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Barst R.J.,Columbia University | Ivy D.D.,Aurora University | Gaitan G.,UNICAR | Szatmari A.,Gottsegen Gyorgy Hungarian Institute of Cardiology | And 7 more authors.
Circulation | Year: 2012

Background - Safe, effective therapy is needed for pediatric pulmonary arterial hypertension. Methods and Results - Children (n=235; weight ≥8 kg) were randomized to low-, medium-, or high-dose sildenafil or placebo orally 3 times daily for 16 weeks in the Sildenafil in Treatment-Naive Children, Aged 1-17 Years, With Pulmonary Arterial Hypertension (STARTS-1) study. The primary comparison was percent change from baseline in peak oxygen consumption (PVO 2) for the 3 sildenafil doses combined versus placebo. Exercise testing was performed in 115 children able to exercise reliably; the study was powered for this population. Secondary end points (assessed in all patients) included hemodynamics and functional class. The estimated mean±SE percent change in PVO 2 for the 3 doses combined versus placebo was 7.7±4.0% (95% confidence interval, -0.2% to 15.6%; P=0.056). PVO 2, functional class, and hemodynamics improved with medium and high doses versus placebo; low-dose sildenafil was ineffective. Most adverse events were mild to moderate in severity. STARTS-1 completers could enter the STARTS-2 extension study; patients who received sildenafil in STARTS-1 continued the same dose, whereas placebo-treated patients were randomized to low-, medium-, or high-dose sildenafil. In STARTS-2 (ongoing), increased mortality was observed with higher doses. Conclusions - Sixteen-week sildenafil monotherapy is well tolerated in pediatric pulmonary arterial hypertension. Percent change in PVO 2 for the 3 sildenafil doses combined was only marginally significant; however, PVO 2, functional class, and hemodynamic improvements with medium and high doses suggest efficacy with these doses. Combined with STARTS-2 data, the overall profile favors the medium dose. Further investigation is warranted to determine optimal dosing based on age and weight. © 2011 American Heart Association, Inc.


Jing Z.-C.,Tongji University | Parikh K.,Care Institute of Medical Science | Pulido T.,Instituto Nacional Of Cardiologia | White R.J.,University of Rochester | And 6 more authors.
Circulation | Year: 2013

BACKGROUND-: Pulmonary arterial hypertension (PAH) is a progressive, fatal disease with no cure. Parenteral and inhaled prostacyclin analogue therapies are effective for the treatment of PAH, but complicated administration requirements can limit the use of these therapies in patients with less severe disease. This study was designed to evaluate the safety and efficacy of the oral prostacyclin analogue treprostinil diolamine as initial treatment for de novo PAH. METHODS AND RESULTS-: Three hundred forty-nine patients (intent-to-treat population) not receiving endothelin receptor antagonist or phosphodiesterase type-5 inhibitor background therapy were randomized (treprostinil, n=233; placebo, n=116). The primary analysis population (modified intent-to-treat) included 228 patients (treprostinil, n=151; placebo, n=77) with access to 0.25-mg treprostinil tablets at randomization. The primary end point was change from baseline in 6-minute walk distance at week 12. Secondary end points included Borg dyspnea index, clinical worsening, and symptoms of PAH. The week 12 treatment effect for 6-minute walk distance (modified intent-to-treat population) was 23.0 m (P=0.0125). For the intent-to-treat population, 6-minute walk distance improvements were observed at peak (26.0 m; P=0.0001) and trough (17.0 m; P=0.0025) plasma study drug concentrations. Other than an improvement in the combined 6-minute walk distance/Borg dyspnea score, there were no significant changes in secondary end points. Oral treprostinil therapy was generally well tolerated; the most common adverse events (intent-to-treat) were headache (69%), nausea (39%), diarrhea (37%), and pain in jaw (25%). CONCLUSIONS-: Oral treprostinil improves exercise capacity in PAH patients not receiving other treatment. Oral treprostinil could provide a convenient, first-line prostacyclin treatment option for PAH patients not requiring more intensive therapy. CLINICAL TRIAL REGISTRATION:-: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00325403. © 2012 American Heart Association, Inc.


