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1.
World J Urol ; 42(1): 113, 2024 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-38431689

RESUMO

PURPOSE: To compare the efficacy and safety of mirabegron and vibegron in female OAB patients. METHODS: We conducted a multicenter, prospective, randomized crossover study of female patients with OAB. The patients were assigned to Group MV (mirabegron for 8 weeks, followed by vibegron for 8 weeks) or group VM (vibegron for 8 weeks, followed by mirabegron for 8 weeks). The primary endpoint was the change in OABSS from baseline, and the secondary endpoint was the change in FVC parameters. After completion of the study, each patient was asked which drug was preferable. RESULTS: A total of 83 patients were enrolled (40 and 43 in groups MV and VM, respectively). At 8th and 16th week, 33 and 29 in Group MV and 34 and 27 in Group VM continued to receive the treatment. The change in PVR was not significantly different between treatment with mirabegron and vibegron. The changes in OABSS, nighttime frequency, mean, and maximum voided volume were similar between mirabegron and vibegron. The mean change in the daytime frequency was greater in the vibegron than in the mirabegron. Of the 56 patients, 15 (27%) and 30 (53%) preferred mirabegron and vibegron, respectively. The remaining 11 patients (20%) showed no preference. The change in the urgency incontinence score during vibegron was better in patients who preferred vibegron to mirabegron. CONCLUSION: The efficacies of mirabegron and vibegron in female patients was similar. The patients' preference for vibegron could depend on the efficacy of vibegron for urgency incontinence.


Assuntos
Pirimidinonas , Pirrolidinas , Tiazóis , Bexiga Urinária Hiperativa , Incontinência Urinária , Agentes Urológicos , Humanos , Feminino , Bexiga Urinária Hiperativa/tratamento farmacológico , Bexiga Urinária Hiperativa/complicações , Estudos Cross-Over , Estudos Prospectivos , Acetanilidas/uso terapêutico , Resultado do Tratamento , Método Duplo-Cego , Agentes Urológicos/uso terapêutico , Agonistas de Receptores Adrenérgicos beta 3/uso terapêutico
2.
Molecules ; 29(5)2024 Feb 29.
Artigo em Inglês | MEDLINE | ID: mdl-38474577

RESUMO

While numerous Fabaceae seeds are a good nutritional source of high-quality protein, the use of some species is hampered by toxic effects caused by exposure to metabolites that accumulate in the seeds. One such species is the faba or broad bean (Vicia faba L.), which accumulates vicine and convicine. These two glycoalkaloids cause favism, the breakdown of red blood cells in persons with a glucose-6-phosphate dehydrogenase deficiency. Because this is the most common enzyme deficiency worldwide, faba bean breeding efforts have focused on developing cultivars with low levels of these alkaloids. Consequently, quantification methods have been developed; however, they quantify vicine and convicine only and not the derivatives of these compounds that potentially generate the same bio-active molecules. Based on the recognition of previously unknown (con)vicine-containing compounds, we screened the fragmentation spectra of LC-MS/MS data from five faba bean cultivars using the characteristic fragments generated by (con)vicine. This resulted in the recognition of more than a hundred derivatives, of which 89 were tentatively identified. (Con)vicine was mainly derivatized through the addition of sugars, hydroxycinnamic acids, and dicarboxylic acids, with a group of compounds composed of two (con)vicine residues linked by dicarboxyl fatty acids. In general, the abundance profiles of the different derivatives in the five cultivars mimicked that of vicine and convicine, but some showed a derivative-specific profile. The description of the (con)vicine diversity will impact the interpretation of future studies on the biosynthesis of (con)vicine, and the content in potentially bio-active alkaloids in faba beans may be higher than that represented by the quantification of vicine and convicine alone.


Assuntos
Alcaloides , Fabaceae , Glucosídeos , Pirimidinonas , Uridina/análogos & derivados , Vicia faba , Vicia faba/química , Cromatografia Líquida , Espectrometria de Massas em Tandem , Melhoramento Vegetal
3.
Sci Rep ; 14(1): 6266, 2024 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-38491114

RESUMO

There is an unmet need for antifibrotic therapies to prevent the progression of liver cirrhosis. Previously, we conducted an exploratory trial to assess the safety and antifibrotic efficacy of PRI-724, a selective CBP/ß-catenin inhibitor, in patients with liver cirrhosis. PRI-724 was well tolerated and exerted a potential antifibrotic effect. Here, we investigated whether the profiles of circulating microRNAs packaged in extracellular vesicles (EV-miRNAs) are associated with responses to liver fibrosis treatments. Eighteen patients who received PRI-724 for 12 weeks in a phase 1/2a study were classified as responders (n = 10) or non-responders (n = 8) based on changes in liver stiffness. Plasma samples were obtained before and after PRI-724 administration and the levels of EV-miRNAs were analyzed. Three miRNAs (miR-6510-5p, miR-6772-5p, and miR-4261) were identified as predictors of response or non-response to PRI-724, and the levels of three other miRNAs (miR-939-3p, miR-887-3p, and miR-7112-5p) correlated with the efficacy of treatment. Expression of miR-887-3p was detected in hepatocytes and was decreased significantly in liver tissue following PRI-724 treatment. In addition, transfection of a miR-887-3p mimic activated hepatic stellate cells. Thus, decreases in the miR-887-3p level in blood may reflect recovery from liver fibroses in patients with liver cirrhosis treated with PRI-724, although further validation studies are warranted to confirm this.


