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Clinical Cancer Research : An Official... Jan 2024On March 16, 2023, the FDA approved dabrafenib in combination with trametinib (Tafinlar, Mekinist; Novartis Pharmaceuticals Corporation) for the treatment of pediatric... (Randomized Controlled Trial)
Randomized Controlled Trial
On March 16, 2023, the FDA approved dabrafenib in combination with trametinib (Tafinlar, Mekinist; Novartis Pharmaceuticals Corporation) for the treatment of pediatric patients with low-grade glioma (LGG) with a BRAFV600E mutation who require systemic therapy. FDA also approved oral formulations of both drugs suitable for patients who cannot swallow pills. This approval was based on the LGG cohort from study CDRB436G2201 (NCT02684058), a multicenter, open-label trial in which pediatric patients with LGG with a BRAFV600E mutation were randomly assigned 2:1 to dabrafenib plus trametinib (D+T) or carboplatin plus vincristine (C+V). The overall response rate (ORR) by independent review based on Response Assessment in Neuro-oncology LGG (2017) criteria was assessed in 110 patients randomly assigned to D+T (n = 73) or C+V (n = 37). ORR was 47% [95% confidence interval (CI), 35-59] in the D+T arm and 11% (95% CI, 3.0-25) in the C+V arm. Duration of response (DOR) was 23.7 months (95% CI, 14.5-NE) in the D+T arm and not estimable (95% CI, 6.6- NE) in the C+V arm. Progression-free survival (PFS) was 20.1 months (95% CI: 12.8, NE) and 7.4 months (95% CI, 3.6- 11.8) [HR, 0.31 (95% CI, 0.17-0.55); P < 0.001] in the D+T and C+V arms, respectively. The most common (>20%) adverse reactions were pyrexia, rash, headache, vomiting, musculoskeletal pain, fatigue, diarrhea, dry skin, nausea, hemorrhage, abdominal pain, and dermatitis acneiform. This represents the first FDA approval of a systemic therapy for the first-line treatment of pediatric patients with LGG with a BRAFV600E mutation.
Topics: Humans; Child; Pyridones; Pyrimidinones; Oximes; Glioma; Mutation; Proto-Oncogene Proteins B-raf; Antineoplastic Combined Chemotherapy Protocols; Imidazoles
PubMed: 37610803
DOI: 10.1158/1078-0432.CCR-23-1503 -
Scientific Reports Jul 2023Rhabdomyolysis is a syndrome potentially fatal and has been associated with selective serotonin reuptake inhibitors (SSRIs) treatment in a few case reports. Herein, we...
Rhabdomyolysis is a syndrome potentially fatal and has been associated with selective serotonin reuptake inhibitors (SSRIs) treatment in a few case reports. Herein, we purpose to establish the correlation between SSRIs use and rhabdomyolysis using the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) database. We conducted an analysis on reports that were submitted to the FAERS database during the period between January 1, 2004, and December 31, 2022. Four algorithms, including reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and empirical Bayes geometric mean (EBGM), were employed to quantify the signals of rhabdomyolysis associated with SSRIs. In total, 16,011,277 non-duplicated reports were obtained and analyzed. Among 33,574 reports related to rhabdomyolysis, SSRIs were classified as primary suspected drug in 889 cases. Disproportionality analysis identified a positive signal between rhabdomyolysis and SSRIs (ROR: 2.86, 95% CI 2.67-3.05; PRR: 2.84, χ: 1037.16; IC = 1.39; EBGM = 2.64). Among six SSRIs, fluvoxamine had the strongest signal (ROR: 11.64, 95% CI 8.00-16.93; PRR: 11.38, χ: 265.51; IC = 2.41; EBGM = 8.31), whereas no significant signal of rhabdomyolysis was detected for paroxetine (ROR: 1.83, 95% CI 1.55-2.15; PRR: 1.82, χ: 53.82; IC = 0.73; EBGM = 1.59). After excluding cases co-administered with statins, the signal of rhabdomyolysis associated with SSRIs remains significant. Our analysis reveals that there are differences in safety signals among six SSRIs in respect to the risk of rhabdomyolysis, with fluvoxamine displaying the highest risk signal, while paroxetine did not show a significant signal. Given the potentially lethal nature of rhabdomyolysis, healthcare professionals should inform patients of the potential risk of rhabdomyolysis associated with SSRIs prior to initiating treatment.
