ABSTRACT
JUSTIFICATIVA E OBJETIVOS: Pacientes com fibrilação atrial (FA) estão mais propensos à ocorrência de eventos vasculares, como acidente vascular encefálico (AVE) e fenômenos tromboembólicos, sendo necessária anticoagulação oral. A varfarina, o anticoagulante mais utilizado, tem uma série de limitações referentes ao seu uso. Nesse contexto, foram desenvolvidos novos anticoagulantes orais (NOACs): inibidores da trombina (dabigatrana) e do fator Xa (rivaroxabana e apixabana). Essa revisão sistemática procurou elencar os principais resultados de Ensaios Clínicos Randomizados (ECRs) abordando o tema NOACs em pacientes com fibrilação atrial para a prevenção de acidente vascular encefálico e/ou fenômenos tromboembólicos. CONTEÚDO: Foram pesquisados Ensaios Clínicos Randomizados, cegos ou abertos, em indivíduos adultos, nas bases PubMed, Scopus, Web of Science, SciELO, LILACS e Cochrane CENTRAL. A avaliação da qualidade dos estudos foi feita utilizando a escala Downs & Black. Foram selecionados cinco Ensaios Clínicos Randomizados e descritos os seus resultados. A rivaroxabana se mostrou não inferior a varfarina no que diz respeito ao desfecho combinado embolismo sistêmico e acidente vascular encefálico, enquanto que a apixabana e a dabigatrana 150mg mostraram-se superiores. Todos os três medicamentos estiveram associados a menor incidência de hemorragia intracraniana quando comparado a varfarina. A apixabana mostrou perfil mais favorável em relação à ocorrência de qualquer sangramento. CONCLUSÕES: os Ensaios Clínicos Randomizados selecionados demonstraram a eficácia dos NOACs na prevenção de acidente vascular encefálicos e/ou embolismo sistêmico em pacientes com fibrilçao atrial. Contudo, são necessários mais estudos para preencher as lacunas do conhecimento quanto à eficácia e segurança desta nova classe de anticoagulantes orais.
BACKGROUND AND OBJECTIVES: Patients with atrial fibrillation (AF) are more likely to the occurrence of vascular events including stroke and thromboembolism systemic. Thus anticoagulation is necessary to prevent these events. Warfarin is the current gold standard but has a number of limitations regarding your use. In this context, new oral anticoagulants (NOACs) were developed: thrombin inhibitors (dabigatran) and factor Xa inhibitors (rivaroxaban and apixaban). The aim of this systematic review was to analyze the results of the main randomized clinical trials (RCTs) envolving NOACs in patients with atrial fibrillation for the prevention of stroke and/or thromboembolic events. CONTENTS: Double blinded or open label randomized clinical trials envolving patients with FA testing these drugs were researched in PubMed, Scopus, Web of Science, SciELO, LILACS and Cochrane CENTRAL. The quality assessment of studies used the Downs & Black Scale Five randomized clinical trials were selected, envolving 57.457 patients. Dabigatran, apixaban and rivaroxaban were at least non inferior to the warfarin in the outcome of stroke and systemic embolism. Apixaban and dabigatran 150mg were also superior than warfarin in efficacy. All three drugs were associated with a lower incidence of intracranial hemorrhage. Apixaban was related to lower risk of total bleeding. CONCLUSIONS: NOACs have efficacy to prevent AVE and systemic thromboembolism in patients with FA. However further studies are needed to resolve the issues that remain open and to provide more security to the use of these drugs in clinical practice.
Subject(s)
Humans , Stroke/prevention & control , Stroke/therapy , Anticoagulants/adverse effects , Anticoagulants/therapeutic use , Atrial Fibrillation/complications , Administration, Oral , Anticoagulants/pharmacology , Drugs, Investigational , WarfarinABSTRACT
BACKGROUND:To date, rivaroxaban has been a clinical y common anticoagulant in China;however, effective prophylaxis for venous thrombosis is associated with a markedly higher incidence of perioperative hemorrhagic complications. Although it has been reported that aspirin effectively prevents deep vein thrombosis and pulmonary embolism, the use of aspirin as a routine drug for venous thrombosis after total knee arthroplasty is stil controversial. OBJECTIVE:To compare the efficacy and safety of aspirin and rivaroxaban for prevention of deep vein thrombosis after total knee arthroplasty. METHODS:Total y 324 patients with osteoarthritis who underwent primary unilateral total knee arthroplasty were randomly divided into three groups. Twelve hours after the surgery, three groups were given aspirin, rivaroxaban and low-molecular-weight heparin respectively. Al three groups were treated for 14 days, and al of the patients were fol owed for 4 weeks. RESULTS AND CONCLUSION:Compared with the low-molecular-weight heparin group, the incidence of deep vein thrombosis was lower (P0.05). The results confirmed that rivaroxaban has a positive anticoagulation effect but leads to increases in wound complications in patients;there are no differences in efficacy and safety between aspirin and low-molecular-weight heparin, so aspirin as part of a multimodal anticoagulation therapy after total knee arthroplasty has good clinical safety and efficacy.
