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1.
World Neurosurg ; 132: e99-e108, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31518751

RESUMO

BACKGROUND: High cholesterol has been correlated with a greater risk of cerebrovascular diseases. Whether pre-existing high cholesterol exacerbates traumatic brain injury (TBI), and whether treatment with the cholesterol-lowering agent simvastatin has neuroprotective effects, especially anti-neuroinflammatory effects, after TBI are not well investigated. METHODS: Five-week-old male Sprague-Dawley rats were fed a high-fat diet for 8 weeks to induce hypercholesterolemia. Anesthetized male Sprague-Dawley rats were divided into 5 groups, including the sham-operated control, TBI control, and TBI with simvastatin treatment (4 mg/kg, 10 mg/kg, or 20 mg/kg) groups. Simvastatin was intraperitoneally injected at 0, 24, and 48 hours after TBI. Motor function was measured using an inclined plane. Neuronal apoptosis (maker Neu-N, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling), tumor necrosis factor-α expression in microglia (marker OX42) and astrocytes (marker glial fibrillary acidic protein), and Tumor necrosis factor-alpha receptor (TNFR) 1 and TNFR2 expression in neurons in the ischemic cortex were investigated using an immunofluorescence assay. All of the parameters were measured on the third day after TBI. RESULTS: TBI significantly increased the serum levels of cholesterol. The TBI-induced motor deficit was significantly attenuated by 4, 10, and 20 mg/kg simvastatin therapy on the third day after TBI. TBI-induced neuronal TNFR1 activation and apoptosis, as well as tumor necrosis factor-α expression in astrocytes in the ischemic cortex, were significantly attenuated by simvastatin, particularly when 20 mg/kg was administered. Simultaneously, the serum cholesterol remained high despite simvastatin treatment. CONCLUSIONS: The neuroprotection effects of simvastatin on the pre-existing hypercholesterolemia during TBI in rats may be related to its anti-neuroinflammatory effects but not to its cholesterol-lowing effects.


Assuntos
Anticolesterolemiantes/uso terapêutico , Lesões Encefálicas Traumáticas/complicações , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Hipercolesterolemia/etiologia , Fármacos Neuroprotetores/uso terapêutico , Sinvastatina/uso terapêutico , Animais , Lesões Encefálicas Traumáticas/psicologia , Colesterol/sangue , Ativação de Macrófagos/efeitos dos fármacos , Masculino , Desempenho Psicomotor/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores do Fator de Necrose Tumoral/biossíntese , Fator de Necrose Tumoral alfa/sangue
2.
BMC Res Notes ; 12(1): 386, 2019 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-31288848

RESUMO

OBJECTIVE: Although most clinical practice guidelines endorsed statin use in type 2 diabetes (T2D) patients for reducing cardiovascular diseases (CVD), little is known about statin utilization in case of Ethiopia. Hence, this study was aimed to evaluate prescribing pattern of statins for primary prevention of CVD in T2D patients. A retrospective study conducted in T2D patients with the age group of 40-75 years. Prescriptions were audited for details of statin use and dose intensity. Descriptive analysis was performed using SPSS version 22.0. RESULTS: We included a total of 323 study subjects. Of those, 55.7% study subjects were found to be received statin for their primary prevention of CVD. Commonly prescribed type of statins was simvastatin (37.2%), atorvastatin (32.8%) and rosuvastatin (15.6%). Low, moderate and high intensive dose of statins were prescribed in 27.8%, 46.1%, and 26.1%, respectively. Of those subjects received statin, 60.6% had on target cholesterol level. Overall, a significant percentage of subjects did not receive their recommended statin for primary prevention of CVD which is below the guidelines' recommendation. Therefore, adherence to guidelines may help to promote the use of statins for primary prevention of CVD in T2D and advance interventions to improve statin prescribing should be considered.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Padrões de Prática Médica , Adulto , Idoso , Atorvastatina/uso terapêutico , Etiópia , Feminino , Humanos , Masculino , Adesão à Medicação/estatística & dados numéricos , Pessoa de Meia-Idade , Estudos Retrospectivos , Rosuvastatina Cálcica/uso terapêutico , Sinvastatina/uso terapêutico
3.
Oxid Med Cell Longev ; 2019: 3201873, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31316716

RESUMO

Objective: In this study, we evaluated the efficacy of simvastatin in the treatment of nonalcoholic steatohepatitis induced by methionine and choline-deficient diet in mice and its possible effect on factors involved in the pathogenesis of the disease including oxidative stress and endoplasmic reticulum stress. Method: Male C57BL6 mice were fed either a normal diet (control) or a methionine and choline-deficient diet for four weeks and then treated orally with simvastatin (4 mg/kg once a day) for two final weeks. At the end of the experimental period, liver integrity, biochemical analysis, hepatic lipids, histology, DNA damage, biomarkers of oxidative stress, and endoplasmic reticulum stress were assessed. Results: Simvastatin treatment was able to significantly reduce hepatic damage enzymes and hepatic lipids and lower the degree of hepatocellular ballooning, without showing genotoxic effects. Simvastatin caused significant decreases in lipid peroxidation, with some changes in antioxidant enzymes superoxide dismutase and glutathione peroxidase. Simvastatin activates antioxidant enzymes via Nrf2 and inhibits endoplasmic reticulum stress in the liver. Conclusions: In summary, the results provide evidence that in mice with experimental nonalcoholic steatohepatitis induced by a methionine and choline-deficient diet, the reduction of liver damage by simvastatin is associated with attenuated oxidative and endoplasmic reticulum stress.


