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1.
Circulation ; 127(4): 517-26, 2013 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-23261867

RESUMO

BACKGROUND: Pharmacogenetics in warfarin clinical trials have failed to show a significant benefit in comparison with standard clinical therapy. This study demonstrates a computational framework to systematically evaluate preclinical trial design of target population, pharmacogenetic algorithms, and dosing protocols to optimize primary outcomes. METHODS AND RESULTS: We programmatically created an end-to-end framework that systematically evaluates warfarin clinical trial designs. The framework includes options to create a patient population, multiple dosing strategies including genetic-based and nongenetic clinical-based, multiple-dose adjustment protocols, pharmacokinetic/pharmacodynamics modeling and international normalization ratio prediction, and various types of outcome measures. We validated the framework by conducting 1000 simulations of the applying pharmacogenetic algorithms to individualize dosing of warfarin (CoumaGen) clinical trial primary end points. The simulation predicted a mean time in therapeutic range of 70.6% and 72.2% (P=0.47) in the standard and pharmacogenetic arms, respectively. Then, we evaluated another dosing protocol under the same original conditions and found a significant difference in the time in therapeutic range between the pharmacogenetic and standard arm (78.8% versus 73.8%; P=0.0065), respectively. CONCLUSIONS: We demonstrate that this simulation framework is useful in the preclinical assessment phase to study and evaluate design options and provide evidence to optimize the clinical trial for patient efficacy and reduced risk.


Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Farmacogenética/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Teoria de Sistemas , Trombose/tratamento farmacológico , Varfarina/uso terapêutico , Animais , Anticoagulantes/uso terapêutico , Simulação por Computador , Humanos , Modelos Teóricos , Trombose/genética
2.
Am Heart J ; 162(3): 518-26.e5, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21884870

RESUMO

BACKGROUND: Pharmacodynamic studies reported an amplified on-clopidogrel platelet inhibition in smokers potentially caused by an increased metabolic drug activation via induction of cytochrome P450 1A2. The aims of this analysis were to evaluate the impact of smoking on the antiplatelet effect of clopidogrel and prasugrel and to test the potential interaction of smoking with the treatment effect of these drugs. METHODS: A variety of platelet function results was analyzed from 2 large cohorts of patients undergoing coronary intervention after loading with clopidogrel 600 mg (n = 2,533 and n = 1,996), a cohort of patients undergoing dose adaptation from 75 to 150 mg according to response to clopidogrel (n = 117) and a crossover trial comparing clopidogrel 150 mg with prasugrel 10 mg (n = 87). Linear regression analyses were used to test the impact of smoking on platelet function and to identify independent predictors of on-treatment platelet reactivity. The potential interaction of smoking with the clinical effect of clopidogrel versus prasugrel was analyzed in the TRITON-TIMI 38 cohort (n = 13,608). RESULTS: No significant association of smoking with platelet reactivity on clopidogrel was seen in unadjusted and adjusted analyses. The variables most consistently associated with on-clopidogrel platelet function were age, sex, diabetes, and body mass index. There was no significant interaction of smoking status at presentation with the clinical efficacy of prasugrel versus clopidogrel (P for interaction = .39). CONCLUSIONS: Smoking does not impact on platelet reactivity in patients after loading or on different maintenance doses of clopidogrel. The clinical treatment effect of clopidogrel versus prasugrel is not affected by smoking status at presentation.


Assuntos
Doença da Artéria Coronariana/tratamento farmacológico , Piperazinas/administração & dosagem , Fumar/efeitos adversos , Tiofenos/administração & dosagem , Ticlopidina/análogos & derivados , Idoso , Plaquetas/fisiologia , Clopidogrel , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/etiologia , Estudos Cross-Over , Citocromo P-450 CYP1A2/sangue , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Piperazinas/farmacocinética , Agregação Plaquetária/fisiologia , Inibidores da Agregação de Plaquetas/administração & dosagem , Inibidores da Agregação de Plaquetas/farmacocinética , Cloridrato de Prasugrel , Antagonistas do Receptor Purinérgico P2Y/administração & dosagem , Antagonistas do Receptor Purinérgico P2Y/farmacocinética , Fatores de Risco , Fumar/sangue , Tiofenos/farmacocinética , Ticlopidina/administração & dosagem , Ticlopidina/farmacocinética , Fatores de Tempo , Resultado do Tratamento
3.
Circulation ; 123(23): 2681-9, 2011 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-21606391

RESUMO

BACKGROUND: The balance between benefit (ischemia protection) and risk (bleeding) is a key consideration in choosing the intensity of antiplatelet therapy for patients with acute coronary syndromes. The goals of this analysis were to identify baseline characteristics that independently predict bleeding and to determine how bleeding events impact the subsequent mortality in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel--Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI 38). METHODS AND RESULTS: Multivariable Cox regression analyses adjusted for treatment, baseline, and procedural variables were used to determine the predictors for serious (TIMI major or minor) bleeding. To analyze the hazard ratio and time dependency of bleeding on mortality, we used iterative day-to-day landmark analyses after the bleed. From the 13 420 patients with acute coronary syndromes included in this analysis, 534 (4.0%) experienced a serious bleeding event. Variables with the highest strength of association with risk of serious bleeding were female sex, use of a glycoprotein IIb/IIIa inhibitor, duration of intervention, age, assignment to prasugrel, regional characteristics, admission diagnosis of ST-elevation myocardial infarction, femoral access for angiography, creatinine clearance, hypercholesterolemia, and arterial hypertension. Serious bleeding was associated with a significantly increased adjusted hazard ratio of 5.84 (95% confidence interval 4.11 to 8.29) for mortality. However, the hazard ratio did not differ statistically from baseline risk by 40 days after the bleeding event. CONCLUSIONS: The major predictors of serious bleeding were a combination of patient and procedural characteristics and antiplatelet therapies. Although serious bleeding was strongly associated with mortality within the first month of the bleeding event, this association was not significant beyond 40 days. CLINICAL TRIAL REGISTRATION INFORMATION: http://www.clinicaltrial.gov. Unique identifier NCT00097591.


