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Journal of Infection and Chemotherapy :... Mar 2024Baloxavir marboxil (BXM), a newly developed cap-dependent endonuclease inhibitor, is widely used to treat influenza virus infections in inpatients and outpatients. A... (Meta-Analysis)
Meta-Analysis
Comparison of clinical efficacy and safety of baloxavir marboxil versus oseltamivir as the treatment for influenza virus infections: A systematic review and meta-analysis.
INTRODUCTION
Baloxavir marboxil (BXM), a newly developed cap-dependent endonuclease inhibitor, is widely used to treat influenza virus infections in inpatients and outpatients. A previous meta-analysis included only outpatients and patients suspected of having an influenza virus infection based on clinical symptoms. However, whether BXM or oseltamivir is safer and more effective for inpatients remains controversial. Therefore, we conducted a systematic review and meta-analysis validating the effectiveness and safety of BXM versus oseltamivir in inpatients with influenza virus.
METHODS
The Scopus, EMBASE, PubMed, Ichushi, and CINAHL databases were systematically searched for articles published until January 2023. The outcomes were mortality, hospitalization period, incidence of BXM- or oseltamivir-related adverse events, illness duration, and changes of virus titers and viral RNA load in patients with influenza virus infections.
RESULTS
Two randomized controlled trials with 1624 outpatients and two retrospective studies with 874 inpatients were enrolled. No deaths occurred in outpatients treated with BXM or oseltamivir. Among inpatients, BXM reduced mortality (p = 0.06) and significantly shortened hospitalization period (p = 0.01) compared to oseltamivir. In outpatients, BXM had a significantly lower incidence of adverse events (p = 0.03), reductions in influenza virus titers (p < 0.001) and viral RNA loads (p < 0.001), and a tendency to be a shorter illness duration compared with that of oseltamivir (p = 0.27).
CONCLUSIONS
Our meta-analysis showed that BXM was safer and more effective in patients than oseltamivir; thus, supporting the use of BXM for the initial treatment of patients with proven influenza virus infection.
Topics: Humans; Oseltamivir; Influenza, Human; Retrospective Studies; Antiviral Agents; Oxazines; Pyridines; Thiepins; Orthomyxoviridae Infections; Treatment Outcome; RNA, Viral; Dibenzothiepins; Morpholines; Pyridones; Triazines
PubMed: 37866622
DOI: 10.1016/j.jiac.2023.10.017 -
Cancer Letters Aug 2023Glioblastoma (GBM) is an aggressive malignant primary brain tumor. Radioresistance largely contributes to poor clinical outcomes in GBM patients. We targeted...
Glioblastoma (GBM) is an aggressive malignant primary brain tumor. Radioresistance largely contributes to poor clinical outcomes in GBM patients. We targeted ribonucleotide reductase subunit 2 (RRM2) with triapine to radiosensitize GBM. We found RRM2 is associated with increasing tumor grade, is overexpressed in GBM over lower grade gliomas and normal tissue, and is associated with worse survival. We found silencing or inhibition of RRM2 by siRNA or triapine sensitized GBM cells to ionizing radiation (IR) and delayed resolution of IR-induced γ-H2AX nuclear foci. In vivo, triapine and IR reduced tumor growth and increased mouse survival. Intriguingly, triapine led to RRM2 upregulation and CHK1 activation, suggesting a CHK1-dependent RRM2 upregulation following RRM2 inhibition. Consistently, silencing or inhibition of CHK1 with rabusertib abolished the triapine-induced RRM2 upregulation. Accordingly, combining rabusertib and triapine resulted in synthetic lethality in GBM cells. Collectively, our results suggest RRM2 is a promising therapeutic target for GBM, and targeting RRM2 with triapine sensitizes GBM cells to radiation and independently induces synthetic lethality of GBM cells with CHK1 inhibition. Our findings suggest combining triapine with radiation or rabusertib may improve therapeutic outcomes in GBM.
Topics: Animals; Mice; Cell Line, Tumor; Glioblastoma; Pyridines; Synthetic Lethal Mutations
PubMed: 37482342
DOI: 10.1016/j.canlet.2023.216308 -
Current Pharmaceutical Design 2024The escalation of cancer worldwide is one of the major causes of economy burden and loss of human resources. According to the American Cancer Society, there will be... (Review)
Review
BACKGROUND
The escalation of cancer worldwide is one of the major causes of economy burden and loss of human resources. According to the American Cancer Society, there will be 1,958,310 new cancer cases and 609,820 projected cancer deaths in 2023 in the United States. It is projected that by 2040, the burden of global cancer is expected to rise to 29.5 million per year, causing a death toll of 16.4 million. The hemostasis regulation by cellular protein synthesis and their targeted degradation is required for normal cell growth. The imbalance in hemostasis causes unbridled growth in cells and results in cancer. The DNA of cells needs to be targeted by chemotherapeutic agents for cancer treatment, but at the same time, their efficacy and toxicity also need to be considered for successful treatment.
