40-301 : Special Drug Use-Results Survey of ADLUMIZ
Ontology highlight
ABSTRACT:
DISEASE(S): Cancer Cachexia: Non-small Cell Lung Cancer, Gastric Cancer, Pancreatic Cancer, Large Intestine Canc
PROVIDER: 2613087 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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Project description:Primary outcome(s): [Safety]Occurrence status of adverse drug reactions and infections, Occurrence status of adverse drug reactions corresponding to specified safety concerns, Factors that are considered to affect safety
Specified safety concerns: Cutaneous malignancies, palmar-plantar erythrodysaesthesia syndrome, eye disorders, cardiac dysfunction, hypertension, rhabdomyolysis, hepatic dysfunction, and haemorrhage
[Efficacy]Antitumor effect and overall survival (OS)
| 2613085 | ecrin-mdr-crc
Project description:In drug development, a system for predicting drug metabolism and drug-induced toxicity is necessary to ensure drug safety. Cytochrome P450 family 3 subfamily A member 4 (CYP3A4) is an important drug-metabolizing enzyme expressed in the liver and small intestine, and predicting CYP3A4-mediated drug metabolism and drug-induced toxicity is essential. We previously developed procedures to differentiate human induced pluripotent stem (iPS) cells into hepatocyte-like cells (HLCs) or intestinal epithelial-like cells (IECs) with a fetal phenotype as well as a highly efficient genome editing technology that could enhance the homologous recombination efficiency at any locus, including CYP3A4. By using human iPS cells and our genome editing technology, we generated CYP3A4-knockout (KO) iPS cell-derived HLCs and IECs for the evaluation of CYP3A4-mediated drug metabolism and drug-induced toxicity. CYP3A4 deficiency did not affect pluripotency and hepatic and intestinal differentiation capacities, and CYP3A4 activity was entirely eradicated by CYP3A4 KO. Off-target effects (e.g., inhibition of bile acid excretion) were hardly observed in CYP3A4-KO cells but were observed in CYP3A4 inhibitor-treated (e.g., ketoconazole) cells. To evaluate whether drug-induced hepatotoxicity and enterotoxicity could be predicted using our model, we exposed CYP3A4-KO HLCs and IECs to acetaminophen, amiodarone, desipramine, leflunomide, tacrine, and tolcapone and confirmed that these cells could predict CYP3A4-mediated toxicity. Finally, we examined whether the therapeutic effects of an anti-hepatitis C virus (HCV) drug metabolized by CYP3A4 would be predicted using our model. CYP3A4-KO HLCs were treated with asunaprevir (antiviral drug metabolized by CYP3A4) after HCV infection, and the anti-viral effect was indeed strengthened by CYP3A4 KO. Conclusion: We succeeded in generating a novel evaluation system for prediction of CYP3A4-mediated drug metabolism and drug-induced toxicity.
2021-05-06 | GSE159159 | GEO
Project description:Human liver organoids, an in vitro 3D culture system to recapitulate biological tissue, are expected to be used for drug discovery. However, Matrigel, the most widely used extracellular matrix for organoid culture, has concerns about safety and reproducibility since it is murine-derived. Morever, low hepatic functions of human liver organoids compared to primary human hepatocytes is considered a challenge. Herein, we attempted to culture human liver organoids, established from primary (cryopreserved) human hepatocytes (PHH), using HYDROX, a chemically defined 3D nanofiber. While proliferative capacity of human liver organoids was lost by HYDROX-culture, the gene expression level of a hepatocyte marker CYP3A4 and the CYP3A4 metabolic activity in HYDROX-cultured liver organoids were significantly improved, comparable to those of PHH. HYDROX-cultured liver organoids when treated with hepatotoxic drugs such as acetaminophen showed similar cell viability to that of PHH, suggesting that HYDROX-cultured liver organoids could be applied to drug-induced hepatotoxicity test. Furthermore, HYDROX-cultured liver organoids maintained its functions for up to 35 days and could be used to estimate chronic drug-induced hepatotoxicity such as those of fialuridine. Our findings demonstrated that human liver organoids obtained high liver functions by HYDROX-culture, meaning that HYDROX could contribute to drug discovery as a novel biomaterial.
2024-05-22 | GSE239375 | GEO
Project description:In light of the widespread adoption of antibiotics, the imperative to promptly manage and regulate their use, ensuring accuracy and safety, is evident. Such misuse can lead to frequent adverse drug reactions, causing unnecessary harm, and prolonged erroneous use may culminate in irreversible injuries and fatalities. Of particular concern is the prevalent use of moxifloxacin (MXF), a fourth-generation fluoroquinolone antibiotic, across various infections and disease prevention scenarios. This have been reported to have immunomodulatory effects on a variety of immune cells and even anti-proliferative and pro-apoptotic effects, but the mechanism of action is not fully clear. There exists an urgent necessity to investigate the safety and mechanisms of action on immunomodulation of this drugs.
