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1.
Sci Rep ; 14(1): 5847, 2024 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-38462660

RESUMO

This study aimed to assess the effects of thienopyridine-class antiplatelet agents (including ticlopidine, clopidogrel, and prasugrel) on bleeding complications in patients who underwent robot-assisted radical prostatectomy. This cohort study used a database for robot-assisted radical prostatectomy at 23 tertiary centers nationwide between 2011 and 2022. Patients who received thienopyridines (thienopyridine group) were compared with those who received aspirin monotherapy (aspirin group). The primary outcome was the incidence of bleeding complications. High-grade complications were defined as Clavien-Dindo grade III or higher. The risks of these outcomes were evaluated using inverse probability of treatment weighted regression models. The study results demonstrated that thienopyridine therapy was associated with a higher risk of overall bleeding complications (OR: 3.62, 95%CI 1.54-8.49). The increased risks of the thienopyridine group were detected for low-grade bleeding complications (OR: 3.20, 95%CI 1.23-8.30) but not for high-grade bleeding complications (OR: 5.23, 95%CI 0.78-34.9). The increased risk of bleeding complications was not observed when thienopyridine was discontinued (OR: 2.52, 95%CI 0.83-7.70); however, it became apparent when it was continued perioperatively (OR: 4.35, 95%CI 1.14-16.61). In conclusion, thienopyridine increased the incidence of bleeding complications, particularly low-grade bleeding complications, following robot-assisted radical prostatectomy. These bleeding effects emerged when thienopyridine was continued perioperatively.


Assuntos
Inibidores da Agregação Plaquetária , Piridinas , Robótica , Masculino , Humanos , Inibidores da Agregação Plaquetária/efeitos adversos , Estudos de Coortes , Hemorragia/induzido quimicamente , Aspirina/efeitos adversos , Tienopiridinas , Prostatectomia/efeitos adversos
2.
Br J Pharmacol ; 181(4): 515-531, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37771103

RESUMO

Inflammation is a complex pathophysiological process underlying many clinical conditions. Platelets contribute to the thrombo-inflammatory response. Platelet P2Y12 receptors amplify platelet activation, potentiating platelet aggregation, degranulation and shape change. The contents of platelet alpha granules, in particular, act directly on leucocytes, including mediating platelet-leucocyte aggregation and activation via platelet P-selectin. Much evidence for the role of platelet P2Y12 receptors in inflammation comes from studies using antagonists of these receptors, such as the thienopyridines clopidogrel and prasugrel, and the cyclopentyltriazolopyrimidine ticagrelor, in animal and human experimental models. These suggest that antagonism of P2Y12 receptors decreases markers of inflammation with some evidence that this reduces incidence of adverse clinical sequelae during inflammatory conditions. Interpretation is complicated by pleiotropic effects such as those of the thienopyridines on circulating leucocyte numbers and of ticagrelor on adenosine reuptake. The available evidence suggests that P2Y12 receptors are prominent mediators of inflammation and P2Y12 receptor antagonism as a potentially powerful strategy in a broad range of inflammatory conditions. LINKED ARTICLES: This article is part of a themed issue on Platelet purinergic receptor and non-thrombotic disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.4/issuetoc.


Assuntos
Inibidores da Agregação Plaquetária , Antagonistas do Receptor Purinérgico P2Y , Animais , Humanos , Ticagrelor/farmacologia , Inibidores da Agregação Plaquetária/farmacologia , Antagonistas do Receptor Purinérgico P2Y/farmacologia , Plaquetas , Inflamação/tratamento farmacológico , Agregação Plaquetária , Cloridrato de Prasugrel/farmacologia , Tienopiridinas/farmacologia , Receptores Purinérgicos P2Y12
3.
Clin Gastroenterol Hepatol ; 21(13): 3258-3269.e6, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37276989

RESUMO

BACKGROUND & AIMS: Currently, large, nationwide, long-term follow-up data on acute lower gastrointestinal bleeding (ALGIB) are scarce. We investigated long-term risks of recurrence after hospital discharge for ALGIB using a large multicenter dataset. METHODS: We retrospectively analyzed 5048 patients who were urgently hospitalized for ALGIB at 49 hospitals across Japan (CODE BLUE-J study). Risk factors for the long-term recurrence of ALGIB were analyzed by using competing risk analysis, treating death without rebleeding as a competing risk. RESULTS: Rebleeding occurred in 1304 patients (25.8%) during a mean follow-up period of 31 months. The cumulative incidences of rebleeding at 1 and 5 years were 15.1% and 25.1%, respectively. The mortality risk was significantly higher in patients with out-of-hospital rebleeding episodes than in those without (hazard ratio, 1.42). Of the 30 factors, multivariate analysis showed that shock index ≥1 (subdistribution hazard ratio [SHR], 1.25), blood transfusion (SHR, 1.26), in-hospital rebleeding (SHR, 1.26), colonic diverticular bleeding (SHR, 2.38), and thienopyridine use (SHR, 1.24) were significantly associated with increased rebleeding risk. Multivariate analysis of colonic diverticular bleeding patients showed that blood transfusion (SHR, 1.20), in-hospital rebleeding (SHR, 1.30), and thienopyridine use (SHR, 1.32) were significantly associated with increased rebleeding risk, whereas endoscopic hemostasis (SHR, 0.83) significantly decreased the risk. CONCLUSIONS: These large, nationwide follow-up data highlighted the importance of endoscopic diagnosis and treatment during hospitalization and the assessment of the need for ongoing thienopyridine use to reduce the risk of out-of-hospital rebleeding. This information also aids in the identification of patients at high risk of rebleeding.