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Objective To investigate the effects of signal pathway inhibitors PD98059 and LY294002 on cell proliferation, apoptosis, expressions of phosphorylated extracellular signal-regulared kinase (p-ERK) and phosphorylated protein kinase B ( p-Akt) in endometrial carcinoma xenografts. Methods Human endometrial carcinoma Ishikawa cells were cultured in vitro. The effects of PD98059 and LY294002 on proliferation, apoptosis, and cell cycle distribution of endometrial cancer cells were detected by monotetrazolium ( MTT) assay and fluorescence-activated cell sorting technique. The models of xenografted tumor were established by the subcutaneous inoculation in 24 nude mice, and then they were randomly divided into 4 groups ( n = 6) , normal saline group, PD98059 group (PD group) , LY294002 group ( LY group) or PD98059 + LY294002 group ( PD + LY group) by intraperitoneal injections, respectively. The anti-tumor efficacy was evaluated by measuring tumor volume and tumor growth status. The histopathological change of tumor specimens was observed using HE staining and terminal deoxynucleotidyl transferasemediated dUTP-digoxigen in nick and labeling method (TUNEL) testing and the expression levels of p-ERK and p-Akt were detected by immunohistochemistry method. Results ( 1) The proliferation of Ishikawa cells were suppressed after treated by PD98059 and ( or) Y294002, in which A570 values of cells decreased showing both time-dependent and concentration-dependent manner ( LY294002: Fgroup = 9. 801, P = 0. 002; Ftime = 10. 398, P = 0. 001. PD98059: Fgroup= 8. 213, P = 0. 015; Ftime = 6. 839, P = 0. 036). Cell cycle distribution analysis revealed that percentage of Ishikawa cells at G0/G1 phase(Ftime =35.049, P= 0.004; Fgroup = 32. 024, P ＜0. 01) increased and percentage of S phase cells (Ftime = 7. 789, P = 0. 049; Fgroup = 30. 132, P ＜0. 01) decreased significantly. The percentage of apoptotic cells increased significantly among PD group, LY group and PD + LY group, in which there were significant difference [(63. 3 ±0.5)% vs (30. 7 ± 20. 1) % vs(40. 8 ± 1. 3) % ; F = 621. 059, P ＜ 0. 01]. (2) Compared with the control group, the increasing of transplanting tumor volume in the treated groups were obviously ( F = 23. 545 , P ＜ 0. 01) , and the inhibited rate of the tumor was higher in PD + LY group than that in PD group or LY group [(68 ± 9 ) % vs ( 32 ± 16 ) % or ( 38 ± 17 ) % ; F = 10. 283 , P ＜ 0. 05]. ( 3 ) HE staining shown that there were different degrees of necrosis for endometrial carcinoma cell in different groups. The apoptosis of tumor cells were significantly increased in treated groups by TUNEL testing [(13. 7 ± 1. 5)% , ( 14. 1 ± 1. 2)% , (29. 0 ± 1. 8 ) % ; F = 320. 344, P ＜ 0. 01]. Immunohistochemistry results demonstrated that the expressions of p-ERK and p-Akt in treated groups were lower than that in control group, of which LY + PD group was the lowest one. Conclusion The signal pathway inhibitors PD98059 and LY294002 could inhibit the growth of human endometrial carcinoma in vivo and in vitro, in which may induce cell apoptosis.
