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Background: This phase 2b/3, randomized, placebo‐controlled trial explored the efficacy and evaluated the safety of ensitrelvir. This trial involved individuals with asymptomatic infection with severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) and patients with mild symptoms of coronavirus disease 2019 (COVID‐19). Methods: The trial was conducted at 57 medical institutions in Japan, South Korea, and Vietnam (study period: January 6–August 14, 2022). Eligible participants were randomized (1:1:1) to the ensitrelvir 125‐mg, ensitrelvir 250‐mg, or placebo group, received the allocated intervention orally, and were followed up until Day 28. Participants self‐rated the severity of 14 typical COVID‐19 symptoms and recorded the data in an electronic diary. Results: In total, 572 participants (194, 189, and 189 in the ensitrelvir 125‐mg, ensitrelvir 250‐mg, and placebo groups, respectively) were included in the intention‐to‐treat population. Ensitrelvir 125‐mg group observed a 77% reduction in the risk of developing any of the 14 COVID‐19 symptoms or fever and a 29% reduction in the risk of worsening of such symptoms or fever versus placebo (statistically nonsignificant). The viral RNA, viral titer, and time to infectious viral clearance observed a statistically significant decrease versus placebo. Most treatment‐related adverse events (TEAEs) were mild to moderate in severity, and the most common TEAE observed across groups was a decrease in high‐density lipoprotein. Conclusions: Our exploratory results suggest a potential reduction in the risk of development or worsening of COVID‐19 symptoms with ensitrelvir. Ensitrelvir showed antiviral efficacy and was well tolerated. Trial Registration: Japan Registry of Clinical Trials identifier: jRCT2031210350. [ABSTRACT FROM AUTHOR]

In a post‐hoc analysis of the phase 3 BLOCKSTONE study (JapicCTI‐184180), we investigated household transmission of baloxavir‐resistant (PA/I38X) influenza viruses. Using baloxavir resistance rates from prior clinical trials and the rate of influenza transmission observed in the study, the predicted number of PA/I38X transmission events was 4.8, assuming wild type and PA/I38X viruses were equally transmissible. However, no PA/I38X viruses were observed. These results suggest a low potential for baloxavir‐resistant influenza virus transmission from treated to untreated individuals, potentially due to reduced viral/transmission fitness for PA/I38X viruses and/or low viral titres at the time when resistant viruses arise. [ABSTRACT FROM AUTHOR]

Baloxavir marboxil (BXM) demonstrated a rapid and profound decline in infectious viral titer 1 day after BXM administration. Rapid reduction in virus titer is a characteristic of BXM. There may be a possibility that drug carryover effects have impacts on the observed antiviral effects due to the poor correlation that was observed between viral titer reduction and alleviation of influenza symptoms. Here, we report possible carryover effects of baloxavir acid (BXA), an active form of BXM, on infectious titer testing. Our findings indicate that there is little impact of BXA carryover on the infectious titer testing. [ABSTRACT FROM AUTHOR]

