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2.
Journal of Experimental Hematology ; (6): 1081-1085, 2020.
Article in Chinese | WPRIM | ID: wpr-827157

ABSTRACT

OBJECTIVE@#To investigate the effect of sphingosine-1-phosphate receptor 2 (S1PR2) specific antagonist JTE-013 on the proliferation of human chronic myeloid leukemia (CML) cell line K562.@*METHODS@#K562 cells were treated with JTE-013 (0, 0.5, 1, 5, 10, 20 μmol/L) for 24 and 48 hours respectively, CCK8 assay was used to detect the cell viability. K562 cells were treated with JTE-013 (0, 5, 10, 20 μmol/L) for 24 hours, propidium iodide (PI) DNA staining was used to analyze the cell cycle, Western blot was used to determine the levels of P21 and Cyclin D1 protein expression.@*RESULTS@#JTE-013 inhibited the proliferation of CML cell line K562 in a dose dependent manner (r=-0.971). The proliferation rate of CML cells showed that the activity of CML cells decreased gradually with the increase of JTE-013 concentration (r=-0.971). The detection demonstrated that JTE-013 suppressed tumor cell proliferation through cell cycle arrest in G/G phase. Further detection of the protein expressions of G phase regulators showed that level of P21 increased, and expression of Cyclin D1 decreased.@*CONCLUSION@#JTE-013, a S1PR2 antagonist, can inhibit the proliferation of human CML K562 cells, which may be achieved by arresting the cells in G/G phase.


Subject(s)
Apoptosis , Cell Proliferation , Humans , K562 Cells , Leukemia, Myelogenous, Chronic, BCR-ABL Positive , Pyrazoles , Pyridines , Receptors, Lysosphingolipid , Sphingosine-1-Phosphate Receptors
3.
Journal of Experimental Hematology ; (6): 1376-1380, 2020.
Article in Chinese | WPRIM | ID: wpr-827109

ABSTRACT

OBJECTIVE@#To establish a secondary hemophagocytic lymphohistiocytosis(HLH) mouse model, and to investigate the effect of ruxolitinib on the disease manifestation of model mice.@*METHODS@#Wild type C57BL/6 mice were randomly divided into 4 groups: two groups of mice were intraperitoneally injected with CpG oligodeoxynucleotide 1826 (CpG-ODN1826) every other day to induce HLH, and other two groups were control groups. One group of the CpG-ODN1826 groups and one of the control groups were given ruxolitinib, and other two groups were given the same amount of PBS. Blood samples, serum ferritin and hepatic/spleen weights of experimental mice were detected and serum cytokine levels were measured by ELISA.@*RESULTS@#Compared with the control groups, the levels of white blood cells, hemoglobin and platelets in the CpG-ODN1826 groups were significantly lower (P<0.05); and liver/body weight, spleen/body weight, serum ferritin, sCD25, IL-10, IL-1β, IFN-Ƴ, IL-12p70, GM-CSF, TNF-α and IL-18 levels significantly increased (P<0.05). There was no significant difference in the levels of IL-2, IL-4, IL-5, IL-6, IL-22, IL-13, IL-27 and IL-23 between the two groups (P>0.05). The spleen in CpG group had disordered internal structure, expanding red pulp and hyperplastic nucleated cells. The liver had severe perivascular inflammations. The spleen/weight of the ruxolitinib-treated mice in the CpG-ODN1826 group was significantly smaller than that of the unapplied ruxolitinib (P<0.05).@*CONCLUSION@#The CpG-ODN1826 can induce secondary HLH symptoms in wild type C57BL/6 mice. Ruxolitinib can alleviate the symptoms of splenomegaly in HLH model mice.


Subject(s)
Animals , Disease Models, Animal , Lymphohistiocytosis, Hemophagocytic , Mice , Mice, Inbred C57BL , Pyrazoles
4.
Rev. méd. Chile ; 147(1): 73-82, 2019. tab, graf
Article in Spanish | LILACS | ID: biblio-991375

ABSTRACT

Direct oral anticoagulants (DOACs), including the direct thrombin inhibitor dabigatran and the direct factor Xa inhibitors rivaroxaban, apixaban and edoxaban have at least comparable efficacy as vitamin K antagonists along with a better safety profile, reflected by a lower incidence of intracranial hemorrhage. Specific reversal agents have been developed in recent years. Namely, idarucizumab, a specific antidote for dabigatran, is currently approved in most countries. Andexanet, which reverses factor Xa inhibitors, has been recently approved by the FDA, and ciraparantag, a universal antidote targeted to reverse all DOACs, is still under investigation. In this review we provide an update on the pharmacology of DOACs, the risk of hemorrhagic complications associated with their use, the measurement of their anticoagulant effect and the reversal strategies in case of DOAC-associated bleeding.