Flaker G.,University of Missouri | Lopes R.D.,Duke University | Al-Khatib S.M.,Duke University | Hermosillo A.G.,Instituto Nacional Of Cardiologia | And 12 more authors.
Journal of the American College of Cardiology | Year: 2014

Objectives The aim of this study was to determine the risk of major clinical and thromboembolic events after cardioversion for atrial fibrillation in subjects treated with apixaban, an oral factor Xa inhibitor, compared with warfarin. Background In patients with atrial fibrillation, thromboembolic events may occur after cardioversion. This risk is lowered with vitamin K antagonists and dabigatran. Methods Using data from the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial, we conducted a post-hoc analysis of patients undergoing cardioversion. Results A total of 743 cardioversions were performed in 540 patients: 265 first cardioversions in patients assigned to apixaban and 275 in those assigned to warfarin. The mean time to the first cardioversion for patients assigned to warfarin and apixaban was 243 ± 231 days and 251 ± 248 days, respectively; 75% of the cardioversions occurred by 1 year. Baseline characteristics were similar between groups. In patients undergoing cardioversion, no stroke or systemic emboli occurred in the 30-day follow-up period. Myocardial infarction occurred in 1 patient (0.2%) receiving warfarin and 1 patient receiving apixaban (0.3%). Major bleeding occurred in 1 patient (0.2%) receiving warfarin and 1 patient receiving apixaban (0.3%). Death occurred in 2 patients (0.5%) receiving warfarin and 2 patients receiving apixaban (0.6%). Conclusions Major cardiovascular events after cardioversion of atrial fibrillation are rare and comparable between warfarin and apixaban. (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation [ARISTOTLE]; NCT00412984) © 2014 by the American College of Cardiology Foundation.


Ralph S.J.,Griffith University | Moreno-Sanchez R.,Instituto Nacional Of Cardiologia | Neuzil J.,Griffith University | Neuzil J.,Academy of Sciences of the Czech Republic | Rodriguez-Enriquez S.,Instituto Nacional Of Cardiologia
Pharmaceutical Research | Year: 2011

Succinate:quinone reductase (SQR) of Complex II, occupying a unique central point in the mitochondrial respiratory system as a major source of electrons driving reactive oxygen species (ROS) production, is an ideal pharmaceutical target for modulating ROS levels in normal cells to prevent oxidative stressinduced damage or increase ROS in cancer cells, inducing cell death. Value of drugs like diazoxide to prevent ROS production, protecting normal cells, while vit. E analogues promote ROS in cancer cells to kill them, is highlighted. As pharmaceuticals, agents may prevent degenerative disease; their modes of action are being fully explored. Evidence that SDH/Complex II is tightly coupled to NADH/NAD + ratio in all cells, impacted by available supplies of Krebs cycle intermediates as essential NAD-linked substrates, and NAD +-dependent regulation of SDH/Complex II are reviewed, as are links to NAD +-dependent dehydrogenases, Complex I and E3 dihiydrolipoamide dehydrogenase to produce ROS. We collate and discuss diverse sources of information relating to ROS production in different biological systems, focussing on evidence for SQR as main source of ROS production in mitochondria, particularly its relevance to protection from oxidative stress and to mitochondrial-targeted anticancer drugs (mitocans) as novel cancer therapies. © Springer Science+Business Media, LLC 2011.