Assuntos
Doenças Diverticulares , Hemostase Endoscópica , Humanos , Alta do Paciente , Estudos de Coortes , Estudos Retrospectivos , Hemorragia Gastrointestinal/epidemiologia , Hemorragia Gastrointestinal/etiologia , Hemorragia Gastrointestinal/diagnóstico , Doença Aguda , Fatores de Risco , Hospitais , Tienopiridinas , Recidiva
4.
Bioorg Med Chem Lett ; 91: 129348, 2023 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-37217025

RESUMO

Pairing immunostimulatory small molecules with the targeting capability of an antibody has emerged as a novel therapeutic modality with the potential to treat a variety of solid tumors. A series of compounds based on an imidazo-thienopyridine scaffold were synthesized and tested for their ability to agonize the innate immune sensors toll-like receptor 7 and 8 (TLR7/8). Structure-activity relationship (SAR) studies revealed that certain simple amino-substituents could enable TLR7 agonism at low nanomolar concentrations. Drug-linkers containing either payload 1 or 20h were conjugated to the HER2-targeting antibody trastuzumab at the interchain disulfide cysteine residues using a cleavable valine-citrulline dipeptide linker and stochastic thiol-maleimide chemistry. In vitro, these immune-stimulating antibody drug-conjugates (ADCs) were found to induce cytokine release in a murine splenocyte assay when co-cultured with the HER2-high NCI-N87 cancer cell line. In vivo, tumor regression was observed with a single dose in an NCI-N87 gastric carcinoma xenograft model in BALB/c nude mice.


Assuntos
Antineoplásicos , Imunoconjugados , Camundongos , Humanos , Animais , Receptor 7 Toll-Like , Imunoconjugados/química , Camundongos Nus , Trastuzumab/química , Adjuvantes Imunológicos , Linhagem Celular Tumoral , Tienopiridinas , Antineoplásicos/farmacologia , Antineoplásicos/química
5.
Dig Dis Sci ; 68(5): 1950-1958, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36609733

RESUMO

BACKGROUND: The present guidelines stratify endoscopic ultrasound-guided tissue acquisition (EUS-TA) as a high-bleeding risk procedure in patients on antithrombotics. However, the data regarding the same are conflicting. Therefore, this meta-analysis aimed to analyze the bleeding event rates associated with EUS-TA in patients receiving antithrombotic therapy. METHODS: A literature search from January 2000 to August 2022 was done for studies on EUS-guided TA in patients receiving antithrombotics. The primary outcome was incidence of overall and major bleeding. Pooled event rates across studies were expressed with summative statistics. RESULTS: A total of 12 studies were included in the meta-analysis. The pooled risk of overall bleeding and major bleeding in patients on antithrombotics was 2.0% (0.6-3.4) and 0.8% (0.0-1.6), respectively. In patients taking thienopyridine or anticoagulants, the pooled risk of overall bleeding and major bleeding was 2.4% (0.9-3.9) and 1.7% (0.4-3.1), respectively. Patients on antithrombotics had a higher odd of overall bleeding (OR 2.12, 1.20-3.83) and major bleeding (OR 3.58, 1.11-11.52) compared to controls. The odds of overall bleeding (OR 0.95, 95%CI 0.38-2.42) and major bleeding (OR 1.57, 95%CI 0.45-5.54) were comparable between patients on antithrombotics who continued and those who discontinued it preprocedural. CONCLUSION: Despite an increase risk of bleeding with EUS-TA in patients on antithrombotics, the pooled incidence remains low. Compared to the previous guidelines stating thienopyridine use as high risk for bleeding, the present analysis showed a bleeding rate of less than 1%. Discontinuing antithrombotics prior to EUS-TA does not reduce the bleeding risk significantly, requiring strict monitoring.


Assuntos
Fibrinolíticos , Hemorragia , Humanos , Fibrinolíticos/efeitos adversos , Hemorragia/induzido quimicamente , Hemorragia/epidemiologia , Anticoagulantes , Ultrassonografia de Intervenção , Tienopiridinas
6.
Gastrointest Endosc ; 97(5): 889-897, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36639059