Assuntos
Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Sinvastatina/uso terapêutico , Animais , Antioxidantes/metabolismo , Deficiência de Colina/complicações , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Glutationa Peroxidase/metabolismo , Inflamação/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Metionina/deficiência , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/etiologia , Estresse Oxidativo/efeitos dos fármacos , Superóxido Dismutase/metabolismo
4.
Thromb Res ; 180: 74-85, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31229924

RESUMO

BACKGROUND: The incretin hormone Glucagon-like peptide 1(GLP-1) plays a pivotal role in maintaining glucose homeostasis with effects also on the cardiovascular system. GLP-1 influences platelet functions by increasing the inhibitory action of nitric oxide (NO) and reducing oxidative stress. To date, the role of hypercholesterolemia (HyC) on platelet GLP-1 effects needs to be elucidated. METHODS: Forty-five subjects with primary HyC and twenty normocholesterolemic controls (NoC) were enrolled. In platelets from all subjects, the native GLP-1 (7-36), the truncated GLP-1 (9-36) and the GLP-1 analogue Liraglutide were evaluated in their ability to interfere with the activation of NO/PKG/VASP, PI-3K/Akt e MAPK/ERK-1/2 pathways and oxidative stress. Furthermore, in HyC subjects the role of a lipid-lowering therapy with statin on GLP-1 related peptide effects on platelet function was evaluated. RESULTS: Unlike in NoC, in platelets from HyC subjects the GLP-1 related peptides GLP-1 (7-36), GLP-1 (9-36) and Liraglutide all failed to: i) increase the antiaggregating effects of NO and the NO-induced VASP-ser239 phosphorylation, ii) decrease phosphorylation levels of Akt and ERK-2 and iii) reduce reactive oxygen species (ROS) generation. The treatment with simvastatin (40 mg/die) in HyC (n = 18) significantly reduced total and LDL cholesterol levels, platelet aggregability/activation, ROS production and NO action but did not modify platelet sensitivity to the GLP-1 effects. CONCLUSION: Collectively, these results indicate that hypercholesterolemia per se is characterized by a resistance to GLP-1 effects on platelets and this impairment is not corrected by treatment with simvastatin.


Assuntos
Plaquetas/efeitos dos fármacos , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Hipercolesterolemia/tratamento farmacológico , Hipolipemiantes/uso terapêutico , Sinvastatina/uso terapêutico , Adulto , Plaquetas/metabolismo , Feminino , Humanos , Hipercolesterolemia/sangue , Hipercolesterolemia/metabolismo , Masculino , Pessoa de Meia-Idade , Óxido Nítrico/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Agregação Plaquetária/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo
5.
Crit Care ; 23(1): 156, 2019 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-31053084

RESUMO

BACKGROUND: Randomised controlled trials (RCTs) enrolling patients with sepsis or acute respiratory distress syndrome (ARDS) generate heterogeneous trial populations. Non-random variation in the treatment effect of an intervention due to differences in the baseline risk of death between patients in a population represents one form of heterogeneity of treatment effect (HTE). We assessed whether HTE in two sepsis and one ARDS RCTs could explain indeterminate trial results and inform future trial design. METHODS: We assessed HTE for vasopressin, hydrocortisone and levosimendan in sepsis and simvastatin in ARDS patients, on 28-day mortality, using the total Acute Physiology And Chronic Health Evaluation II (APACHE II) score as the baseline risk measurement, comparing above (high) and below (low) the median score. Secondary risk measures were the acute physiology component of APACHE II and predicted risk of mortality using the APACHE II score. HTE was quantified both in additive (difference in risk difference (RD)) and multiplicative (ratio of relative risks (RR)) scales using estimated treatment differences from a logistic regression model with treatment risk as the interaction term. RESULTS: The ratio of the odds of death in the highest APACHE II quartile was 4.9 to 7.4 times compared to the lowest quartile, across the three trials. We did not observe HTE for vasopressin, hydrocortisone and levosimendan in the two sepsis trials. In the HARP-2 trial, simvastatin reduced mortality in the low APACHE II group and increased mortality in the high APACHE II group (difference in RD = 0.34 (0.12, 0.55) (p = 0.02); ratio of RR 3.57 (1.77, 7.17) (p < 0.001). The HTE patterns were inconsistent across the secondary risk measures. The sensitivity analyses of HTE effects for vasopressin, hydrocortisone and levosimendan were consistent with the main analyses and attenuated for simvastatin. CONCLUSIONS: We assessed HTE in three recent ICU RCTs, using multivariable baseline risk of death models. There was considerable within-trial variation in the baseline risk of death. We observed potential HTE for simvastatin in ARDS, but no evidence of HTE for vasopressin, hydrocortisone or levosimendan in the two sepsis trials. Our findings could be explained either by true lack of HTE (no benefit of vasopressin, hydrocortisone or levosimendan vs comparator for any patient subgroups) or by lack of power to detect HTE. Our results require validation using similar trial databases.