OBJECTIVE
The objective of this study is to review the published work on pyrrole and pyridine, which have been prominent in the diagnosis and possess anticancer activity, to obtain some novel lead molecules of improved cancer therapeutic.
METHODS
A literature search was carried out using different search engines, like Sci-finder, Elsevier, ScienceDirect, RSC etc., for small molecules based on pyrrole and pyridine helpful in diagnosis and inducing apoptosis in cancer cells. The research findings on the application of these compounds from 2018-2023 were reviewed on a variety of cell lines, such as breast cancer, liver cancer, epithelial cancer, etc. Results: In this review, the published small molecules, pyrrole and pyridine and their derivatives, which have roles in the diagnosis and treatment of cancers, were discussed to provide some insight into the structural features responsible for diagnosis and treatment. The analogues with the chromeno-furo-pyridine skeleton showed the highest anticancer activity against breast cancer. The compound 5-amino-N-(1-(pyridin-4- yl)ethylidene)-1H-pyrazole-4-carbohydrazides was highly potent against HEPG2 cancer cell. Redaporfin is used for the treatment of cholangiocarcinoma, biliary tract cancer, cisplatin-resistant head and neck squamous cell carcinoma, and pigmentation melanoma, and it is in clinical trials for phase II. These structural features present a high potential for designing novel anticancer agents for diagnosis and drug development.
CONCLUSION
Therefore, the N- and C-substituted pyrrole and pyridine-based novel privileged small Nheterocyclic scaffolds are potential molecules used in the diagnosis and treatment of cancer. This review discusses the reports on the synthesis of such molecules during 2018-2023. The review mainly discusses various diagnostic techniques for cancer, which employ pyrrole and pyridine heterocyclic scaffolds. Furthermore, the anticancer activity of N- and C-substituted pyrrole and pyridine-based scaffolds has been described, which works against different cancer cell lines, such as MCF-7, A549, A2780, HepG2, MDA-MB-231, K562, HT- 29, Caco-2 cells, Hela, Huh-7, WSU-DLCL2, HCT-116, HBL-100, H23, HCC827, SKOV3, etc. This review will help the researchers to obtain a critical insight into the structural aspects of pyrrole and pyridine-based scaffolds useful in cancer diagnosis as well as treatment and design pathways to develop novel drugs in the future.
Topics: Humans; Neoplasms; Antineoplastic Agents; Pyridines; Pyrroles; Heterocyclic Compounds; Animals
PubMed: 38711394
DOI: 10.2174/0113816128280082231205071504 -
British Journal of Cancer Oct 2023Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibition yields differential cellular responses in multiple tumor models due to redundancy in cell cycle. We investigate...
BACKGROUND
Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibition yields differential cellular responses in multiple tumor models due to redundancy in cell cycle. We investigate whether the differential requirements of CDKs in multiple cell lines function as determinant of response to pharmacological agents that target these kinases.
METHODS
We utilized proteolysis-targeted chimeras (PROTACs) that are conjugated with palbociclib (Palbo-PROTAC) to degrade both CDK4 and CDK6. FN-POM was synthesized by chemically conjugating pomalidomide moiety with a multi-kinase inhibitor, FN-1501. Patient derived PDAC organoids and PDX model were utilized to investigate the effect of FN-POM in combination with palbociclib.
RESULTS
Palbo-PROTAC mediates differential impact on cell cycle in different tumor models, indicating that the dependencies to CDK4 and 6 kinases are heterogenous. Cyclin E overexpression uncouples cell cycle from CDK4/6 and drives resistance to palbo-PROTAC. Elevated expression of P16INK4A antagonizes PROTAC-mediated degradation of CDK4 and 6. FN-POM degrades cyclin E and CDK2 and inhibits cell cycle progression in P16INK4A-high tumor models. Combination of palbociclib and FN-POM cooperatively inhibit tumor cell proliferation via RB activation.
CONCLUSION
Resistance to CDK4/6 inhibition could be overcome by pharmacologically limiting Cyclin E/CDK2 complex and proves to be a potential therapeutic approach.
Topics: Humans; Proteolysis; Cyclin-Dependent Kinase 4; Pyridines; Piperazines; Cyclin-Dependent Kinase 6; Cell Cycle; Protein Kinase Inhibitors; Cell Line, Tumor; Mice; Animals; Thalidomide; Xenograft Model Antitumor Assays; Cell Proliferation
PubMed: 37626264
DOI: 10.1038/s41416-023-02399-4 -
Journal of Oncology Pharmacy Practice :... Jan 2024Cabozantinib is a multikinase inhibitor agent used in the treatment of hepatocellular, renal, and thyroid cancers. The development of heart failure after cabozantinib...