Subject(s)
Humans , Blood Coagulation Factors/therapeutic use , Antithrombins/administration & dosage , Antithrombins/adverse effects , Antibodies, Monoclonal, Humanized/therapeutic use , Hemorrhage/chemically induced , Hemorrhage/therapy , Pyrazoles/administration & dosage , Pyrazoles/adverse effects , Pyridines/administration & dosage , Pyridines/adverse effects , Pyridones/administration & dosage , Pyridones/adverse effects , Thiazoles/administration & dosage , Thiazoles/adverse effects , Administration, Oral , Risk Factors , Rivaroxaban/administration & dosage , Rivaroxaban/adverse effects , Dabigatran/administration & dosage , Dabigatran/adverse effects , Antidotes/therapeutic use
5.
Braz. j. pharm. sci ; 55: e00249, 2019. tab, graf, ilus
Article in English | LILACS | ID: biblio-1011652

ABSTRACT

A series of N-substituted-3-(napthalen-2-yl)-5-substituted phenyl-4,5-dihydropyrazole-1-carbothioamide derivatives (4a-n) were synthesized with the view of structural requirements of pharmacophore for potential anticonvulsant agents. The synthesized compounds were assayed intraperitoneally (i.p.) and subcutaneously (s.c.) in mice against seizures induced by MES and scPTZ methods, respectively.Neurologic deficit was evaluated by rotarod method. Among the tested compounds, 4g, 4i, 4j and 4n emerged as the most active molecule in the MES model at a dose of 30 mg/kg at 0.5h comparable to standardscarbamazepine and phenytoin. In the scPTZ test,4e and 4l were found to be most active compounds at the lowest dose of 30 mg/kg at 0.5h, in the management of the convulsive disorder. Molecular docking studies of the titled compounds were also donewith 3D crystal structure of human cytosolic branched chain amino transferase (hBCATc) enzyme and compound 4e was found to have five hydrogen bond interactions with the most important active site residues.In neurotoxicity studies, except compounds 4b, 4c, 4h and 4k, rest of the compounds showed no sign of toxicity.


Subject(s)
Animals , Male , Female , Mice , Pyrazoles/analysis , Anticonvulsants/analysis , Epilepsy/diagnosis , Molecular Docking Simulation/classification
6.
Rev. méd. Chile ; 146(9): 1074-1078, set. 2018. tab, graf
Article in Spanish | LILACS | ID: biblio-978800

ABSTRACT

We report a 51-year-old female who had a first episode of thrombocytopenia at 23 years of age during a pregnancy. At the age of fifty, a hysterectomy was indicated due to a metrorrhagia: a platelet count of 21,000/ul was detected. She was treated with eltrombopag with a good response. The family history of the patient revealed the presence of thrombocytopenia in several family members. Suspecting a hereditary thrombocytopenia, a genetic study revealed a mutation in the MYH-9 gene. This mutation can be suspected when there is a family history of thrombocytopenia with autosomal dominant inheritance, macrothrombocytopenia and in this particular case, due to the response to thrombopoietin receptor agonist, eltrombopag.


Subject(s)
Humans , Female , Middle Aged , Thrombocytopenia/congenital , Hearing Loss, Sensorineural/diagnosis , Hearing Loss, Sensorineural/genetics , Platelet Count , Pyrazoles , Thrombocytopenia/diagnosis , Thrombocytopenia/genetics , Benzoates , Biopsy , Genetic Diseases, Inborn , Hydrazines , Mutation
8.
An. acad. bras. ciênc ; 90(1): 239-245, Mar. 2018. tab
Article in English | LILACS | ID: biblio-886915

ABSTRACT

ABSTRACT This study evaluated the in vitro toxicity and motor activity changes in African-derived adult honey bees (Apis mellifera L.) exposed to lethal or sublethal doses of the insecticides fipronil and imidacloprid. Mortality of bees was assessed to determine the ingestion and contact lethal dose for 24 h using probit analysis. Motor activities in bees exposed to lethal (LD50) and sublethal doses (1/500th of the lethal dose) of both insecticides were evaluated in a behavioral observation box at 1 and 4 h. Ingestion and contact lethal doses of fipronil were 0.2316 ? 0.0626 and 0.0080 ? 0.0021 μg/bee, respectively. Ingestion and contact lethal doses of imidacloprid were 0.1079 ? 0.0375 and 0.0308 ? 0.0218 μg/bee, respectively. Motor function of bees exposed to lethal doses of fipronil and imidacloprid was impaired; exposure to sublethal doses of fipronil but not imidacloprid impaired motor function. The insecticides evaluated in this study were highly toxic to African-derived A. mellifera and caused impaired motor function in these pollinators.