Assuntos
Hemorragia/induzido quimicamente , Hemorragia/mortalidade , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/mortalidade , Piperazinas/efeitos adversos , Inibidores da Agregação de Plaquetas/efeitos adversos , Tiofenos/efeitos adversos , Idoso , Aspirina/administração & dosagem , Aspirina/efeitos adversos , Clopidogrel , Quimioterapia Combinada , Feminino , Hemorragia/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Piperazinas/administração & dosagem , Inibidores da Agregação de Plaquetas/administração & dosagem , Cloridrato de Prasugrel , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , Antagonistas do Receptor Purinérgico P2Y/administração & dosagem , Antagonistas do Receptor Purinérgico P2Y/efeitos adversos , Fatores de Risco , Tiofenos/administração & dosagem , Terapia Trombolítica/efeitos adversos , Terapia Trombolítica/métodos , Ticlopidina/administração & dosagem , Ticlopidina/efeitos adversos , Ticlopidina/análogos & derivados
4.
Circulation ; 123(17): 1854-63, 2011 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-21502571

RESUMO

BACKGROUND: Thrombin is a key mediator of platelet activation. Atopaxar is a reversible protease-activated receptor-1 antagonist that interferes with thrombin-mediated platelet effects. The phase II Lessons From Antagonizing the Cellular Effect of Thrombin-Coronary Artery Disease (LANCELOT-CAD) trial examined the safety and tolerability of prolonged therapy with atopaxar in subjects with CAD. METHODS AND RESULTS: Subjects with a qualifying history were randomized in a double-blind fashion to 3 dosing regimens of atopaxar (50, 100, or 200 mg daily) or matching placebo for 24 weeks and followed up for an additional 4 weeks. The key safety end points were bleeding according to the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) and Thrombolysis in Myocardial Infarction (TIMI) classifications. Secondary objectives included platelet aggregation and major adverse cardiac events. Seven hundred and twenty subjects were randomized. Overall bleeding rates tended to be higher with atopaxar compared with placebo by CURE criteria (placebo, 0.6%; atopaxar, 3.9%; relative risk, 6.82, P=0.03; 50 mg, 3.9%; 100 mg, 1.7%; 200 mg, 5.9%; P for trend=0.01) and TIMI criteria (placebo, 6.8%; atopaxar, 10.3%; relative risk, 1.52, P=0.17; 50 mg, 9.9%; 100 mg, 8.1%; 200 mg, 12.9%; P for trend=0.07). There was no difference in major bleeding. Major adverse cardiac events were numerically lower in the atopaxar subjects. All atopaxar regimens achieved high levels of platelet inhibition. A transient elevation in liver transaminases and dose-dependent QTc prolongation without apparent complications were observed in higher-dose atopaxar treatment groups. CONCLUSIONS: In this dose-ranging study of patients with CAD, treatment with atopaxar resulted in platelet inhibition, more minor bleeding, and numerically but not statistically fewer ischemic events. Larger-scale trials are needed to determine whether these patterns translate into clinically meaningful effects. CLINICAL TRIAL REGISTRATION: URL: http://www.ClinicalTrials.gov. Unique identifier: NCT00312052.


Assuntos
Doença da Artéria Coronariana/tratamento farmacológico , Iminas/administração & dosagem , Ativação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/administração & dosagem , Piridinas/administração & dosagem , Receptores de Trombina/antagonistas & inibidores , Idoso , Biomarcadores , Plaquetas/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Hemorragia/induzido quimicamente , Humanos , Iminas/efeitos adversos , Masculino , Pessoa de Meia-Idade , Inibidores da Agregação de Plaquetas/efeitos adversos , Piridinas/efeitos adversos
5.
Circulation ; 123(17): 1843-53, 2011 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-21502577

RESUMO

BACKGROUND: Atopaxar (E5555) is a reversible protease-activated receptor-1 thrombin receptor antagonist that interferes with platelet signaling. The primary objective of the Lessons From Antagonizing the Cellular Effects of Thrombin-Acute Coronary Syndromes (LANCELOT­ACS) trial was to evaluate the safety and tolerability of atopaxar in patients with ACS. METHODS AND RESULTS: Six hundred and three subjects were randomized within 72 hours of non-ST-elevation ACS to 1 of 3 doses of atopaxar (400-mg loading dose followed by 50, 100, or 200 mg daily) or matching placebo. The incidence of Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) major or minor bleeding did not differ significantly between the combined atopaxar and placebo groups (3.08% versus 2.17%, respectively; P=0.63), and there was no dose-related trend (P=0.80). The incidence of CURE major bleeding was numerically higher in the atopaxar group compared with the placebo group (1.8% versus 0%; P=0.12). The incidence of cardiovascular death, myocardial infarction, stroke, or recurrent ischemia was similar between the atopaxar and placebo arms (8.03% versus 7.75%; P=0.93). The incidence of CV death, MI, or stroke was 5.63% in the placebo group and 3.25% in the combined atopaxar group (P=0.20). Dose-dependent trends for efficacy were not seen. Atopaxar significantly reduced ischemia on continuous ECG monitoring (Holter) at 48 hours compared with placebo (relative risk, 0.67; P=0.02). Transient dose-dependent transaminase elevation and relative QTc prolongation were observed with the highest doses of atopaxar. CONCLUSION: In patients after ACS, atopaxar significantly reduced early ischemia on Holter monitoring without a significant increase in major or minor bleeding. Larger trials are required to fully establish the efficacy and safety of atopaxar. CLINICAL TRIAL REGISTRATION: URL: http://www.ClinicalTrials.gov. Unique identifier: NCT00548587.