Assuntos
Vesículas Extracelulares , MicroRNAs , Pirimidinonas , Humanos , MicroRNAs/metabolismo , beta Catenina/genética , beta Catenina/metabolismo , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/genética , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Vesículas Extracelulares/metabolismo
4.
Se Pu ; 42(3): 256-263, 2024 Mar 08.
Artigo em Chinês | MEDLINE | ID: mdl-38503702

RESUMO

Herbicides play an important role in preventing and controlling weeds and harmful plants and are increasingly used in agriculture, forestry, landscaping, and other fields. However, the effective utilization rate of herbicides is only 20%-30%, and most herbicides enter the atmosphere, soil, sediment, and water environments through drift, leaching, and runoff after field application. Herbicide residues in the environment pose potential risks to ecological safety and human health. Therefore, establishing analytical methods to determine herbicide residues in environmental samples is of great importance. In this study, an analytical method based on liquid chromatography-tandem mass spectrometry (LC-MS/MS) in positive electrospray ionization mode (ESI+) was developed for the determination of isoxaflutole, metazachlor, and saflufenacil residues in soil, sediment, and water. The instrumental detection parameters, including electrospray ionization mode, mobile phase, and chromatographic column, were optimized. The mobile phases were methanol (A) and 0.1% formic acid aqueous solution (B). Gradient elution was performed as follows: 0-1.0 min, 60%A; 1.0-2.0 min, 60%A-90%A; 2.0-3.0 min, 90%A; 3.0-4.0 min, 90%A-60%A; 4.0-5.0 min, 60%A. The samples were salted after extraction with acetonitrile and cleaned using a C18 solid-phase extraction column. Different solid-phase extraction columns and leaching conditions were investigated during sample pretreatment. Working curves in the neat solvent and matrix were constructed by plotting the measured peak areas as a function of the concentrations of the analytes in the neat solvent and matrix. Good linearities were found for isoxaflutole, metazachlor, and saflufenacil in the solvent and matrix-matched standards in the range of 0.0005-0.02 mg/L, with r≥0.9961. The matrix effects of the three herbicides in soil, sediment, and water ranged from -10.1% to 16.5%. The limits of detection (LODs, S/N=3) for isoxaflutole, metazachlor, and saflufenacil were 0.05, 0.01, and 0.02 µg/kg, respectively. The limits of quantification (LOQs, S/N=10) for isoxaflutole, metazachlor, and saflufenacil were 0.2, 0.05, and 0.05 µg/kg, respectively. The herbicides were applied to soil, sediment, and water at spiked levels of 0.005, 0.1, and 2.0 mg/kg, respectively. The average recoveries for isoxaflutole, metazachlor, and saflufenacil in soil, sediment, and water were in the ranges of 77.2%-101.9%, 77.9%-105.1%, and 80.8%-107.1%, respectively. The RSDs for isoxaflutole, metazachlor, and saflufenacil were in the ranges of 1.4%-12.8%, 1.2%-7.7%, and 1.5%-11.5%, respectively. The established method was used to analyze actual samples collected from four different sites in Zhejiang Province (Xiaoshan, Taizhou, Dongyang, and Yuhang) and one site in Heilongjiang (Jiamusi). The proposed method is simple, rapid, accurate, stable, and highly practical. It can be used to detect isoxaflutole, metazachlor, and saflufenacil residues in soil, sediment, and water and provides a reference for monitoring the residual pollution and environmental behavior of herbicides.


Assuntos
Acetamidas , Herbicidas , Pirimidinonas , Sulfonamidas , Humanos , Cromatografia Líquida , Herbicidas/análise , Cromatografia Líquida de Alta Pressão , Espectrometria de Massas em Tandem/métodos , Água/análise , Solo/química , Solventes/análise , Extração em Fase Sólida
5.
Genes Chromosomes Cancer ; 63(2): e23222, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38340027

RESUMO

INTRODUCTION: Pancreatic acinar cell carcinomas are rare malignant neoplasms. High-quality evidence about the best treatment strategy is lacking. We present the case of a 52-year-old male with a BRAFV600E -mutated PACC who experienced a complete remission after chemotherapy with BRAF-/MEK-inhibitors. CASE: The patient presented with upper abdomen pain, night sweat, and weight loss. CT scan showed a pancreatic tumor extending from the pancreas head to body. Histological workup identified an acinar cell carcinoma. As the tumor was inoperable, chemotherapy with FOFIRNIOX was initiated and initially showed a slight regression of disease. The regimen had to be discontinued due to severe side effects. Molecular analysis identified a BRAFV600E mutation, so the patient was started on BRAF- and MEK-inhibitors (dabrafenib/trametinib). After 16 months, CT scans showed a near complete remission with a markedly improved overall health. DISCUSSION: Studies suggest that up to one-fourth of PACCs carry a BRAF mutation and might therefore be susceptible to a BRAF-/MEK-inhibitor therapy. This offers a new therapeutic pathway to treat this rare but malignant neoplasm.


Assuntos
Carcinoma de Células Acinares , Neoplasias Pancreáticas , Humanos , Masculino , Pessoa de Meia-Idade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Acinares/tratamento farmacológico , Carcinoma de Células Acinares/genética , Carcinoma de Células Acinares/induzido quimicamente , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Mutação , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Piridonas/farmacologia , Pirimidinonas/farmacologia
6.
Sci Rep ; 14(1): 3308, 2024 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-38332020

RESUMO

Ultraviolet (UV) component of solar radiation impairs genome stability by inducing the formation of pyrimidine-pyrimidone (6-4) photoproducts [(6-4)PPs] in plant genomes. (6-4)PPs disrupt growth and development by interfering with transcription and DNA replication. To resist UV stress, plants employ both photoreactivation and nucleotide excision repair that excises oligonucleotide containing (6-4)PPs through two subpathways: global and transcription-coupled excision repair (TCR). Here, we analyzed the genome-wide excision repair-mediated repair of (6-4)PPs in Arabidopsis thaliana and found that (6-4)PPs can be repaired by TCR; however, the main subpathway to remove (6-4)PPs from the genome is global repair. Our analysis showed that open chromatin genome regions are more rapidly repaired than heterochromatin regions, and the repair level peaks at the promoter, transcription start site and transcription end site of genes. Our study revealed that the repair of (6-4)PP in plants showed a distinct genome-wide repair profile compared to the repair of other major UV-induced DNA lesion called cyclobutane pyrimidine dimers (CPDs).