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Objective To study the influence of survivin mutant-T34A ( survivinT34A) and survivin deletant-N-terminal 8 amino acids residues ( survivinN-8AA ) on the cell cycle distribution and chemosensitivity in human ovarian cancer HO-8910 cells for explorating the roles of modified survivin-mediated apoptosis induced by chemotherapeutic agents and possible signaling pathways involved. Methods pcDNA3.1 plasmid contained wild-type, survivinT34A and survivinN-8AA genes were transfected into HO-8910 cells,respectively, the control groups were HO-8910 cells transfected with pcDNA3. 1 plasmids. The expression of mRNA was examined by reverse transcription(RT) PCR and identified by DNA sequencing; the cell cycles were determined by flow cytometer analysis ( FCM ); the growth inhibitions rate of cisplatin ( DDP),paclitaxel (PTX) and LY294002 on the transfected cells were determined using methyl thiazolyl tetrazolium (MTT) assay. Results (1) The RT-PCR procedures and genome sequences showed that the survivin mRNA were expressed stable in the transfected HO-8910 cells. (2) There was lower percent of G0/G1 phase cells in SN-HO-8910 cells than that in PC-HO-8910 cells (44. 72% vs. 49.64%, P ＜0. 05) ;while higher percentage of G2/M phase and S phase cells( 1.06% and 54. 22% vs. 0. 56% and 49. 80%, P ＜ 0. 05 ).There was lower the G2/M phase and S phase cells in M-HO-8910 cells 0. 16% and 36. 33%, than that in PC-HO-8910 cells( P ＜ 0. 05 ); while higher percentage of G0/G1 phase cells(63. 51% ,P ＜ 0. 05 ). G0/G1 ,G2/M and S phase cells in Sur-HO-8910 cells were 54. 46%, 0. 62% and 44. 92%, and there were not significantly difference ( P ＞ 0. 05 ), compared to those in PC-HO-8910 cells. ( 3 ) The inhibitory concentration ( IC50 ) of DDP and PTX were higher in Sur-HO-8910 cells than those in control cells [(20. 4 ±6. 1)vs. (14.4 ±3.9)μmol/L,(36.7 ±4.0) vs. (28.6 ±3.6) μmol/L;all P＜0.05]. The IC50 of DDP and LY294002 in SN-HO-8910 cells were lower than those in control cells[(7. 6 ± 1.0) vs. ( 14. 4 ± 3.9)μmol/L, ( 13.2 ± 4. 0) vs. (41.0 ± 7. 9 ) μmol/L; all P ＜ 0. 01]. The IC50 of PTX [( 37. 9 ± 4. 8 ) μmol/L]in SN-HO-8910 cells were higher than that in control cells(P ＜0. 05). The IC50 of DDP in M-HO-8910 cells [(9.9 ± 1.2) μmol/L] were lower than that in control cells(P ＜0. 05) ,and the IC50 of LY294002 in M-HO-8910 cells [(66. 9 ± 4. 8) μ mol/L] higher than that in control cells ( P ＜ 0. 01 ). Conclusions The changes of cells cycle distribution caused by survivinT34A or survivinN-8AA enhanced the G2/M cell cycle-dependent chemosensitivity of PTX. Compared to survivinT34A, survivinN-8AA preferentially to mediate the cytotoxicity of DDP and LY294002, suggesting that it may be related to the cell cycle-dependence of survivin function and to blockage of the formation of its active dimer.
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Objective To explore the expression and significance of phosphatidylinositol-3 kinase (PI3K)in ovarian cancer,and the effect of combined PI3K inhibitor(LY294002)therapy with cisplatin on epithelial ovarian carcinoma,and to explore if there is a synergistic effect between the two therapies. Methods The expression levels of PI3K p85 subunit proteins and mRNA were evaluated by western blot and RT-PCR in normal ovarian tissue(G1),ovarian benign tumor tissue(G2),ovarian borderline tumor tissue(G3)and ovarian cancer tissue(G4),and the relevant clinical pathological parameters were analyzed.SKOV3 ceils were isolated and cultured by enzymolysis method.SKOV3 cells were treated with culture medium only,LY294002(1,10,30,50,100 ?mol/L),cisplatin(0.33,1.25,2.5,5, 10 ?mol/L),LY294002(50 ?mol/L)+cisplatin(10 ?mol/L)for 2 days,respectively.The effect of LY294002 and cisplatin on the growth of SKOV3 cells was measured by methyl thiazolyl tetrazolium assay. Results There was no positive expression of PI3K p85 subunit proteins in G1 and G2,while the expression was 2/6 in G3,and 85%(33/39)in G4.PI3K p85 subunit mRNA expression levels were 0.178?0.102 in G1,0.643?0.112 in G2,0.847?0.058 in G3,1.689?0.423 in G4;there was a significant difference between G1,G2,G3 and G4(P0.05).Significant differences were noted between protein expression levels in G4(Ⅲ,Ⅳ)and G4(Ⅰ,Ⅱ;P
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Objective To study the modulation of mdr1 and P glycoprotein (P gp) by 1 phenyl 2 palmitoylamino 3 morpholino 1 propanol (PPMP) in SKOV3 adriamycin resistant (SKOV3/AdrR) cell line Methods SKOV3/AdrR cells were treated with PPMP, mRNA expression of multidrug resistant (mdr1) gene was analyzed by reverse transcriptase polymerase chain reaction Intracellular rhodamine (Rh123) concentration was measured by flow cytometry Results PPMP was found to inhibit mdr1 expression of SKOV3/AdrR at the mRNA level This modulation of gene expression was content dependent and complete inhibition appeared at 25 ?mol/L PPMP treatment PPMP could increase intracellular Rh123 accumulation in SKOV3/AdrR cells After 15, 25 ?mol/L PPMP treatment, Rh123 accumulation in SKOV3/AdrR was markedly enhanced Rh123 fluorescence intensity were 389 98,426 08 respectively ( P