharmacokinetic characteristics, and little accumulation occurred after multiple administrations. The parent drug was not detected in urine. Dose-related pharmacological effects were obvious for dose groups of 150 mg and higher in the single-dose study. The mean intragastric pH and the percentage of time at pH > 4were significantly increased. The onset of drug effect was rapid, and maximal effects were observed on the first day of administration during multiple dosing. Serum gastrin levels also showed rapid increases during dosing but with a weak doseeffect relationship. Neither serious nor dose-limiting adverse effects were observed. YH1885 was found to be safe and well tolerated and effectively inhibited acid secretion with dosedependent increases in intragastric pH. The acid-suppressing efficacy of YH1885 needs to be further evaluated in patients with gastric acid-related diseases. [ABSTRACT FROM AUTHOR]

Objective. To evaluate the effect of the CYP2D6 genotype on the pharmacokinetics of tropisetron in healthy Korean subjects. Methods. A single 5-mg capsule of tropisetron was administered orally to 13 healthy subjects. Plasma concentrations were determined by validated HPLC procedures and data were analyzed by using noncompartmental linear PK methods. Four alleles, CYP2D6*1, CYP2D6*2 ×2, CYP2D6*5, and CYP2D6*10, were identified by PCR. Results. Thirteen subjects, consisting of two homozygous carriers of the wild type allele (*1/*1), four heterozygous carriers of poor metabolizer (PM)-associated allele (*1/*10), six homozygous carriers of PM-associated alleles (four with *10/*10 and two with *5/*10), and one carrier of a duplicated allele *1/*2 ×2. All tested pharmacokinetic parameters (AUCinf, AUCinfNL70, Cmax, CmaxNL70, T1/2, and Tec) were significantly different among four different genotypic groups. The mean AUCs of carriers with the heterozygous PM-associated allele and the homozygous PM-associated allele were 1.9- and 6.8-higher than those of carriers with the wild type allele, respectively. In contrast, the mean AUC of carriers with a duplicated allele was 0.5-fold lower than that of those carriers with the wild type allele. Conclusion. The presence of CYP2D6*5, CYP2D6*10, and CYP2D6*2 ×2 has an important impact on the pharmacokinetics of tropisetron, which may influence clinical response to tropisetron therapy. [ABSTRACT FROM AUTHOR]

Abstract Background Excessive submental fat under the chin is a known aesthetic concern because of its negative impact on facial appearance and psychological well-being. AYP-101 is a newly developed injectable agent containing 93% soybean phosphatidylcholine (SPC) designed to reduce submental fat. We conducted a phase 1 study to evaluate the safety, pharmacokinetic (PK), and lipid profile effects of AYP-101. Methods This study was a randomized, double-blind, placebo-controlled, single-dose, two-cohort trial. Participants were randomized into groups receiving 250 mg of AYP-101, 500 mg of AYP-101, or placebo at a 9:9:8 ratio across both cohorts. Safety was assessed through standard clinical evaluations. Blood samples were collected up to 144 h postdose in cohort 1 and up to 48 h postdose in cohort 2. The PK parameters were calculated via noncompartmental analysis. Results All 26 randomized subjects completed the study. A total of 72 solicited adverse drug reactions (ADRs) were reported by 24 subjects, all of which were mild. The most common ADRs were injection site pain and bruising. There were 29 ADR cases in the 250 mg group; 26 cases in the 500 mg group; and 18 cases in the placebo group, indicating that there were no clinically significant differences in the safety profiles between the groups. All the dose groups presented similar PK profiles, with Cmax values of 12.86, 13.44, and 13.61 µg/L and AUC0−24 h values of 278.06, 274.79, and 267.63 µg*h/L, respectively. No clinically significant differences in PK or lipid profiles were observed between the postdose group and the baseline group for any of the dose groups. Conclusions AYP-101 appears to be a safe candidate for treating submental fat, with localized reactions and no systemic exposure at single subcutaneous doses of up to 500 mg. Trial registration ClinicalTrials.gov NCT05476094.

Histopathological findings of eosinophilic myositis in the carcass of a slaughtered Korean native cow are presented. Lesions contained massive fibrous septae with vacuolar changes in some lesions, and the hypercontraction and rupturing of muscle bundles, with replacement by eosinophils. Necrosis and severe eosinophil infiltration were observed. Sarcoplasmic fragmentation and atrophy developed. Typical of granuloma, calcified myofibers were focally surrounded by macrophages and numerous inflammatory cells, and multinucleated giant cell formation was evident. [ABSTRACT FROM AUTHOR]