RESUMO

BACKGROUND AND AIMS: Data are lacking regarding post-endoscopic submucosal dissection (ESD) bleeding in patients with early gastric cancer (EGC) who take antiplatelet agents (APAs), particularly in those taking thienopyridine and cilostazol. We aimed to clarify the association between the status of APA medication and post-ESD bleeding risk. METHODS: This study is a secondary analysis using data from a recently conducted nationwide multicenter study in Japan. We retrospectively reviewed patients treated with APAs or on no antithrombotic therapy recruited from 33 institutions who underwent ESD for EGC between November 2013 and October 2016. The primary outcome of this study was the relationship between the rate of post-ESD bleeding and the status of each APA medication. RESULTS: A total of 9736 patients were included in the analysis. Among 665 aspirin users, the continuation group was significantly associated with post-ESD bleeding (odds ratio [OR], 2.79; 95% confidence interval [CI], 1.77-4.37). Among 227 thienopyridine users, the aspirin or cilostazol replacement group was not significantly associated with post-ESD bleeding (OR, 1.85; 95% CI, .72-4.78). Among 158 cilostazol users, there was no significant association with post-ESD bleeding, irrespective of medication status. The rate of post-ESD bleeding was approximately 10% to 20% irrespective of the status of APA administration among dual-antiplatelet therapy users. No patients experienced thromboembolic events in this study. CONCLUSIONS: Replacement of thienopyridine with aspirin or cilostazol may be acceptable for minimizing both the risk of post-ESD bleeding and thromboembolism in patients with EGC. In patients on cilostazol monotherapy undergoing ESD, continuation of therapy may be acceptable.


Assuntos
Ressecção Endoscópica de Mucosa , Neoplasias Gástricas , Tromboembolia , Humanos , Inibidores da Agregação Plaquetária/uso terapêutico , Neoplasias Gástricas/etiologia , Ressecção Endoscópica de Mucosa/efeitos adversos , Estudos Retrospectivos , Cilostazol/uso terapêutico , Hemorragia Pós-Operatória/epidemiologia , Hemorragia Pós-Operatória/tratamento farmacológico , Hemorragia Gastrointestinal/etiologia , Fatores de Risco , Gastroscopia/efeitos adversos , Aspirina/uso terapêutico , Tromboembolia/etiologia , Tromboembolia/prevenção & controle , Tienopiridinas/uso terapêutico , Mucosa Gástrica/cirurgia
7.
Bioorg Med Chem Lett ; 75: 128969, 2022 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-36058469

RESUMO

A series of novel thienopyridine derivatives were designed and synthesized as P2Y12 receptor inhibitors. Several solid compounds were assessed for inhibitory effect where they exhibited stronger potency than clopidogrel. Compound 6b and 6g were evaluated for metabolism to verify that they could overcome clopidogrel resistance and for toxicity where they showed lower toxicity than prasugrel. Compound 6b exhibited lower risk of bleeding than prasugrel and showed good stability under stress testing. Overall, as a promising antiplatelet agent, representative compound 6b showed the following advantages: (1) no drug resistance for CYP2C19 poor metabolizers; (2) higher potency than clopidogrel; (3) lower toxicity than prasugrel; (4) lower risk of bleeding than prasugrel; (5) good stability as a non-salt solid.


Assuntos
Inibidores da Agregação Plaquetária , Tienopiridinas , Clopidogrel/farmacologia , Citocromo P-450 CYP2C19 , Inibidores da Agregação Plaquetária/farmacologia , Cloridrato de Prasugrel/farmacologia , Antagonistas do Receptor Purinérgico P2Y/farmacologia , Receptores Purinérgicos P2Y12 , Tiofenos/farmacologia
8.
Coron Artery Dis ; 33(7): 566-573, 2022 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-35866498

RESUMO

BACKGROUND: The risk of recurrent spontaneous coronary artery dissection (SCAD) is a major concern to SCAD patients and clinicians. Identifying the high-risk subsets of recurrent SCAD remains an ongoing challenge. The meta-analysis aimed to assess the potential predictors for SCAD recurrence. METHODS: A literature search was performed in PubMed to collect studies that assessed potential factors associated with recurrence of SCAD among angiographically confirmed SCAD patients, including pregnancy, ventricular arrhythmia at presentation, history of hypertension, migraine, fibromuscular dysplasia (FMD), extracoronary vascular abnormalities (EVA), recent emotional or physical stress, and use of thienopyridine, beta-blocker, or statin. A meta-analytic approach was employed to estimate the relative risk (RR) with a 95% confidence interval (CI) by fitting random-effects models using the generic inverse variance weighted method. RESULTS: A total of 14 studies representing 4206 SCAD patients were included. Hypertension (RR, 1.49; 95% CI, 1.05-2.12; P = 0.0247) and FMD (RR, 2.02; 95% CI, 1.03-3.94; P = 0.0404) were associated with a greater risk of SCAD recurrence. The use of beta-blocker (RR, 0.51; 95% CI, 0.33-0.77; P = 0.0013) was associated with a lower risk of SCAD recurrence. Pregnancy, ventricular arrhythmia at presentation, migraine, EVA, recent emotional or physical stress, and use of thienopyridine or statin were not significantly associated with recurrent SCAD ( P > 0.05). CONCLUSION: SCAD patients with hypertension or FMD were at a higher risk of recurrence, whereas beta-blocker usage was related to a reduced risk. These findings may provide insights into risk prediction and management after the SCAD episode.


