Neonatal hypoxic-ischemic brain damage (HIBD) is a form of perinatal neonatal asphyxia-induced hypoxic-ischemic brain damage. The mechanism of HIBD injury is not completely clear. Using TMT-based quantitative proteomics, we found that HIBD is closely related to early-stage ferroptosis. GSH and MUFA contents were significantly decreased, while Fe and MDA contents were significantly increased in the HIBD brain. However, no relevant research is available on the regulatory mechanism of ferroptosis in HIBD. Because UTX activity is directly regulated by oxygen, UTX may play an important role in the initial stage of HIBD. We confirmed that UTX has a protective effect on neuronal damage in UTX neuron conditional knockout mice with HIBD. GSH and MUFA levels were further significantly decreased, Fe and MDA levels were further significantly increased, and TUNEL levels were further significantly increased in the brains of UTX neuron conditional knockout mice with HIBD. Our results also revealed that UTX, ARID1A, and SCD1 have protective effects on OGD/R-induced neuronal damage in cell models. UTX knockdown also significantly aggravated ferroptosis in neurons, and SCD1 mRNA levels were significantly decreased after UTX knockdown both in vitro and in vivo. Co-IP confirmed that UTX bound to ARID1A. Chip experiments revealed that UTX and ARID1A could bind to the same promoter of SCD1. We also found that the amount of UTX bound to the SCD1 promoter was significantly reduced after knocking down AIRD1A. Our results revealed the mechanism of ferroptosis in HIBD and provide an effective target for new drug development.

Background: Several poly ADP ribose polymerase inhibitors (PARPis) are currently approved for the treatment of a variety of cancers. The safety profile of PARPis has not yet been systemically analyzed in the real world. We conducted this pharmacovigilance analysis using the US FDA's Adverse Event Reporting System (FAERS) database to explore the difference in adverse events (AEs) among PARPis.Methods: FAERS data (December 2014 to October 2021) were searched for reports of all FDA-approved PARPis across all indications. We used the standardized MedDRA query (SMQ) generalized search AEs on the preferred term (PT) level based on case reports. After filtering duplicate reports, disproportionality analysis was used to detect safety signals by calculating reporting odds ratios (ROR). Reports were considered statistically significant if the 95% confidence interval did not contain the null value.Results: Within the standardized MedDRA queries, significant safety signals were found, including those for olaparib [blood premalignant disorders (ROR = 17.06)], rucaparib [taste and smell disorders (ROR = 9.17)], niraparib [hematopoietic throbocytopenia (ROR = 28.2)], and talazoparib [hematopoietic erythropenia (ROR = 9.38)]. For AEs on the PT level, we found several significant signals, including platelet count decreased with niraparib (ROR = 52.78); red blood cell count decreased with niraparib (ROR = 70.47) and rucaparib (ROR = 15.09); myelodysplastic syndrome with olaparib (ROR = 35.47); acute myeloid leukaemia with olaparib (ROR = 25.14); blood pressure fluctuation with niraparib (ROR = 20.54); lymphangioleiomyomatosis with niraparib (ROR = 471.20); photosensitivity reaction with niraparib (ROR = 21.77) and rucaparib (ROR = 18.92); renal impairment with rucaparib (ROR = 33.32); and interstitial lung disease with Olaparib (ROR = 11.31). All the detected safety signals were confirmed using signals of disproportionality reporting methods.Conclusion: PARPis differed in their safety profile reports. The analysis of the FAERS database revealed significant safety signals that matched previously published case reports, including serious gastrointestinal, blood and lymphatic system, cardiovascular and respiratory complications, which require individualized drug administration according to patients' conditions.

Backgrounds: Proteasome inhibitors (PI) cause toxic peripheral neuropathy (PN), which is one of the dose-limiting adverse events of these treatments. Recent preclinical studies find that factor Xa inhibitor (FXaI), rivaroxaban, promotes PN in animals receiving oxaliplatin. Cancer patients can receive combined therapy of PI and FXaI. This study aimed to identify and characterize the interaction signals for the concomitant use of PI and FXaI resulting in PN. Methods: Reports from the United States FDA Adverse Event Reporting System (FAERS) were extracted from the first quarter of 2004 to the first quarter of 2020 for analysis. The Standardized Medical Dictionary for Regulatory Activities (MedDRA) query was used to identify PN cases. We conducted an initial disproportionality investigation to detect PN adverse event signals associated with the combined use of PI and FXaI by estimating a reporting odds ratio (ROR) with a 95% confidence interval (CI). The adjusted RORs were then analyzed by logistic regression analysis (adjusting for age, gender, and reporting year), and additive/multiplicative models were performed to further confirm the findings. Additionally, subset data analysis was performed on the basis of a single drug of PI and FXaI. Results: A total of 159,317 adverse event reports (including 2,822 PN reports) were included. The combined use of PI and FXaI was associated with a higher reporting of PN (RORadj = 7.890, 95%CI, 5.321–11.698). The result remained significant based on additive/multiplicative methods. The observed association was consistent in the analysis restricted to all specific PI agents (bortezomib and ixazomib) and FXaI (rivaroxaban), except apixaban. Conclusion: Analysis of FAERS data identified reporting associations of PN in the combined use of PI and FXaI, suggesting the need for more robust preclinical and clinical studies to elucidate the relationship.