Assuntos
Estado Terminal/terapia , Fidelidade a Diretrizes/tendências , Síndrome do Desconforto Respiratório do Adulto/tratamento farmacológico , Sepse/tratamento farmacológico , Resultado do Tratamento , APACHE , Adulto , Idoso , Anti-Inflamatórios/uso terapêutico , Cardiotônicos/uso terapêutico , Estado Terminal/mortalidade , Feminino , Mortalidade Hospitalar/tendências , Humanos , Hidrocortisona/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Unidades de Terapia Intensiva/organização & administração , Unidades de Terapia Intensiva/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto , Síndrome do Desconforto Respiratório do Adulto/mortalidade , Sepse/mortalidade , Simendana/uso terapêutico , Sinvastatina/uso terapêutico , Vasoconstritores/uso terapêutico , Vasopressinas/uso terapêutico
6.
Am J Chin Med ; 47(4): 751-767, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31094214

RESUMO

To systematically evaluate the efficacy and safety of berberine for the treatment of hyperlipidemia, six electronic literature databases including SinoMed, CNKI, WanFang Data, PubMed, Embase and The Cochrane Library were searched to collect clinical randomized controlled trials (RCTs) of berberine alone or combined with statins for the treatment of hyperlipidemia from the inception to 8 March 2018. Two reviewers independently screened literature, extracted data and assessed the risk of bias of included RCTs. Then, meta-analysis was performed by using RevMan 5.3 software. A total of 11 RCTs involving 1386 patients were finally included. The results of meta-analysis showed that compared with the placebo group, berberine could significantly reduce the total cholesterol and low-density lipoprotein levels and elevate the high density lipoprotein level ( P<0.05 ). Compared with the simvastatin group, berberine was effective only in reducing the level of triglyceride ( MD=-0.37 , 95% CI: - 0.66, - 0.07, P=0.02 ). There, however, was no statistical significance between the BBR group and simvastatin group in the low density lipoprotein and high density lipoprotein levels. Compared with the simvastatin group, berberine plus simvastatin was more effective in reducing the level of triglyceride ( MD=-0.33 , 95% CI: - 0.46, - 0.20, P<0.00001 ) and total cholesterol ( MD=-0.36 , 95% CI: - 0.60, - 0.12, P=0.003 ). In terms of adverse reactions, the incidence of adverse reactions including transaminase elevation and muscle aches was lower in the berberine alone or combined with simvastatin group than that in the control group, while the instance of constipation was higher. This study suggests that berberine is effective for hyperlipidemia. The quality and quantity of included studies, however, were dissatisfactory, which might decrease the reliability of the results. Higher quality studies are needed to provide more high quality evidence.


Assuntos
Berberina/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperlipidemias/tratamento farmacológico , Fitoterapia , Ensaios Clínicos Controlados Aleatórios como Assunto , Sinvastatina/uso terapêutico , Berberina/efeitos adversos , Colesterol/sangue , Bases de Dados Bibliográficas , Quimioterapia Combinada , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Hiperlipidemias/sangue , Lipoproteínas HDL/sangue , Lipoproteínas LDL/sangue , Fitoterapia/efeitos adversos , Sinvastatina/efeitos adversos , Resultado do Tratamento , Triglicerídeos/sangue
7.
Genes (Basel) ; 10(4)2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30939847

RESUMO

There is a special interest in the implementation of pharmacogenetics in clinical practice, although there are some barriers that are preventing this integration. A large part of these pharmacogenetic tests are focused on drugs used in oncology and psychiatry fields and for antiviral drugs. However, the scientific evidence is also high for other drugs used in other medical areas, for example, in cardiology. In this article, we discuss the evidence and guidelines currently available on pharmacogenetics for clopidogrel, warfarin, acenocoumarol, and simvastatin and its implementation in daily clinical practice.


Assuntos
Anticoagulantes/efeitos adversos , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/genética , Farmacogenética , Acenocumarol/efeitos adversos , Acenocumarol/uso terapêutico , Anticoagulantes/uso terapêutico , Hidrocarboneto de Aril Hidroxilases/genética , Doenças Cardiovasculares/epidemiologia , Clopidogrel/efeitos adversos , Clopidogrel/uso terapêutico , Citocromo P-450 CYP2C9/genética , Guias como Assunto , Humanos , Medicina de Precisão , Sinvastatina/efeitos adversos , Sinvastatina/uso terapêutico , Varfarina/efeitos adversos , Varfarina/uso terapêutico
8.
Contrast Media Mol Imaging ; 2019: 2538909, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30863219

