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1.
Biomed Pharmacother ; 112: 108595, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30784911

RESUMO

This study was designed to investigate the inflammatory responses in fat embolism syndrome (FES) and the relationship of ALX/FPR2 receptors and lipoxin A4 (LXA4) in FES models. In this model, lung injury score, lung tissue wet-to-dry (W/D) ratio and total protein concentration in bronchoalveolar lavage fluid (BALF) were increased compared with those of the control group. Meanwhile, the number of leukocytes and neutrophils was significantly increased in the FES group, as was the myeloperoxidase (MPO) activity and mRNA expression. In addition, the release of TNF-α and IL-1ß was increased. Then, we explored whether LXA4 and ALX/FPR2 were involved in the pathological process of FES. The LXA4 concentration in the experimental groups was markedly higher than that in the control group. At the same time, the protein and mRNA levels of ALX/FPR2 were upregulated in the rat model of FES. Moreover, rats treated with BML-111, an agonist for the ALX/FPR2 receptor of LXA4, showed a lower inflammatory response than mice treated with fat alone. However, the role of BML-111 in fat emboli (FE)-induced acute lung injury (ALI) was attenuated by BOC-2, an antagonist of the ALX/FPR2 receptor of LXA4. Our results demonstrated that the inflammatory response may play an important role in the pathogenesis of FES and that the activation of the ALX/FPR2 receptor for LXA4 can decrease the inflammatory response and may be a therapeutic target for FE-induced ALI.


Assuntos
Embolia Gordurosa/metabolismo , Embolia Gordurosa/patologia , Lesão Pulmonar/metabolismo , Lesão Pulmonar/patologia , Receptores de Lipoxinas/metabolismo , Animais , Embolia Gordurosa/tratamento farmacológico , Ácidos Heptanoicos/farmacologia , Ácidos Heptanoicos/uso terapêutico , Lesão Pulmonar/tratamento farmacológico , Masculino , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Receptores de Lipoxinas/agonistas
2.
Int Immunopharmacol ; 69: 289-298, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30753968

RESUMO

The timely resolution of pulmonary inflammation coordinated by endogenous pro-resolving mediators helps limit lung tissue injury, but few endogenous pro-resolving mediators that are normally operative during acute inflammation. The protective effects of BML-111 (5(S)-6(R)-7-trihydroxyheptanoic acid methyl ester), a potent commercially available anti-inflammatory and pro-resolving mediator, on ventilation-induced lung injury (VILI) have been extensively studied, but its characteristics as a pro-resolving mediator have not. Here, anesthetized Sprague-Dawley rats were ventilated with a high tidal volume (20 mL/kg, HVT) for 1 h and randomly allocated to recover for 6, 12, 24, 48, 72, 96 or 168 h; BML-111 was administered at the peak of inflammation to evaluate its pro-resolving effect on VILI. The one-hour HVT induced a maximal pulmonary inflammatory response at 12 h that was largely resolved by 72 h. BML-111 largely resolved the maximal inflammatory response at 48 h; the resolution interval (Ri) was shortened by 26 h. Similarly, HVT elicited a time course of changes in histopathology and pulmonary edema, and BML-111 alleviates these changes. Mechanistically, neutrophil apoptosis was significantly increased in BML-111-treated rats subjected to HVT. The apoptosis inhibitor z-VAD-fmk partially reversed the proapoptotic actions of BML-111 on neutrophil and the resolving effects of BML-111 on VILI but had no effect alone. Importantly, the HVT treatment activated the nuclear factor E2-related factor 2(Nrf2)/heme oxygenase-1(HO-1) and NF-κB signaling pathways in the lung tissue, and BML-111 further induced Nrf2 and HO-1 expression but inhibited the NF-κB pathway. Intriguingly, when we inhibited the Nrf2/HO-1 pathway with the HO-1 inhibitor zinc protoporphyrin IX (ZnPPIX), Nrf2 expression was further increased, but the inhibitory effects of BML-111 on the NF-κB pathway and on the subsequent inflammatory response, and the proapoptotic actions on neutrophil were reversed. The results suggest that BML-111 promotes the resolution of HVT-induced inflammation to mitigate VILI in rats, perhaps by modulating the Nrf2/HO-1 and NF-κB pathways and subsequently increasing neutrophil apoptosis.