Assuntos
Síndrome Coronariana Aguda/tratamento farmacológico , Iminas/administração & dosagem , Inibidores da Agregação de Plaquetas/administração & dosagem , Piridinas/administração & dosagem , Receptores de Trombina/antagonistas & inibidores , Síndrome Coronariana Aguda/mortalidade , Idoso , Morte Súbita Cardíaca/epidemiologia , Feminino , Hemorragia/epidemiologia , Humanos , Iminas/efeitos adversos , Incidência , Hepatopatias/epidemiologia , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia , Inibidores da Agregação de Plaquetas/efeitos adversos , Piridinas/efeitos adversos , Fatores de Risco , Prevenção Secundária , Acidente Vascular Cerebral/epidemiologia
6.
J Rheumatol ; 38(6): 1071-8, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21459935

RESUMO

OBJECTIVE: Patients with arthritis frequently are at increased risk for future cardiovascular (CV) events. We investigated the performance of the cardiac biomarkers N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high sensitivity C-reactive protein (hsCRP) for predicting CV events in patients with arthritis taking chronic nonsteroidal antiinflammatory drugs (NSAID). METHODS: We evaluated 2-year CV outcomes in a prospective, nested biomarker study among patients (N = 6273) with rheumatoid arthritis and osteoarthritis treated with NSAID in the MEDAL (Multinational Etoricoxib and Diclofenac Arthritis Long-term) trial. Patients were stratified by quartiles of baseline NT-proBNP and established cutpoints of NT-proBNP and hsCRP. RESULTS: NT-proBNP demonstrated a strong graded relationship with CV outcomes, including CV death (p for trend < 0.0001), myocardial infarction (MI) (p for trend = 0.02), heart failure (HF) (p for trend < 0.0001), and a composite of thrombotic events (CV death, MI, stroke) or HF (p for trend < 0.0001). Baseline levels of hsCRP were not associated with CV events (CV death/MI/stroke/HF; p for trend = 0.65). NT-proBNP remained strongly predictive of CV events after adjustment for age, sex, diabetes, hypertension, hyperlipidemia, smoking, type of arthritis, body mass index, creatinine clearance, history of CV disease, and hsCRP (CV death/MI/stroke/HF: Q4 vs Q1 hazard ratio 3.53, 95% CI 1.89-6.58). Patients with a NT-proBNP level below 100 pg/ml had a 0.94% rate of thrombotic events or heart failure at 2 years. CONCLUSION: NT-proBNP is a simple and robust noninvasive indicator of CV risk in patients with arthritis. Risk stratification based on NT-proBNP may facilitate identification of patients with arthritis who are at low CV risk during chronic NSAID treatment.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Proteína C-Reativa/metabolismo , Doenças Cardiovasculares/epidemiologia , Peptídeo Natriurético Encefálico/sangue , Osteoartrite/tratamento farmacológico , Fragmentos de Peptídeos/sangue , Idoso , Artrite Reumatoide/sangue , Biomarcadores/sangue , Diclofenaco/uso terapêutico , Etoricoxib , Feminino , Insuficiência Cardíaca/epidemiologia , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia , Osteoartrite/sangue , Estudos Prospectivos , Piridinas/uso terapêutico , Estudos Retrospectivos , Fatores de Risco , Sulfonas/uso terapêutico , Trombose , Resultado do Tratamento
7.
Ups J Med Sci ; 115(4): 221-31, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20977314

RESUMO

INTRODUCTION: Traumatic brain injury makes the brain vulnerable to secondary insults. Post-traumatic alterations in intracranial dynamics, such as reduced intracranial compliance (IC), are thought to further potentiate the effects of secondary insults. Reduced IC combined with intracranial volume insults leads to metabolic disturbances in a rat model. The aim of the present study was to discern whether a post-traumatic hypotensive insult in combination with reduced IC caused more pronounced secondary metabolic disturbances in the injured rat brain. MATERIALS AND METHODS: Rats were randomly assigned to four groups (n = 8/group): 1) trauma with hypotension; 2) trauma and reduced IC with hypotension; 3) sham injury with hypotension; and 4) sham injury and reduced IC with hypotension. A weight drop model of cortical contusion trauma was used. IC was reduced by gluing rubber film layers on the inside of bilateral bone flaps before replacement. Microdialysis probes were placed in the perimeter of the trauma zone. Hypotension was induced 2 h after trauma. Extracellular (EC) levels of lactate, pyruvate, hypoxanthine, and glycerol were analyzed. RESULTS: The trauma resulted in a significant increase in EC dialysate levels of lactate, lactate/pyruvate ratio, hypoxanthine, and glycerol. A slight secondary increase in lactate was noted for all groups but group 2 during hypotension, otherwise no late effects were seen. There were no effects of reduced IC. DISCUSSION: In conclusion, reduced IC did not increase the metabolic disturbances caused by the post-traumatic hypotensive insult. The results suggest that a mild to moderate hypotensive insult after initial post-traumatic resuscitation may be tolerated better than an early insult before resuscitation.