Moreno-Sanchez R.,Instituto Nacional Of Cardiologia | Marin-Hernandez A.,Instituto Nacional Of Cardiologia | Saavedra E.,Instituto Nacional Of Cardiologia | Pardo J.P.,National Autonomous University of Mexico | And 3 more authors.
International Journal of Biochemistry and Cell Biology | Year: 2014

Applying basic biochemical principles, this review analyzes data that contrasts with the Warburg hypothesis that glycolysis is the exclusive ATP provider in cancer cells. Although disregarded for many years, there is increasing experimental evidence demonstrating that oxidative phosphorylation (OxPhos) makes a significant contribution to ATP supply in many cancer cell types and under a variety of conditions. Substrates oxidized by normal mitochondria such as amino acids and fatty acids are also avidly consumed by cancer cells. In this regard, the proposal that cancer cells metabolize glutamine for anabolic purposes without the need for a functional respiratory chain and OxPhos is analyzed considering thermodynamic and kinetic aspects for the reductive carboxylation of 2-oxoglutarate catalyzed by isocitrate dehydrogenase. In addition, metabolic control analysis (MCA) studies applied to energy metabolism of cancer cells are reevaluated. Regardless of the experimental/environmental conditions and the rate of lactate production, the flux-control of cancer glycolysis is robust in the sense that it involves the same steps: glucose transport, hexokinase, hexosephosphate isomerase and glycogen degradation, all at the beginning of the pathway; these steps together with phosphofructokinase 1 also control glycolysis in normal cells. The respiratory chain complexes exert significantly higher flux-control on OxPhos in cancer cells than in normal cells. Thus, determination of the contribution of each pathway to ATP supply and/or the flux-control distribution of both pathways in cancer cells is necessary in order to identify differences from normal cells which may lead to the design of rational alternative therapies that selectively target cancer energy metabolism. © 2014 Elsevier Ltd. All rights reserved.


Migowski A.,Instituto Nacional Of Cardiologia | Silva G.A.,State University of Rio de Janeiro
Revista de Saude Publica | Year: 2010

OBJECTIVE: To assess survival rates and clinical (pretreatment) prognostic factors in patients with clinically localized adenocarcinoma of the prostate. METHODS: Hospital cohort including 258 patients registered in the National Cancer Institute, in the city of Rio de Janeiro, southeastern Brazil, from 1990 to 1999. Five- and ten-year survival functions were estimated using the Kaplan- Meier estimator from the histological diagnosis (initial time of follow-up) to death due to prostate cancer (events). Prognostic factors were assessed using hazard ratios (HR) with confidence intervals of 95%, following the Cox's proportional hazards model. The assumption of proportionality of risks was tested using Schoenfeld residuals and the impact of outliers in the model fitness was analyzed using martingale and score residuals. RESULTS: Of 258 patients studied, 46 died during follow-up. The overall five- year and ten-year survival rates were 88% and 71%, respectively. A Gleason score higher than 6, PSA levels higher than 40 ng/mL, B2 stage, and white skin color were independent markers of poor prognosis. CONCLUSIONS: Gleason score, digital rectal examination and PSA levels have great predictive power and must be used in pretreatment risk stratification of patients with localized prostate cancer.


Martinez-Lavin M.,Instituto Nacional Of Cardiologia
Best Practice and Research: Clinical Rheumatology | Year: 2011

Pachydermoperiostosis (PDP), also known as primary hypertrophic osteoarthropathy, is a rare disease of the skin and bones that has clear genetic predisposition and well-defined clinical features. PDP is characterised by the presence of exuberant skin hypertrophy that, at the most distal parts of the extremities, takes a drumstick configuration. This deformity is conventionally known as digital clubbing. In advanced stages, skin hypertrophy may also be present in the head with furrowing of the facial features and eyelids ptosis. Another characteristic feature of the disease is periosteal proliferation of the long bones. Abnormal vascular endothelial growth factor and/or genetically determined prostaglandins overexpression may play a key role on its pathogenesis. No therapy has been shown to be effective in reversing hypertrophic changes. When bone pain is present, non-steroidal anti-inflammatory drugs are frequently useful. Isolated case reports have described that bisphosphonates may ease recalcitrant bone pain. © 2011 Elsevier Ltd. All rights reserved.