Subject(s)
Animals , Pyrazoles/toxicity , Bees/drug effects , Neonicotinoids/toxicity , Insecticides/toxicity , Motor Activity/drug effects , Nitro Compounds/toxicity , Bees/physiology , Behavior, Animal/drug effects , Lethal Dose 50
9.
Clinics ; 73: e216, 2018. tab
Article in English | LILACS | ID: biblio-890747

ABSTRACT

OBJECTIVES: Chronic thromboembolic pulmonary hypertension is one of the most prevalent forms of pulmonary hypertension and is a major complication of acute pulmonary embolism. One mainstay of chronic thromboembolic pulmonary hypertension treatment is lifelong anticoagulation. The recent advent of direct oral anticoagulants for acute pulmonary embolism treatment has provided a viable and effective alternative for treating this condition. However, little is known about the efficacy of this new class of drugs for treating chronic thromboembolic pulmonary hypertension. We aimed to evaluate the safety and efficacy of direct oral anticoagulants in the treatment of chronic thromboembolic pulmonary hypertension. METHODS: A cohort of chronic thromboembolic pulmonary hypertension patients who initiated treatment with direct oral anticoagulants between June 2015 and November 2016 were enrolled in this study. RESULTS: Sixteen patients used rivaroxaban, three used dabigatran and one used apixaban for a mean follow-up of 20.9 months. The mean age was 51 years, and eighteen patients were classified as functional class II/III. Eight patients underwent a pulmonary endarterectomy and exhibited clinical, hemodynamic and functional improvement and currently continue to use direct oral anticoagulants. No episode of venous thromboembolism recurrence was identified during the follow-up period, but there was one episode of major bleeding after a traumatic fall. CONCLUSIONS: Although direct oral anticoagulants appear to be a safe and effective alternative for treating chronic thromboembolic pulmonary hypertension, larger studies are needed to support their routine use.


Subject(s)
Humans , Male , Female , Adult , Middle Aged , Aged , Pulmonary Embolism/drug therapy , Pyrazoles/administration & dosage , Pyridones/administration & dosage , Antithrombins/administration & dosage , Dabigatran/administration & dosage , Hypertension, Pulmonary/drug therapy , Vitamin K/antagonists & inhibitors , Chronic Disease , Administration, Oral , Reproducibility of Results , Treatment Outcome
10.
Article in Chinese | WPRIM | ID: wpr-771449

ABSTRACT

OBJECTIVE@#To investigate the effect of danusertib (Danu), an inhibitor of Aurora kinase, on the proliferation, cell cycle, apoptosis, and autophagy of hepatocellular carcinoma HepG2 cells and explore the underlying mechanisms.@*METHODS@#MTT assay was used to examine the effect of Danu on the viability of HepG2 cells to determine the IC50 of Danu. The effect of Danu on cell cycle distribution, apoptosis and autophagy were determined using flow cytometry. Western blotting was used to detect the expressions of the proteins related to cell cycle, apoptosis and autophagy. Chloroquine was used to suppress Danuinduced autophagy to test the apoptosis-inducing effect of Danu.@*RESULTS@#Danu significantly inhibited the proliferation of HepG2 cells with IC of 39.4 μmol and 14.4 μmol at 24 h and 48 h, respectively. Danu caused cell cycle arrest in G/M phase in HepG2 cells and led to polyploidy accumulation via up-regulating the expressions of p53 and p21 and down-regulating the expressions of cyclin B1 and DC2. Danu also caused apoptosis of HepG2 cells through up-regulating the expressions of Bax, Puma, cleaved caspase-3, cleaved caspase-9, cleaved PARP and cytochrome C and down-regulating the expressions of Bcl-xl and Bcl-2. Danu induced autophagy via activating AMPK signaling and inhibiting PI3K/PTEN/AKT/mTOR axis, and inhibition of Danu-induced autophagy with chloroquine enhanced the pro-apoptotic effect of Danu.@*CONCLUSIONS@#Danu inhibits cell proliferation and induces cell cycle arrest in G/M phase, apoptosis and cytoprotective autophagy in HepG2 cells.