Assuntos
Arabidopsis , Reparo do DNA , Arabidopsis/genética , Pirimidinonas , Dímeros de Pirimidina , Dano ao DNA , Receptores de Antígenos de Linfócitos T/genética , Raios Ultravioleta
7.
Sci Rep ; 14(1): 4008, 2024 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-38369538

RESUMO

Triple-negative breast cancer (TNBC) is regarded as the deadliest subtype of breast cancer because of its high heterogeneity, aggressiveness, and limited treatment options. Toxoflavin has been reported to possess antitumor activity. In this study, a series of toxoflavin analogs were synthesized, among which D43 displayed a significant dose-dependent inhibitory effect on the proliferation of TNBC cells (MDA-MB-231 and HCC1806). Additionally, D43 inhibited DNA synthesis in TNBC cells, leading to cell cycle arrest at the G2/M phase. Furthermore, D43 consistently promoted intracellular ROS generation, induced DNA damage, and resulted in apoptosis in TNBC cells. These effects could be reversed by N-acetylcysteine. Moreover, D43 significantly inhibited the growth of breast cancer patient-derived organoids and xenografts with a favorable biosafety profile. In conclusion, D43 is a potent anticancer agent that elicits significant antiproliferation, oxidative stress, apoptosis, and DNA damage effects in TNBC cells, and D43 holds promise as a potential candidate for the treatment of TNBC.


Assuntos
Pirimidinonas , Triazinas , Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/genética , Espécies Reativas de Oxigênio/metabolismo , Proliferação de Células , Linhagem Celular Tumoral , Apoptose , Dano ao DNA
8.
Clin Nucl Med ; 49(4): 342-343, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38389206

RESUMO

ABSTRACT: A 79-year-old man with a history of metastatic prostate cancer was initially treated with Eligard and switched to relugolix in 2021. The 2022 bone scan presented superscan and extensive osseous metastatic lesions; some had intense PSMA uptake on the initial PSMA PET scan without nodal or visceral metastatic lesions. We treated him with Pluvicto and relugolix. The intermediate PSMA scan demonstrated prominent bone marrow PSMA uptake. However, PSA decreased 58.5%. We hypothesized that the patient might have a bone flare. The final PSMA scan confirmed our hypothesis. Based on our knowledge, this is the first case of Pluvicto-induced bone flare.


Assuntos
Osso e Ossos , Pirimidinonas , Tomografia Computadorizada por Raios X , Masculino , Humanos , Idoso , Osso e Ossos/diagnóstico por imagem , Compostos de Fenilureia , Tomografia por Emissão de Pósitrons
9.
Chin Med J (Engl) ; 137(2): 222-231, 2024 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-38167245

RESUMO

BACKGROUND: Radiation (IR)-induced DNA damage triggers cell cycle arrest and has a suppressive effect on the tumor microenvironment (TME). Wee1, a cell cycle regulator, can eliminate G2/M arrest by phosphorylating cyclin-dependent kinase 1 (CDK1). Meanwhile, programed death-1/programed death ligand-1 (PD-1/PDL-1) blockade is closely related to TME. This study aims to investigate the effects and mechanisms of Wee1 inhibitor AZD1775 and anti-PD-1 antibody (anti-PD-1 Ab) on radiosensitization of hepatoma. METHODS: The anti-tumor activity of AZD1775 and IR was determined by 3-(4,5-dimethylthiazol-2-y1)-2,5-diphenyltetrazolium bromide (MTT) assay on human and mouse hepatoma cells HepG2, Hepa1-6, and H22. The anti-hepatoma mechanism of AZD1775 and IR revealed by flow cytometry and Western blot in vitro . A hepatoma subcutaneous xenograft mice model was constructed on Balb/c mice, which were divided into control group, IR group, AZD1775 group, IR + AZD1775 group, IR + anti-PD-1 Ab group, and the IR + AZD1775 + anti-PD-1 Ab group. Cytotoxic CD8 + T cells in TME were analyzed by flow cytometry. RESULTS: Combining IR with AZD1775 synergistically reduced the viability of hepatoma cells in vitro . AZD1775 exhibited antitumor effects by decreasing CDK1 phosphorylation to reverse the IR-induced G2/M arrest and increasing IR-induced DNA damage. AZD1775 treatment also reduced the proportion of PD-1 + /CD8 + T cells in the spleen of hepatoma subcutaneous xenograft mice. Further studies revealed that AZD1775 and anti-PD-1 Ab could enhance the radiosensitivity of hepatoma by enhancing the levels of interferon γ (IFNγ) + or Ki67 + CD8 T cells and decreasing the levels of CD8 + Tregs cells in the tumor and spleen of the hepatoma mice model, indicating that the improvement of TME was manifested by increasing the cytotoxic factor IFNγ expression, enhancing CD8 + T cells proliferation, and weakening CD8 + T cells depletion. CONCLUSIONS: This work suggests that AZD1775 and anti-PD-1 Ab synergistically sensitize hepatoma to radiotherapy by enhancing IR-induced DNA damage and improving cytotoxic CD8 + T cells in TME.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Pirazóis , Pirimidinonas , Humanos , Animais , Camundongos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/radioterapia , Proteínas de Ciclo Celular/metabolismo , Proteínas Tirosina Quinases/genética , Apoptose , Receptor de Morte Celular Programada 1 , Linhagem Celular Tumoral , Pontos de Checagem da Fase G2 do Ciclo Celular , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/radioterapia , Microambiente Tumoral
10.
Hum Reprod ; 39(3): 526-537, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38243752

