Pharmacogenetic Analysis of an 8-Year Old Girl with Reye Syndrome Associated with Use of Naproxen.

BACKGROUND Reye syndrome is a rare, yet potentially life-threatening disease characterized by acute encephalopathy and hepatic failure. This report presents the case of an 8-year-old girl with Reye syndrome and seizures after the use of naproxen. CASE REPORT An 8-year-old girl experienced a 3-day episode of fever and abdominal pain. After receiving naproxen (375 mg twice daily) starting from day -3, she exhibited hypotension, tonic seizure, and loss of consciousness (day 1). Physical examination and laboratory test results revealed acute kidney injury, metabolic acidosis, and elevated levels of lactate dehydrogenase (LDH), liver enzymes, and ferritin. On day 2, the maximum values of aspartate aminotransferase, alanine aminotransferase, LDH, creatinine, and ferritin were 955 U/L, 132 U/L, 8040 U/L, 2 mg/dL, and >40000 ug/L, respectively. She was given supportive care and recovered after 11 days (day 12), with normalization of kidney function and metabolic abnormalities. To identify possible genetic polymorphisms associated with the patient's symptoms, genotypes were tested using a drug metabolizing enzymes and transporters (DMET) gene chip. Among genes involved in the metabolism of naproxen, UGT1A6 (*1/*2) and UGT2B7 (*1/*2) resulted in possibly decreased function. Other results which may have had clinical significance included homozygote results for NAT2*6/*6 (rs1799930). CONCLUSIONS A rare case of Reye syndrome after administration of naproxen was presented in this case. A DMET gene chip was used to screen for possible genetic polymorphisms associated with Reye syndrome, but the result was inconclusive.

DLM-DTI: a dual language model for the prediction of drug-target interaction with hint-based learning.

The drug discovery process is demanding and time-consuming, and machine learning-based research is increasingly proposed to enhance efficiency. A significant challenge in this field is predicting whether a drug molecule's structure will interact with a target protein. A recent study attempted to address this challenge by utilizing an encoder that leverages prior knowledge of molecular and protein structures, resulting in notable improvements in the prediction performance of the drug-target interactions task. Nonetheless, the target encoders employed in previous studies exhibit computational complexity that increases quadratically with the input length, thereby limiting their practical utility. To overcome this challenge, we adopt a hint-based learning strategy to develop a compact and efficient target encoder. With the adaptation parameter, our model can blend general knowledge and target-oriented knowledge to build features of the protein sequences. This approach yielded considerable performance enhancements and improved learning efficiency on three benchmark datasets: BIOSNAP, DAVIS, and Binding DB. Furthermore, our methodology boasts the merit of necessitating only a minimal Video RAM (VRAM) allocation, specifically 7.7GB, during the training phase (16.24% of the previous state-of-the-art model). This ensures the feasibility of training and inference even with constrained computational resources.

Analysis of the distribution of trial sites in South Korea using social network analysis.

Location of trial sites can be a potential source of study bias. Considering that clinical trials have been mostly conducted in urban areas, the distribution of trial sites need to be evaluated. We analyzed clinical trial approval data using social network analysis to quantitatively assess the site-by-site connections. The approval list of clinical trials from the Ministry of Food and Drug Safety database between 2014 and 2021 was analyzed. The number of clinical trials per trial site was counted according to the approval year and study phase and evaluated for distribution using empirical cumulative distribution function plots. Trial sites and conducts of a clinical trial were mapped into nodes and edges in the social network analysis, and basic network parameters were obtained. The clinical trials were concentrated at several trial sites. Forty-nine to 60.6% of phase 1 and up to 30% of the other study phases of clinical trials were at the top 5 trial sites. The annual distribution of the number of clinical trials per site was comparable across the study period. Connections among the trial sites in the metropolitan area were prominent. Graph size and density were higher in phase 3 trials than in the other phases. We demonstrated that the conduct of clinical trials was concentrated in the Seoul Metropolitan Area in both number of trials and connections using social network analysis.

Considerations for clinical evaluation of the effects of bariatric surgery on the pharmacokinetics of orally administered drugs.