Topics: United States; Humans; Selective Serotonin Reuptake Inhibitors; Bayes Theorem; Pharmacovigilance; Fluvoxamine; Paroxetine; Adverse Drug Reaction Reporting Systems; Rhabdomyolysis; United States Food and Drug Administration
PubMed: 37507539
DOI: 10.1038/s41598-023-39482-y -
Angewandte Chemie (International Ed. in... Jun 2024Nitrogen oxides (NOx) are major environmental pollutants and to neutralize this long-term environmental threat, new catalytic methods are needed. Although there are...
Nitrogen oxides (NOx) are major environmental pollutants and to neutralize this long-term environmental threat, new catalytic methods are needed. Although there are biological denitrification processes involving four different enzymatic reactions to convert nitrate (NO3-) to dinitrogen (N2), it is unfortunately difficult to apply in industry due to the complexity of the processes. In particular, nitrate is difficult to functionalize because of its chemical stability. Thus, there is no organometallic catalysis to convert nitrate to useful chemicals. In this article, we present that a nickel pincer complex is effective as a bifunctional catalyst to stepwise deoxygenate NO3- by carbonylation and further to C-N coupling. By using this nickel catalysis, nitrate salts can be selectively transformed into various oximes (>20 substrates) with excellent conversion (>90%). Here, we demonstrate for the first time that the highly inert nitrate ion can be functionalized to produce useful chemicals by a new organonickel catalysis. Our results show that the NOx conversion and utilization (NCU) technology is a successful pathway for environmental restoration coupled with value-added chemical generation.
PubMed: 38853142
DOI: 10.1002/anie.202408457 -
Molecules (Basel, Switzerland) Aug 2023Indoleamine-2,3-dioxygenase 1 (IDO1) and signal transducer and activator of transcription 3 (STAT3) have emerged as significant targets in the tumor microenvironment for...
Indoleamine-2,3-dioxygenase 1 (IDO1) and signal transducer and activator of transcription 3 (STAT3) have emerged as significant targets in the tumor microenvironment for cancer therapy. In this study, we synthesized three novel 2-amino-1,4-naphthoquinone amide-oxime derivatives and identified them as dual inhibitors of IDO1 and STAT3. The representative compound demonstrated effective binding to IDO1 and exhibited good inhibitory activity (hIDO1 IC = 0.06 μM), leading to its selection for further investigation. The direct interactions between compound and IDO1 and STAT3 proteins were confirmed through surface plasmon resonance analysis. A molecular docking study of compound revealed key interactions between and IDO1, with the naphthoquinone-oxime moiety coordinating with the heme iron. In the in vitro anticancer assay, compound displayed potent antitumor activity against selected cancer cell lines and effectively suppressed nuclear translocation of STAT3. Moreover, in vivo assays conducted on CT26 tumor-bearing Balb/c mice and an athymic HepG2 xenograft model revealed that compound exhibited potent antitumor activity with low toxicity relative to 1-methyl-L-tryptophan (1-MT) and doxorubicin (DOX). Overall, these findings provided evidence that the dual inhibitors of IDO1 and STAT3 may offer a promising avenue for the development of highly effective drug candidates for cancer therapy.
Topics: Humans; Animals; Mice; STAT3 Transcription Factor; Molecular Docking Simulation; Prospective Studies; Amides; Mice, Inbred BALB C; Naphthoquinones; Oximes
PubMed: 37630387
DOI: 10.3390/molecules28166135 -
Angewandte Chemie (International Ed. in... Jul 2023Synthesis of cyclohexanone oxime via the cyclohexanone-hydroxylamine process is widespread in the caprolactam industry, which is an upstream industry for nylon-6...