Subject(s)
Apoptosis , Autophagy , Benzamides , Pharmacology , Carcinoma, Hepatocellular , Pathology , Cell Cycle , Cell Division , Cell Proliferation , Hep G2 Cells , Humans , Liver Neoplasms , Pathology , Neoplasm Proteins , Metabolism , Protein Kinase Inhibitors , Pharmacology , Pyrazoles , Pharmacology
11.
Article in Chinese | WPRIM | ID: wpr-690960

ABSTRACT

<p><b>OBJECTIVE</b>To evaluate the efficacy and safety of ruxolitinib in treatment of myeloproliferative neoplasm.</p><p><b>METHODS</b>Random clinical trials (~September 30, 2017) were identified from PubMed, Embase, Cochrane Library, Clinical Trials, CBM and Chinese Journal Full-text Database. The quality of RCT was assessed by Cochrane risk bias. Meta analysis was performed with Revman 5.3.</p><p><b>RESULTS</b>Ruxolitinib was efficacious in relieving splenomegaly (RR 49.12, 95% CI [15.81-152.59], P<0.001). The incidence of anemia significantly increased after ruxolitinib treatment (RR 1.71, 95% CI [1.05-2.77], P=0.16), while the thrombocytopenia (RR 1.04, 95% CI [0.50-2.16], P=0.92) and neutropenia (RR 2.46, 95% CI [0.91-6.61], P=0.07) had no statistical difference as compared with that in control group. Ischemia events had no significant difference as compared with control (RR 0.57, 95% CI [0.33-1.00], P=0.05). Infection events had no significant difference as compared with the control group (RR 1.18, 95% CI [0.79-1.78], P=0.24).</p><p><b>CONCLUSION</b>Ruxolitinib is an efficacious therapeutic strategy on MPD with controlling splenomegaly. However,anemia events and bleeding events may threat its clinical safety, so more high quality RCT are needed.</p>


Subject(s)
Humans , Myeloproliferative Disorders , Neoplasms , Pyrazoles , Thrombocytopenia
12.
Braz. j. med. biol. res ; 50(6): e6141, 2017. graf
Article in English | LILACS | ID: biblio-839302

ABSTRACT

Cannabinoid type 1 receptor (CB1R) inhibition tends to be one of the promising strategies for the treatment of obesity and other related metabolic disorders. Although CB1R inhibition may cause adverse psychiatric effects including depression and anxiety, the investigation of the role of peripheral CB1R on weight loss and related metabolic parameters are urgently needed. We first explored the effect of rimonabant, a selective CB1R antagonist/inverse agonist, on some metabolic parameters in high fat-diet (HFD)-induced obesity in mice. Then, real-time PCR and electrophysiology were used to explore the contribution of high voltage-activated Ca2+ channels (HVACCs), especially Cav1.1, on rimonabant's effect in skeletal muscle (SM) in HFD-induced obesity. Five-week HFD feeding caused body weight gain, and decreased glucose/insulin tolerance in mice compared to those in the regular diet group (P<0.05), which was restored by rimonabant treatment compared to the HFD group (P<0.05). Interestingly, HVACCs and Cav1.1 were decreased in soleus muscle cells in the HFD group compared to the control group. Daily treatment with rimonabant for 5 weeks was shown to counter such decrease (P<0.05). Collectively, our findings provided a novel understanding for peripheral CB1R's role in the modulation of body weight and glucose homeostasis and highlight peripheral CB1R as well as Cav1.1 in the SM as potential targets for obesity treatment.


Subject(s)
Animals , Male , Blood Glucose/drug effects , Calcium Channels/drug effects , Cannabinoid Receptor Antagonists/pharmacology , Muscle, Skeletal/drug effects , Piperidines/pharmacology , Pyrazoles/pharmacology , Receptor, Cannabinoid, CB1/antagonists & inhibitors , Body Weight/drug effects , Calcium Channels, L-Type/drug effects , Calcium Channels, L-Type/metabolism , Calcium Channels/metabolism , Diet, High-Fat/adverse effects , Glucose Intolerance/etiology , Insulin Resistance , Mice, Inbred C57BL , Models, Animal , Muscle, Skeletal/metabolism , Obesity/etiology , Receptor, Cannabinoid, CB1/physiology
13.
Säo Paulo med. j ; 134(4): 322-329, July-Aug. 2016. tab, graf
Article in English | SES-SP, LILACS, SES-SP | ID: lil-792817