Assuntos
Lesões Encefálicas/complicações , Hipotensão/fisiopatologia , Animais , Encéfalo/patologia , Edema Encefálico , Lesões Encefálicas/fisiopatologia , Modelos Animais de Doenças , Glicerol/química , Hipoxantina/química , Ácido Láctico/química , Masculino , Ácido Pirúvico/química , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Fatores de Tempo
8.
N Engl J Med ; 363(20): 1909-17, 2010 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-20925534

RESUMO

BACKGROUND: Gastrointestinal complications are an important problem of antithrombotic therapy. Proton-pump inhibitors (PPIs) are believed to decrease the risk of such complications, though no randomized trial has proved this in patients receiving dual antiplatelet therapy. Recently, concerns have been raised about the potential for PPIs to blunt the efficacy of clopidogrel. METHODS: We randomly assigned patients with an indication for dual antiplatelet therapy to receive clopidogrel in combination with either omeprazole or placebo, in addition to aspirin. The primary gastrointestinal end point was a composite of overt or occult bleeding, symptomatic gastroduodenal ulcers or erosions, obstruction, or perforation. The primary cardiovascular end point was a composite of death from cardiovascular causes, nonfatal myocardial infarction, revascularization, or stroke. The trial was terminated prematurely when the sponsor lost financing. RESULTS: We planned to enroll about 5000 patients; a total of 3873 were randomly assigned and 3761 were included in analyses. In all, 51 patients had a gastrointestinal event; the event rate was 1.1% with omeprazole and 2.9% with placebo at 180 days (hazard ratio with omeprazole, 0.34, 95% confidence interval [CI], 0.18 to 0.63; P<0.001). The rate of overt upper gastrointestinal bleeding was also reduced with omeprazole as compared with placebo (hazard ratio, 0.13; 95% CI, 0.03 to 0.56; P = 0.001). A total of 109 patients had a cardiovascular event, with event rates of 4.9% with omeprazole and 5.7% with placebo (hazard ratio with omeprazole, 0.99; 95% CI, 0.68 to 1.44; P = 0.96); high-risk subgroups did not show significant heterogeneity. The two groups did not differ significantly in the rate of serious adverse events, though the risk of diarrhea was increased with omeprazole. CONCLUSIONS: Among patients receiving aspirin and clopidogrel, prophylactic use of a PPI reduced the rate of upper gastrointestinal bleeding. There was no apparent cardiovascular interaction between clopidogrel and omeprazole, but our results do not rule out a clinically meaningful difference in cardiovascular events due to use of a PPI. (Funded by Cogentus Pharmaceuticals; ClinicalTrials.gov number, NCT00557921.).


Assuntos
Doença da Artéria Coronariana/tratamento farmacológico , Hemorragia Gastrointestinal/prevenção & controle , Omeprazol/uso terapêutico , Inibidores da Agregação de Plaquetas/uso terapêutico , Inibidores da Bomba de Prótons/uso terapêutico , Ticlopidina/análogos & derivados , Idoso , Aspirina/efeitos adversos , Aspirina/uso terapêutico , Doenças Cardiovasculares/epidemiologia , Clopidogrel , Interações Medicamentosas , Quimioterapia Combinada , Feminino , Hemorragia Gastrointestinal/induzido quimicamente , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Omeprazol/efeitos adversos , Inibidores da Agregação de Plaquetas/efeitos adversos , Inibidores da Bomba de Prótons/efeitos adversos , Ticlopidina/efeitos adversos , Ticlopidina/uso terapêutico
9.
JAMA ; 304(12): 1350-7, 2010 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-20805624

RESUMO

CONTEXT: Clinicians and trialists have difficulty with identifying which patients are highest risk for cardiovascular events. Prior ischemic events, polyvascular disease, and diabetes mellitus have all been identified as predictors of ischemic events, but their comparative contributions to future risk remain unclear. OBJECTIVE: To categorize the risk of cardiovascular events in stable outpatients with various initial manifestations of atherothrombosis using simple clinical descriptors. DESIGN, SETTING, AND PATIENTS: Outpatients with coronary artery disease, cerebrovascular disease, or peripheral arterial disease or with multiple risk factors for atherothrombosis were enrolled in the global Reduction of Atherothrombosis for Continued Health (REACH) Registry and were followed up for as long as 4 years. Patients from 3647 centers in 29 countries were enrolled between 2003 and 2004 and followed up until 2008. Final database lock was in April 2009. MAIN OUTCOME MEASURES: Rates of cardiovascular death, myocardial infarction, and stroke. RESULTS: A total of 45,227 patients with baseline data were included in this 4-year analysis. During the follow-up period, a total of 5481 patients experienced at least 1 event, including 2315 with cardiovascular death, 1228 with myocardial infarction, 1898 with stroke, and 40 with both a myocardial infarction and stroke on the same day. Among patients with atherothrombosis, those with a prior history of ischemic events at baseline (n = 21,890) had the highest rate of subsequent ischemic events (18.3%; 95% confidence interval [CI], 17.4%-19.1%); patients with stable coronary, cerebrovascular, or peripheral artery disease (n = 15,264) had a lower risk (12.2%; 95% CI, 11.4%-12.9%); and patients without established atherothrombosis but with risk factors only (n = 8073) had the lowest risk (9.1%; 95% CI, 8.3%-9.9%) (P < .001 for all comparisons). In addition, in multivariable modeling, the presence of diabetes (hazard ratio [HR], 1.44; 95% CI, 1.36-1.53; P < .001), an ischemic event in the previous year (HR, 1.71; 95% CI, 1.57-1.85; P < .001), and polyvascular disease (HR, 1.99; 95% CI, 1.78-2.24; P < .001) each were associated with a significantly higher risk of the primary end point. CONCLUSION: Clinical descriptors can assist clinicians in identifying high-risk patients within the broad range of risk for outpatients with atherothrombosis.