Synthesis of cyclohexanone oxime via the cyclohexanone-hydroxylamine process is widespread in the caprolactam industry, which is an upstream industry for nylon-6 production. However, there are two shortcomings in this process, harsh reaction conditions and the potential danger posed by explosive hydroxylamine. In this study, we presented a direct electrosynthesis of cyclohexanone oxime using nitrogen oxides and cyclohexanone, which eliminated the usage of hydroxylamine and demonstrated a green production of caprolactam. With the Fe electrocatalysts, a production rate of 55.9 g h g can be achieved in a flow cell with almost 100 % yield of cyclohexanone oxime. The high efficiency was attributed to their ability of accumulating adsorbed hydroxylamine and cyclohexanone. This study provides a theoretical basis for electrocatalyst design for C-N coupling reactions and illuminates the tantalizing possibility to upgrade the caprolactam industry towards safety and sustainability.
PubMed: 37232096
DOI: 10.1002/anie.202305491 -
Forensic Science International Oct 2023Manufacture and recreational use of methamphetamine can result in widespread chemical contamination throughout a property. Hydrogen peroxide (HO)-based cleaning products...
Manufacture and recreational use of methamphetamine can result in widespread chemical contamination throughout a property. Hydrogen peroxide (HO)-based cleaning products have shown success against a number of chemical contaminants including agents of chemical warfare, and biological contaminants such as anthrax. They are considered to be environmentally friendly and economically viable and, as such, are used by many companies within the methamphetamine decontamination industry. The oxidative decontamination of methamphetamine and ephedrine hydrochloride was investigated in this current study, employing a commercially available HO-based decontamination product, Bio-Oxygen® Chem Decon. Methamphetamine and ephedrine were observed to degrade following pseudo-first order kinetics of (1.9 ± 0.4) × 10 min and (2.2 ± 0.3) × 10 min, respectively. Major oxidation products identified through GC-MS analyses were phenylacetone oxime (from methamphetamine) and benzaldehyde (from ephedrine). LC-MS analysis revealed the presence of a number of N-oxygenated intermediates which allowed for the elucidation of an N-oxidation decomposition pathway reminiscent of flavin-containing monooxygenase enzymes. Using this information, further targeted research can be performed to understand the behaviour and persistence of these reaction products and accurate assessments can be achieved to estimate their impact on the exposure risks associated with chemical decontamination of amphetamine-type stimulants (ATS).
Topics: Ephedrine; Methamphetamine; Peroxides; Hydrogen Peroxide; Decontamination
PubMed: 37690396
DOI: 10.1016/j.forsciint.2023.111816 -
The Journal of Organic Chemistry Oct 2023A robust synthesis of phenanthridines has been described via Pd(II)-catalyzed domino C(sp)-H activation/-arylation using oxime esters with aryl acyl peroxides in a...
A robust synthesis of phenanthridines has been described via Pd(II)-catalyzed domino C(sp)-H activation/-arylation using oxime esters with aryl acyl peroxides in a highly regioselective manner. This protocol is compatible with acetophenone as well as benzophenone-derived oxime esters and allows modular construction of functionalized phenanthridines with wide tolerance of electronic functionality. Further transformations were conducted to synthesize key building blocks, and control experiments were performed to understand the plausible reaction mechanism.
PubMed: 37738300
DOI: 10.1021/acs.joc.3c01234 -
Current Drug Delivery 2024The cellular membrane hinders the effective delivery of therapeutics to targeted sites. Cellpenetrating peptide (CPP) is one of the best options for rapidly... (Review)
Review
The cellular membrane hinders the effective delivery of therapeutics to targeted sites. Cellpenetrating peptide (CPP) is one of the best options for rapidly internalizing across the cellular membrane. CPPs have recently attracted lots of attention because of their excellent transduction efficiency and low cytotoxicity. The CPP-cargo complex is an effective and efficient method of delivering several chemotherapeutic agents used to treat various diseases. Additionally, CPP has become another strategy to overcome some of the current therapeutic agents' limitations. However, no CPP complex is approved by the US FDA because of its limitations and issues. In this review, we mainly discuss the cellpenetrating peptide as the delivery vehicle, the cellular uptake mechanism of CPPs, their design, and some strategies to synthesize the CPP complex via some linkers such as disulfide bond, oxime, etc. Here, we also discuss the recent status of CPPs in the market.