Assuntos
Anomalias dos Vasos Coronários , Displasia Fibromuscular , Inibidores de Hidroximetilglutaril-CoA Redutases , Hipertensão , Transtornos de Enxaqueca , Doenças Vasculares , Antagonistas Adrenérgicos beta/uso terapêutico , Angiografia Coronária/métodos , Anomalias dos Vasos Coronários/complicações , Anomalias dos Vasos Coronários/diagnóstico por imagem , Anomalias dos Vasos Coronários/epidemiologia , Vasos Coronários , Feminino , Humanos , Transtornos de Enxaqueca/complicações , Gravidez , Fatores de Risco , Tienopiridinas , Doenças Vasculares/complicações , Doenças Vasculares/congênito , Doenças Vasculares/diagnóstico por imagem , Doenças Vasculares/epidemiologia
9.
J Gastroenterol Hepatol ; 37(9): 1792-1800, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35844140

RESUMO

BACKGROUND AND AIM: Whether antithrombotic drugs increase the risk of post-esophageal endoscopic resection bleeding is unknown. This study examined the effect of antithrombotic drugs, aspirin, thienopyridine, direct oral anticoagulants (DOAC), and warfarin, on post-esophageal endoscopic resection bleeding. METHODS: We enrolled 957 patients (1202 esophageal tumors) treated with endoscopic resection and classified them based on antithrombotic drug use as no use, aspirin, thienopyridine, DOAC, and warfarin. Patients using antiplatelet drugs (i.e. aspirin and thienopyridine) were further sub-classified based on their continued or discontinued use before endoscopic resection. The bleeding rates were compared between these groups to assess the effects of antithrombotic drug use and interruption of antiplatelet therapy on post-esophageal endoscopic resection bleeding. RESULTS: The post-endoscopic resection bleeding rate was 0.3% (95% CI, 0.1-1) in the group without antithrombotic drug use, 4.5% (95% CI, 0.1-23) in the aspirin-continued group, 2.9% (95% CI, 0.1-15) in the aspirin-discontinued group, 0% (95% CI, 0-78) in the replaced thienopyridine with aspirin group, 0% (95% CI, 0-26) in the thienopyridine-discontinued group, 13% (95% CI, 1.6-38) in the DOAC group, and 0% (95% CI, 0-45) in the warfarin group. The post-endoscopic resection bleeding rate in the DOAC group was significantly higher than that in the group without antithrombotic drugs (P = 0.003). The post-endoscopic resection bleeding rates did not differ between the other groups. CONCLUSIONS: Our results suggest that discontinuing aspirin is not necessary for esophageal endoscopic resection while we must be careful regarding DOAC.


Assuntos
Ressecção Endoscópica de Mucosa , Varfarina , Anticoagulantes , Aspirina/efeitos adversos , Ressecção Endoscópica de Mucosa/métodos , Fibrinolíticos/efeitos adversos , Hemorragia Gastrointestinal/etiologia , Humanos , Inibidores da Agregação Plaquetária/efeitos adversos , Hemorragia Pós-Operatória/induzido quimicamente , Hemorragia Pós-Operatória/prevenção & controle , Estudos Retrospectivos , Fatores de Risco , Tienopiridinas/uso terapêutico , Varfarina/efeitos adversos
10.
Bioorg Chem ; 127: 105964, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35759881

RESUMO

Multitargeting kinase inhibitors recently proved to be a profitable approach for conquering cancer proliferation. The current study represents the design and synthesis of new thiophene, thienopyridine, and thiazoline-based derivatives 4-14a,b. All the target compounds were examined in vitro against three cancer cell lines; the liver (HepG-2), breast (MCF-7), and colon (HCT-116) where the thiophene-based compounds 5a-c, demonstrated the most potent activity. Furthermore, the latter derivatives revealed a safety profile against WI-38 normal cell line of selectivity indices ranging from 4.43 to 17.44. In vitro enzyme assay of 5a-c revealed that the carbohydrazide analog 5c has the most promising multitargeting inhibiting activity against Pim-1, VEGFR-2, and EGFRWT enzymes of IC50 values; 0.037 ± 0.02, 0.95 ± 0.24, and 0.16 ± 0.05 µM, respectively. As it was the most potent analog, 5c was further subjected to cell cycle and apoptosis analysis. The results indicated that it induced preG1 arrest and an apoptotic effect in the early and late stages. Moreover, further apoptosis studies were carried out for 5c to evaluate its proapoptotic potential. Interestingly, 5c enhanced the levels of Bax/Bcl-2 ratio, p53, and active caspase 3 by 18, 6.4, and 24 folds, respectively compared to the untreated cells. The antimicrobial evaluation showed that only compounds 3 and 5a produced broad-spectrum potency, while 5b and 5c exhibited outstanding antifungal effects. Finally, a molecular docking study was carried out to discover the probable interactions of compound 5c with the active sites of Pim-1, VEGFR-2, and EGFRWT kinases.


Assuntos
Antineoplásicos , Receptor 2 de Fatores de Crescimento do Endotélio Vascular , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases , Relação Estrutura-Atividade , Tienopiridinas/farmacologia , Tiofenos/química
11.
Org Lett ; 24(17): 3167-3172, 2022 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-35467892

RESUMO

To develop of an effective synthetic methodology for biologically relevant thienopyridines, a concise and efficient protocol is described for the synthesis of a series of substituted thienopyridine and thienoquinoline derivatives with high selectivity using EtOCS2K as the sulfur source. The reaction proceeds via metal-free, site-selective C-H bond thiolation and cyclization of the alkynylpyridine and alkynylquinoline substrates.