Assuntos
Aterosclerose/epidemiologia , Infarto do Miocárdio/epidemiologia , Acidente Vascular Cerebral/epidemiologia , Trombose/epidemiologia , Idoso , Aterosclerose/complicações , Doenças Cardiovasculares/mortalidade , Diabetes Mellitus/epidemiologia , Feminino , Previsões , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/etiologia , Pacientes Ambulatoriais , Doenças Vasculares Periféricas/epidemiologia , Prognóstico , Sistema de Registros/estatística & dados numéricos , Medição de Risco , Fatores de Risco , Acidente Vascular Cerebral/etiologia , Trombose/complicações
10.
Lancet ; 374(9692): 787-95, 2009 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-19717184

RESUMO

BACKGROUND: Otamixaban is an intravenous direct factor Xa inhibitor. We aimed to assess its efficacy and safety in non-ST-elevation acute coronary syndromes and to identify the optimum dose range for further assessment in a phase 3 study. METHODS: In this double-blind, phase 2 trial undertaken in 196 sites in 36 countries, 3241 patients with non-ST-elevation acute coronary syndromes were randomly assigned via a central, telephone-based interactive voice response system to one of five doses of otamixaban (0.08 mg/kg bolus followed by infusions of 0.035 [n=125], 0.070 [676], 0.105 [662], 0.140 [658], or 0.175 [671] mg/kg/h) or to a control of unfractionated heparin (60 IU/kg intravenous bolus followed by an infusion of 12 IU/kg/h) plus eptifibatide (180 microg/kg intravenous bolus followed by an infusion of 1.0-2.0 microg/kg/min [n=449]). Both investigators and patients were unaware of treatment allocation. Enrolment into the lowest dose group was stopped early at the recommendation of the Data Monitoring Committee. The primary efficacy endpoint was a composite of death, myocardial infarction, urgent revascularisation, or bailout glycoprotein IIb/IIIa inhibitor use up to 7 days. The primary safety endpoint was TIMI major or minor bleeding not related to coronary-artery bypass grafting. Efficacy analyses were by intention to treat; safety analyses were in treated patients. This study is registered with ClinicalTrials.gov, number NCT00317395. FINDINGS: Rates of the primary efficacy endpoint in the five otamixaban doses were 7.2% (nine of 125) with 0.035 mg/kg/h, 4.6% (31/676) with 0.070 mg/kg/h, 3.8% (25/662) with 0.105 mg/kg/h, 3.6% (24/658) with 0.140 mg/kg/h, and 4.3% (29/671) with 0.175 mg/kg/h (p=0.34 for trend). In the control group, the rate was 6.2% (28/449), yielding relative risks for the five otamixaban doses of 1.16 (95% CI 0.56-2.38), 0.74 (0.45-1.21), 0.61 (0.36-1.02), 0.58 (0.34-1.00), and 0.69 (0.42-1.15), respectively. Rates of the primary safety endpoint in the five otamixaban doses were 1.6% (two of 122), 1.6% (11/669), 3.1% (20/651), 3.4% (22/651), and 5.4% (36/664), respectively (p=0.0001 for trend); the rate in the control group was 2.7% (12/448). INTERPRETATION: In patients with non-ST-elevation acute coronary syndromes, otamixaban infusions of 0.100-0.140 mg/kg/h might reduce ischaemic events and have a safety profile similar to unfractionated heparin plus eptifibatide. Further testing in a phase 3 trial is warranted. FUNDING: Sanofi-Aventis.


Assuntos
Síndrome Coronariana Aguda/tratamento farmacológico , Óxidos N-Cíclicos/uso terapêutico , Piridinas/uso terapêutico , Síndrome Coronariana Aguda/complicações , Síndrome Coronariana Aguda/diagnóstico , Síndrome Coronariana Aguda/mortalidade , Idoso , Angioplastia Coronária com Balão , Anticoagulantes/uso terapêutico , Angiografia Coronária , Óxidos N-Cíclicos/farmacologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Quimioterapia Combinada , Eptifibatida , Feminino , Seguimentos , Hemorragia/induzido quimicamente , Heparina/uso terapêutico , Humanos , Infusões Intravenosas , Injeções Intravenosas , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Peptídeos/uso terapêutico , Inibidores da Agregação de Plaquetas/uso terapêutico , Piridinas/farmacologia , Segurança , Resultado do Tratamento
11.
Am J Cardiol ; 102(4): 434-9, 2008 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-18678301

RESUMO

The weak peroxisome proliferator activated receptor-alpha (PPAR-alpha) agonists gemfibrozil and fenofibrate achieve only small increases in high-density lipoprotein (HDL) cholesterol. CP-778,875 is a more potent PPAR-alpha agonist developed to produce greater HDL cholesterol increases. This randomized, multicenter, double-blinded, placebo-controlled study evaluated the efficacy and safety of CP-778,875 in subjects with mixed dyslipidemia and type 2 diabetes. Eight-six subjects with low HDL cholesterol (< or =45 mg/dl for men and < or =55 mg/dl for women) and increased triglycerides (150 to 500 mg/dl) who had coexisting type 2 diabetes were randomized. Subjects received CP-778,875 doses of 0.5, 2, or 6 mg/day or placebo for 6 weeks. Any other lipid-altering therapy was stopped at screening. The primary end point was percent change in HDL cholesterol from baseline. The 2-mg/day dose of CP-778,875 significantly increased HDL cholesterol by 14%. The 2-mg dose also increased concentrations of apolipoprotein (apo) A-I, HDL(2) cholesterol, and HDL(3) cholesterol by 13%, 12%, and 19%, respectively. An unusual dose-response pattern was observed in that at 6 mg/day CP-778,875 only increased HDL cholesterol by 3% and decreased HDL(2) cholesterol by 24%. Fasting triglyceride levels were significantly decreased to a similar extent (26%) by all 3 doses of CP-778,875. CP-778,875 significantly increased homocysteine levels. There was no significant relation between change in homocysteine and change in apoA-I or HDL cholesterol. No subjects developed myopathy. In conclusion, CP-778,875 2 mg/day significantly increased HDL cholesterol, significantly lowered fasting triglycerides, and increased apoA-I and HDL subfractions. The clinical relevance of the increase in homocysteine levels is unknown.