Topics: Cell-Penetrating Peptides; Drug Delivery Systems; Biological Transport
PubMed: 37026498
DOI: 10.2174/1567201820666230407092924 -
Biomedicine & Pharmacotherapy =... Nov 2023Colorectal cancer (CRC) patients with BRAF mutations develop resistance to BRAF inhibitors at a very early stage. Understanding the molecular mechanisms involved in BRAF...
Colorectal cancer (CRC) patients with BRAF mutations develop resistance to BRAF inhibitors at a very early stage. Understanding the molecular mechanisms involved in BRAF inhibitor resistance is critical for the development of novel therapeutic opportunities for this subtype of CRC patients. CRC cells bearing BRAF mutations are mostly sensitive to the abrogation of Mitogen-Activated Protein Kinase Kinase 3 (MKK3), a specific activator of p38MAPKs signaling, suggesting that BRAF alterations might addict CRC cells to the MKK3/p38MAPK signaling. Interestingly, publicly available gene expression profiling data show significantly higher MKK3 transcript levels in CRC lines with acquired resistance to BRAF inhibitors. Herein, we investigated the roles of MKK3 in the response to BRAF targeting (dabrafenib) with COLO205 and HT29 BRAF CRC lines and derived dabrafenib-resistant (DABR) sublines. Dabrafenib treatments reduce MKK3 activation by inducing autophagy in parental but not DABR cells. The MKK3 knockdown induces cell death in DABR cells, whereas ectopic MKK3 expression reduces dabrafenib sensitivity in parental cells. Mechanistically, activated MKK3 interacts and co-localizes with c-Myc oncoprotein (MYC), sustaining MYC protein stability and thus preventing the dabrafenib induced effects in CRC DABR cells both in vitro and in vivo. Overall, we identify a novel molecular mechanism beyond the dabrafenib resistance, shedding light on an uncovered vulnerability for the development of novel therapeutic opportunities in BRAF CRC.
Topics: Humans; Cell Line, Tumor; Colorectal Neoplasms; Mutation; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Signal Transduction; MAP Kinase Kinase 3; Proto-Oncogene Proteins c-myc; Drug Resistance, Neoplasm
PubMed: 37713993
DOI: 10.1016/j.biopha.2023.115480 -
Journal of Inorganic Biochemistry Oct 2023Heme enzymes are involved in the binding and metabolism of hydroxylamine (RNHOH) and aldoxime (RCH=NOH) compounds (R = H, alkyl, aryl). We report the synthesis and...
Heme enzymes are involved in the binding and metabolism of hydroxylamine (RNHOH) and aldoxime (RCH=NOH) compounds (R = H, alkyl, aryl). We report the synthesis and X-ray crystal structure of a metalloporphyrin in complex with an arylhydroxylamine, namely that of (TPP)Rh(PhNHOH)(CHCl) (TPP = tetraphenylpophryinato dianion). The crystal structure reveals, in addition to N-binding of PhNHOH to Rh, the presence of an intramolecular H-bond between the hydroxylamine -OH proton and a porphyrin N-atom. Results from density functional theory (DFT) calculations support the presence of this intramolecular H-bond in this global minimum structure, and a natural bond order (NBO) analysis reveals that this H-bond comprises a donor π N=C (porphyrin) to acceptor σ* O-H (hydroxylamine) interaction of 2.32 kcal/mol. While DFT calculations predict the presence of similar intramolecular H-bond interactions in the related aldoxime complexes (TPP)Rh(RCH=NOH)(CHCl) in their global minima structures, the X-ray crystal structure obtained for the (TPP)Rh(CH(CH)CH=NOH)(CHCl) complex is consistent with the local (non-global) minima conformation that does not have this intramolecular H-bond interaction.
Topics: Porphyrins; Rhodium; Metalloporphyrins; Hydroxylamines; Oximes
PubMed: 37517330
DOI: 10.1016/j.jinorgbio.2023.112337