Assuntos
Piridinas , Tienopiridinas , Ciclização , Enxofre , Tienopiridinas/química
12.
Biomed Pharmacother ; 149: 112808, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35290889

RESUMO

Krabbe disease is a rare, inherited neurodegenerative disease due to impaired lysosomal ß-galactosylceramidase (GALC) activity and formation of neurotoxic ß-galactosylsphingosine ('psychosine'). We investigated substrate reduction therapy with a novel brain-penetrant inhibitor of galactosylceramide biosynthesis, RA 5557, in twitcher mice that lack GALC activity and model Krabbe disease. This thienopyridine derivative selectively inhibits uridine diphosphate-galactose glycosyltransferase 8 (UGT8), the final step in the generation of galactosylceramides which are precursors of sulphatide and, in the pathological lysosome, the immediate source of psychosine. Administration of RA 5557, reduced pathologically elevated psychosine concentrations (72-86%) in the midbrain and cerebral cortex in twitcher mice: the inhibitor decreased galactosylceramides by about 70% in midbrain and cerebral cortex in mutant and wild type animals. Exposure to the inhibitor significantly decreased several characteristic inflammatory response markers without causing apparent toxicity to myelin-producing cells in wild type and mutant mice; transcript abundance of oligodendrocyte markers MBP (myelin basic protein) and murine UGT8 was unchanged. Administration of the inhibitor before conception and during several breeding cycles to mice did not impair fertility and gave rise to healthy offspring. Nevertheless, given the unchanged lifespan, it appears that GALC has critical functions in the nervous system beyond the hydrolysis of galactosylceramide and galactosylsphingosine. Our findings support further therapeutic exploration of orally active UGT8 inhibitors in Krabbe disease and related galactosphingolipid disorders. The potent thienopyridine derivative with effective target engagement here studied appears to have an acceptable safety profile in vivo; judicious dose optimization will be needed to ensure efficacious clinical translation.


Assuntos
Leucodistrofia de Células Globoides , Doenças Neurodegenerativas , Animais , Encéfalo/metabolismo , Modelos Animais de Doenças , Galactosilceramidas/metabolismo , Galactosilceramidas/farmacologia , Leucodistrofia de Células Globoides/tratamento farmacológico , Leucodistrofia de Células Globoides/metabolismo , Leucodistrofia de Células Globoides/patologia , Camundongos , Doenças Neurodegenerativas/patologia , Psicosina/metabolismo , Tienopiridinas
13.
Arch Pharm (Weinheim) ; 354(12): e2100300, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34697820

RESUMO

The antithrombotic prodrugs ticlopidine and clopidogrel are thienotetrahydro-pyridine derivatives that are metabolized in the liver to produce thiols that irreversibly block adenosine diphosphate (ADP)-activated P2Y12 receptors on thrombocytes. In their native, nonmetabolized form, both drugs were reported to act as inhibitors of ectonucleoside triphosphate diphosphohydrolase-1 (NTPDase1, CD39). CD39 catalyzes the extracellular hydrolysis of nucleoside tri- and diphosphates, mainly adenosine 5'-triphosphate (ATP) and ADP, yielding adenosine monophosphate, which is further hydrolyzed by ecto-5'-nucleotidase (CD73) to produce adenosine. While ATP has proinflammatory effects, adenosine is a potent anti-inflammatory, immunosuppressive agent. Inhibitors of CD39 and CD73 have potential as novel checkpoint inhibitors for the immunotherapy of cancer and infection. In the present study, we investigated 2-substituted thienotetrahydropyridine derivatives, structurally related to ticlopidine, as CD39 inhibitors. Due to their substituent on the 2-position, they will not be metabolically transformed into reactive thiols and can, therefore, be expected to be devoid of P2Y12 receptor-antagonistic activity in vivo. Several of the investigated 2-substituted thienotetrahydropyridine derivatives showed concentration-dependent inhibition of CD39. The most potent derivative, 32, showed similar CD39-inhibitory potency to ticlopidine, both acting as allosteric inhibitors. Compound 32 showed an improved selectivity profile: While ticlopidine blocked several NTPDase isoenzymes, 32 was characterized as a novel dual inhibitor of CD39 and CD73.


Assuntos
5'-Nucleotidase/antagonistas & inibidores , Apirase/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Tienopiridinas/farmacologia , Regulação Alostérica/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Proteínas Ligadas por GPI/antagonistas & inibidores , Humanos , Relação Estrutura-Atividade , Tienopiridinas/síntese química , Tienopiridinas/química , Ticlopidina/farmacologia
14.
J Gastroenterol Hepatol ; 36(10): 2769-2777, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33960518