Assuntos
Diabetes Mellitus Tipo 2/complicações , Dislipidemias/tratamento farmacológico , Fenofibrato/uso terapêutico , Genfibrozila/uso terapêutico , Hipolipemiantes/uso terapêutico , PPAR alfa/agonistas , Adulto , Idoso , Apolipoproteína A-I/efeitos dos fármacos , Apolipoproteína B-100/efeitos dos fármacos , Proteína C-Reativa/efeitos dos fármacos , HDL-Colesterol/efeitos dos fármacos , Diabetes Mellitus Tipo 2/fisiopatologia , Método Duplo-Cego , Dislipidemias/fisiopatologia , Feminino , Fenofibrato/efeitos adversos , Genfibrozila/efeitos adversos , Homocisteína/efeitos dos fármacos , Humanos , Hipolipemiantes/efeitos adversos , Masculino , Pessoa de Meia-Idade
12.
J Clin Monit Comput ; 20(1): 25-31, 2006 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-16532279

RESUMO

OBJECTIVE: The aims of this study were to get an impression of the relationships between intracranial compliance (IC) and Lactate/Pyruvate (L/P) ratio and temperature and L/P ratio, and to determine if patients with low IC had an increased vulnerability for the secondary insult hyperthermia (as reflected in the L/P ratio). The effects of coma treatment on the results were also studied. METHODS: Ten TBI patients were monitored for IC, in vivo microdialysis (MD) and bladder temperature. Mean Glasgow Coma Scale (GCS) score was 7 (range 4-10). Three patients underwent induced coma treatment. Three statistical models were used to look at the relationships between IC, temperature and L/P ratio in patients with and without coma. RESULTS: We found that with high temperature L/P ratios increased as IC decreased (P < 0.0001). The patients with coma treatment had significantly higher average L/P ratios (P < 0.02). The effect of IC on the L/P ratio differed by coma treatment (P < 0.02). The temperature effect was not dependent on coma treatment (P < 0.49). CONCLUSIONS: These findings suggest the importance of avoiding hyperthermia in TBI patients, especially in patients with low or decreased IC (monitored or anticipated). The present technical solution seems promising for analysis of complex clinical data.


Assuntos
Lesões Encefálicas/fisiopatologia , Microdiálise/métodos , Modelos Estatísticos , Monitorização Fisiológica/métodos , Adulto , Lesões Encefálicas/complicações , Lesões Encefálicas/metabolismo , Coma/fisiopatologia , Complacência (Medida de Distensibilidade) , Feminino , Febre/etiologia , Febre/fisiopatologia , Escala de Coma de Glasgow , Humanos , Ácido Láctico/metabolismo , Masculino , Pessoa de Meia-Idade , Ácido Pirúvico/metabolismo , Fatores de Risco , Índice de Gravidade de Doença
13.
J Neuropsychiatry Clin Neurosci ; 17(3): 350-6, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-16179657

RESUMO

This study evaluated the prevalence and specificity of diagnostic criteria for postconcussional syndrome (PCS) in 178 adults with mild to moderate traumatic brain injury (TBI) and 104 with extracranial trauma. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) and International Classification of Diseases (ICD-10) criteria for PCS were evaluated 3 months after injury. The results showed that prevalence of PCS was higher using ICD-10 (64%) than DSM-IV criteria (11%). Specificity to TBI was limited because PCS criteria were often fulfilled by patients with extracranial trauma. The authors conclude that further refinement of the DSM-IV and ICD-10 criteria for PCS is needed before these criteria are routinely employed.


Assuntos
Lesões Encefálicas/complicações , Síndrome Pós-Concussão/diagnóstico , Síndrome Pós-Concussão/etiologia , Adulto , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Exame Neurológico , Testes Neuropsicológicos/estatística & dados numéricos , Síndrome Pós-Concussão/epidemiologia , Prevalência , Estudos Prospectivos , Escalas de Graduação Psiquiátrica , Estudos Retrospectivos
14.
J Neuropsychiatry Clin Neurosci ; 16(4): 493-9, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-15616177

RESUMO

The objectives of this study were to compare diagnoses of postconcussional syndrome between the International Classification of Diseases, 10th revision (ICD-10) and Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV). The patient sample was comprised of 178 adults with mild-moderate traumatic brain injury (TBI). The study design was inception cohort, and the main outcome measure was a structured interview 3 months after injury. The results were that, despite concordance of DSM-IV and ICD-10 symptom criteria (kappa=0.73), agreement between overall DSM-IV and ICD-10 diagnoses was slight (kappa=0.13) because fewer patients met the DSM-IV cognitive deficit and clinical significance criteria. Agreement between DSM-IV postconcussional disorder and ICD-10 postconcussional syndrome appears limited by different prevalences and thresholds.