Assuntos
Ácidos Heptanoicos/uso terapêutico , Inflamação/tratamento farmacológico , Pulmão/efeitos dos fármacos , Neutrófilos/patologia , Lesão Pulmonar Induzida por Ventilação Mecânica/tratamento farmacológico , Animais , Apoptose , Células Cultivadas , Modelos Animais de Doenças , Heme Oxigenase-1/metabolismo , Humanos , Pulmão/patologia , Masculino , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Protoporfirinas/farmacologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais
3.
Respir Res ; 19(1): 243, 2018 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-30518355

RESUMO

BACKGROUND: Acute lung injury (ALI) is a life-threatening lung disease where alveolar macrophages (AMs) play a central role both in the early phase to initiate inflammatory responses and in the late phase to promote tissue repair. In this study, we examined whether BML-111, a lipoxin A4 receptor agonist, could alter the phenotypes of AM and thus present prophylactic benefits for ALI. METHODS: In vitro, isolated AMs were treated with lipopolysaccharide (LPS) to induce ALI. In response to BML-111 pre-treatment, apoptosis and autophagy of AMs were examined by flow cytometry, and by measuring biomarkers for each process. The potential involvement of MAPK1 and mTOR signaling pathway was analyzed. In vivo, an LPS-induced septic ALI model was established in rats and the preventative significance of BML-111 was assessed. On the cellular and molecular levels, the pro-inflammatory cytokines TNF-α and IL-6 from bronchoalveolar lavage were measured by ELISA, and the autophagy in AMs examined using Western blot. RESULTS: BML-111 inhibited apoptosis and induced autophagy of AMs in response to ALI inducer, LPS. The enhancement of autophagy was mediated through the suppression of MAPK1 and MAPK8 signaling, but independent of mTOR signaling. In vivo, BML-111 pre-treatment significantly alleviated LPS-induced ALI, which was associated with the reduction of apoptosis, the dampened production of pro-inflammatory cytokines in the lung tissue, as well as the increase of autophagy of AMs. CONCLUSIONS: This study reveals the prophylactic significance of BML-111 in ALI and the underlying mechanism: by targeting the MAPK signaling but not mTOR pathway, BML-111 stimulates autophagy in AMs, attenuates the LPS-induced cell apoptosis, and promotes the resolution of ALI.


Assuntos
Lesão Pulmonar Aguda/enzimologia , Autofagia/fisiologia , Ácidos Heptanoicos/uso terapêutico , Sistema de Sinalização das MAP Quinases/fisiologia , Macrófagos Alveolares/enzimologia , Receptores de Lipoxinas/agonistas , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/prevenção & controle , Animais , Autofagia/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/fisiologia , Ácidos Heptanoicos/farmacologia , Lipopolissacarídeos/toxicidade , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Macrófagos Alveolares/efeitos dos fármacos , Masculino , Ratos , Ratos Sprague-Dawley
4.
Chem Biol Interact ; 290: 77-87, 2018 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-29852127

RESUMO

Obesity and its major co-morbidity, type 2 diabetes, have been an alarming epidemic prevalence without an effective treatment available. Sterol regulatory element-binding proteins (SREBPs) are major transcription factors regulating the expression of genes involved in biosynthesis of cholesterol, fatty acid and triglyceride. Therefore, inhibition of SREBP pathway may be a useful strategy to treat obesity with type 2 diabetes. Here, we identify a small molecule, Ganoderic Acid A (GAA), inhibits the SREBP expression and decreases the cellular levels of cholesterol and fatty acid in vitro. GAA also ameliorates body weight gain and fat accumulation in liver or adipose tissues, and improves serum lipid levels and insulin sensitivity in high fat diet (HFD)-induced obese mice. Consistently, GAA regulates SREBPs target genes and metabolism associated genes in liver or adipose tissues, which may directly contribute to the lower lipid level and improvement of insulin resistance. Taken together, GAA could be a potential leading compound for development of drugs for the prevention of obesity and insulin resistance.


Assuntos
Dieta Hiperlipídica , Ácidos Heptanoicos/farmacologia , Lanosterol/análogos & derivados , Metabolismo dos Lipídeos/efeitos dos fármacos , Obesidade/etiologia , Proteínas de Ligação a Elemento Regulador de Esterol/metabolismo , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Animais , Aspartato Aminotransferases/análise , Aspartato Aminotransferases/sangue , Peso Corporal/efeitos dos fármacos , Colesterol/sangue , Metabolismo Energético/efeitos dos fármacos , Teste de Tolerância a Glucose , Células Hep G2 , Ácidos Heptanoicos/química , Ácidos Heptanoicos/uso terapêutico , Humanos , Resistência à Insulina , Lanosterol/química , Lanosterol/farmacologia , Lanosterol/uso terapêutico , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/prevenção & controle , Transdução de Sinais/efeitos dos fármacos , Triglicerídeos/sangue
5.
Arch Biochem Biophys ; 649: 15-21, 2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-29704485