RESUMO

BACKGROUND AND AIM: This study aimed to reveal the timing of bleeding and thromboembolism associated with endoscopic submucosal dissection (ESD) for early gastric cancer (EGC). METHODS: We retrospectively reviewed  10,320 patients who underwent ESD for EGC during November 2013-October 2016. We evaluated overall bleeding rates and their inter-group differences. Factors associated with early/late (cut-off 5 days) bleeding and thromboembolism frequency and its association with the intake of antithrombotic agents were investigated. RESULTS: Overall, the post-ESD bleeding rate was 4.7% (489/10 320); the median time to post-ESD bleeding was 4 days. The post-ESD bleeding rates were 3.2%, 8.7%, 15.5%, and 29.9% in those not taking antithrombotic agents, those taking antiplatelet agents, those taking anticoagulants (ACs), and those taking antiplatelet agents and ACs. Warfarin (odds ratio [OR], 9.16), direct oral ACs (OR, 4.16), chronic kidney disease with hemodialysis (OR, 2.93), thienopyridine (OR, 2.25), aspirin (OR, 1.66), tumor size >30 mm (OR, 1.86), multiple tumors' resection (OR, 1.54), and tumor in the lower third of the stomach (OR, 1.40) were independent risk factors for early bleeding. The independent risk factors for late bleeding were direct oral ACs (OR, 7.42), chronic kidney disease with hemodialysis (OR, 4.99), warfarin (OR, 3.90), thienopyridine (OR, 3.09), liver cirrhosis (OR, 2.43), cilostazol (OR, 1.93), aspirin (OR, 1.92), ischemic heart disease (OR, 1.77), and male sex (OR, 1.65). There were three (0.03%) thromboembolic events (cerebral infarction = 2, transient ischemic attack = 1). CONCLUSION: We revealed the timing of bleeding and risk factors for early/late bleeding and showed the thromboembolism frequency associated with ESD for EGC.


Assuntos
Ressecção Endoscópica de Mucosa , Insuficiência Renal Crônica , Neoplasias Gástricas , Tromboembolia , Anticoagulantes/efeitos adversos , Aspirina/efeitos adversos , Ressecção Endoscópica de Mucosa/efeitos adversos , Fibrinolíticos/efeitos adversos , Mucosa Gástrica , Humanos , Japão/epidemiologia , Masculino , Inibidores da Agregação Plaquetária/efeitos adversos , Hemorragia Pós-Operatória/epidemiologia , Hemorragia Pós-Operatória/etiologia , Estudos Retrospectivos , Fatores de Risco , Neoplasias Gástricas/cirurgia , Tienopiridinas , Tromboembolia/epidemiologia , Tromboembolia/etiologia , Varfarina/efeitos adversos
15.
JAMA Netw Open ; 4(5): e2110703, 2021 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-34019087

RESUMO

Importance: Anticipating the risk of gastrointestinal bleeding (GIB) when initiating antithrombotic treatment (oral antiplatelets or anticoagulants) is limited by existing risk prediction models. Machine learning algorithms may result in superior predictive models to aid in clinical decision-making. Objective: To compare the performance of 3 machine learning approaches with the commonly used HAS-BLED (hypertension, abnormal kidney and liver function, stroke, bleeding, labile international normalized ratio, older age, and drug or alcohol use) risk score in predicting antithrombotic-related GIB. Design, Setting, and Participants: This retrospective cross-sectional study used data from the OptumLabs Data Warehouse, which contains medical and pharmacy claims on privately insured patients and Medicare Advantage enrollees in the US. The study cohort included patients 18 years or older with a history of atrial fibrillation, ischemic heart disease, or venous thromboembolism who were prescribed oral anticoagulant and/or thienopyridine antiplatelet agents between January 1, 2016, and December 31, 2019. Exposures: A cohort of patients prescribed oral anticoagulant and thienopyridine antiplatelet agents was divided into development and validation cohorts based on date of index prescription. The development cohort was used to train 3 machine learning models to predict GIB at 6 and 12 months: regularized Cox proportional hazards regression (RegCox), random survival forests (RSF), and extreme gradient boosting (XGBoost). Main Outcomes and Measures: The performance of the models for predicting GIB in the validation cohort, evaluated using the area under the receiver operating characteristic curve (AUC), sensitivity, specificity, positive predictive value, and prediction density plots. Relative importance scores were used to identify the variables that were most influential in the top-performing machine learning model. Results: In the entire study cohort of 306 463 patients, 166 177 (54.2%) were male, 193 648 (63.2%) were White, the mean (SD) age was 69.0 (12.6) years, and 12 322 (4.0%) had experienced a GIB. In the validation data set, the HAS-BLED model had an AUC of 0.60 for predicting GIB at 6 months and 0.59 at 12 months. The RegCox model performed the best in the validation set, with an AUC of 0.67 at 6 months and 0.66 at 12 months. XGBoost was similar, with AUCs of 0.67 at 6 months and 0.66 at 12 months, whereas for RSF, AUCs were 0.62 at 6 months and 0.60 at 12 months. The variables with the highest importance scores in the RegCox model were prior GI bleed (importance score, 0.72); atrial fibrillation, ischemic heart disease, and venous thromboembolism combined (importance score, 0.38); and use of gastroprotective agents (importance score, 0.32). Conclusions and Relevance: In this cross-sectional study, the machine learning models examined showed similar performance in identifying patients at high risk for GIB after being prescribed antithrombotic agents. Two models (RegCox and XGBoost) performed modestly better than the HAS-BLED score. A prospective evaluation of the RegCox model compared with HAS-BLED may provide a better understanding of the clinical impact of improved performance.