Terrazas C.A.,National Autonomous University of Mexico | Gomez-Garcia L.,Instituto Nacional Of Cardiologia | Terrazas L.I.,National Autonomous University of Mexico
International Journal for Parasitology | Year: 2010

In cysticercosis, a parasitic disease caused by cestodes, the details of early interactions between parasite antigens and innate cells from the host are not well understood. In this study, the role of cestode-conditioned dendritic cells (DCs) in priming Th1 versus Th2 responses to bystander antigen was examined by using CD11c+ DCs as antigen-presenting cells and naive CD4+ DO11.10 lymphocytes specific to ovalbumin (OVA) as responding cells. No conventional maturation was induced in DCs exposed to Taenia crassiceps excreted/secreted antigens (TcES). The ability of TcES to affect Toll-like receptor (TLR)-mediated maturation and the pro-inflammatory response was analyzed by co-pulsing DCs with TcES and TLR ligands. DCs exposed to TcES blocked TLR4, TLR9 and Toxoplasma soluble antigen-induced phenotypic maturation. TcES-exposed DCs also blocked secretion of pro-inflammatory cytokines and alloreactive T cell proliferation, while preserving IL-10 production. DCs pulsed with TcES+OVA suppressed IFN-γ, whereas they induced greater IL-4 production by CD4+ DO11.10 cells. TcES with chemically-altered glycans failed to modulate TLR-mediated activation of DCs and their Th1-inhibitng ability, which was STAT6-independent. Our results reflect the capacity of TcES glyco-antigens to modulate Th1-type and inflammatory responses mediated through DC activation. © 2010 Australian Society for Parasitology Inc.


Philip B.,Griffith University | Ito K.,Griffith University | Moreno-Sanchez R.,Instituto Nacional Of Cardiologia | Ralph S.J.,Griffith University
Carcinogenesis | Year: 2013

Hypoxic microenvironments frequently exist in many solid tumours with oxygen levels fluctuating temporally and spatially from normoxia to hypoxia. The response to hypoxia in human cells is mainly regulated by hypoxia-inducible factors (HIFs), a family of transcription factors which orchestrate signalling events leading to angiogenesis and tumorigenesis. Several events conspire together to lead to the stabilization of HIF-a, commonly expressed in many cancer cell types. These events can result from low oxygen tensions occurring within the expanding tumour mass to produce hypoxic microenvironments or from mutations whereby the HIFs cause changes in expression of genes involved in several cellular functions. Hypoxia-mediated HIF-a regulation has gained significant prominence in tumour biology over recent years, and the hypoxic microenvironments have been shown to facilitate and trigger major molecular and immunological processes necessary to drive the progression of tumours to malignancy. More recently, it has been realized that the hypoxic microenvironments also play significant roles in shielding tumour cells from immune attack by promoting immune suppression. In addition, the hypoxic microenvironment promotes many other oncogenic events, such as the metabolic reconfiguration of tumour cells, neovascularization, epithelial to mesenchymal transition (EMT), and cancer stem cell renewal and accumulation. This article reviews the molecular mechanisms underlying tumour hypoxia and their pro-tumour contributions, such as immune suppression, development of nascent and more permeable tumour vasculature, selective cancer stem cell renewal, accumulation, mobilization and promotion of EMT leading to tumour cell metastasis. ©The Author 2013. Published by Oxford University Press. All rights reserved.


Garcia-Contreras R.,Instituto Nacional Of Cardiologia | Maeda T.,Kyushu Institute of Technology | Wood T.K.,Pennsylvania State University
Applied and Environmental Microbiology | Year: 2013

Bacteria have the remarkable ability to communicate as a group in what has become known as quorum sensing (QS), and this trait has been associated with important bacterial phenotypes, such as virulence and biofilm formation. Bacteria also have an incredible ability to evolve resistance to all known antimicrobials. Hence, although inhibition of QS has been hailed as a means to reduce virulence in a manner that is impervious to bacterial resistance mechanisms, this approach is unlikely to be a panacea. Here we review the evidence that bacteria can evolve resistance to quorum-quenching compounds. © 2013, American Society for Microbiology.

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