Obesity has been a growing worldwide concern, and surgical intervention including bariatric surgery is considered as one of the options for treatment. However, there still is controversy over the change in pharmacokinetics (PKs) of drugs after the surgery. To investigate the potential covariates that can influence the area under the curve (AUC) and maximum plasma concentration (Cmax), the design of previous studies was reviewed based on pre-determined eligibility criteria. Each study calculated the ratios of the AUC and Cmax before and after bariatric surgery. These studies investigated whether the PK parameters were affected by the time after the surgery or by the type of control group. The ratio of the AUC calculated in the early and late follow-up period was similar across Roux-en Y gastric bypass patients. No significant difference in the PK parameters was found between the pre-surgical patients and matched healthy subjects. However, certain control groups could be preferable depending on the purpose of the clinical trial. Although Cmax was inconsistent compared to the AUC, insufficient sampling of the time points may have caused such an inconsistency. This is the first article exploring the appropriate methodology in designing clinical studies for changes in the PK characteristics of orally administered drugs in patients with bariatric surgery.

Therapeutic drug monitoring on the use of transplacental digoxin in fetal tachyarrhythmia: a case report.

Fetal tachycardia (FT) is a rare disorder and is associated with significant mortality of fetus. Digoxin is one of the antiarrhythmic agents used to treat FT via transplacental therapy. In this report, we describe a therapeutic drug monitoring (TDM) case of digoxin during the treatment of FT. A 40-year-old woman, gravida 2 para 1, hospitalized to control FT as the fetal heart rate (FHR) showed over 200 bpm on ultrasonography at 29 weeks of gestation. She did not have any medical or medication history and showed normal electrolytes level on clinical laboratory test results. For the treatment of FT loading and maintenance dose of intravenous digoxin (loading dose: 0.6 mg; maintenance dose: 0.3 mg every 8 hours) were administered. To monitor the efficacy and safety of the treatment, TDM was conducted with a target maternal serum trough digoxin concentration of 1.0 to 2.0 ng/mL, as well as ultrasonography and maternal electrocardiogram. The observed digoxin serum concentrations were 0.67, 0.83, and 1.05 ng/mL after 1, 2, and 5 days after the initiation of digoxin therapy, respectively. Although the serum digoxin concentrations reached the target range, the FHR did not improve. Therefore, digoxin was discontinued, and oral flecainide therapy was started. The FHR adjusted to the normal range within 2 days from changing treatment and remained stable. TDM of digoxin along with the monitoring of clinical responses can give valuable information for decision-making during the treatment FT.

METORY: Development of a Demand-Driven Blockchain-Based Dynamic Consent Platform Tailored for Clinical Trials.

The recent advent of the dynamic consent concept intensified the data integrity issue in clinical trials. Incorporating blockchain technology into a dynamic consent platform can be a feasible solution. Due to various clinical trial settings, a demand-driven development strategy is required. We developed a blockchain-based dynamic consent platform named METORY tailored for clinical trials. The platform consisted of three parts: web and mobile application user interface, study management platform, and blockchain platform. Hyperledger Fabric, an enterprise-grade private blockchain framework, was used to integrate blockchain into the study consent platform. We conducted user acceptance tests and applied feedback to the improvement of the platform. Identity and role-based access control was constructed by combining mobile-application-based certificate system and access control functionalities in Hyperledger fabric. Data were encrypted using SHA-256 prior to transmission to blockchain server and TLS protocol was used for in-transit encryption. File-system level encryption was separated implemented within the security measures from Amazon RDS. Users' experience in the clinical trial was acceptable in the ease and usefulness of the platform.

The necessary conduct: Exploratory multiregional clinical trials in East Asia.

Various studies have highlighted the importance of ethnic differences. The consideration of ethnic differences in the field of individualized pharmacotherapy is imperative. Therefore, various organizations and networks across countries should aim to conduct multicountry and multiregional clinical trials (MRCTs). If there is solid evidence available to evaluate the existence of ethnic differences between the same regional areas, it will lead to an increase in the efficiency of drug development. The purpose of this paper was to compare the approval dosing regimen among four Asian countries (Korea, Japan, China, and Taiwan) and elucidate the readiness and current status of the implementation of the International Conference on Harmonization (ICH) E17 guidelines on MRCTs. Reducing unnecessary clinical trials via multinational clinical trials in East Asian countries is also suggested. The approved dosing regimens for some drugs in the four Asian countries were similar; however, some differences might be caused by differences in legislation, even though there were no ethnic differences. This indicates that there are several roles to be expected of the Asia Clinical Pharmacology study network for exploratory MRCTs, which would lead to the accumulation of evidence for MRCTs, ultimately accelerating the efficiency of drug development in East Asian countries. The exposure of the new treatment to the necessary patients through collaborative research coordination and simultaneous multinational subject recruitment would serve its role in providing East Asia with specific personalized medicine with a high treatment success rate.