RESUMO

Purpose: Peripheral artery disease (PAD) causes narrowing of arteries in the limbs, leading to tissue ischemia, gangrene, and eventually limb amputation. The presence of diabetes greatly exacerbates the course of PAD, accounting for the majority of lower limb amputations. Therapeutic strategies focussing on macrovascular repair are less effective in diabetic patients where smaller vessels are affected, and proangiogenic therapies offer a viable adjunct to improve vascularisation in these at risk individuals. The purpose of the current study was to assess the proangiogenic effects of drugs routinely used to treat cardiovascular disease in a diabetic murine model of hind limb ischemia longitudinally using multimodal imaging. Procedures: Diabetic mice underwent surgical intervention to induce hind limb ischemia and were treated with simvastatin, metformin, or a combination orally for 28 days and compared to diabetic and nondiabetic mice. Neovascularisation was assessed using [18F]FtRGD PET imaging, and macrovascular volume was assessed by quantitative time of flight MRI. At each imaging time point, VEGF expression and capillary vessel density were quantified using immunohistochemical analysis, and functional recovery and disease progression were assessed. Results: Combined use of simvastatin and metformin significantly increased neovascularisation above levels measured with either treatment alone. Early angiogenic events were accurately assessed using PET [18F]FtRGD, showing maximal retention in the ischemic hind limb by day 8, which translated to a sustained increase in vascular volume at later time points. Immunohistochemical analysis shows that combined therapy significantly increased VEGF expression and capillary density (CD31+) in a similar time course and also slowed disease progression while simultaneously improving functional foot use. Conclusions: Combined treatment with simvastatin and metformin led to a significant improvement in limb angiogenesis, vascular volume, and sustained functional recovery in a diabetic murine model of HLI. PET imaging with [18F]FtRGD provides a robust method for early detection of these proangiogenic effects preclinically and may be useful for the assessment of proangiogenic therapies used clinically to treat diabetic PAD patients.


Assuntos
Fármacos Cardiovasculares/uso terapêutico , Diabetes Mellitus Experimental/tratamento farmacológico , Membro Posterior/diagnóstico por imagem , Isquemia/diagnóstico por imagem , Isquemia/tratamento farmacológico , Animais , Membro Posterior/efeitos dos fármacos , Membro Posterior/patologia , Imuno-Histoquímica , Imagem por Ressonância Magnética/métodos , Masculino , Metformina/uso terapêutico , Camundongos , Camundongos Endogâmicos BALB C , Músculo Esquelético/diagnóstico por imagem , Músculo Esquelético/efeitos dos fármacos , Oligopeptídeos/química , Sinvastatina/uso terapêutico
9.
Expert Opin Pharmacother ; 20(8): 917-928, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30908086

RESUMO

INTRODUCTION: Cardiovascular disease is a major cause of morbidity and mortality throughout the world and hypercholesterolemia is one of the key risk factors. Statins are the first line treatment to reduce atherogenic lipids and there is substantial and robust evidence with atorvastatin for reduction of cardiovascular events and mortality. Ezetimibe can be combined with any dose of atorvastatin for incremental lipid-lowering effects. Areas covered: In this review, the authors summarize the pharmacokinetics, pharmacodynamics and clinical efficacy of the components and the combination of ezetimibe and atorvastatin. Clinical benefits have been seen with ezetimibe combined with simvastatin but studies of its combination with atorvastatin are generally limited to the effects on lipid parameters where the addition of ezetimibe to atorvastatin is generally more effective than titrating the atorvastatin dose. Expert opinion: Although there are no cardiovascular outcomes studies with the combination of ezetimibe and atorvastatin, the greater reduction in atherogenic lipids can be assumed to have greater benefits in reducing cardiovascular events. The ezetimibe-atorvastatin combination is very effective in this respect and well tolerated. Fixed-dose combinations improve medication adherence and this combination should be useful for patients who cannot reach their lipid targets with maximally tolerated statin doses.


Assuntos
Atorvastatina/administração & dosagem , Ezetimiba/administração & dosagem , Hipercolesterolemia/tratamento farmacológico , Anticolesterolemiantes/administração & dosagem , Anticolesterolemiantes/uso terapêutico , Aterosclerose/tratamento farmacológico , Doenças Cardiovasculares/prevenção & controle , Combinação de Medicamentos , Ezetimiba/uso terapêutico , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Lipídeos/sangue , Fatores de Risco , Sinvastatina/administração & dosagem , Sinvastatina/uso terapêutico
10.
Mil Med ; 184(Suppl 1): 644-651, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30901461

RESUMO

Ionizing radiation exposure is a major concern for active military service members, as well as civilian population. Considering that the exposure is not predictable, it is imperative that strategies to counteract radiation damage must be discovered. Recent in vitro studies performed in our laboratory demonstrated that the vitamin E analog gamma-tocotrienol (GT3) in combination with cholesterol-lowering drugs (Statins), synergistically induced endothelial thrombomodulin, an anticoagulant with radio-protective efficacy. It was hypothesized that the combination of treatment with both GT3 along with Statins would provide better radiation protection in vivo than each drug individually. CD2F1 mice were injected subcutaneously with either vehicle or single dose of GT3 (200 mg/kg body weight) 24 hours before irradiation followed by oral or subcutaneous administration of various doses of simvastatin (25, 50, and 100 mg/kg body weight) before exposure to lethal doses (11.5 and 12 Gy) of Cobalt-60 (60Co) gamma-irradiation. The combined treatment group exhibited enhanced radiation lethality protection substantially, accelerated white blood cell recovery, and augmented restoration of bone marrow cellularity when compared to the animals treated with either drug exclusively. This information clearly suggests that combined treatment could be used as a safeguard for military personnel from exposure to harmful ionizing radiation.


