OBJECTIVETo analyze the occurrence of adverse drug events (ADEs) associated with Stiripentol (STP) use in children aged 0-17 years in real-world clinical settings.METHODSADE reports on STP in children aged 0-17 years were collected from the WHO Global Case Safety Pathology Reporting Database (VigiBase), the U.S. Food and Drug Administration's Spontaneous Adverse Event Reporting System database (FAERS), and the European Medicines Agency's Pharmacovigilance database (Eudra Vigilance). Pharmacovigilance signals were identified through Reporting Odds Ratio (ROR), and Proportional Reporting Ratio (PRR).RESULTSIn total, 31,990 ADEs were reported with "Stiripentol" as the primary suspect drug. This includes 595 ADEs from the Eudra Vigilance, 1,353 ADEs from the FAERS, and 998 ADEs from the VigiBase. All three databases indicate a higher incidence of ADEs related to STP in the categories of nervous system disorders, general disorders and administration site conditions, injury, poisoning and procedural complications, and metabolism and nutrition disorders. A higher proportion of children aged 3-11 years reported (16.48 %-32.44 %). The FAERS data shows that cerebellar atrophy (PRR of 332.94, ROR of 532.10) is the strongest signal for children aged 0-2 years, while changes in seizure presentation (PRR of 110.76, ROR of 121.06) is the strongest signal for children aged 3-11 years. For children aged 12-17 years, seizures (PRR of 46.99, ROR of 47.40) and decreased appetite(PRR of 45.51, ROR of 45.96) are the strongest signals. The Eudra Vigilance results show that boys have higher ADEs than girls for investigations, blood and lymphatic system disorders, hepatobiliary disorders, infections and infestations in children aged 0-17 years. On the other hand, girls have higher ADEs than boys for skin and subcutaneous tissue disorders, injury, poisoning and procedural complications, general disorders and administration site conditions, and gastrointestinal disorders.CONCLUSIONIn the clinical application of STP in pediatrics, it is important to examine ADEs in Nervous system disorders, Injury, poisoning and procedural complications, General disorders and administration site conditions, and Metabolism and nutrition disorders. Further studies should confirm whether there are age and gender differences in different ADEs.

01 Dec 2024·Journal of Hazardous Materials

3D-printed controllable bio-accelerators with sustained release property to boost chromium (VI) inhibited denitrification recovery

Article

Author: Zhao, Minghao ; Wu, Yichen ; Zhai, Siyuan ; Liu, Yinuo ; Niu, Jiaojiao ; Wang, Qian ; Zhao, Yingxin ; Chao, Chunfang ; Wan, Huilin

Although soluble bio-accelerators have proven effective in mitigating Cr(VI) inhibition within denitrification system, issues persist in immobilizing bio-accelerators and making them slow-release for sustained regulation. In this study, a novel strategy was proposed to fabricate immobilized bio-accelerators with controlled structure, sustained release property by 3D printing technology. Notably, the sustained release of bio-accelerators from 3D-printed bio-accelerators (3DP-B) lasted for at least 144 h. Compared to control group, 3DP-B with basic components (3DP-BB) shortened the recovery time by 1.4 folds, and the COD and NO₃^--N removal efficiency was 36.5 % and 38.0 % higher than that of natural recovery. Correspondingly, the activity of key enzymes (nitrate reductase, nitrite reductase, nitric oxide reductase, and nitrous oxide reductase), electron transfer system activity and extracellular polymer substances of denitrification biofilm maintained at relatively high levels. Furthermore, introducing 60 mg·L^-1 anthraquinone-2,6-disulfonate (AQDS) into the ink showed noticeable superiority on the bio-inhibition release over 1000 mg·L^-1 AQDS. The released AQDS facilitated the electron transport capacity by 1.25 times compared with control group. The groundbreaking findings of this study could advance the development of 3D printing technology and utilization of bio-accelerators in the field of wastewater treatment.

01 Oct 2024·HemaSphere

Combined inhibition of CTPS1 and ATR is a metabolic vulnerability in p53‐deficient myeloma cells

Article

Author: Bellanger, Céline ; Parker, Andrew ; Maïga, Sophie ; Moreau‐Aubry, Agnès ; Derrien, Jennifer ; Devilder, Marie‐Claire ; Gomez‐Bougie, Patricia ; Chiron, David ; Touzeau, Cyrille ; Thirouard, Laura ; Pellat‐Deceunynck, Catherine ; Bouard, Louise ; Asnagli, Hélène ; Beer, Philip ; Moreau, Philippe ; Dousset, Christelle ; Durand, Romane ; Descamps, Géraldine

AbstractIn multiple myeloma, as in B‐cell malignancies, mono‐ and especially bi‐allelic TP53 gene inactivation is a high‐risk factor for treatment resistance, and there are currently no therapies specifically targeting p53 deficiency. In this study, we evaluated if the loss of cell cycle control in p53‐deficient myeloma cells would confer a metabolically actionable vulnerability. We show that CTP synthase 1 (CTPS1), which encodes a CTP synthesis rate‐limiting enzyme essential for DNA and RNA synthesis in lymphoid cells, is overexpressed in samples from myeloma patients displaying a high proliferation rate (high MKI67 expression) or a low p53 score (synonymous with TP53 deletion and/or mutation). This overexpression of CTPS1 was associated with reduced survival in two cohorts. Using scRNA‐seq analysis in 24 patient samples, we further demonstrate that myeloma cells in the S or G2/M phase display high CTPS1 expression. Pharmacological inhibition of CTPS1 by STP‐B induced cell cycle arrest in early S phase in isogenic NCI‐H929 or XG7 TP53+/+, TP53−/−, and TP53R175H/R175H cells and in a TP53−/R123STOP patient sample. The functional annotation of transcriptional changes in 10 STP‐B‐treated myeloma cell lines revealed a decrease in protein translation and confirmed the blockade of cells into the S phase. The pharmacological inhibition of ATR, which governs the intrinsic S/G2 checkpoint, in STP‐B‐induced S‐phase arrested cells synergistically induced cell death in TP53+/+, TP53−/−, and TP53R175H/R175H isogenic cell lines (Bliss score >15). This combination induced replicative stress and caspase‐mediated cell death and was highly effective in resistant/refractory patient samples with TP53 deletion and/or mutation and in TP53−/− NCI‐H929 xenografted NOD‐scid IL2Rgamma mice. Our in vitro, ex vivo, and in vivo data provide the rationale for combined CTPS1 and ATR inhibition for the treatment of p53‐deficient patients.

100 Deals associated with STP-B

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Indication	Highest Phase	Country/Location	Organization	Date
Prostatic Cancer	Preclinical	US	The Johns Hopkins University	10 Apr 2024
Prostatic Cancer	Preclinical	US	Panbela Therapeutics, Inc.	10 Apr 2024

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