RESUMO

STUDY QUESTION: What is the efficacy and safety of long-term treatment (up to 2 years) with relugolix combination therapy (CT) in women with moderate to severe endometriosis-associated pain? SUMMARY ANSWER: For up to 2 years, treatment with relugolix CT improved menstrual and non-menstrual pain, dyspareunia, and function in women with endometriosis; after an initial decline of <1%, the mean bone mineral density (BMD) remained stable with continued treatment. WHAT IS KNOWN ALREADY: Endometriosis is a chronic condition characterized by symptoms of dysmenorrhea, non-menstrual pelvic pain (NMPP), and dyspareunia, which have a substantial impact on the lives of affected women, their partners, and families. SPIRIT 1 and 2 were phase 3, randomized, double-blind, placebo-controlled studies of once-daily relugolix CT (relugolix 40 mg, oestradiol 1 mg, norethisterone acetate 0.5 mg) in premenopausal women (age 18-50 years) with endometriosis and moderate-to-severe dysmenorrhea and NMPP. These trials demonstrated a significant improvement of dysmenorrhea, NMPP, and dyspareunia in women treated with relugolix CT, with minimal decline (<1%) in BMD versus placebo at 24 weeks. STUDY DESIGN, SIZE, DURATION: Patients participating in this open-label, single-arm, long-term extension (LTE) study of the 24-week SPIRIT pivotal studies (SPIRIT 1 and 2) received up to an additional 80 weeks of once-daily oral relugolix CT treatment between May 2018 and January 2023. PARTICIPANTS/MATERIALS, SETTING, METHODS: Premenopausal women with confirmed endometriosis and moderate to severe dysmenorrhea and NMPP who completed the 24-week pivotal studies (SPIRIT 1 and 2 trials; Giudice et al., 2022) and who met all entry criteria were eligible to enrol. Two-year results were analysed by treatment group based on original randomization in pivotal studies: relugolix CT, delayed relugolix CT (relugolix 40 mg monotherapy for 12 weeks, followed by relugolix CT), or placebo→relugolix CT (placebo for 24 weeks followed by relugolix CT). The primary endpoints of the LTE study were the proportion of dysmenorrhea and NMPP responders at Week 52 and Week 104/end-of-treatment (EOT). A responder was a participant who achieved a predefined, clinically meaningful reduction from baseline in Numerical Rating Scale (NRS) scores (0 = no pain, 10 = worst pain imaginable) for the specific pain type with no increase in analgesic use. The predefined clinically meaningful threshold for dysmenorrhea was 2.8 points and for NMPP was 2.1 points. Secondary efficacy endpoints included change from baseline in Endometriosis Health Profile-30 (EHP-30) pain domain scores, a measure of the effects of endometriosis-associated pain on daily activities (function), NRS scores for dysmenorrhea, NMPP, dyspareunia, and overall pelvic pain, and analgesic/opioid use. Safety endpoints included adverse events and changes in BMD. MAIN RESULTS AND THE ROLE OF CHANCE: Of 1261 randomized patients, 1044 completed the pivotal studies, 802 enrolled in the LTE, 681 completed 52 weeks of treatment, and 501 completed 104 weeks of treatment. Demographics and baseline characteristics of the extension population were consistent with those of the original randomized population. Among patients randomized to relugolix CT at pivotal study baseline who continued in the LTE (N = 277), sustained improvements in endometriosis-associated pain were demonstrated through 104 weeks. The proportion of responders at Week 104/EOT for dysmenorrhea and NMPP was 84.8% and 75.8%, respectively. Decreases in dyspareunia and improvement in function assessed by EHP-30 pain domain were also sustained over 2 years. At Week 104/EOT, 91% of patients were opioid-free and 75% of patients were analgesic-free. Relugolix CT over 104 weeks was well tolerated with a safety profile consistent with that observed over the first 24 weeks. After initial least squares mean BMD loss <1% at Week 24, BMD plateaued at Week 36 and was sustained for the duration of 104 weeks of treatment. Efficacy and safety results were generally consistent in women in the placebo→relugolix CT and delayed relugolix CT groups. LIMITATIONS, REASONS FOR CAUTION: The study was conducted as an open-label study without a control group over the 80 weeks of the extension period. Of the 802 patients who were enrolled in this LTE study, 681 patients (84.9%) and 501 patients (62.5%) of patients completed 52 and 104 weeks of treatment, respectively. In addition, there currently are no comparative data to other hormonal medications. Finally, a third (37.4%) of the study population terminated participation early. WIDER IMPLICATIONS OF THE FINDINGS: In conclusion, relugolix CT offers an additional option to help address an important unmet clinical need for effective, safe, and well-tolerated medical treatments for endometriosis that can be used longer-term, reducing the need for opioids and improving quality of life. The findings from this study may help support the care of women with endometriosis seeking longer-term effective medical management of their symptoms. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by Myovant Sciences GmbH (now Sumitomo Pharma Switzerland GmbH). C.M.B. reports fees from Myovant, grants from Bayer Healthcare, fees from ObsEva, and Chair of ESHRE Endometriosis Guideline Group (all funds went to the University of Oxford); N.P.J. reports personal fees from Myovant Sciences, during the conduct of the study, personal fees from Guerbet, personal fees from Organon, personal fees from Roche Diagnostics; S.A.-S. reports personal fees from Myovant Sciences, personal fees from Bayer, personal fees from Abbvie, personal fees from UpToDate; J.S.P., and R.B.W. are employees and shareholders of Myovant Sciences; J.C.A.F. and S.J.I. are shareholders of Myovant Sciences (but at time of publicaion are no longer employess of Myovant Sciences); M.S.A. and K.W. have no conflicts to declare; V.M. is a consultant to Myovant; L.C.G. reports personal fees from Myovant Sciences, Inc and Bayer. The authors did not receive compensation for manuscript writing, review, and revision. TRIAL REGISTRATION NUMBER: NCT03654274.