Assuntos
Cromanos/farmacologia , Quimioterapia Combinada/normas , Sinvastatina/farmacologia , Vitamina E/análogos & derivados , Animais , Cromanos/uso terapêutico , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Quimioterapia Combinada/métodos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Masculino , Camundongos , Exposição Ocupacional/efeitos adversos , Radiação Ionizante , Sinvastatina/uso terapêutico , Análise de Sobrevida , Vitamina E/farmacologia , Vitamina E/uso terapêutico
11.
Med Decis Making ; 39(3): 264-277, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30873906

RESUMO

BACKGROUND: Patients and clinicians are often required to make tradeoffs between the relative benefits and harms of multiple treatment options. Combining network meta-analysis results with user preferences can be useful when choosing among several treatment alternatives. OBJECTIVE: Using cholesterol-lowering statin drugs as a case study, we aimed to determine whether an interactive web-based platform that combines network meta-analysis findings with patient preferences had an effect on the decision-making process in a general population sample. METHOD: This was a pilot parallel randomized controlled trial. We used Amazon's Mechanical Turk to recruit adults residing in the United States. A total of 349 participants were randomly allocated to view either the interactive tool (intervention) or a series of bar charts (control). The primary endpoint was decisional conflict, and secondary endpoints included decision self-efficacy, preparation for decision making, and the overall ranking of statins. RESULTS: A total of 258 participants completed the trial and were included in the analysis. On the primary outcome, participants randomized to the interactive tool had significantly lower levels of decisional conflict than those in the control group (difference, -8.53; 95% confidence interval [CI], -12.96 to -4.11 on a 100-point scale; P = 0.001). They also appeared to have higher levels of preparation for decision making (difference, 4.19; 95% CI, -0.24 to 8.63 on a 100-point scale; P = 0.031). No difference was found for decision self-efficacy, although groups were statistically significantly different in how they ranked different statins. CONCLUSION: The findings of our proof-of-concept evaluation suggest that an interactive web-based tool combining published clinical evidence with individual preferences can reduce decisional conflict and better prepare individuals for decision making.


Assuntos
Técnicas de Apoio para a Decisão , Inibidores de Hidroximetilglutaril-CoA Redutases/normas , Preferência do Paciente/psicologia , Medicina de Precisão/métodos , Adulto , Atorvastatina/normas , Atorvastatina/uso terapêutico , Comportamento de Escolha , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Lovastatina/normas , Lovastatina/uso terapêutico , Masculino , Preferência do Paciente/estatística & dados numéricos , Projetos Piloto , Pravastatina/normas , Pravastatina/uso terapêutico , Medicina de Precisão/normas , Medicina de Precisão/estatística & dados numéricos , Psicometria/instrumentação , Psicometria/métodos , Rosuvastatina Cálcica/normas , Rosuvastatina Cálcica/uso terapêutico , Autoeficácia , Sinvastatina/normas , Sinvastatina/uso terapêutico
12.
Int. j. cardiovasc. sci. (Impr.) ; 32(2): 110-117, mar.-abr. 2019. tab, graf
Artigo em Inglês | LILACS | ID: biblio-987748

RESUMO

Background: Warfarin is an oral anticoagulant involved in important interactions with foods and other drugs. Objectives: To evaluate the occurrence of adverse events reported by warfarin users and their relationship with drug interactions. Methods: This was an open cohort, prospective study conducted in an 18-month period with warfarin users attending public health clinics of the city of Ijuí, Brazil. Data were collected by means of interviews administered at patients' home every month. Patients' responses were confirmed by review of medical records when patients sought medical care. Data were analyzed by descriptive statistics. Potential drug interactions were evaluated in a database and vitamin K consumption was quantified using a validated method. Results: A total of 68 patients were followed-up; 63 completed the study and 5 died in the study period. Mean number of medications taken by the patients was 9.6 ± 4.5, and mean number of interactions involving warfarin was 2.91 ± 1.52. Most potential interactions increased the risk of bleeding, 61 of them severe interactions and 116 moderate interactions. Eighty-seven episodes of bleeding and 4 episodes of thrombosis were reported by a total of 37 and 4 patients, respectively. At the occurrence of these events, 56.5% of warfarin users were also taking omeprazole, 35.9% were taking simvastatin and 25.0% paracetamol. Most patients had a low vitamin K intake. Conclusions: A high frequency of potential interactions between warfarin and other drugs was detected, but a low intake of foods that could possibly affect the effects of warfarin was observed. Based on our results, it seems prudent to follow patients on warfarin therapy for drug-drug interactions, aiming to control adverse effects and to promote a safe and effective therapy


Assuntos
Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Varfarina/efeitos adversos , Serviços de Saúde Comunitária/estatística & dados numéricos , Interações de Medicamentos , Anticoagulantes/efeitos adversos , Anticoagulantes/uso terapêutico , Vitamina K , Omeprazol/uso terapêutico , Análise Estatística , Estudos Prospectivos , Estatística como Assunto , Resultado do Tratamento , Monitoramento de Medicamentos , Sinvastatina/uso terapêutico , Incompatibilidade de Medicamentos , Farmacovigilância , Acetaminofen
13.
Am J Cardiol ; 123(8): 1193-1201, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30739657