RESUMO

BML-111 is a lipoxin receptor agonist that plays a vital role on inflammation. MALAT1 is reported to mediate lung injury. ALI rat model was established using the method of venous cannula. Pulmonary microvascular endothelial cells (PMVEC) of rats were isolated using immunomagnetic separation method. Hematoxylin-eosin (HE) staining was performed to observe the lung injury degree. Real-time PCR and western blot were performed to detect the genes expression. ELIAS was used to determine the level of TNF-α and IL-6. RNA pull-down and RIP were carried out to affirm the relationship between MALAT1 and TLR4. The lung injury score and lung wet/dry weight ratio was significantly increased in ALI rats, while BML-111 treatment significantly decreased it, the HE staining directly revealed the lung injury. The expression of MALAT1 was decreased, while TLR4 was increased in ALI rats, BML-111 stimulation significantly reversed it. MALAT1 targets TLR4 to regulate its expression. TLR4 regulated the inflammation and cell apoptosis of PMVEC via NF-κB and p38 MAPK signaling pathway. The down-regulated MALAT1 mediates the mechanism of ALI by regulating of NF-κB and p38 MAPK signaling pathways via TLR4, while BML-111 stimulation significantly alleviated the ALI by regulating the expression of MALAT1.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Regulação da Expressão Gênica/efeitos dos fármacos , Ácidos Heptanoicos/uso terapêutico , Substâncias Protetoras/uso terapêutico , RNA Longo não Codificante/genética , Receptores de Lipoxinas/agonistas , Lesão Pulmonar Aguda/genética , Lesão Pulmonar Aguda/patologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Fatores Imunológicos/uso terapêutico , Inflamação/tratamento farmacológico , Inflamação/genética , Inflamação/patologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Masculino , Ratos Sprague-Dawley
6.
Artigo em Inglês | MEDLINE | ID: mdl-28822808

RESUMO

BACKGROUND: It was recently reported Lipoxins (LXs) had protective effects on fibrous diseases, and renin-angiotensin-aldosterone system (RAAS) had played vital and bidirectional roles in hepatic fibrosis. In this paper, a hepatic fibrosis model, induced by carbon tetrachloride (CCL4) in rats, was used to observe the relations between RAAS and LXs, as well as to further explore the alternative anti-fibrosis mechanisms of LXs. METHODS: The model was evaluated by morphological observations and biochemical assays. The activities and contents of angiotensin converting enzyme (ACE) and angiotensin converting enzyme 2 (ACE2) were examined through assay kits and ELISA. The expression levels of angiotensinII (AngII), Angiotensin II type 1 receptor (AT1R), angiotensin-(1-7) (Ang-1-7), and Mas were all measured using real time PCR, ELISA, and Western blot. RESULTS: The model was established successfully and BML-111 significantly ameliorated CCL4-induced hepatic fibrosis, including reduction inflammation injury, decrease extracellular matrix deposition, and improvement hepatic functions. Furthermore, BML-111 could obviously decrease not only the activities of ACE but also the expression levels of ACE, AngII,and AT1R, which were induced by CCL4. On the other hand, BML-111 could markedly increase the activities of ACE2, besides the expression levels of ACE2, Ang-(1-7) and Mas. More importantly, BOC-2, a lipoxin A4 receptor blocker, could reverse all these phenomena. CONCLUSIONS: Equilibrating ACE-AngII-AT1R axis and ACE2-Ang-(1-7)-Mas axis mediated the protective effect of BML-111 on hepatic fibrosis in rats.


Assuntos
Angiotensina II/metabolismo , Angiotensina I/metabolismo , Ácidos Heptanoicos/farmacologia , Cirrose Hepática/tratamento farmacológico , Fragmentos de Peptídeos/metabolismo , Peptidil Dipeptidase A/metabolismo , Receptor Tipo 1 de Angiotensina/metabolismo , Animais , Regulação para Baixo/efeitos dos fármacos , Ácidos Heptanoicos/uso terapêutico , Cirrose Hepática/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Regulação para Cima/efeitos dos fármacos
7.
Naunyn Schmiedebergs Arch Pharmacol ; 390(4): 361-368, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28035464

RESUMO

Sepsis is a systemic inflammatory response associating severe infection leading to multi-organ failure, such as hepatic dysfunction. This study investigates the possible hepatoprotective effect of the lipoxin A4 agonist (BML-111) in cecal ligation and puncture (CLP) model in rats. Pretreatment with BML-111 (1 mg/kg, i.p., 1 h before CLP) protected against CLP-induced mortality after 24 h. BML-111 prevented marked inflammatory cells in liver tissues and decreased elevation in serum hepatic biomarkers [alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TB), gamma-glutamyl transferase (γ-GT)] induced by CLP. Additionally, BML-111 attenuated elevated serum level of interleukin-6 (IL-6) and downregulated hepatic IL-6 mRNA expression. Meanwhile, BML-111 further increased serum IL-10 and upregulated hepatic IL-10 mRNA expression, while it downregulated hepatic mRNA expression of nuclear factor inhibitory protein kappa-B alpha (NFκBia), toll-like receptor-4 (TLR-4), and 5-lipooxygenase (5-LOX). Moreover, BML-111 prevented NF-κB/p65 nuclear translocation and activation. In conclusion, BML-111 attenuated CLP-induced acute hepatic dysfunction through its anti-inflammatory effect by decreasing NF-κB activity, TLR-4, and 5-LOX expression with subsequent decrease in pro-inflammatory IL-6 and elevation in anti-inflammatory IL-10.