ABSTRACT

ABSTRACT CONTEXT AND OBJECTIVE: Randomized clinical trials have shown that the new oral anticoagulants have at least similar impact regarding reduction of thromboembolic events, compared with warfarin, with similar or improved safety profiles. There is little data on real costs within clinical practice. Our aim here was to perform economic analysis on these strategies from the perspective of Brazilian society and the public healthcare system. DESIGN AND SETTING: Cost-minimization analysis; anticoagulation clinic of Hospital Municipal Odilon Behrens, Belo Horizonte, MG, Brazil. METHODS: Patients at the anticoagulation clinic were recruited between August and October 2011, with minimum follow-up of four weeks. Operational and non-operational costs were calculated and corrected to 2015. RESULTS: This study included 633 patients (59% women) of median age 62 years (interquartile range ­49-73). The mean length of follow-up was 64 ± 28 days. The average cost per patient per month was $ 54.26 (US dollars). Direct costs accounted for 32.5% of the total cost. Of these, 69.5% were related to healthcare professionals. With regards to indirect costs, 52.4% were related to absence from work and 47.6% to transportation. Apixaban, dabigatran and rivaroxaban were being sold to Brazilian public institutions, on average, for $ 49.87, $ 51.40 and $ 52.16 per patient per month, respectively, which was lower than the costs relating to warfarin treatment. CONCLUSION: In the Brazilian context, from the perspective of society and the public healthcare system, the cumulative costs per patient using warfarin with follow-up in anticoagulation clinics is currently higher than the strategy of prescribing the new oral anticoagulants.


RESUMO CONTEXTO E OBJETIVO: Estudos clínicos randomizados demonstraram que novos anticoagulantes orais têm pelo menos impacto semelhante em reduzir eventos tromboembólicos quando comparados à varfarina, com perfil de segurança similar ou superior. Há pouca evidência acerca de custos reais na prática clínica. Nosso objetivo é realizar análise econômica dessas estratégias, na perspectiva do sistema de saúde pública e da sociedade brasileiros. TIPO DE ESTUDO E LOCAL: Análise de custo-minimização; Clínica de Anticoagulação do Hospital Municipal Odilon Behrens, Belo Horizonte, MG, Brasil. MÉTODOS: Os pacientes da clínica de anticoagulação foram recrutados de agosto a outubro de 2011, com tempo mínimo de acompanhamento de quatro semanas. Custos operacionais e não operacionais foram computados e corrigidos para 2015. RESULTADOS: Este estudo incluiu 633 pacientes, com idade mediana de 62 (intervalo interquartil 49-73) anos, sendo 59% mulheres. O tempo médio de acompanhamento foi de 64 ± 28 dias. O custo médio por paciente por mês foi de $ 54.26 (dólares). Custos diretos foram responsáveis por 32,5% do custo total. Destes, 69,5% foram relacionados aos profissionais de saúde. Em relação aos custos indiretos, 52,4% estavam relacionados ao absenteísmo ao trabalho e 47,6% ao transporte. Apixaban, dabigatran e rivaroxaban são vendidos a órgãos públicos brasileiros, respectivamente, a um preço médio mensal de $ 49.87, $ 51.40 e $ 52.26 por paciente por mês, valores inferiores aos custos relacionados ao tratamento com varfarina. CONCLUSÃO: No contexto brasileiro, na perspectiva do sistema de saúde pública e da sociedade, os custos cumulativos por paciente em uso de varfarina acompanhados em clínica de anticoagulação são atualmente superiores à estratégia de prescrever novos anticoagulantes orais.


Subject(s)
Humans , Male , Female , Middle Aged , Aged , Thromboembolism/prevention & control , Drug Costs/statistics & numerical data , Anticoagulants/economics , Anticoagulants/therapeutic use , Pyrazoles/economics , Pyrazoles/therapeutic use , Pyridones/economics , Pyridones/therapeutic use , Reference Values , Atrial Fibrillation/economics , Atrial Fibrillation/prevention & control , Warfarin/therapeutic use , Brazil , Administration, Oral , Reproducibility of Results , Age Factors , Treatment Outcome , Costs and Cost Analysis , Delivery of Health Care/economics , Dabigatran/economics , Dabigatran/therapeutic use
14.
J. bras. pneumol ; 42(2): 146-154, Mar.-Apr. 2016. tab, graf
Article in English | LILACS | ID: lil-780891