Assuntos
Síndrome Pós-Concussão/diagnóstico , Adulto , Concussão Encefálica/patologia , Transtornos Cognitivos/epidemiologia , Transtornos Cognitivos/psicologia , Feminino , Humanos , Masculino , Testes Neuropsicológicos , Estudos Prospectivos , Escalas de Graduação Psiquiátrica , Reprodutibilidade dos Testes , Terminologia como Assunto
15.
Clin Neuropsychol ; 18(2): 249-65, 2004 May.
Artigo em Inglês | MEDLINE | ID: mdl-15587672

RESUMO

While there has been strong evidence for the ability of neuropsychological performance at resolution of posttraumatic amnesia to predict later productivity, there has been less conclusive evidence for the relationship of neuropsychological test scores to concurrent productivity status. The purpose of the current study was to evaluate the relationship of neuropsychological test performance at 1 year post-injury to productivity assessed at the same time point. Participants were 518 persons with medically documented TBI who were enrolled in the TBI Model Systems Research and Demonstration Project. Stepwise logistic regression was utilized to determine the contributions of neuropsychological test scores to productivity after accounting for demographic characteristics, injury severity, and pre-injury productivity. Missing neuropsychological test scores were accounted for in the model. Variables that remained in the model and accounted for a significant proportion of the variance included age, duration of impaired consciousness, pre-injury productivity, and scores on measures of GOAT, Logical Memory II, and Trail Making Test, part B. The results indicate that neuropsychological test performance provides important information regarding the ability of persons with injury to return to productive activities. The results also indicate that inability to complete neuropsychological tests at 1 year post-injury is associated with non-productive activity.


Assuntos
Lesões Encefálicas/fisiopatologia , Transtornos Cognitivos/etiologia , Processos Mentais/fisiologia , Testes Neuropsicológicos , Adolescente , Adulto , Demografia , Feminino , Seguimentos , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Desempenho Psicomotor/fisiologia , Recuperação de Função Fisiológica , Reprodutibilidade dos Testes , Estudos Retrospectivos , Índices de Gravidade do Trauma
16.
J Neurotrauma ; 21(7): 894-906, 2004 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15307902

RESUMO

The purpose of this study was to examine the patterns of change in microdialysate concentrations of glucose, lactate, pyruvate, and glutamate in the brain during periods of hypoxia/ischemia identified by monitoring brain tissue pO2 (PbtO2). Of particular interest was a better understanding of what additional information could be obtained by the microdialysis parameters that was not available from the PbtO2. Fifty-seven patients admitted with severe traumatic brain injury who had placement of both a brain tissue pO2 (PbtO2) and microdialysis probe were studied. The microdialysis probe was perfused with Ringer's solution at 0.3 microL/min and dialysate was collected at 1-h intervals. The concentration of glucose, pyruvate, lactate, and glutamate were measured in each dialysate sample. Changes in the microdialysis parameters were examined during episodes where the PbtO2 decreased to below 10 mm Hg. Ten episodes of tissue hypoxia/ischemia identified by a decrease in PbtO2 below 10 mm Hg were observed during the period of monitoring. The concentration of the dialysate glucose closely followed the PbtO2. The dialysate pyruvate concentration was more variable and in some patients transiently increased as the PbtO2 dropped below 10 mm Hg. The dialysate concentration of lactate was significantly increased as the PbtO2 decreased to less than 10 mm Hg. Dialysate glutamate was significantly elevated only when PbtO2 decreased to very low levels. Although changes in the PbtO2 provided the earliest sign of hypoxia/ischemia, the microdialysis assays provided additional information about the consequences that the reduced tissue pO2 has on brain metabolism, which may be helpful in managing these critically ill patients.


Assuntos
Lesões Encefálicas/metabolismo , Lesões Encefálicas/fisiopatologia , Isquemia Encefálica/metabolismo , Isquemia Encefálica/fisiopatologia , Adulto , Lesões Encefálicas/complicações , Isquemia Encefálica/etiologia , Feminino , Escala de Coma de Glasgow , Glucose/análise , Ácido Glutâmico/análise , Humanos , Hipóxia/etiologia , Hipóxia/fisiopatologia , Ácido Láctico/análise , Masculino , Microdiálise , Pessoa de Meia-Idade , Oxigênio/análise , Ácido Pirúvico/análise , Sensibilidade e Especificidade
17.
Neurocrit Care ; 1(1): 69-83, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-16174900

RESUMO

BACKGROUND: It is controversial whether a low cerebral blood flow (CBF) simply reflects the severity of injury or whether ischemia contributes to the brain's injury. It is also not clear whether posttraumatic cerebral hypoperfusion results from intracranial hypertension or from pathologic changes of the cerebral vasculature. The answers to these questions have important implications for whether and how to treat a low CBF. METHODS: We performed a retrospective analysis of 77 patients with severe traumatic brain injury who had measurement of CBF within 12 hours of injury. CBF was measured using xenon-enhanced computed tomography (XeCT). Global CBF, physiological parameters at the time of XeCT, and outcome measures were analyzed. RESULTS: Average global CBF for the 77 patients was 36+/-16 mL/100 g/minutes. Nine patients had an average global CBF<18 (average 12+/-5). The remaining 68 patients had a global CBF of 39+/-15. The initial ICP was >20 mmHg in 90% and >30 mmHg in 80% of patients in the group with CBF<18, compared to 33% and 16%, respectively, in the patients with CBF>or=18. Mortality was 90% at 6 months postinjury in patients with CBF<18. Mortality in the patients with CBF>18 was 19% at 6 months after injury. CONCLUSION: In patients with CBF<18 mL/100 g/minutes, intracranial hypertension plays a major causative role in the reduction in CBF. Treatment would most likely be directed at controlling intracranial pressure, but the early, severe intracranial hypertension also probably indicates a severe brain injury. For levels of CBF between 18 and 40 mL/100 g/minutes, the presence of regional hypoperfusion was a more important factor in reducing the average CBF.


