Background and Aim: More than half of the small-molecule kinase inhibitors (KIs) induced liver injury clinically. Meanwhile, studies have shown a close relationship between mitochondrial damage and drug-induced liver injury (DILI). We aimed to study KIs and the binding between drugs and mitochondrial proteins to find factors related to DILI occurrence.Methods: A total of 1,223 oral FDA-approved drugs were collected and analyzed, including 44 KIs. Fisher’s exact test was used to analyze DILI potential and risk of different factors. A total of 187 human mitochondrial proteins were further collected, and high-throughput molecular docking was performed between human mitochondrial proteins and drugs in the data set. The molecular dynamics simulation was used to optimize and evaluate the dynamic binding behavior of the selected mitochondrial protein/KI complexes.Results: The possibility of KIs to produce DILI is much higher than that of other types (OR = 46.89, p = 9.28E-13). A few DILI risk factors were identified, including molecular weight (MW) between 400 and 600, the defined daily dose (DDD) ≥ 100 mg/day, the octanol–water partition coefficient (LogP) ≥ 3, and the degree of liver metabolism (LM) more than 50%. Drugs that met this combination of rules were found to have a higher DILI risk than controls (OR = 8.28, p = 4.82E-05) and were more likely to cause severe DILI (OR = 8.26, p = 5.06E-04). The docking results showed that KIs had a significant higher affinity with human mitochondrial proteins (p = 4.19E-11) than other drug types. Furthermore, the five proteins with the lowest docking score were selected for molecular dynamics simulation, and the smallest fluctuation of the backbone RMSD curve was found in the protein 5FS8/KI complexes, which indicated the best stability of the protein 5FS8 bound to KIs.Conclusions: KIs were found to have the highest odds ratio of causing DILI. MW was significantly related to the production of DILI, and the average docking scores of KI drugs were found to be significantly different from other classes. Further analysis identified the top binding mitochondrial proteins for KIs, and specific binding sites were analyzed. The optimization of molecular docking results by molecular dynamics simulation may contribute to further studying the mechanism of DILI.
following cost categories were included into the study: general practice care, home care, in-and outpatient care, medical imaging, laboratory diagnostics, pharmaceuticals and medical aids. Patients with female infertility were identified with the following code of the International Classification of Diseases 10 th revision: N97. Results: In 2018, the Hungarian National Health Insurance Fund Administration spent 6.91 billion Hungarian Forints (HUF) on the treatment of patients with female infertility, which equals 25.57 million American Dollars (USD), or 21.67 million Euros (EUR). 99.97% of costs was spent on the treatment of female patients. The highest patient numbers were in outpatient care: 30,112 patients. Acute inpatient care (53.2% of total health insurance costs), pharmaceuticals (42.2%) and outpatient care (3% in women) were the main cost drivers, while all other forms of medical care amounted to 1.6% in women. Annual health care treatment cost per patient was 229.387 HUF (849 USD/719 EUR) for women. Conclusions: Acute inpatient care was the major cost driver in the treatment of female infertility. The treatment of patients aged 25-44 accounted for 96.2% of costs.
BACKGROUND Preventing Drug-induced liver injury (DILI) in advance is an important task to improve drug safety and protect patient health. It was reported that more than half of small-molecule kinase inhibitors (KIs) induced DILI clinically. Meanwhile, numerous studies have shown a close relationship between mitochondrial damage and the generation of DILI. OBJECTIVE We aimed to focused on KIs to find factors related to DILI occurrence and study the binding potential between the whole class of drugs and mitochondrial proteins and further analysis of the key proteins in silico. METHODS 1,223 drugs approved by the Food and Drug Administration (FDA) were collected and analyzed, including 44 KIs. Fisher exact test was used to analyze DILI potential and risk of different factors. 187 human mitochondrial proteins were further collected and high-throughput molecular docking was performed between them and drugs in the data set. RESULTS Be The possibility of KIs to produce DILI is much higher than other types (odds ratio [OR] = 46.89, 95% CI [confidence interval] = 6.44 ~ 341.63, P = 9.28E-13). A few DILI risk factors were found, including molecular weight (MW) between 400 and 600, the defined daily dose (DDD) greater than or equal to 100mg/day, the octanol-water partition coefficient (LogP) greater than or equal to 3, and the degree of liver metabolism (LM) more than 50% (‘400 ≤ MW < 600 & LogP ≥ 3 & DDD ≥ 100 & LM ≥ 50%’). Drugs that met this combination of rules were found to have higher DILI risk than controls (OR = 8.28, 95% CI = 2.46 ~ 27.82, P = 4.82E-05, PPV [positive predictive value] = 88%) and were more likely to cause severe DILI (OR = 8.26, 95% CI = 2.25 ~ 30.26, P = 5.06E-04). The docking results showed that KIs had significant higher affinity with human mitochondrial proteins (P = 4.19E-11), which may be an implication for higher DILI potential. CONCLUSIONS KIs were found to have the highest odds ratio of causing DILI. Some characteristics of KIs were significantly related to the production of DILI. And the average docking scores of KIs drugs were found to be significant different from other classes. Further analysis identified the top binding mitochondrial proteins for KIs, which may help with the study of the mechanism of DILI. CLINICALTRIAL Not applicable.
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