Background: Alcohol‐related liver disease is the main cause of liver‐related mortality worldwide. The development of novel targeted therapies for patients with advanced forms (i.e., alcoholic hepatitis, AH) is hampered by the lack of suitable animal models. Here, we developed a novel mouse model of acute‐on‐chronic alcohol liver injury with cholestasis and fibrosis and performed an extensive molecular comparative analysis with human AH. Methods: For the mouse model of acute‐on‐chronic liver injury, we used 3,5‐diethoxycarbonyl‐1,4‐dihydrocollidine (DDC, 0.05% w/w) diet for 8 weeks to establish cholestatic liver fibrosis. After 1‐week washout period, male mice were fed intragastrically for 4 weeks with up to 24 g/kg of ethyl alcohol in a high‐fat diet. This animal model was phenotyped using histopathology, clinical chemistry, microbiome, and gene expression approaches. Data were compared to the phenotypes of human alcohol‐related liver disease, including AH. Results: Mice with cholestatic liver fibrosis and subsequent alcohol exposure (DDC + EtOH) exhibited exacerbated liver fibrosis with a pericellular pattern, increased neutrophil infiltration, and ductular proliferation, all characteristics of human AH. DDC administration had no effect on urine alcohol concentration or liver steatosis. Importantly, DDC‐ and alcohol‐treated mice showed a transcriptomic signature that resembled that of patients with AH. Finally, we show that mice in the DDC + EtOH group had an increased gut barrier dysfunction, mimicking an important pathophysiological mechanism of human AH. Conclusions: We developed a novel mouse model of acute‐on‐chronic cholestatic alcoholic liver injury that has considerable translational potential and can be used to test novel therapeutic modalities for AH. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma ( HCC) is a prevalent human cancer with rising incidence worldwide. Human HCC is frequently associated with chronic liver inflammation and cirrhosis, pathophysiological processes that are a consequence of chronic viral infection, disturbances in metabolism, or exposure to chemical toxicants. To better characterize the pathogenesis of HCC, we used a human disease-relevant mouse model of fibrosis-associated hepatocarcinogenesis. In this model, marked liver tumor response caused by the promutagenic chemical N-nitrosodiethylamine in the presence of liver fibrosis was associated with epigenetic events indicative of genomic instability. Therefore, we hypothesized that DNA copy number alterations ( CNAs), a feature of genomic instability and a common characteristic of cancer, are concordant between human HCC and mouse models of fibrosis-associated hepatocarcinogenesis. We evaluated DNA CNAs and changes in gene expression in the mouse liver (normal, tumor, and nontumor fibrotic tissues). Additionally, we compared our findings to DNA CNAs in human HCC cases (tumor and nontumor cirrhotic/fibrotic tissues) using publicly available data from The Cancer Genome Atlas ( TCGA). We observed that while fibrotic liver tissue is largely devoid of DNA CNAs, highly frequently occurring DNA CNAs are found in mouse tumors, which is indicative of a profound increase in chromosomal instability in HCC. The cross-species gene-level comparison of CNAs identified shared regions of CNAs between human fibrosis- and cirrhosis-associated liver tumors and mouse fibrosis-associated HCC. Our results suggest that CNAs most commonly arise in neoplastic tissue rather than in fibrotic or cirrhotic liver, and demonstrate the utility of this mouse model in replicating the molecular features of human HCC. [ABSTRACT FROM AUTHOR]

ABSTRACT Traditional biomarkers such as alanine and aspartate aminotransferase (ALT, AST) and total bilirubin (TBIL) have been widely used for detecting drug-induced liver injury (DILI). Although the Food and Drug Administration (FDA) proposed standardized thresholds for human as Hy's law, those for animals have not been determined, and predictability of these biomarkers for future onset of hepatic lesions remains unclear. In this study, we investigated these diagnostic and predictive performance of 10 traditional biomarkers for liver injury by receiver-operating characteristic (ROC) curve, using a free-access database where 142 hepatotoxic or non-hepatotoxic compounds were administrated to male rats ( n = 5253). Standardization of each biomarker value was achieved by calculating the ratio to control mean value, and the thresholds were determined under the condition of permitting 5% false positive. Of these 10 biomarkers, AST showed the best diagnostic performance. Furthermore, ALT and TBIL also showed high performance under the situation of hepatocellular necrosis and bile duct injury, respectively. Additionally, the availability of the diagnostic thresholds in difference testing facility was confirmed by the application of these thresholds to in-house prepared dataset. Meanwhile, incorrect diagnosis by the thresholds was also observed. Regarding prediction, all 10 biomarkers showed insufficient performance for future onset of hepatic lesions. In conclusion, the standardized diagnostic thresholds enable consistent evaluation of traditional biomarkers among different facilities, whereas it was suggested that novel biomarker is required for more accurate diagnosis and prediction of DILI. Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