2024-04-15 | GSE250341 | GEO
Project description:The kidney is important for a number of physiological processes including blood filtering, blood pressure regulation and proper excretion of many drugs and xenobiotics. Age is a predisposing condition for susceptibility to chronic kidney disease and progression as well as acute kidney injury that may arise due to the adverse effects of some drugs. Age-related differences in kidney biology, therefore, are a key concern in understanding drug safety and disease progression. We hypothesize that the underlying suite of genes expressed in the kidney at various life cycle stages will impact susceptibility to adverse drug reactions. Therefore, establishing changes in baseline expression data between these life stages is the first and necessary step in evaluating this hypothesis. Untreated male F344 rats from 2, 5, 6, 8, 15, 21, 78, and 104 weeks of age (n=5) were sacrificed by CO2 asphyxiation, whole kidneys collected and homogenized, total RNA used for whole genome expression arrays (Agilent).
2013-07-31 | E-GEOD-47068 | biostudies-arrayexpress
Project description:Age- and sex-related susceptibility to adverse drug reactions is a key concern in understanding drug safety and disease progression. We hypothesize that the underlying suite of hepatic genes expressed at various developmental and life-cycle stages will impact susceptibility to adverse drug reactions. Thus, understanding the basal expression patterns of genes throughout the life span of the rat model species in both sexes will inform our assessments of adverse drug reactions. The liver plays a central role in the metabolism and biotransformation of drugs via key cellular pathways. Untreated, male and female F344 rats were sacrificed at 2, 5, 6, 8, 15, 21, 52, 78, and 104 weeks of age. Liver tissues were collected for histology and gene expression analysis. Whole-genome rat microarrays (44,000 features) were used to query global expression profiles. An initial list of active genes was selected using a 2-way ANOVA with a p-value cutoff of 0.05 and 1.5 fold-change difference from mean expression. Three dimensional principal component analyses revealed notable expression profile divergence between males and females after 5 weeks with greatest differences observed at 21 and 52 weeks before converging again at 104 weeks. Furthermore, k-means clustering identified groups of genes that displayed specific developmental and age-related patterns of expression. Various adult aging-related clusters included genes involved in pathways related to susceptibility to adverse drug effects such as xenobiotic metabolism, DNA damage repair, and oxidative stress. These results suggest an underlying role for genes in these specific clusters in potentiating age- and sex-related susceptibilities to adverse health effects.
2010-06-24 | GSE21335 | GEO
Project description:The kidney is important for a number of physiological processes including blood filtering, blood pressure regulation and proper excretion of many drugs and xenobiotics. Age is a predisposing condition for susceptibility to chronic kidney disease and progression as well as acute kidney injury that may arise due to the adverse effects of some drugs. Age-related differences in kidney biology, therefore, are a key concern in understanding drug safety and disease progression. We hypothesize that the underlying suite of genes expressed in the kidney at various life cycle stages will impact susceptibility to adverse drug reactions. Therefore, establishing changes in baseline expression data between these life stages is the first and necessary step in evaluating this hypothesis.
2013-07-31 | GSE47068 | GEO
Project description:Concerns about the potential risks to human health due nanoparticulate pollution have been emerging. However, the risks to sensitive populations, such as pregnant individuals and their unborn children are poorly characterised. With increasing evidence of environmental particles passing the placenta, their potential adverse effects of on pregnancy and fetal development need to be assessed. Here, we investigated the impact of copper oxide (CuO) and polystyrene (PS) nanoparticle exposure on gene expression in ex vivo perfused human placental tissue.
2023-10-01 | GSE220756 | GEO
Project description:Owing to safety concerns or insufficient potential for efficacy, only 0.01% to 0.02% of new drug candidates are approved for marketing. Drugs already on the market may be withdrawn or restricted to certain uses due to adverse effects (AEs) discovered after market introduction. Comprehensively investigating the on-/off-target effects of drugs can help expose AEs during the drug development process. In this study, we developed an integrative framework for systematic identification of on-/off-target pathways and elucidation of the underlying mechanisms, by combining expression profiling after drug treatment with gene perturbation of the primary drug target. Expression profiles from statin-treated cells and HMG-CoA reductase knockdowns were analyzed using the framework, allowing for identification of not only reported adverse effects but also novel candidates of off-target effects from statin treatment. Our findings may provide new insights for finding new usages or potential side effects of drug treatment.
2019-07-25 | GSE134817 | GEO
Project description:EXOME ARRAY ANALYSIS OF ADVERSE REACTIONS TO FLUOROPYRIMIDINE-BASED THERAPY FOR GASTROINTESTINAL CANCER
| EGAD00010001499 | EGA