Assuntos
Lesões Encefálicas/fisiopatologia , Circulação Cerebrovascular/fisiologia , Adulto , Lesões Encefálicas/complicações , Lesões Encefálicas/terapia , Isquemia Encefálica/etiologia , Isquemia Encefálica/fisiopatologia , Feminino , Escala de Coma de Glasgow , Escala de Resultado de Glasgow , Humanos , Hipertensão Intracraniana/etiologia , Hipertensão Intracraniana/fisiopatologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento
18.
J Neurotrauma ; 20(10): 995-1006, 2003 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-14588116

RESUMO

Traumatic brain injury causes a reduction in cerebral blood flow, which may cause additional damage to the brain. The purpose of this study was to examine the role of nitric oxide produced by endothelial nitric oxide synthase (eNOS) in these vascular effects of trauma. To accomplish this, cerebral hemodynamics were monitored in mice deficient in eNOS and wild-type control mice that underwent lateral controlled cortical impact injury followed by administration of either L-arginine, 300 mg/kg, or saline at 5 min after the impact injury. The eNOS deficient mice had a greater reduction in laser Doppler flow (LDF) in the contused brain tissue at the impact site after injury, despite maintaining a higher blood pressure. L-Arginine administration increased LDF post-injury only in the wild-type mice. L-Arginine administration also resulted in a reduction in contusion volume, from 2.4 +/- 1.5 to 1.1 +/- 1.2 mm(3) in wild-type mice. Contusion volume in the eNOS deficient mice was not significantly altered by L-arginine administration. These differences in cerebral hemodynamics between the eNOS-deficient and the wild-type mice suggest an important role for nitric oxide produced by eNOS in the preservation of cerebral blood flow in contused brain following traumatic injury, and in the improvement in cerebral blood flow with L-arginine administration.


Assuntos
Lesões Encefálicas/enzimologia , Córtex Cerebral/irrigação sanguínea , Córtex Cerebral/enzimologia , Circulação Cerebrovascular/fisiologia , Óxido Nítrico Sintase/fisiologia , Animais , Arginina/farmacologia , Arginina/uso terapêutico , Lesões Encefálicas/tratamento farmacológico , Córtex Cerebral/efeitos dos fármacos , Circulação Cerebrovascular/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Óxido Nítrico Sintase/deficiência , Óxido Nítrico Sintase/genética , Óxido Nítrico Sintase Tipo II , Óxido Nítrico Sintase Tipo III
19.
J Neurosurg ; 97(5): 1054-61, 2002 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-12450026

RESUMO

OBJECT: The purpose of this study was to evaluate the extent and timing of impairment of cerebral pressure autoregulation after severe head injury. METHODS: In a prospective study of 122 patients with severe head trauma (median Glasgow Coma Scale Score 6), dynamic tests of pressure autoregulation were performed every 12 hours during the first 5 days postinjury and daily during the next 5 days. The autoregulatory index ([ARI] normal value 5 +/- 1.1) was calculated for each test. The changes in the ARI over time were examined and compared with other physiological variables. The ARI averaged 2.8 +/- 1.9 during the first 12 hours postinjury, and continued to decrease to a nadir of 1.7 +/- 1.1 at 36 to 48 hours postinjury. At this nadir, in 87% of the patients the value was less than 2.8. This continued deterioration in the ARI during the first 36 to 48 hours postinjury occurred despite an increase in cerebral blood flow ([CBF], p < 0.05) and in middle cerebral artery blood flow velocity ([BFV], p < 0.001), and could not be explained by changes in cerebral perfusion pressure, end-tidal CO2, or cerebral metabolic rate of O2. A marked decrease in cerebrovascular resistance ([CVR], p < 0.001) accompanied this deterioration in the ARI. Patients with a relatively higher BFV on Day 1 had a lower CVR (p < 0.05) and more impaired pressure autoregulation than those with a lower BFV. CONCLUSIONS: The inability of cerebral vessels to regulate CBF normally may play a role in the vulnerability of the injured brain to secondary ischemic insults. These studies indicate that this vulnerability continues and even increases beyond the first 24 hours postinjury. Local factors affecting cerebrovascular tone may be responsible for these findings.


Assuntos
Pressão Sanguínea , Circulação Cerebrovascular , Traumatismos Craniocerebrais/fisiopatologia , Homeostase , Adulto , Velocidade do Fluxo Sanguíneo , Artérias Cerebrais/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Tempo , Índices de Gravidade do Trauma
20.
J Neurotrauma ; 19(5): 503-57, 2002 May.
Artigo em Inglês | MEDLINE | ID: mdl-12042091

RESUMO

Traumatic brain injury (TBI) remains a major public health problem globally. In the United States the incidence of closed head injuries admitted to hospitals is conservatively estimated to be 200 per 100,000 population, and the incidence of penetrating head injury is estimated to be 12 per 100,000, the highest of any developed country in the world. This yields an approximate number of 500,000 new cases each year, a sizeable proportion of which demonstrate significant long-term disabilities. Unfortunately, there is a paucity of proven therapies for this disease. For a variety of reasons, clinical trials for this condition have been difficult to design and perform. Despite promising pre-clinical data, most of the trials that have been performed in recent years have failed to demonstrate any significant improvement in outcomes. The reasons for these failures have not always been apparent and any insights gained were not always shared. It was therefore feared that we were running the risk of repeating our mistakes. Recognizing the importance of TBI, the National Institute of Neurological Disorders and Stroke (NINDS) sponsored a workshop that brought together experts from clinical, research, and pharmaceutical backgrounds. This workshop proved to be very informative and yielded many insights into previous and future TBI trials. This paper is an attempt to summarize the key points made at the workshop. It is hoped that these lessons will enhance the planning and design of future efforts in this important field of research.


Assuntos
Lesões Encefálicas/terapia , Ensaios Clínicos como Assunto/métodos , Humanos
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