Assuntos
Dispareunia , Endometriose , Compostos de Fenilureia , Pirimidinonas , Humanos , Feminino , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Endometriose/complicações , Endometriose/tratamento farmacológico , Dismenorreia/complicações , Dismenorreia/tratamento farmacológico , Dispareunia/tratamento farmacológico , Dispareunia/etiologia , Qualidade de Vida , Dor Pélvica/tratamento farmacológico , Dor Pélvica/etiologia , Analgésicos Opioides
11.
BMC Cancer ; 24(1): 147, 2024 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-38291372

RESUMO

BACKGROUND: Pediatric low-grade glioma (pLGG) is essentially a single pathway disease, with most tumors driven by genomic alterations affecting the mitogen-activated protein kinase/ERK (MAPK) pathway, predominantly KIAA1549::BRAF fusions and BRAF V600E mutations. This makes pLGG an ideal candidate for MAPK pathway-targeted treatments. The type I BRAF inhibitor, dabrafenib, in combination with the MEK inhibitor, trametinib, has been approved by the United States Food and Drug Administration for the systemic treatment of BRAF V600E-mutated pLGG. However, this combination is not approved for the treatment of patients with tumors harboring BRAF fusions as type I RAF inhibitors are ineffective in this setting and may paradoxically enhance tumor growth. The type II RAF inhibitor, tovorafenib (formerly DAY101, TAK-580, MLN2480), has shown promising activity and good tolerability in patients with BRAF-altered pLGG in the phase 2 FIREFLY-1 study, with an objective response rate (ORR) per Response Assessment in Neuro-Oncology high-grade glioma (RANO-HGG) criteria of 67%. Tumor response was independent of histologic subtype, BRAF alteration type (fusion vs. mutation), number of prior lines of therapy, and prior MAPK-pathway inhibitor use. METHODS: LOGGIC/FIREFLY-2 is a two-arm, randomized, open-label, multicenter, global, phase 3 trial to evaluate the efficacy, safety, and tolerability of tovorafenib monotherapy vs. current standard of care (SoC) chemotherapy in patients < 25 years of age with pLGG harboring an activating RAF alteration who require first-line systemic therapy. Patients are randomized 1:1 to either tovorafenib, administered once weekly at 420 mg/m2 (not to exceed 600 mg), or investigator's choice of prespecified SoC chemotherapy regimens. The primary objective is to compare ORR between the two treatment arms, as assessed by independent review per RANO-LGG criteria. Secondary objectives include comparisons of progression-free survival, duration of response, safety, neurologic function, and clinical benefit rate. DISCUSSION: The promising tovorafenib activity data, CNS-penetration properties, strong scientific rationale combined with the manageable tolerability and safety profile seen in patients with pLGG led to the SIOPe-BTG-LGG working group to nominate tovorafenib for comparison with SoC chemotherapy in this first-line phase 3 trial. The efficacy, safety, and functional response data generated from the trial may define a new SoC treatment for newly diagnosed pLGG. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05566795. Registered on October 4, 2022.


Assuntos
Vaga-Lumes , Glioma , Animais , Criança , Humanos , Adulto Jovem , Vaga-Lumes/metabolismo , Proteínas Proto-Oncogênicas B-raf , Glioma/tratamento farmacológico , Glioma/genética , Glioma/metabolismo , Resultado do Tratamento , Mutação , Proteínas Quinases Ativadas por Mitógeno , Oximas , Piridonas , Pirimidinonas/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
12.
Proc Natl Acad Sci U S A ; 121(4): e2311313121, 2024 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-38241436

RESUMO

Pharmacological therapies are promising interventions to slow down aging and reduce multimorbidity in the elderly. Studies in animal models are the first step toward translation of candidate molecules into human therapies, as they aim to elucidate the molecular pathways, cellular mechanisms, and tissue pathologies involved in the anti-aging effects. Trametinib, an allosteric inhibitor of MEK within the Ras/MAPK (Ras/Mitogen-Activated Protein Kinase) pathway and currently used as an anti-cancer treatment, emerged as a geroprotector candidate because it extended lifespan in the fruit fly Drosophila melanogaster. Here, we confirm that trametinib consistently and robustly extends female lifespan, and reduces intestinal stem cell (ISC) proliferation, tumor formation, tissue dysplasia, and barrier disruption in guts in aged flies. In contrast, pro-longevity effects of trametinib are weak and inconsistent in males, and it does not influence gut homeostasis. Inhibition of the Ras/MAPK pathway specifically in ISCs is sufficient to partially recapitulate the effects of trametinib. Moreover, in ISCs, trametinib decreases the activity of the RNA polymerase III (Pol III), a conserved enzyme synthesizing transfer RNAs and other short, non-coding RNAs, and whose inhibition also extends lifespan and reduces gut pathology. Finally, we show that the pro-longevity effect of trametinib in ISCs is partially mediated by Maf1, a repressor of Pol III, suggesting a life-limiting Ras/MAPK-Maf1-Pol III axis in these cells. The mechanism of action described in this work paves the way for further studies on the anti-aging effects of trametinib in mammals and shows its potential for clinical application in humans.