ABSTRACT

Worldwide, venous thromboembolism (VTE) is among the leading causes of death from cardiovascular disease, surpassed only by acute myocardial infarction and stroke. The spectrum of VTE presentations ranges, by degree of severity, from deep vein thrombosis to acute pulmonary thromboembolism. Treatment is based on full anticoagulation of the patients. For many decades, it has been known that anticoagulation directly affects the mortality associated with VTE. Until the beginning of this century, anticoagulant therapy was based on the use of unfractionated or low-molecular-weight heparin and vitamin K antagonists, warfarin in particular. Over the past decades, new classes of anticoagulants have been developed, such as factor Xa inhibitors and direct thrombin inhibitors, which significantly changed the therapeutic arsenal against VTE, due to their efficacy and safety when compared with the conventional treatment. The focus of this review was on evaluating the role of these new anticoagulants in this clinical context.


O tromboembolismo venoso (TEV) está entre as principais causas de morte por doenças cardiovasculares no mundo, atrás apenas do infarto agudo do miocárdio e do acidente vascular cerebral. O TEV possui espectro de apresentação que vai desde a trombose venosa profunda até o tromboembolismo pulmonar agudo, de acordo com gravidade crescente de acometimento, sendo seu tratamento baseado na anticoagulação plena dos pacientes. Há muitas décadas, sabe-se que a anticoagulação interfere diretamente na mortalidade associada ao TEV. Até o início deste século a terapia anticoagulante se baseava no uso de heparina, em suas formas não fracionada ou de baixo peso molecular, e de antagonistas da vitamina K, principalmente a varfarina. Ao longo das últimas décadas, foram desenvolvidos novas classes de medicamentos anticoagulantes, inibidores do fator Xa e inibidores diretos da trombina, que mudaram significativamente o arsenal terapêutico do TEV, em função de suas características de eficácia e segurança em relação ao tratamento convencional, sendo o foco principal de esta revisão avaliar seu papel neste contexto clínico.


Subject(s)
Humans , Anticoagulants/therapeutic use , Venous Thromboembolism/drug therapy , Dabigatran/therapeutic use , Pyrazoles/therapeutic use , Pyridines/therapeutic use , Pyridones/therapeutic use , Rivaroxaban/therapeutic use , Thiazoles/therapeutic use , Time Factors , Warfarin/therapeutic use
16.
Article in English | WPRIM | ID: wpr-353725

ABSTRACT

<p><b>INTRODUCTION</b>Direct oral anticoagulants (DOACs) are establishing themselves as principle choices for the treatment of a variety of thrombotic disorders. DOACs are also known to affect common coagulation tests which are routinely performed for patients in clinical practice. An understanding of their varied effects is crucial for the appropriate ordering of coagulation tests and their interpretation.</p><p><b>MATERIALS AND METHODS</b>Laboratories in public and private healthcare institutions and commercial sectors were surveyed on coagulation tests offered and their methods. A Medline and bibliography search, including a search on search engines, was performed for publications reporting the effects of dabigatran, apixaban and rivaroxaban on these coagulation tests. These papers were reviewed and summarised for consensus recommendations.</p><p><b>RESULTS</b>Prothrombin time (PT) and activated partial thromboplastin time (aPTT) are variably affected by the DOACs and dependent of the coagulation assays used. Clinicians must know which laboratory has performed these tests to logically interpret test results. A normal PT or aPTT does not exclude the presence of residual DOACs effect. The thrombin time is sensitive to dabigatran but not apixaban or rivaroxaban. Specialised coagulation tests such as thrombophilia tests are also variably affected by the DOACs. All laboratories in Singapore however, employ similar test methods permitting a common set of recommendations for specialised coagulation testing.</p><p><b>CONCLUSION</b>Knowledge of the effects of DOACs on coagulation testing is essential to determine the appropriateness of performing such tests and interpreting them coherently. Practical recommendations which are tests and location-specific are set out in this paper.</p>


Subject(s)
Antithrombins , Therapeutic Uses , Blood Coagulation Tests , Dabigatran , Therapeutic Uses , Factor Xa Inhibitors , Therapeutic Uses , Humans , Partial Thromboplastin Time , Practice Guidelines as Topic , Prothrombin Time , Pyrazoles , Therapeutic Uses , Pyridones , Therapeutic Uses , Rivaroxaban , Therapeutic Uses , Singapore
17.
Braz. j. med. biol. res ; 49(9): e5388, 2016. tab, graf
Article in English | LILACS | ID: biblio-951696