RESUMO

Risk prediction following acute coronary syndrome (ACS) remains challenging. Data-driven machine-learning algorithms can potentially identify patients at high risk of clinical events. The Improved Reduction of Outcomes: Vytorin Efficacy International Trial randomized 18,144 post-ACS patients to ezetimibe + simvastatin or placebo + simvastatin. We performed hierarchical cluster analysis to identify patients at high risk of adverse events. Associations between clusters and outcomes were assessed using Cox proportional hazards models. The primary outcome was cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, unstable angina hospitalization, or coronary revascularization ≥30 days after randomization. We evaluated ezetimibe's impact on outcomes across clusters and the ability of the cluster analysis to discriminate for outcomes compared with the Global Registry of Acute Coronary Events (GRACE) score. Five clusters were identified. In cluster 1 (n = 13,252), most patients experienced a non-STEMI (54.8%). Cluster 2 patients (n = 2,719) had the highest incidence of unstable angina (n = 83.3%). Cluster 3 patients (n = 782) all identified as Spanish descent, whereas cluster 4 patients (n = 803) were primarily from South America (56.2%). In cluster 5 (n = 587), all patients had ST elevation. Cluster analysis identified patients at high risk of adverse outcomes (log-rank p <0.0001); Cluster 2 (vs 1) patients had the highest risk of outcomes (hazards ratio 1.33, 95% confidence interval 1.24 to 1.43). Compared with GRACE risk, cluster analysis did not provide superior outcome discrimination. A consistent ezetimibe treatment effect was identified across clusters (interaction p = 0.882). In conclusion, cluster analysis identified significant difference in risk of outcomes across cluster groups. Data-driven strategies to identify patients who may differentially benefit from therapies and for risk stratification require further evaluation.


Assuntos
Síndrome Coronariana Aguda/terapia , Ponte de Artéria Coronária/métodos , Combinação Ezetimiba e Simvastatina/uso terapêutico , Ezetimiba/uso terapêutico , Medição de Risco/métodos , Sinvastatina/uso terapêutico , Síndrome Coronariana Aguda/diagnóstico , Síndrome Coronariana Aguda/mortalidade , Idoso , Anticolesterolemiantes/uso terapêutico , Causas de Morte/tendências , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Seguimentos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Masculino , Pessoa de Meia-Idade , América do Norte/epidemiologia , Fenótipo , Fatores de Risco , Taxa de Sobrevida/tendências , Resultado do Tratamento
14.
Rev Assoc Med Bras (1992) ; 65(1): 3-8, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30758413

RESUMO

OBJECTIVE: Diabetes is one of the leading causes of cardiovascular mortality. Over the last years, mortality has decreased significantly, more in individuals with diabetes than in healthy ones. That is mostly due to the control of other cardiovascular risk factors. The objective of our study was to analyze the dyslipidemia control in two diabetes cohorts. METHODS: Patients from two distinct cohorts were studied, 173 patients from the BHS (Brasília Heart Study) and 222 patients from the BDS (Brazilian Diabetes Study). The data on dyslipidemia control were studied in both different populations. All patients had diabetes. RESULTS: There are significant differences concerning comorbidities between the LDL-C and BDS groups. The average glycated hemoglobin is of 8.2 in the LDL-C > 100 group in comparison with 7.7 and 7.5 in the 70-100 and < 70 groups, respectively (p = 0.024). There is a higher percentage of hypertensive patients with LDL between 70-100 (63.9%), when comparing the < 70 and > 100 groups (54.3% and 54.9%, respectively; p = 0.005). Diastolic pressure is higher in the group with LDL > 100, with an average of 87 mmHg, in comparison with 82.6 mmHg and 81.9 mmHg in the 70-100 and < 70 groups, respectively (p = 0.019). The group with LDL > 100 has the greatest percentage of smokers (8.7%) in comparison with the groups with LDL between 70-100 and < 70 (5.6% and 4.3%, respectively; p = 0.015). There is also a difference in the previous incidence of coronaropathy. In the group with LDL < 70, 28.3% of patients had already experienced a previous infarction, compared with 11.1% and 10.6% in the 70-100 and > 100 groups, respectively (p < 0.001). CONCLUSIONS: The data in our study have shown that the dyslipidemia control in diabetic patients is inadequate and there is a tendency of direct association between lack of blood glucose control and lack of dyslipidemia control, in addition to the association with other cardiovascular risk factors, such as diastolic hypertension and smoking. This worsened control might be related to the plateau in the descending curve of mortality, and investments in this regard can improve the cardiovascular health in diabetic patients.


Assuntos
Anticolesterolemiantes/uso terapêutico , Diabetes Mellitus Tipo 2/complicações , Dislipidemias/complicações , Sinvastatina/uso terapêutico , Pressão Sanguínea , Brasil/epidemiologia , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Estudos de Coortes , Comorbidade , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/mortalidade , Dislipidemias/tratamento farmacológico , Dislipidemias/epidemiologia , Dislipidemias/prevenção & controle , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Fatores de Risco , Triglicerídeos/sangue
15.
Acta Pharmacol Sin ; 40(8): 1049-1057, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30728467