Assuntos
Drosophila melanogaster , Drosophila , Piridonas , Pirimidinonas , Animais , Masculino , Humanos , Feminino , Idoso , Drosophila melanogaster/genética , Envelhecimento/fisiologia , Células-Tronco/metabolismo , Mamíferos
13.
Trials ; 25(1): 68, 2024 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-38243317

RESUMO

BACKGROUND: Uterine leiomyomas are common for reproductive-aged women and affect women's quality of life due to heavy menstrual bleeding or dysmenorrhea. Leiomyomas grow according to estradiol exposure and decrease after post-menopause. In case serious symptoms are caused by leiomyomas, pharmacotherapy or surgical treatment is proposed. Prior to surgical treatment, pharmacotherapies aimed at the reduction of leiomyoma and uterine volume or improvement of anemia are introduced to conduct minimum invasive surgery (i.e., to reduce blood loss or surgical duration). Recently, relugolix (40 mg orally once daily) as a gonadotropin-releasing hormone (GnRH) receptor antagonist has proved its sufficient efficacy in suppressing estradiol levels without the transient estradiol flare-up compared with GnRH agonist. However, long-term administration should not be permitted liable to for climacteric disorder or osteoporosis, and evidence is lacking on the actual efficacy and extent of adverse effects of the every-other-day dosing regimen. This trial aimed to prove non-inferiority in volume reduction effect on leiomyoma and safety (i.e., reduction of adverse effects) by every-other-day administration after 2 months of everyday administration compared to daily administration throughout the duration. METHODS: A minimization adaptive randomized control trial (RCT) will be conducted. Patients (over 20 years old) harboring leiomyoma who will be undergoing surgical treatment will be invited to participate. Patients who are enrolled in the intervention group will receive every-other-day administration for 16 weeks after 8 weeks of daily administration. Patients who are enrolled in the control group will receive daily throughout the 24 weeks. The primary outcome is the leiomyoma volume reduction, and the secondary endpoints are the reduction of uterine volume, the occurrence of the climacteric disorder, genital bleeding days, change rate of serum hormone or bone turnover markers, and bone mineral density after 24 weeks compared to before administration. DISCUSSION: This study aims to prove both the non-inferiority in leiomyoma volume reduction and superiority in adverse effects occurrence reduction, which will provide a novel method to escape adverse effects while maintaining the effect of leiomyoma reduction. TRIAL REGISTRATION: Japan Registry of Clinical Trials jRCTs051230078. Registered on 26 July 2023.


Assuntos
Leiomioma , Compostos de Fenilureia , Pirimidinonas , Neoplasias Uterinas , Adulto , Feminino , Humanos , Adulto Jovem , Estradiol/metabolismo , Hormônio Liberador de Gonadotropina , Antagonistas de Hormônios , Leiomioma/tratamento farmacológico , Leiomioma/cirurgia , Compostos de Fenilureia/uso terapêutico , Pirimidinonas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Neoplasias Uterinas/tratamento farmacológico , Neoplasias Uterinas/cirurgia
14.
Thyroid ; 34(3): 336-346, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38226606

RESUMO

Background: The dabrafenib plus trametinib combination (DT) has revolutionized the treatment of BRAFV600E-mutated anaplastic thyroid carcinoma (BRAFm-ATC). However, patients eventually develop resistance and progress. Single-agent anti-PD-1 inhibitor spartalizumab has shown a median overall survival (mOS) of 5.9 months. Combination of immunotherapy with BRAF/MEK inhibitors (BRAF/MEKi) seems to improve outcomes compared with BRAF/MEKi alone, although no direct comparison is available. BRAF-targeted therapy before surgery (neoadjuvant approach) has also shown improvement in survival. We studied the efficacy and safety of DT plus pembrolizumab (DTP) compared with current standard-of-care DT alone as an initial treatment, as well as in the neoadjuvant setting. Methods: Retrospective single-center study of patients with BRAFm-ATC treated with first-line BRAF-directed therapy between January 2014 and March 2023. Three groups were evaluated: DT, DTP (pembrolizumab added upfront or at progression), and neoadjuvant (DT before surgery, and pembrolizumab added before or after surgery). The primary endpoint was mOS between DT and DTP. Secondary endpoints included median progression-free survival (mPFS) and response rate with DT versus DTP as initial treatments, and the exploratory endpoint was mOS in the neoadjuvant group. Results: Seventy-one patients were included in the primary analysis: n = 23 in DT and n = 48 in DTP. Baseline demographics were similar between groups, including the presence of metastatic disease at start of treatment (p = 0.427) and prior treatments with surgery (p = 0.864) and radiation (p = 0.678). mOS was significantly longer with DTP (17.0 months [confidence interval CI, 11.9-22.1]) compared with DT alone (9.0 months [CI, 4.5-13.5]), p = 0.037. mPFS was also significantly improved with DTP as the initial treatment (11.0 months [CI, 7.0-15.0]) compared with DT alone (4.0 months [CI, 0.7-7.3]), p = 0.049. Twenty-three patients were in the exploratory neoadjuvant group, where mOS was the longest (63.0 months [CI, 15.5-110.5]). No grade 5 adverse events (AEs) occurred in all three cohorts, and 32.4% had immune-related AEs, most frequently hepatitis and colitis. Conclusions: Our results show that in BRAFm-ATC, addition of pembrolizumab to dabrafenib/trametinib may significantly prolong survival. Surgical resection of the primary tumor after initial BRAF-targeted therapy in selected patients may provide further survival benefit. However, conclusions are limited by the retrospective nature of the study. Additional prospective data are needed to confirm this observation.