Assuntos
Anticoagulantes/efeitos adversos , Antifibrinolíticos/efeitos adversos , Tomada de Decisão Clínica/métodos , Fibrinolíticos/efeitos adversos , Hemorragia Gastrointestinal/induzido quimicamente , Aprendizado de Máquina , Valor Preditivo dos Testes , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/uso terapêutico , Antifibrinolíticos/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Estudos de Coortes , Estudos Transversais , Feminino , Fibrinolíticos/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Isquemia Miocárdica/tratamento farmacológico , Estudos Retrospectivos , Medição de Risco , Tienopiridinas/efeitos adversos , Tienopiridinas/uso terapêutico , Estados Unidos , Tromboembolia Venosa/tratamento farmacológico , Adulto Jovem
16.
Molecules ; 26(6)2021 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-33805741

RESUMO

A series of novel functionalized methyl 3-(hetero)arylthieno[3,2-b]pyridine-2-carboxylates 2a-2h were synthesized by C-C Pd-catalyzed Suzuki-Miyaura cross-coupling of methyl 3-bromothieno[3,2-b]pyridine-2-carboxylate with (hetero)aryl pinacol boranes, trifluoro potassium boronate salts or boronic acids. Their antitumoral potential was evaluated in two triple negative breast cancer (TNBC) cell lines-MDA-MB-231 and MDA-MB-468, by sulforhodamine B assay. Their effects on the non-tumorigenic MCF-12A cells were also evaluated. The results demonstrated that three compounds caused growth inhibition in both TNBC cell lines, with little or no effect against the non-tumorigenic cells. The most promising compound was further studied concerning possible effects on cell viability (by trypan blue exclusion assay), cell proliferation (by bromodeoxyuridine assay) and cell cycle profile (by flow cytometry). The results demonstrated that the GI50 concentration of compound 2e (13 µM) caused a decreased in MDA-MB-231 cell number, which was correlated with a decreased in the % of proliferating cells. Moreover, this compound increased G0/G1 phase and decreased S phases, when compared to control cells (although was not statistic significant). Interestingly, compound 2e also reduced tumor size using an in ovo CAM (chick chorioallantoic membrane) model. This work highlights the potential antitumor effect of a novel methyl 3-arylthieno[3,2-b]pyridine-2-carboxylate derivative.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Tienopiridinas/síntese química , Tienopiridinas/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Animais , Antineoplásicos/química , Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Membrana Corioalantoide/cirurgia , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Glândulas Mamárias Humanas/efeitos dos fármacos , Glândulas Mamárias Humanas/patologia , Estrutura Molecular , Transplante de Neoplasias , Relação Estrutura-Atividade , Tienopiridinas/química , Neoplasias de Mama Triplo Negativas/patologia
17.
Cardiovasc Drugs Ther ; 35(1): 51-60, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32845391

RESUMO

PURPOSE: Hyperuricemia carries an increased risk of atherothrombotic events in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI). This may at least in part be due to inadequate P2Y12 inhibition. The aim of this study was to prospectively investigate the potential association between hyperuricemia and decreased platelet inhibition by P2Y12 antagonists. METHODS: Levels of uric acid as well as on-treatment residual platelet reactivity in response to adenosine diphosphate (ADP) were assessed in 301 clopidogrel-treated patients undergoing elective angioplasty and stenting, and in 206 prasugrel- (n = 118) or ticagrelor-treated (n = 88) ACS patients following acute PCI. Cut-off values for high on-treatment residual ADP-inducible platelet reactivity (HRPR) were based on previous studies showing an association of test results with clinical outcomes. RESULTS: Hyperuricemia was significantly associated with increased on-treatment residual ADP-inducible platelet reactivity in clopidogrel- and prasugrel-treated patients in univariate analyses and after adjustment for differences in patient characteristics by multivariate regression analyses. In contrast, ticagrelor-treated patients without and with hyperuricemia showed similar levels of on-treatment residual platelet reactivity to ADP. HRPR occurred more frequently in clopidogrel- and prasugrel-treated patients with hyperuricemia than in those with normal uric acid levels. In contrast, hyperuricemic patients receiving ticagrelor did not have a higher risk of HRPR compared with those with normal uric acid levels. CONCLUSION: Hyperuricemia is associated with decreased platelet inhibition by thienopyridines but a normal response to ticagrelor. It remains to be established if lowering uric acid increases the antiplatelet effects of clopidogrel and prasugrel in hyperuricemic patients with HRPR.