ABSTRACT Cardiotoxicity is one of the major safety concerns in drug development. Therefore, detecting and monitoring cardiotoxicity throughout preclinical and clinical studies is important for pharmaceutical companies. The present study was conducted in order to explore a plasma miRNA biomarker for cardiotoxicity in rats. As organ specificity is an important factor for a biomarker, we analyzed the miRNA microarray dataset in 55 organs/tissues in normal male rats. Based on this analysis, 5 miRNAs consisting of miR-208 (heart-specific), miR-1, miR-133a, miR-133b (heart and skeletal muscle-specific) and miR-206 (skeletal muscle-specific) were selected. Next, we evaluated the usefulness of those 5 miRNAs as circulating biomarkers in rats administered with single-dose isoproterenol or doxorubicin. Plasma miR-208 was consistently increased through 24 h after dosing in rats administered with isoproterenol, whereas plasma concentrations of cardiac troponin (cTn) showed transient elevation. In contrast, the plasma levels of miR-1, miR-133a, miR-133a and miR-206 were elevated after treatment with doxorubicin, probably as a result of skeletal muscle toxicity. Additionally, the plasma miR-208 level was elevated even after repeat-dose administration (once daily for 7 days) of isoproterenol under which the pathological condition proceeded to the sub-chronic phase such as fibrosis. Thus, our data suggest that miR-208 is a promising plasma biomarker for cardiotoxicity in rats. Monitoring of plasma miR-208 levels in rats may lead to more accurate evaluation of cardiotoxicity in preclinical studies. Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

ABSTRACT Nephrotoxicity is a common side effect observed during both nonclinical and clinical drug development investigations. The present study aimed to identify metabolomic biomarkers that could provide early and sensitive indication of nephrotoxicity in rats. Metabolomic analyses were performed using capillary electrophoresis-time-of-flight mass spectrometry on rat plasma collected at 9 and 24 h after a single dose of 2-bromoethylamine or n-phenylanthranilic acid and at 24 h after 7 days of repeated doses of gentamicin, cyclosporine A or cisplatin. Among a total of 169 metabolites identified, 3-methylhistidine (3-MH), 3-indoxyl sulfate (3-IS) and guanidoacetate (GAA) were selected as candidate biomarkers. The biological significance and reproducibility of the observed changes were monitored over time in acute nephrotoxicity model rats treated with a single dose of cisplatin, with the glomerular filtration rate monitored by determination of creatinine clearance. Increased plasma levels of 3-MH and 3-IS were related to a decline in glomerular filtration due to a renal failure. In contrast, the decrease in plasma GAA, which is synthesized from arginine and glycine in the kidneys, was considered to reflect decreased production due to renal malfunction. Although definitive validation studies are required to confirm their usefulness and reliability, 3-MH, 3-IS and GAA may prove to be valuable plasma biomarkers for monitoring nephrotoxicity in rats. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is one of the most prevalent cancers and is rising in incidence worldwide. The molecular mechanisms leading to the development of HCC are complex and include both genetic and epigenetic events. To determine the relative contribution of these alterations in liver tumorigenesis, we evaluated epigenetic modifications at both global and gene specific levels, as well as the mutational profile of genes commonly altered in liver tumors. A mouse model of fibrosis-associated liver cancer that was designed to emulate cirrhotic liver, a prevailing disease state observed in most humans with HCC, was used. Tumor and nontumor liver samples from B6C3F1 mice treated with N-nitrosodiethylamine (DEN; a single ip injection of 1 mg/kg at 14 days of age) and carbon tetrachloride (CCl4; 0.2 ml/kg, 2 times/week ip starting at 8 weeks of age for 14 weeks), as well as corresponding vehicle control animals, were analyzed for genetic and epigenetic alterations. H-ras, Ctnnb1 and Hnf1α genes were not mutated in tumors in mice treated with DEN+CCl4. In contrast, the increased tumor incidence in mice treated with DEN+CCl4 was associated with marked epigenetic changes in liver tumors and nontumor liver tissue, including demethylation of genomic DNA and repetitive elements, a decrease in histone 3 lysine 9 trimethylation (H3K9me3) and promoter hypermethylation and functional downregulation of Riz1, a histone lysine methyltransferase tumor suppressor gene. Additionally, the reduction in H3K9me3 was accompanied by increased expression of long interspersed nucleotide elements 1 and short interspersed nucleotide elements B2, which is an indication of genomic instability. In summary, our results suggest that epigenetic events, rather than mutations in known cancer-related genes, play a prominent role in increased incidence of liver tumors in this mouse model of fibrosis-associated liver cancer. [ABSTRACT FROM AUTHOR]