AST-001, a novel syrup formulation of L-serine, was developed for the treatment of autism spectrum disorders (ASD) in pediatric patients. This study aimed to establish a pharmacokinetic (PK)-pharmacodynamic (PD) model to elucidate the effect of AST-001 on adaptive behavior in children with ASD. Due to the absence of PK samples in pediatric patients, a previously published population PK model was used to link the PD model by applying an allometric scale to body weight. The time courses of Korean-Vineland Adaptive Behavior Scale-II Adaptive Behavior Composite (K-VABS-II-ABC) scores were best described by an effect compartment model with linear drug effects (Deff, 0.0022 L/μg) and linear progression, where an equilibration half-life to the effect compartment was approximately 15 weeks. Our findings indicated a positive correlation between the baseline K-VABS-II-ABC score (E0, 48.51) and the rate of natural progression (Kprog, 0.015 day−1), suggesting enhanced natural behavioral improvements in patients with better baseline adaptive behavior. Moreover, age was identified as a significant covariate for E0 and was incorporated into the model using a power function. Based on our model, the recommended dosing regimens for phase III trials are 2, 4, 6, 10, and 14 g, administered twice daily for weight ranges of 10–13, 14–20, 21–34, 35–49, and >50 kg, respectively. These doses are expected to significantly improve ASD symptoms. This study not only proposes an optimized dosing strategy for AST-001 but also provides valuable insights into the PK-PD relationship in pediatric ASD treatment.

Abstract Introduction GB-5001 is an intramuscular (IM) formulation of donepezil under development for the treatment of Alzheimer’s disease. The objective of this study was to develop a population pharmacokinetic (PK) model for donepezil in both IM and oral formulations, and to optimize the IM dosage of GB-5001 using bioequivalence (BE) simulation. Methods A population PK model of donepezil was developed using NONMEM. It was based on plasma concentration data from a Phase 1 dose escalation study, which involved a single administration of donepezil IM formulation at doses of 70, 140, and 280 mg, and the oral formulation at 10 mg. The model was evaluated based on goodness-of-fit plots, conditional weighted residuals, visual predictive checks, and bootstrapping. BE simulations were conducted using a parallel design between various doses of the IM formulation and the 10-mg dose of oral formulation. Results The PKs of donepezil were best described by a two-compartment model, which incorporated distinct absorption compartments for the IM (dual first-order absorption and simultaneous zero-order absorption with lag time) and oral (first-order absorption with lag time) formulations. Based on the simulation results, an IM dosage range of 210–215 mg in a sample size of over 92 was estimated to achieve a success rate of approximately 80% for BE. Conclusion The population PK model well explained the PKs of donepezil following administration of both the IM and oral formulations. This model could be applied for the design and dose selection of future BE trials. Trial Registration ClinicalTrials.gov identifier, NCT05525780.

Abstract Fexuprazan, a novel potassium‐competitive acid blocker, is expected to be used for the prevention of nonsteroidal anti‐inflammatory drugs (NSAIDs) induced ulcer. This study aimed to evaluate pharmacokinetic (PK) interactions between fexuprazan and NSAIDs in healthy subjects. A randomized, open‐label, multicenter, six‐sequence, one‐way crossover study was conducted in healthy male subjects. Subjects randomly received one of the study drugs (fexuprazan 40 mg BID, celecoxib 200 mg BID, naproxen 500 mg BID, or meloxicam 15 mg QD) for 5 or 7 days in the first period followed by the combination of fexuprazan and one of NSAIDs for the same days and the perpetrator additionally administered for 1–2 days in the second period. Serial blood samples for PK analysis were collected until 48‐ or 72‐h post‐dose at steady state. PK parameters including maximum plasma concentration at steady state (Cmax,ss) and area under plasma concentration–time curve over dosing interval at steady state (AUCτ,ss) were compared between monotherapy and combination therapy. The PKs of NSAIDs were not significantly altered by fexuprazan. For fexuprazan, differences in PK parameters (22% in Cmax, 19% in AUCτ,ss) were observed when co‐administered with naproxen, but not clinically significant. The geometric mean ratio (90% confidence interval) of combination therapy to monotherapy for Cmax,ss and AUCτ,ss was 1.22 (1.02–1.46) and 1.19 (1.00–1.43), respectively. There were no significant changes in the systemic exposure of fexuprazan by celecoxib and meloxicam. Fexuprazan and NSAIDs did not show clinically meaningful PK interactions.

Abstract Genetic variants affect drug responses, making pre‐emptive genotyping crucial for averting serious adverse events (SAEs) and treatment failure. However, assessing the benefits of pre‐emptive genotyping based on genetic distribution, drug exposure, and demographics is challenging. This study aimed to estimate the population‐level benefits of pre‐emptive genotyping in the Korean population using nationwide cohort data. We reviewed actionable gene‐drug combinations recommended by both the Clinical Pharmacogenomics Implementation Consortium (CPIC) and the Dutch Pharmacogenetics Working Group (DPWG) as of February 2022, identifying high‐risk phenotypes. We collected reported risk reduction from genotyping and standardized it into population attributable risks. Healthcare reimbursement costs for SAEs and treatment failures were obtained from the Health Insurance Review and Assessment Service Statistics in 2021. The benefits of pre‐emptive genotyping for a specific group were determined by multiplying drug exposure from nationwide cohort data by individual genotyping benefits. We identified 31 gene‐drug‐event pairs, with CYP2D6 and CYP2C19 demonstrating the greatest benefits for both male and female patients. Individuals aged 65–70 years had the highest individual benefit from pre‐emptive genotyping, with $84.40 for men and $100.90 for women. Pre‐emptive genotyping, particularly for CYP2D6 and CYP2C19, can provide substantial benefits.