ABSTRACT

Galunisertib (LY2157299), a selective ATP-mimetic inhibitor of TGF-β receptor I (TGF-βRI), is the only known TGF-β pathway inhibitor. In the present study, we investigated the effect of galunisertib on taurocholate (TAC)-induced acute pancreatitis (AP) in rats, and the role of TGF-β and NF-κB signaling pathways. AP was induced by infusion of TAC into the pancreatic duct of Sprague-Dawley male rats (n=30). The rats (220±50 g) were administered galunisertib intragastrically [75 mg·kg-1·day-1 for 2 days (0 and 24 h)]. Serum IL-1β, IL-6, TNF-α, amylase (AMY), lipase (LIP), and myeloperoxidase (MPO) levels were measured by ELISA. NF-κB activity was detected by electrophoretic mobility shift assay (EMSA); NF-κBp65 and TGF-β1 proteins, as well as TGF-βRI and p-Smad2/3 proteins, were detected by western blot assay. Cell apoptosis was detected by TUNEL assay. H&E staining was used to evaluate the histopathological alterations of the pancreas. Galunisertib treatment attenuated the severity of AP and decreased the pancreatic histological score. In addition, number of apoptotic cells were significantly increased in the galunisertib-treated group (16.38±2.26) than in the AP group (8.14±1.27) and sham-operated group (1.82±0.73; P<0.05 and P<0.01, respectively). Galunisertib decreased the expression levels of TGF-βRI and p-Smad2/3 and inhibited NF-κB activation and p65 translocation compared with the sham-operated group. Furthermore, serum IL-1β, IL-6, TNF-α, AMY and LIP levels and tissue MPO activity were significantly decreased in the galunisertib-treated group. Our data demonstrate that galunisertib attenuates the severity of TAC-induced experimental AP in rats by inducing apoptosis in the pancreas, inhibiting the activation of TGF-β signals and NF-κB as well as the secretion of pro-inflammatory cytokines.


Subject(s)
Animals , Male , Pancreatitis/drug therapy , Pyrazoles/therapeutic use , Quinolines/therapeutic use , Protein-Serine-Threonine Kinases/antagonists & inhibitors , Protein Kinase Inhibitors/therapeutic use , Pancreas/drug effects , Pancreas/pathology , Pancreatitis/pathology , Enzyme-Linked Immunosorbent Assay , Blotting, Western , Acute Disease , Interleukin-6/blood , Treatment Outcome , Apoptosis , Peroxidase/analysis , In Situ Nick-End Labeling , Electrophoretic Mobility Shift Assay , Interleukin-1beta/blood , Amylases/blood , Lipase/blood
18.
Braz. j. phys. ther. (Impr.) ; 19(3): 194-200, May-Jun/2015. tab, graf
Article in English | LILACS | ID: lil-751384

ABSTRACT

Objective: To investigate the relationship between self-perceived fatigue with different physical functioning tests and functional performance scales used for evaluating mobility-related disability among community-dwelling older persons. Method: This is a cross-sectional, population-based study. The sample was composed of older persons with 65 years of age or more living in Cuiabá, MT, and Barueri, SP, Brazil. The data for this study is from the FIBRA Network Study. The presence of self-perceived fatigue was assessed using self-reports based on the Center for Epidemiologic Studies-Depression Scale. The Lawton instrumental activities of daily living scale (IADL) and the advanced activities of daily living scale (AADL) were used to assess performance and participation restriction. The following physical functioning tests were used: five-step test (FST), the Short Physical Performance Battery (SPPB), and usual gait speed (UGS). Three models of logistic regression analysis were conducted, and a significance level of α<0.05 was adopted. Results: The sample was composed of 776 older adults with a mean age (SD) of 71.9 (5.9) years, of whom the majority were women (74%). The prevalence of self-perceived fatigue within the participants was 20%. After adjusting for covariates, SPPB, UGS, IADL, and AADL remained associated with self-perceived fatigue in the final multivariate regression model. Conclusion: Our results suggest that there is an association between self-perceived fatigue and lower extremity function, usual gait speed and activity limitation and participation restriction in older adults. Further cohort studies are needed to investigate which physical performance measure may be able to predict the negative impact of fatigue in older adults. .