ABSTRACT Long-term carcinogenicity testing of a compound is exceedingly time-consuming and costly, and requires many test animals, whereas the Ames test, which is based on the assumption that any substance that is mutagenic may also exert carcinogenic potential, is useful as a short-term screening assay but has major drawbacks. Although, in fact, 90% of compounds that give a positive Ames test cause cancer in laboratory animals, a good proportion of compounds that give a negative Ames test are also carcinogens; that is, there is no good correlation between carcinogenicity and negative Ames test results. As an alternative to these two approaches, we have tried applying toxicogenomics to predict the carcinogenicity of a compound from the gene expression profile induced in vivo. To establish our model, male Sprague-Dawley rats were orally administered test compounds (12 hepatocarcinogens and 26 non-hepatocarcinogens) for 28 days. Analysis of liver gene expression data by Support Vector Machines (SVM) dividing compounds into 'for training' and 'for test' (20 cases assigned randomly) allowed a set of marker genes to be tested for prediction of hepatocarcinogenicity. The developed prediction model was then validated with reference to the concordance rate with training data and test data, and a good performance was obtained. We will have new gene expression data and continue the validation of our model. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

ABSTRACT The development of safer drugs is a high priority for pharmaceutical companies. Among the various toxicities caused by drugs, cardiotoxicity is an important issue because of its lethality. In addition, cardiovascular toxicity leads to the attrition of many drug candidates in both preclinical and clinical phases. Although histopathological and blood chemistry examinations are the current gold standards for detecting cardiotoxicity in preclinical studies, the large number of withdrawals from clinical studies owing to safety problems indicate that a more sensitive tool is required. We recently identified 32 genes that were candidate genomic biomarkers for cardiotoxicity in rats. Based on their functions, the present study focused on 8 of these 32 genes ( Spp1, Fhl1, Timp1, Serpine1, Bcat1, Lmcd1, Rnd1 and Tgfb2). Diagnostic accuracy for the genes was determined by a receiver-operating characteristic (ROC) analysis using more cardiotoxic and non-cardiotoxic compounds. In addition, an optimized support vector machine (SVM) model that was composed of Spp1 and Timp1 was newly constructed. This new multi-gene model exhibited a much higher diagnostic accuracy than that observed for plasma cardiac troponin I (cTnI), which is one of the most useful plasma biomarkers for cardiotoxicity detection. Furthermore, we determined that this multi-gene model could predict potential cardiotoxicity in rats in the absence of any cardiac histopathological lesions or elevations of plasma cTnI. Overall, this multi-gene model exhibited advantages over classic tools commonly used for cardiotoxicity evaluations in rats. Our current results suggest that application of the model could potentially lead to the production of safer drugs. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The article presents two experiments which sought to determine the time course of changes of nedaplatin (NDP)-induced nephrotoxicity and to examine whether hydration is useful for amelioration of nephrotoxicity. The first experiment employed eight-week-old male rats, while the second experiment used nonhydrated (Nhyd) or hydrated (Hyd) rats treated with NDP. Results of the experiments suggested that NDP has the potential risk to cause nephrotoxicity at a human therapeutic dose without hydration and that pre- and post-hydration at dosing can enhance this nephrotoxicity.