RESUMO

Second-generation antipsychotic drug (SGA)-induced metabolic abnormalities, such as dyslipidemia, are a major clinical problem for antipsychotic therapy. Accumulated evidences have shown the efficacy of statins in reducing SGA-induced dyslipidemia, but the underlying mechanisms are unclear. In this study, we explored whether mTOR signaling was involved in olanzapine (OLZ)-induced dyslipidemia as well as the lipid-lowering effects of cotreatment of simvastatin (Sim) in rats. Model rats received OLZ (1.0 mg/kg, t.i.d.) for 7 weeks; from the third week a group of model rats were cotreatment of Sim (3.0 mg/kg, t.i.d.) for 5 weeks. We found that OLZ treatment significantly increased the plasma triglyceride (TG) and total cholesterol (TC) levels, and promoted lipid accumulation in the liver, whereas cotreatment of Sim reversed OLZ-induced dyslipidemia. Hepatic mTORC1 and p-mTORC1 expression was accelerated in the OLZ treatment group, with upregulation of mRNA expression of sterol regulatory element-binding protein 1c (SREBP1c) and its target genes, whereas these alterations were ameliorated by Sim cotreatment. In HepG2 cells, rapamycin (a mTOR inhibitor) significantly reduced the OLZ-stimulated hepatocellular lipid contents and weakened the ability of Sim to lower lipids via a mechanism associated with the upregulation of SREBP1c-mediated de novo lipogenesis. Our data suggest that OLZ induces lipid accumulation in both plasma and liver, and Sim ameliorates OLZ-induced lipid metabolic dysfunction through its effects on mTOR signaling via reducing SREBP1c activation and the downregulation of gene expression involved in lipogenesis. These data provide a new insight into the prevention of metabolic side effects induced by antipsychotic drugs.


Assuntos
Dislipidemias/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Sinvastatina/uso terapêutico , Serina-Treonina Quinases TOR/metabolismo , Animais , Regulação para Baixo , Dislipidemias/induzido quimicamente , Fígado Gorduroso/induzido quimicamente , Fígado Gorduroso/tratamento farmacológico , Feminino , Células Hep G2 , Humanos , Lipogênese/efeitos dos fármacos , Lipogênese/genética , Fígado/patologia , Olanzapina , Ratos Sprague-Dawley , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo
17.
Stroke ; 50(3): 738-744, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30744543

RESUMO

Background and Purpose- Previously, murine models Krit1 +/- Msh2 -/ - and Ccm2 +/ - Trp53 -/ - showed a reduction or no effect on cerebral cavernous malformation (CCM) burden and favorable effects on lesional hemorrhage by the robust Rock (Rho-associated protein kinase) inhibitor fasudil and by simvastatin (a weak pleiotropic inhibitor of Rock). Herein, we concurrently investigated treatment of the more aggressive Pdcd10/Ccm3 model with fasudil, simvastatin, and higher dose atorvastatin to determined effectiveness of Rock inhibition. Methods- The murine models, Pdcd10 +/ - Trp53 -/ - and Pdcd10 +/ - Msh2 -/ -, were contemporaneously treated from weaning to 5 months of age with fasudil (100 mg/kg per day in drinking water, n=9), simvastatin (40 mg/kg per day in chow, n=11), atorvastatin (80 mg/kg per day in chow, n=10), or with placebo (n=16). We assessed CCM volume in mouse brains by microcomputed tomography. Lesion burden was calculated as lesion volume normalized to total brain volume. We analyzed chronic hemorrhage in CCM lesions by quantitative intensity of Perls staining in brain sections. Results- The Pdcd10 +/ - Trp53 -/ - /Msh2 -/ - models showed a mean CCM lesion burden per mouse reduction from 0.0091 in placebos to 0.0042 ( P=0.027) by fasudil, and to 0.0047 ( P=0.025) by atorvastatin treatment, but was not changed significantly by simvastatin. Hemorrhage intensity per brain was commensurately decreased by Rock inhibition. Conclusions- These results support the exploration of proof of concept effect of high-dose atorvastatin on human CCM disease for potential therapeutic testing.


Assuntos
Inibidores Enzimáticos/uso terapêutico , Hemangioma Cavernoso do Sistema Nervoso Central/tratamento farmacológico , Hemangioma Cavernoso do Sistema Nervoso Central/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Hemorragias Intracranianas/tratamento farmacológico , Hemorragias Intracranianas/genética , Quinases Associadas a rho/antagonistas & inibidores , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/uso terapêutico , Animais , Proteínas Reguladoras de Apoptose , Atorvastatina/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hemorragias Intracranianas/diagnóstico por imagem , Proteína KRIT1/genética , Camundongos , Camundongos Knockout , Sinvastatina/uso terapêutico , Microtomografia por Raio-X
18.
Seizure ; 66: 47-52, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30798113

RESUMO

PURPOSE: This study aimed to analyze the extent of co-medication and to assess potential interactions between antiepileptic drugs (AEDs) and other drugs among patients with epilepsy. METHODS: We studied 663 consecutive patients with epilepsy seen in tertiary outpatient clinic. Data on epilepsy and current treatment with AED(s) were collected from structured interview and medical records. Other medications used regularly were classified according to the Anatomical Therapeutic Chemical classification system. Possible drug interactions between AEDs and other drugs were analyzed with the use of IBM Micromedex® database. RESULTS: Studied sample included 395 women; 54.5% of subjects were on monotherapy. Enzyme-inducing AED(s) were used by 127 patients (19.2%). Among 265 patients who used medications other than AEDs (40.0% of all subjects), potential major and moderate interactions between AEDs and other drugs were found in 80 patients (30.1%). Most prevalent major interactions included: ethinylestradiol/estradiol - valproate/oxcarbazepine/carbamazepine, sertraline-carbamazepine, and simvastatin-carbamazepine. A total number of currently used medications (OR = 1.26 [1.07-1.48] per one additional medication; p = 0.005) and the use of enzyme-inducing AEDs (OR = 2.78 [1.51-5.12]; p < 0.001) were independent predictors of interactions between AEDs and other drugs. CONCLUSIONS: Co-medication is common (40%) among patients with epilepsy. Potential major or moderate interactions between AED(s) and other drugs are noted in 30.1% of patients exposed to at least one medication other than AED (12.1% of the entire cohort). The risk of potential interactions increases with the number of medications used chronically and with the use of hepatic enzyme-inducing AEDs.