Subject(s)
Adult , Humans , Male , Adenocarcinoma/genetics , Carcinoma, Non-Small-Cell Lung/genetics , Gene Rearrangement , Lung Neoplasms/genetics , Protein Kinase Inhibitors/therapeutic use , Pyrazoles/therapeutic use , Pyridines/therapeutic use , Receptor Protein-Tyrosine Kinases/genetics , Adenocarcinoma/metabolism , Adenocarcinoma/secondary , Carcinoma, Non-Small-Cell Lung/metabolism , Carcinoma, Non-Small-Cell Lung/secondary , Immunoenzyme Techniques , In Situ Hybridization, Fluorescence , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Prognosis , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction , RNA, Messenger/genetics , Receptor Protein-Tyrosine Kinases/metabolism
19.
Indian J Biochem Biophys ; 2015 Feb; 52 (1): 23-28
Article in English | IMSEAR | ID: sea-157951

ABSTRACT

Crizotinib is the potential anticancer drug used for the treatment of non-small cell lung cancer (NSCLC) approved by FDA in 2011. The main target for the crizotinib is anaplastic lymphoma kinase (ALK). Evidences available indicate that double mutant ALK (L1196M and G1269A) confers resistance to crizotinib. However, how mutation confers drug resistance is not well-understood. Hence, in the present study, molecular dynamic (MD) simulation approach was employed to study the impact of crizotinib binding efficacy with ALK structures at a molecular level. Docking results indicated that ALK double mutant (L1196M and G1269A) significantly affected the binding affinity for crizotinib. Furthermore, MD studies revealed that mutant ALK-crizotinib complex showed higher deviation, higher fluctuation and decreased number of intermolecular H-bonds, when compared to the native ALK-crizotinib complex. These results may be immense importance for the molecular level understanding of the crizotinib resistance pattern and also for designing potential drug molecule for the treatment of lung cancer.


Subject(s)
Carcinoma, Non-Small-Cell Lung/drug therapy , Drug Resistance, Neoplasm/etiology , Molecular Dynamics Simulation/statistics & numerical data , Pyrazoles/pharmacology , Pyridines/pharmacology
20.
Chinese Journal of Pathology ; (12): 164-169, 2015.
Article in Chinese | WPRIM | ID: wpr-298086

ABSTRACT

To explore the automated immunostainer screening anaplastic lymphoma kinase (ALK) gene fusion non-small cell lung cancer (NSCLC) and clinicopathological characteristics of the molecular subtype lung cancers. Methods Five hundred and sixty-six cases of NSCLC were collected over a 16 month period. The test for ALK was performed by Ventana automated immunostainer with anti-ALK D5F3. The histological features, treatment and outcome of patients were assessed. Results Thirty-eight cases (6.7%, 38/566) of NSCLC showed ALK gene fusion. The frequency of ALK gene fusion was higher in male (7.1%, 25/350) than that in female (6.0%, 13/216) patients, but not achieving statistical significance (chi2 = 0.270, P = 0.604). ALK + NSCLC was more significantly more frequent in patients < or = 60 years (9.9%, 28/282) than >60 years (3.5% , 10/284) of age. Histologically, the ALK + NSCLCs were mostly adenocarcinoma (81.6%, 31/38) , among which eighteen cases were solid predominant subtype with mucin production; nine cases were acinar predominant subtype; one case was papillary predominant subtype and three cases were invasive mucinous adenocarcinoma. The ALK + non-adenocarcinoma included three cases of squamous cell carcinoma, three cases of adenosquamous carcinoma and one case of pleomorphic carcinoma. Among the ALK + NSCLC patients, the number of non/light cigarette smokers (86. 8% , 33/38) was more than that of heavy smokers. Twenty-nine cases were stages III and IV; twenty-nine cases showed lymph node metastasis; twenty cases showed metastases mostly to brain and bone; and one case showed EGFR gene mutation coexisting with ALK gene fusion. Twelve of fifteen patients received crizotinib therapy and remained stable. Conclusions NSCLC with ALK gene rearrangement shows distinctive clinical and histological features. Ventana-IHC may he a feasible and valid technique for detection of ALK rearrangement in NSCLC.


Subject(s)
Adenocarcinoma , Genetics , Pathology , Carcinoma, Adenosquamous , Genetics , Pathology , Carcinoma, Non-Small-Cell Lung , Genetics , Pathology , Carcinoma, Squamous Cell , Genetics , Pathology , Female , Gene Fusion , Gene Rearrangement , Humans , Lung Neoplasms , Genetics , Pathology , Male , Middle Aged , Protein Kinase Inhibitors , Therapeutic Uses , Pyrazoles , Therapeutic Uses , Pyridines , Therapeutic Uses , Receptor Protein-Tyrosine Kinases , Genetics , Sex Factors
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