Hepatic Adaptation to Therapeutic Doses of Acetaminophen: An Exploratory Study in Healthy Individuals.

PURPOSE: Acetaminophen (APAP) has hepatotoxic potential when overdosed. Recent studies have reported serum alanine aminotransferase (ALT) elevations that resolve spontaneously with continued use of the drug, referred to as adaptation, in several individuals receiving therapeutic doses of APAP. However, the clinical significance of these ALT elevations remains unclear. This study was performed to investigate the incidence and characteristics of hepatic adaptation to therapeutic doses of APAP in healthy individuals. METHODS: In a randomized, single-blind, placebo-controlled study, 242 healthy Japanese individuals were enrolled. Each person received 3 g/d of APAP (n = 202) or placebo (n = 40) for 28 days. All study participants underwent analysis of genetic polymorphisms of CYP2E1 and UGT1A1; measurements of plasma APAP concentration and urine metabolites (glucuronide, sulfate, cysteine, and mercapturate); liver function monitoring, including ALT, microRNA-122, and high-mobility group box 1. Individuals with ALT levels remaining below the upper limit of normal (ULN; 40 U/L) during the study period were defined as tolerant and those with ALT elevations above the ULN as susceptible. Susceptible individuals who developed ALT elevations exceeding 2 × ULN discontinued use of the study drug for tolerability consideration. Susceptible individuals who had ALT elevations that decreased toward the ULN spontaneously with continued use of the study drug were classified as adaptation. FINDINGS: In the APAP group, 129 individuals (66%) were classified as tolerant and 65 (34%) as susceptible. Among 65 susceptible individuals, 12 (18%) discontinued use of APAP because of ALT elevations (>2 × ULN), whereas 53 (82%) completed 28-day APAP dosing. Thirty of 65 susceptible individuals (46%) had adaptation within 28 days. In the placebo group, no individuals was withdrawn from the study because of elevated ALT levels, 33 individuals (89%) were classified as tolerant, and 4 (11%) were classified as susceptible. None had clinical signs of liver injury. ALT level correlated significantly with microRNA-122 but not with high-mobility group box 1. No association was found between plasma APAP concentrations and ALT levels. Urinary excretion of APAP mercapturate was higher in susceptible than in tolerant individuals (P = 0.018, Wilcoxon or Kruskal-Wallis test). The frequency of homozygotes and compound heterozygotes for UGT1A1∗28 and UGT1A1∗6 (∗28/∗28, ∗6/∗6, and ∗6/∗28) was higher in susceptible than in tolerant individuals (13.9% vs 3.9%; P = 0.011, χ2 test). IMPLICATIONS: These findings indicate that in healthy individuals, APAP at a therapeutic dose can cause transient and self-limiting ALT elevation, reflecting subclinical hepatocellular damage, and these ALT elevations may be associated with the disposition of APAP metabolites and genetic factors. UMIN-CTR identifier: UMIN000019607.

Delta-shaped anastomosis vs circular stapler anastomosis after laparoscopic distal gastrectomy with Billroth I reconstruction: A randomized controlled trial.