The vaginal routes of administration of terconazole, a synthetic triazole derivative, is widely used by patients with uncomplicated vulvovaginal candidiasis (VVC). A 32-year-old woman suffered from chills, fatigue, and chest distress after receiving one 80-mg terconazole vaginal suppository for the treatment of uncomplicated VVC. Then, the symptom persisted for 10 hours until the residue of terconazole was removed, and the vagina was repeatedly washed with iodophor. In addition, white blood cell (WBC), neutrophil, C-reactive protein (CRP), and procalcitonin (PCT) were tested and showed marked increase when the patient visited our hospital again on the next day after the treatment with terconazole. Intriguingly, these parameters gradually decreased after a single dose of intravenous fluids (0.9% sodium chloride injection 500 mL and 10% glucose injection 500 mL) instead of the antibiotic therapy. On the third day, WBC and neutrophils returned to normal levels. Thus, according to the Naranjo adverse drug reaction probability scale, terconazole was the probable cause of the symptoms and the elevated WBC, neutrophil, CRP, and PCT. To date, this is the first report that chest distress, and at the same time, elevation of WBC, neutrophil, CRP, and PCT were caused by terconazole. This would be beneficial to avoid the overuse of antibiotics. Resolving the adverse drug reaction with drug removal and intravenous fluids would be beneficial to avoid the overuse of antibiotics. Resolving the adverse drug reaction with drug removal and intravenous fluids would be beneficial to avoid the overuse of antibiotics.

This current investigation was aimed to generate signals for adverse events (AEs) of darunavir-containing agents by data mining using the US Food and Drug Administration Adverse Event Reporting System (FAERS). All AE reports for darunavir, darunavir/ritonavir, or darunavir/cobicistat between July 2006 and December 2019 were identified. The reporting Odds Ratio (ROR), proportional reporting ratio (PRR), and Bayesian confidence propagation neural network (BCPNN) were used to detect the risk signals. A suspicious signal was generated only if the results of the three algorithms were all positive. A total of 10,756 reports were identified commonly observed in hepatobiliary, endocrine, cardiovascular, musculoskeletal, gastrointestinal, metabolic, and nutrition system. 40 suspicious signals were generated, and therein 20 signals were not included in the label. Severe high signals (i.e. progressive extraocular muscle paralysis, acute pancreatitis, exfoliative dermatitis, acquired lipodystrophy and mitochondrial toxicity) were identified. In pregnant women, umbilical cord abnormality, fetal growth restriction, low birth weight, stillbirth, premature rupture of membranes, premature birth and spontaneous abortion showed positive signals. Darunavir and its boosted agents induced AEs in various organs/tissues, and were shown to be possibly associated with multiple adverse pregnant conditions. This study highlighted some novel and severe AEs of darunavir which need to be monitored prospectively.

IntroductionPre-eclampsia is an important cause of death and complication for pregnant women and perinatal infant. Low-dose aspirin has been most commonly used to prevent pre-eclampsia in high-risk pregnant women. Recently, heparins have also been used alone or in combination with aspirin to prevent pre-eclampsia. However, the optimal doses and combination therapy of aspirin and heparins are not well established. Therefore, we aim to compare aspirin, heparins and their combination to prevent pre-eclampsia in a network meta-analysis.Methods and analysisWe will search the following electronic databases from the date of database establishment to 8 January 2019: PubMed, Embase, Cochrane Library, Web of Science and ProQuest. We will also search additional studies manually. There will be no restriction on the language of publications. Only randomised clinical trials will be eligible in our network meta-analysis. We will include pregnant women who have been recommended for aspirin according to the standard of the American Congress of Obstetricians and Gynecologists, or were designated as high risk in some recent studies. We will include studies comparing the effects of any single or combination of aspirin and heparins with placebo or observation or another intervention in pregnancy. We will include studies that reported one of the following outcomes: pre-eclampsia, severe pre-eclampsia, preterm delivery, perinatal death and full-term pre-eclampsia with delivery at ≥37 weeks. Traditional pairwise meta-analysis will be performed initially, and then network meta-analysis will be performed using frequency analysis method. Subgroup analyses and sensitivity analyses will be conducted to assess the robustness of the findings.Ethics and disseminationThis network meta-analysis does not require ethical certification. An overview and information on the prevention of pre-eclampsia in high-risk pregnant women will be provided by this network meta-analysis.PROSPERO registration numberCRD42018084248.