INTRODUCTION
Cabozantinib is a multikinase inhibitor agent used in the treatment of hepatocellular, renal, and thyroid cancers. The development of heart failure after cabozantinib initiation is an extremely rare side effect, with only four case reports published in the literature. We describe a case of cabozantinib-induced cardiac failure in a patient with thyroid cancer refractory to standard treatment.
CASE REPORT
Fifty-seven-year-old woman had no history of cardiovascular disease. Echocardiography prior to chemotherapy revealed normal cardiac function. However, she developed pretibial edema and shortness of breath after 2 months of cabozantinib treatment. Ejection fraction was found to be 30% in the echocardiography of the patient, and global hypokinesia was detected in cardiac functions.
MANAGEMENT AND OUTCOME
Cabozantinib treatment of the patient was discontinued. After discontinuation of treatment, the patient's cardiac functions did not return to normal. Heart failure due to cabozantinib treatment was thought to be permanent.
DISCUSSION
There are only four cases on this subject in the literature. Although the use of cabozantinib rarely causes heart failure, this side effect can have extremely serious consequences. Even if it is a rare condition, cardiological evaluations should be performed before and after cabozantinib therapy because it can be reversible after discontinuation of the treatment.
Topics: Female; Humans; Middle Aged; Pyridines; Anilides; Thyroid Neoplasms; Heart Failure
PubMed: 37817663
DOI: 10.1177/10781552231203703 -
Alimentary Pharmacology & Therapeutics Jun 2024While filgotinib, an oral Janus kinase (JAK) 1 preferential inhibitor, is approved for moderately to severely active ulcerative colitis (UC), real-world studies...
BACKGROUND AND AIMS
While filgotinib, an oral Janus kinase (JAK) 1 preferential inhibitor, is approved for moderately to severely active ulcerative colitis (UC), real-world studies assessing its short- and long-term efficacy and safety are limited.
METHODS
This is a multicenter, retrospective study of UC patients who started filgotinib between March 2022 and September 2023. The primary outcome was clinical remission, defined as a partial Mayo score ≤1 with a rectal bleeding score of 0, or Simple Clinical Colitis Activity Index (SCCAI) ≤2 with a blood-in-stool score of 0. Secondary outcomes included clinical response, corticosteroid-free remission, and endoscopic improvement. Outcomes were assessed at 10, 26, and 58 weeks based on patients with available follow-up. Adverse events were evaluated.
RESULTS
We identified 238 UC patients and 54% had prior exposure to biologics/JAK inhibitors. The median baseline partial Mayo score and SCCAI were 5 (IQR 3-6) and 4 (IQR 2-7). Clinical remission rates based on per-protocol analysis at 10, 26, and 58 weeks were 47% (70/149), 55.8% (48/86), and 64.6% (31/48), respectively. At a median follow-up of 28 weeks (IQR 10-54) with a discontinuation rate of 39%, the rates of clinical remission, clinical response, corticosteroid-free remission, and endoscopic improvement were 39.9% (81/203), 54.7% (111/203), and 36.5% (74/203), and 43.5% (10/23), respectively. These rates were comparable between biologic/JAK inhibitor-naïve and -experienced patients. While three patients (1.3%) developed herpes zoster infection, no cases of thrombosis or death were reported.
CONCLUSIONS
Real-world data demonstrate favourable clinical and safety outcomes of filgotinib for UC.
Topics: Humans; Colitis, Ulcerative; Male; Retrospective Studies; Female; Adult; Middle Aged; Japan; Treatment Outcome; Triazoles; Pyridines; Remission Induction; Janus Kinase Inhibitors; Severity of Illness Index; Aged
PubMed: 38494867
DOI: 10.1111/apt.17961 -
Organic & Biomolecular Chemistry Oct 2023Lipid droplets (LDs) have emerged as major regulators of cellular metabolism, encompassing lipid storage, membrane synthesis, viral replication, and protein degradation....
Lipid droplets (LDs) have emerged as major regulators of cellular metabolism, encompassing lipid storage, membrane synthesis, viral replication, and protein degradation. Exclusive studies have suggested a direct link between LDs and cancer, as a notable abundance of LDs is found in cancerous cells. Therefore, monitoring the location, distribution, and movements of LDs is of paramount importance for understanding their involvement in biological processes. To target LDs, we designed and synthesized fluorophores with a styryl scaffold bearing electron-donating amino groups and pyridine--oxide, a zwitterionic acceptor moiety. We explored their photophysical properties in various solvents and conducted systematic DFT calculations on the synthesized fluorescent molecules, comparing them with neutral pyridine and cationic pyridinium styryl dyes. The results demonstrate that diphenylaminostyryl pyridine--oxide (TNO) shows excellent imaging of LDs, in contrast to the behavior of cationic styrylpyridinium (TNC), which primarily localizes within the mitochondria. Notably, pyridine -oxide offers several benefits: an increased dipole moment facilitating charge separation between donors and acceptors, substantial HOMO and LUMO stabilization, improved water solubility, favorable redox properties, and bathochromic-shifted absorption/emission spectra, showing promise as a fluorescent tool for probing the cellular-biological realm.