Assuntos
Anticonvulsivantes/uso terapêutico , Epilepsia/tratamento farmacológico , Adulto , Interações de Medicamentos , Eletroencefalografia , Epilepsia/diagnóstico por imagem , Epilepsia/fisiopatologia , Feminino , Humanos , Linestrenol/uso terapêutico , Imagem por Ressonância Magnética , Masculino , Sertralina/uso terapêutico , Sinvastatina/uso terapêutico
19.
Am Heart J ; 210: 18-28, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30716508

RESUMO

The current guidelines of statins for primary cardiovascular disease (CVD) prevention were based on results from systematic reviews and meta-analyses that suffer from limitations. METHODS: We searched in PubMed for existing systematic reviews and individual open-label or double-blinded randomized controlled trials that compared a statin with a placebo or another, which were published in English until January 01, 2018. We performed a random-effect pairwise meta-analysis of all statins as a class and network meta-analysis for the specific statins on different benefit and harm outcomes. RESULTS: In the pairwise meta-analyses, statins as a class showed statistically significant risk reductions on non-fatal MI (risk ratio [RR] 0.62, 95% CI 0.53-0.72), CVD mortality (RR 0.80, 0.71-0.91), all-cause mortality (RR 0.89, 0.85-0.93), non-fatal stroke (RR 0.83, 0.75-0.92), unstable angina (RR 0.75, 0.63-0.91), and composite major cardiovascular events (RR 0.74, 0.67-0.81). Statins increased statistically significantly relative and absolute risks of myopathy (RR 1.08, 1.01-1.15; Risk difference [RD] 13, 2-24 per 10,000 person-years); renal dysfunction (RR 1.12, 1.00-1.26; RD 16, 0-36 per 10,000 person-years); and hepatic dysfunction (RR 1.16, 1.02-1.31; RD 8, 1-16 per 10,000 person-years). The drug-level network meta-analyses showed that atorvastatin and rosuvastatin were most effective in reducing CVD events while atorvastatin appeared to have the best safety profile. CONCLUSIONS: All statins showed statistically significant risk reduction of CVD and all-cause mortality in primary prevention populations while increasing the risk for some harm risks. However, the benefit-harm profile differed by statin type. A quantitative assessment of the benefit-harm balance is thus needed since meta-analyses alone are insufficient to inform whether statins provide net benefit.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Meta-Análise em Rede , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Atorvastatina/efeitos adversos , Atorvastatina/uso terapêutico , Doenças Cardiovasculares/mortalidade , Causas de Morte , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Método Duplo-Cego , Fluvastatina/efeitos adversos , Fluvastatina/uso terapêutico , Cefaleia/induzido quimicamente , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Nefropatias/induzido quimicamente , Lovastatina/efeitos adversos , Lovastatina/uso terapêutico , Pessoa de Meia-Idade , Doenças Musculares/induzido quimicamente , Náusea/induzido quimicamente , Neoplasias/induzido quimicamente , Placebos/uso terapêutico , Pravastatina/efeitos adversos , Pravastatina/uso terapêutico , Medição de Risco , Rosuvastatina Cálcica/efeitos adversos , Rosuvastatina Cálcica/uso terapêutico , Sinvastatina/efeitos adversos , Sinvastatina/uso terapêutico , Suspensão de Tratamento
20.
Drug Dev Ind Pharm ; 45(4): 664-668, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30649976

RESUMO

Piperine has been widely used as a bioenhancer. Simvastatin belongs to a group of medicines known as statins. It acts by inhibiting HMG CoA reductase and acts primarily as a hypolipidemic agent. In this study some derivatives of Piperine were synthesized. They were studied for their bioenhencing effect (10 mg kg-1) and this effect was compared with that of Piperine. The pharmacokinectic profile of Simvastatin alone and in combination with Piperine and Piperine derivatives were investigated by validated HPLC method as per USFDA guidelines. It was seen that the two synthesized derivatives of Piperine significantly improved the bioavailability of Simvastatin in Wistar rats. The 5-(benzo) [1,3]dioxol-5-yl)-N-(pyridin-4-yl)penta-2,4-dienamide was better amongst the synthesized in increasing the bioavailability of Simvastatin in Wistar rat.


Assuntos
Alcaloides/farmacologia , Benzodioxóis/farmacologia , Composição de Medicamentos/métodos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Piperidinas/farmacologia , Alcamidas Poli-Insaturadas/farmacologia , Sinvastatina/farmacologia , Administração Oral , Alcaloides/química , Animais , Benzodioxóis/química , Disponibilidade Biológica , Sinergismo Farmacológico , Dislipidemias/tratamento farmacológico , Estudos de Viabilidade , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Masculino , Piperidinas/química , Alcamidas Poli-Insaturadas/química , Ratos , Ratos Wistar , Sinvastatina/uso terapêutico
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