Assuntos
Imidazóis , Piridonas , Pirimidinonas , Carcinoma Anaplásico da Tireoide , Neoplasias da Glândula Tireoide , Humanos , Carcinoma Anaplásico da Tireoide/tratamento farmacológico , Carcinoma Anaplásico da Tireoide/genética , Estudos Retrospectivos , Proteínas Proto-Oncogênicas B-raf/genética , Estudos Prospectivos , Protocolos de Quimioterapia Combinada Antineoplásica , Oximas , Inibidores de Proteínas Quinases/uso terapêutico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/genética , Mutação
15.
J Pharm Biomed Anal ; 240: 115937, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38198885

RESUMO

Mirabegron and vibegron, both newly identified beta-3 adrenergic agonists, have significantly improved the quality of life for patients suffering from overactive bladder. In order to comprehensively assess the plasma exposure levels of these agents, the development of a rapid and highly sensitive bioanalytical method becomes imperative. The primary objective of this study was to establish a robust high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method for the concurrent quantification of mirabegron and vibegron in human plasma. The analytes were extracted from a 100 µL plasma sample through protein precipitation, employing 300 µL of methanol. Subsequently, samples underwent separation and quantification using a Waters XBridge C18 column (2.1 × 100 mm, 3.5 µm), with a mobile phase consisting of 0.1% formic acid in water and 0.1% formic acid in acetonitrile. The mass analysis was conducted using positive electrospray ionization (ESI+) operated in a multiple reaction monitoring (MRM) mode. The proposed method was meticulously validated in accordance with the guidelines set forth by the U.S. Food and Drug Administration (FDA) for bioanalytical method validation. The regression equations demonstrated exceptional linearity for both mirabegron (r² ≥ 0.994) and vibegron (r² ≥ 0.996) across the concentration range of 0.5 - 200 ng/mL. Furthermore, the assay exhibited accuracy (inter-day relative error ≤ 6.90%) and precision (inter-day coefficient of variation ≤ 8.88%). The average recoveries of the analytes were found to range from 81.94% to 102.02%, with mean matrix effects falling within the range of 89.77% to 110.58%. As a result, this method was deemed highly suitable for the precise determination of the concentrations of both mirabegron and vibegron in the context of therapeutic drug monitoring and bioequivalence studies.


Assuntos
Acetanilidas , Formiatos , Neoplasias , Pirimidinonas , Pirrolidinas , Tiazóis , Bexiga Urinária Hiperativa , Humanos , Cromatografia Líquida de Alta Pressão/métodos , Espectrometria de Massas em Tandem/métodos , Bexiga Urinária Hiperativa/tratamento farmacológico , Qualidade de Vida , Reprodutibilidade dos Testes
16.
Bioorg Chem ; 144: 107114, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38224637

RESUMO

Acute myelogenous leukemia (AML) is the most common form of acute leukemia in adults. PDE1 (Phosphodiesterase 1) is a subfamily of the PDE super-enzyme families that can hydrolyze the second messengers cAMP and cGMP simultaneously. Previous research has shown that suppressing the gene expression of PDE1 can trigger apoptosis of human leukemia cells. However, no selective PDE1 inhibitors have been used to explore whether PDE1 is a potential target for treating AML. Based on our previously reported PDE9/PDE1 dual inhibitor 11a, a series of novel pyrazolopyrimidinone derivatives were designed in this study. The lead compound 6c showed an IC50 of 7.5 nM against PDE1, excellent selectivity over other PDEs and good metabolic stability. In AML cells, compound 6c significantly inhibited the proliferation and induced apoptosis. Further experiments indicated that the apoptosis induced by 6c was through a mitochondria-dependent pathway by decreasing the ratio of Bcl-2/Bax and increasing the cleavage of caspase-3, 7, 9, and PARP. All these results suggested that PDE1 might be a novel target for AML.


Assuntos
Leucemia Mieloide Aguda , Inibidores de Fosfodiesterase , Pirazóis , Pirimidinonas , Adulto , Humanos , Inibidores de Fosfodiesterase/farmacologia , Diester Fosfórico Hidrolases/metabolismo , Leucemia Mieloide Aguda/tratamento farmacológico , GMP Cíclico/metabolismo
17.
Oncogene ; 43(11): 789-803, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38273024

RESUMO

WEE1 and CHEK1 (CHK1) kinases are critical regulators of the G2/M cell cycle checkpoint and DNA damage response pathways. The WEE1 inhibitor AZD1775 and the CHK1 inhibitor SRA737 are in clinical trials for various cancers, but have not been thoroughly examined in prostate cancer, particularly castration-resistant (CRPC) and neuroendocrine prostate cancers (NEPC). Our data demonstrated elevated WEE1 and CHK1 expressions in CRPC and NEPC cell lines and patient samples. AZD1775 resulted in rapid and potent cell killing with comparable IC50s across different prostate cancer cell lines, while SRA737 displayed time-dependent progressive cell killing with 10- to 20-fold differences in IC50s. Notably, their combination synergistically reduced the viability of all CRPC cell lines and tumor spheroids in a concentration- and time-dependent manner. Importantly, in a transgenic mouse model of NEPC, both agents alone or in combination suppressed tumor growth, improved overall survival, and reduced the incidence of distant metastases, with SRA737 exhibiting remarkable single agent anticancer activity. Mechanistically, SRA737 synergized with AZD1775 by blocking AZD1775-induced feedback activation of CHK1 in prostate cancer cells, resulting in increased mitotic entry and accumulation of DNA damage. In summary, this preclinical study shows that CHK1 inhibitor SRA737 alone and its combination with AZD1775 offer potential effective treatments for CRPC and NEPC.