Assuntos
Síndrome Coronariana Aguda/cirurgia , Hiperuricemia/epidemiologia , Inibidores da Agregação Plaquetária/farmacologia , Antagonistas do Receptor Purinérgico P2Y/farmacologia , Tienopiridinas/farmacologia , Difosfato de Adenosina/farmacologia , Idoso , Angioplastia/efeitos adversos , Angioplastia/métodos , Clopidogrel/farmacologia , Comorbidade , Citocromo P-450 CYP2C9/genética , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Ativação Plaquetária/efeitos dos fármacos , Estudos Prospectivos , Stents/efeitos adversos , Ticagrelor/farmacologia , Ticlopidina/farmacologia , Ácido Úrico/sangue
18.
Int J Mol Sci ; 21(20)2020 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-33086667

RESUMO

Human dental pulp stem cells (DPSCs) have high clonogenic and proliferative potential. We previously reported that a helioxanthin derivative (4-(4-methoxyphenyl)pyrido[40,30:4,5]thieno[2-b]pyridine-2-carboxamide (TH)) enhances osteogenic differentiation of DPSCs derived from young patients. However, in the clinical field, elderly patients more frequently require bone regenerative therapy than young patients. In this study, we examined and compared the osteogenic differentiation potential of TH-induced DPSCs from elderly patients and young patients to explore the potential clinical use of DPSCs for elderly patients. DPSCs were obtained from young and elderly patients and cultured in osteogenic medium with or without TH. We assessed the characteristics and osteogenic differentiation by means of specific staining and gene expression analyses. Moreover, DPSC sheets were transplanted into mouse calvarial defects to investigate osteogenesis of TH-induced DPSCs by performing micro-computed tomography (micro-CT). We demonstrated that osteogenic conditions with TH enhance the osteogenic differentiation marker of DPSCs from elderly patients as well as young patients in vitro. In vivo examination showed increased osteogenesis of DPSCs treated with TH from both elderly patients and young patients. Our results suggest that the osteogenic differentiation potential of DPSCs from elderly patients is as high as that of DPSCs from young patients. Moreover, TH-induced DPSCs showed increased osteogenic differentiation potential, and are thus a potentially useful cell source for bone regenerative therapy for elderly patients.


Assuntos
Regeneração Óssea/efeitos dos fármacos , Polpa Dentária/citologia , Lignanas/farmacologia , Osteogênese/efeitos dos fármacos , Células-Tronco/citologia , Adolescente , Adulto , Idoso , Animais , Diferenciação Celular , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Crânio/diagnóstico por imagem , Crânio/efeitos dos fármacos , Crânio/patologia , Tienopiridinas/farmacologia
19.
Molecules ; 25(14)2020 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-32668631

RESUMO

Malaria causes hundreds of thousands of deaths every year, making it one of the most dangerous infectious diseases worldwide. Because the pathogens have developed resistance against most of the established anti-malarial drugs, new antiplasmodial agents are urgently needed. In analogy to similar antiplasmodial ketones, 4-arylthieno[2,3-b]pyridine-2-carboxamides were synthesized by Thorpe-Ziegler reactions. In contrast to the related ketones, these carboxamides are only weak inhibitors of the plasmodial enzyme PfGSK-3 but the compounds nevertheless show strong antiparasitic activity. The most potent representatives inhibit the pathogens with IC50 values in the two-digit nanomolar range and exhibit high selectivity indices (>100).


Assuntos
Amidas/farmacologia , Antimaláricos/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Tienopiridinas/farmacologia , Amidas/síntese química , Amidas/química , Antimaláricos/síntese química , Antimaláricos/química , Descoberta de Drogas , Células HEK293 , Humanos , Relação Estrutura-Atividade , Tienopiridinas/química
20.
Acta Pharmacol Sin ; 41(1): 65-72, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31213671

RESUMO

Urea transporters (UTs) are transmembrane proteins selectively permeable to urea and play an important role in urine concentration. UT-knockout mice exhibit the urea-selective urine-concentrating defect, without affecting electrolyte balance, suggesting that UT-B inhibitors have the potential to be developed as novel diuretics. In this study, we characterized a novel compound 5-ethyl-2-methyl-3-amino-6-methylthieno[2,3-b]pyridine-2,5-dicarboxylate (CB-20) with UT inhibitory activity as novel diuretics with excellent pharmacological properties. This compound was discovered based on high-throughput virtual screening combined with the erythrocyte osmotic lysis assay. Selectivity of UT inhibitors was assayed using transwell chambers. Diuretic activity of the compound was examined in rats and mice using metabolic cages. Pharmacokinetic parameters were detected in rats using LC-MS/MS. Molecular docking was employed to predict the potential binding modes for the CB-20 with human UT-B. This compound dose-dependently inhibited UT-facilitated urea transport with IC50 values at low micromolar levels. It exhibited nearly equal inhibitory activity on both UT-A1 and UT-B. After subcutaneous administration of CB-20, the animals showed polyuria, without electrolyte imbalance and abnormal metabolism. CB-20 possessed a good absorption and rapid clearance in rat plasma. Administration of CB-20 for 5 days did not cause significant morphological abnormality in kidney or liver tissues of rats. Molecular docking showed that CB-20 was positioned near several residues in human UT-B, including Leu364, Val367, and so on. This study provides proof of evidence for the prominent diuretic activity of CB-20 by specifically inhibiting UTs. CB-20 or thienopyridine analogs may be developed as novel diuretics.


Assuntos
Diuréticos/farmacologia , Proteínas de Membrana Transportadoras/metabolismo , Tienopiridinas/farmacologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Diuréticos/administração & dosagem , Diuréticos/química , Cães , Relação Dose-Resposta a Droga , Eritrócitos/efeitos dos fármacos , Injeções Subcutâneas , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Simulação de Acoplamento Molecular , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Tienopiridinas/administração & dosagem , Tienopiridinas/química
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