Abstract To investigate pharmacokinetic and pharmacodynamic differences of zolpidem between males and females and their causes, including CYP3A4 activity. A single oral dose of zolpidem (10 mg) was administered to 15 male and 15 female healthy subjects. Blood samples were collected up to 12 h post-dose to determine plasma zolpidem concentrations. Pharmacokinetic parameters were obtained using non-compartmental analysis. Digit symbol substitution test, choice reaction time, and visual analog scale of sleepiness were used to evaluate pharmacodynamics. We measured CYP3A4 activity using 4β-hydroxycholesterol, an endogenous metabolite. Mean maximum plasma concentration and area under the plasma concentration–time curve were higher for females than for males (9.9% and 32.5%, respectively); other pharmacokinetic parameters showed no significant differences. Pharmacodynamic scores for females showed delayed recovery compared with that for males. CYP3A4 activity was higher in females than in males (p = 0.030). There was no serious adverse event, and adverse event incidence was not different between the sexes. Zolpidem exposure was about 30% higher in females than in males. Delayed pharmacodynamic score recovery in females could be related to higher zolpidem concentrations. Although apparent clearance was lower in females, systemic clearance might not be the cause of the different exposures to zolpidem.

Abstract Metformin is a major treatment for type 2 diabetes. This study was conducted to investigate the impact of gut microbiome dysbiosis on the pharmacokinetics and antihyperglycemic effects of metformin. Healthy adult males aged 19–45 years with no defecation abnormalities were recruited for this 4‐period clinical study: baseline; post‐metformin (i.e., multiple oral doses of 1000 mg metformin on days 1–4); post‐vancomycin (i.e., multiple oral doses of 500 mg vancomycin on days 11–17 inducing gut microbiome changes); and post‐metformin + vancomycin (i.e., multiple oral doses of 1000 mg metformin on days 16–19). In each period, serum glucose and insulin concentrations following an oral glucose tolerance test, fecal samples for gut microbiome composition, and safety data were obtained. Following metformin dosing, plasma and urine samples for pharmacokinetics were collected. Nine subjects completed the study. The pharmacokinetics of metformin remained unchanged, and the antihyperglycemic effect was significantly decreased after vancomycin administration (p value = 0.039), demonstrating the weak relationship between the pharmacokinetics and pharmacodynamics of metformin. Relative abundances of some genus were changed after vancomycin administration, and tended to correlate with the antihyperglycemic effects of metformin (p value = 0.062 for Erysipelatoclostridium; p value = 0.039 for Enterobacter; and p value = 0.086 for Faecalibacterium). Adverse events occurred in all subjects and were resolved without sequelae. In conclusion, a decrease in the antihyperglycemic effect of metformin was observed after concomitant administration with vancomycin, without changes in metformin pharmacokinetics. The antihyperglycemic effect was tended to correlate with the relative abundance of several genus, suggesting that the effect of metformin is partly attributable to the gut microbiome (ClinicalTrials.gov, NCT03809260).

Abstract Purpose Herpes zoster (HZ), or shingles, is a clinical syndrome resulting from the reactivation of latent varicella zoster virus (VZV) within the sensory ganglia. We evaluated the safety and tolerability of ES16001 (ethanol extract of Elaeocarpus sylvestris var. ellipticus), a novel inhibitor of varicella zoster virus reactivation in healthy adults. Method Single-center, randomized, double-blind, placebo-controlled, single and multiple ascending dose (SAD and MAD, respectively) studies were conducted in 20- to 45-year-old healthy adults without chronic disease. In the SAD study (n = 32), subjects randomly received a single oral dose of 240, 480, 960, or 1440 mg ES16001 or a placebo. In the MAD study (n = 16), subjects randomly received once daily doses of 480 or 960 mg ES16001 or a placebo for 5 days. The safety and tolerability of the drug were evaluated by monitoring participants’ treatment emergent adverse events (TEAEs) and vital signs, electrocardiograms (ECGs), physical examinations, and clinical laboratory tests. Results In the SAD study, 11 adverse reactions were seen in 5 subjects, and in the MAD study, 8 adverse reactions were seen in 6 subjects. All adverse reactions were mild, and no serious adverse reactions occurred. The most common adverse reaction was an increase in alanine aminotransferase (ALT), but all test values were in the clinically non-significant range, and their clinical significance was judged to be small considering the fact that most of the test values returned to normal immediately after the end of drug administration. Conclusion ES16001 has good safety and tolerability when administered both once and repeatedly to healthy subjects. Further research is needed to identify any possible drug-induced hepatotoxicity, which appears infrequently. Our findings provide a rationale for further clinical investigations of ES16001 for the prevention of HZ. Trial registration: CRIS, KCT0006066. Registered 7 April 2021—Retrospectively registered, https://cris.nih.go.kr/cris/search/detailSearch.do/19071 ).