Assuntos
Proteínas de Ciclo Celular , Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Camundongos , Animais , Proteínas de Ciclo Celular/genética , Proteínas Tirosina Quinases/genética , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Proteínas Nucleares/metabolismo , Pirimidinonas/farmacologia , Dano ao DNA , Linhagem Celular Tumoral
18.
Artigo em Inglês | MEDLINE | ID: mdl-38188891

RESUMO

Ensifentrine is a novel inhalational phosphodiesterase (PDE)3 and PDE4 inhibitor which improves bronchodilation and decreases inflammatory markers by acting locally on the bronchial tissue, with minimal systemic effects. Both preclinical and clinical trials have demonstrated benefits of this therapy, including improvement in lung function and reduction in exacerbations. This therapy is currently under review by the US Food and Drug Administration with a decision expected in 2024.


Assuntos
Doença Pulmonar Obstrutiva Crônica , Estados Unidos , Humanos , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Isoquinolinas , Pirimidinonas , Brônquios
19.
J Agric Food Chem ; 72(2): 999-1006, 2024 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-38175165

RESUMO

A series of novel pyrido [1,2-α] pyrimidinone mesoionic derivatives bearing a propenylbenzene group at the 1-position were synthesized on the basis of the structure of mesoionic insecticides triflumezopyrim and dicloromezotiaz via a rationally conceived pharmacophore model and evaluated for their insecticidal activities against three insect vectors. The bioassay results showed that some compounds exerted remarkable insecticidal activities against M. domestica, Ae. albopictus, and B. germanica. Particularly, compound 26l displayed outstanding insecticidal activity against Ae. Albopictus, with an LC50 value of 0.45 µg/mL, far superior to that of imidacloprid (LC50 = 1.82 µg/mL) and equivalent to that of triflumezopyrim (0.35 µg/mL). Meanwhile, compound 34l presented a broad insecticidal spectrum, with LC50 values of 1.51 µg/g sugar, 0.52 µg/mL and 0.14 µg/adult, which were about 2.88, 3.50, and 1.50 times better than that of imidacloprid (LC50 = 4.35 µg/g sugar, 1.82 µg/mL and 0.21 µg/adult against M. domestica, Ae. albopictus, and B. germanica, respectively) and equivalent to that of triflumezopyrim against M. domestica (1.13 µg/g sugar) and Ae. albopictus (0.35 µg/mL) but lower than the potency against B. germanica (0.06 µg/g sugar). The molecular docking study by energy minimizations revealed that introducing propenylbenzene at the 1-position of compounds 26l and 34l could embed into the binding pocket of nicotinic acetylcholine receptors and form pi-alkyl interaction with LEU306. These results demonstrated that compounds 26l and 34l could be promising candidates for vector control insecticides, which deserved further investigation.


Assuntos
Inseticidas , Neonicotinoides , Nitrocompostos , Inseticidas/química , Simulação de Acoplamento Molecular , Pirimidinonas/química , Açúcares
20.
Bratisl Lek Listy ; 124(2): 84-91, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38219060

RESUMO

OBJECTIVES: Cisplatin is a widely used anticancer drug for the treatment of many solid cancers. DNA damage is thought to be the key mechanism of cisplatin's anticancer activity. However, cisplatin may also affect cellular metabolism. The aim of this study was to determine the effect of cisplatin on the types of ATP production (OXPHOS versus glycolysis) and their rate in prostate cancer cells and to determine the potentially protective effect of autophagy and amino acids during cisplatin treatment. We also wanted to investigate the potential synergy between the metabolic effects of cisplatin on ATP production and the inhibition of autophagy. METHODS: Cisplatin treatment can significantly affect the metabolism of cancer cells. Important metabolic pathways can be altered, leading to changes in energy production and nutrient utilization. Autophagy and amino acid pool modulations can serve as protective mechanisms significantly affecting tumor cell survival under metabolic stress caused by anticancer treatment. By enabling the recycling of amino acids, autophagy helps cancer cells maintain cellular homeostasis and overcome nutrient limitations. Thus, inhibition of autophagy could have a supportive effect on the metabolic effects of cisplatin. RESULTS: After cisplatin treatment, ATP production by way of OXPHOS was significantly decreased in 22Rv1 and PC-3 cells. On the other hand, ATP production by glycolysis was not significantly affected in 22Rv1 cells. DU145 cells with dysfunctional autophagy were the most sensitive to cisplatin treatment and showed the lowest ATP production. However, short-term autophagy inhibition (24h) by autophinib or SAR405 in 22Rv1 and PC-3 cells did not alter the effect of cisplatin on ATP production. Levels of some amino acids (arginine, methionine) significantly affected the fitness of cancer cells. CONCLUSION: Persistent defects of autophagy can affect the metabolic sensitivity of cancer cells due to interference with arginine metabolism. Amino acids contained in the culture medium had an impact on the overall effect of cisplatin (Fig. 3, Ref. 38).


Assuntos
Cisplatino , Neoplasias da Próstata , Pirazóis , Piridinas , Pirimidinas , Pirimidinonas , Masculino , Humanos , Cisplatino/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Autofagia , Linhagem Celular Tumoral , Aminoácidos/farmacologia , Aminoácidos/metabolismo , Trifosfato de Adenosina/farmacologia , Arginina
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