INTRODUCTION: The aim of this study is to evaluate the efficacy of delta-shaped anastomosis compared to circular stapler anastomosis in laparoscopic distal gastrectomy with Billroth I reconstruction. METHODS: This is a single-center randomized controlled study. Eligibility criteria included histologically proven gastric adenocarcinoma in the lower third of the stomach, clinical stage I tumor. Patients were preoperatively randomized to circular stapler anastomosis or delta-shaped anastomosis. The primary endpoint is the number of analgesics used during three days after surgery. We compared the surgical outcomes of the two groups. Postoperative quality of life was evaluated using the Postgastrectomy Syndrome Assessment Scale-45. This trial was registered at the UMIN Clinical Trials Registry as UMIN000025160. RESULTS: Between December 2016 and September 2018, 39 patients (delta-shaped anastomosis 18, circular stapler anastomosis 21) were enrolled. There was no difference in the number of analgesics used during three days after surgery (median nine: delta-shaped anastomosis vs nine: circular stapler anastomosis, P = .91). There was no difference in the overall proportion with in-hospital grade II-IIIB surgical complications (11%: delta-shaped anastomosis, 14%: circular stapler anastomosis). There was no operation-related death in either arm. Regarding postoperative quality of life evaluated one month after surgery, diarrhea subscale was significantly worse in delta-shaped anastomosis than in circular stapler anastomosis. CONCLUSION: We did not demonstrate the advantage of delta-shaped anastomosis in terms of postoperative pain. Since delta-shaped anastomosis tended to cause postoperative abdominal symptoms related to diarrhea, we should carefully apply the delta-shaped anastomosis to laparoscopic distal gastrectomy with Billroth I reconstruction.

Safety and Feasibility of Robotic Distal Gastrectomy for Stage IA Gastric Cancer: A Phase II Trial.

BACKGROUND: Conventional laparoscopic and open distal gastrectomy procedures have inherent limitations such as restricted movement of straight forceps and tremor of the tip of the devices that can potentially be overcome using robotic distal gastrectomy (RDG). This single-institutional phase II trial aimed to evaluate the safety and feasibility of RDG with lymph node dissection for clinical stage IA gastric cancer. METHODS: The study included patients with clinical stage IA gastric cancer in the lower two-thirds of the stomach considered to be curatively resected via distal gastrectomy. The primary end point was the proportion of patients who developed intra-abdominal complications, requiring medical or interventional treatment. The planned sample size was 25, calculated based on an expected complication rate of 3% and a threshold complication rate of 15%, with a one-sided alpha of 10%, power of 70%. RESULTS: Overall postoperative complications rate was 16%. The proportion of patients who developed intra-abdominal complications, requiring treatment was 0% (90% confidence interval, 0-9.8%). No patient developed in-hospital adverse events of grade 3 or higher. The short-term clinical outcomes were as follows: the median duration of postoperative hospital stay was 7 d, and 10 patients (40.0%) had a body temperature of 38°C or higher during their hospital stay. CONCLUSIONS: This trial confirmed the safety of RDG with limitation by the restriction of dedicated surgeons. A phase III trial to confirm the superiority of RDG to conventional laparoscopic distal gastrectomy is warranted.

Population Pharmacokinetic-Pharmacodynamic Analysis to Compare the Effect of Moxifloxacin on QT Interval Prolongation Between Healthy Korean and Japanese Subjects.

PURPOSE: The goal of this study was to evaluate the moxifloxacin-induced QT interval prolongation in healthy male and female Korean and Japanese volunteers to investigate interethnic differences. METHODS: This multicenter, randomized, double-blind, placebo-controlled, 2-way crossover study was conducted in healthy male and female Korean and Japanese volunteers. In each period, a single dose of moxifloxacin or placebo 400 mg was administered orally under fasting conditions. Triplicate 12-lead ECGs were recorded at defined time points before, up to 24 hours after dosing, and at corresponding time points during baseline. Serial blood sampling was conducted for pharmacokinetic analysis of moxifloxacin. The pharmacokinetic-pharmacodynamic data between the 2 ethnic groups were compared by using a typical analysis based on the intersection-union test and a nonlinear mixed effects method. FINDINGS: A total of 39 healthy subjects (Korean, male: 10, female: 10; Japanese, male: 10, female: 9) were included in the analysis. The concentration-effect analysis revealed that there was no change in slope (and confirmed that the difference was caused by a change in the pharmacokinetic model of moxifloxacin). A 2-compartment model with first-order absorption provided the best description of moxifloxacin's pharmacokinetic parameters. Weight and sex were selected as significant covariates for central volume of distribution and intercompartmental clearance, respectively. An Emax model (E[C]=[Emax⋅C]/[EC50+C]) described the QT interval data of this study well. However, ethnicity was not found to be a significant factor in a pharmacokinetic-pharmacodynamic link model. IMPLICATIONS: The drug-induced QTc prolongations evaluated using moxifloxacin as the probe did not seem to be significantly different between these Korean and Japanese subjects. ClinicalTrials.gov identifier: NCT01876316.