Topics: Lipid Droplets; Fluorescent Dyes; Pyridines; Oxides
PubMed: 37819137
DOI: 10.1039/d3ob01365k -
Molecules (Basel, Switzerland) Apr 2024Since the discovery of cisplatin in the 1960s, the search for metallo-drugs that are more efficient than platinum complexes with negligible side effects has attracted... (Review)
Review
Since the discovery of cisplatin in the 1960s, the search for metallo-drugs that are more efficient than platinum complexes with negligible side effects has attracted much interest. Among the other metals that have been examined for potential applications as anticancer agents is copper. The interest in copper was recently boosted by the discovery of cuproptosis, a recently evidenced form of cell death mediated by copper. However, copper is also known to induce the proliferation of cancer cells. In view of these contradictory results, there is a need to find the most suitable copper chelators, among which Schiff-based derivatives offer a wide range of possibilities. Gathering several metal complexes in a single, larger entity may provide enhanced properties. Among the nanometric objects suitable for such purpose are dendrimers, precisely engineered hyperbranched macromolecules, which are outstanding candidates for improving therapy and diagnosis. In this review article, we present an overview of the use of a particular Schiff base, namely pyridine-imine, linked to the surface of dendrimers, suitable for complexing copper, and the use of such dendrimer complexes in biology, in particular against cancers.
Topics: Animals; Humans; Antineoplastic Agents; Chelating Agents; Coordination Complexes; Copper; Dendrimers; Imines; Neoplasms; Pyridines; Schiff Bases
PubMed: 38675623
DOI: 10.3390/molecules29081800 -
Journal of Medicinal Chemistry Dec 2023Janus kinase 1 (JAK1) plays a pivotal role in regulating inflammation and fibrosis via the JAK/STAT signaling pathway, making it a promising target for associated...
Janus kinase 1 (JAK1) plays a pivotal role in regulating inflammation and fibrosis via the JAK/STAT signaling pathway, making it a promising target for associated diseases. In this study, we explored the modification of an -methyl 1-pyrrolo[2,3-]pyridine-5-carboxylate core, leading to the identification of 4-(((2,4)-1-(4-trifluoromethyl)-2-methylpiperidin-4-yl)amino)--methyl-1-pyrrolo[2,3-]pyridine-5-carboxamide () as a highly potent and selective JAK1 inhibitor. Compound exhibited an impressive IC value of 0.044 nM for JAK1 and demonstrated remarkable selectivity of 382-fold, 210-fold, and 1325-fold specificity over JAK2, JAK3, and TYK2, respectively. The kinase panel assays further confirmed its specificity, and cell-based experiments established its efficacy in inhibiting JAK1-STAT phosphorylation in human L-132 or SK-MES-1 cells. Pharmacokinetic studies revealed that compound boasts an oral bioavailability exceeding 36%. In a bleomycin-induced fibrosis mouse model, compound significantly reduced STAT3 phosphorylation, resulting in improvement in body weight and reduced collagen deposition, all achieved without significant side effects.
Topics: Mice; Animals; Humans; Structure-Activity Relationship; Protein Kinase Inhibitors; Pulmonary Fibrosis; Janus Kinase Inhibitors; Janus Kinase 1; Pyridines
PubMed: 38031930
DOI: 10.1021/acs.jmedchem.3c01712 -
Critical Reviews in Analytical Chemistry 2024Pyridine derivatives are the most common and significant heterocyclic compounds, which play an important role in various fields ranging from medicinal to chemosensing... (Review)
Review
Pyridine derivatives are the most common and significant heterocyclic compounds, which play an important role in various fields ranging from medicinal to chemosensing applications. Pyridine derivatives possess different biological activities such as antifungal, antibacterial, antioxidant, antiglycation, analgesic, antiparkinsonian, anticonvulsant, anti-inflammatory, ulcerogenic, antiviral, and anticancer activity. Furthermore, these derivatives have a high affinity for various ions and neutral species and can be used as a highly effective chemosensor for the determination of different species. In this review article, generally used synthetic routes of pyridine, structural characterization, medicinal applications, and potential of pyridine derivatives in analytical chemistry as chemosensors have been discussed. We hope this study will support the new thoughts to design biological active compounds and highly selective and effective chemosensors for the detection of various species (anions, cations, and neutral species) in various samples (environmental, agricultural, and biological). [Figure: see text].
Topics: Pyridines; Humans; Animals
PubMed: 35724248
DOI: 10.1080/10408347.2022.2089839