Assuntos
Ácidos Heptanoicos/uso terapêutico , Lipoxinas/agonistas , Hepatopatias/tratamento farmacológico , Substâncias Protetoras/uso terapêutico , Alanina Transaminase/sangue , Animais , Araquidonato 5-Lipoxigenase/genética , Aspartato Aminotransferases/sangue , Bilirrubina/sangue , Ceco/lesões , Ceco/cirurgia , Ácidos Heptanoicos/farmacologia , Interleucina-10/sangue , Interleucina-10/genética , Interleucina-6/sangue , Interleucina-6/genética , Ligadura , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Hepatopatias/etiologia , Hepatopatias/metabolismo , Hepatopatias/patologia , Masculino , NF-kappa B/genética , NF-kappa B/metabolismo , Substâncias Protetoras/farmacologia , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Receptor 4 Toll-Like/genética , gama-Glutamiltransferase/sangue
8.
Orv Hetil ; 157(11): 425-9, 2016 Mar 13.
Artigo em Húngaro | MEDLINE | ID: mdl-26947091

RESUMO

INTRODUCTION: Hypertension and dyslipidemia are modifiable cardiovascular risk factors. In Hungary hypertension and dyslipidemia are quite frequent conditions. The patients' adherence is very important factor to reach the targets. AIM: The aim of the authors was to investigate the one-year persistence of the atorvastatin therapy and atorvastatin and amlodipine fixed dose combination. METHOD: National Health Insurance Found prescriptions database of Hungary on pharmacy claims between October 1, 2012 and September 30, 2013 was analyzed. The authors identified patients who filled prescriptions for atorvastatin and amlodipine fixed dose combination and atorvastatin prescribed for the first time. Patients did not receive similar drugs for one year before the study. To model the persistence, the apparatus of survival analysis was used, where "survival" was the time to abandon the medication. As it was available to month precision, discrete time survival analysis was applied: a generalized linear model was estimated with complementary log-log link function with the kind of drug being the only explanatory variable. RESULTS: During the trial period, atorvastatin and atorvastatin plus amlodipine fixed dose combination was started in 192,579 and 24,433 patients, respectively. One year persistence rate in patients with atorvastatin and amlodipine fixed dose combination was 43%, and 21% in patients with atorvastatin therapy. The 360-days-restricted study period, the mean duration of persistence was 221.4 (SE: 0.894) days in patients on atorvastatin and amlodipine fixed dose combination and 153.0 days (SE: 0.297) in those on atorvastatin regimen. The hazard of discontinuation was almost twofold higher during treatment with atorvastatin therapy compared with the use of the atorvastatin and amlodipine fixed dose combination (hazard ratio = 1.85, p<0.0001). CONCLUSIONS: There is a significant difference between the one-year persistence of atorvastatin therapy and atorvastatin plus amlodipine fixed dose combination. The result demonstrate that atorvastatin and amlodipine fixed dose combination is favourable to reach double goals on blood pressure and LDL-cholesterol.


Assuntos
Anlodipino/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Atorvastatina/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , LDL-Colesterol/sangue , Ácidos Heptanoicos/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Hipertensão/tratamento farmacológico , Pirróis/uso terapêutico , Adulto , Idoso , Anlodipino/administração & dosagem , Anti-Hipertensivos/administração & dosagem , Atorvastatina/administração & dosagem , LDL-Colesterol/efeitos dos fármacos , Combinação de Medicamentos , Feminino , Ácidos Heptanoicos/administração & dosagem , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Hipercolesterolemia/sangue , Hipertensão/sangue , Hipertensão/fisiopatologia , Modelos Lineares , Masculino , Adesão à Medicação/estatística & dados numéricos , Pessoa de Meia-Idade , Pirróis/administração & dosagem , Estudos Retrospectivos , Resultado do Tratamento
10.
J Surg Res ; 200(2): 619-30, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26432471

RESUMO

BACKGROUND: BML-111 is a lipoxin receptor agonist that has protective effects in various lung injury models. We tried to elucidate whether BML-111 could mitigate lung injury in a mouse model of endotoxemia and endothelial hyperpermeability in vitro. METHODS: The effect of BML-111 on lung injury was evaluated using C57BL/6 mice and human umbilical vein endothelial cells (HUVECs). Male C57BL/6 mice were intraperitoneally injected with normal saline, BML-111, and/or the lipoxin receptor antagonist Boc-2. Then, either lipopolysaccharide (LPS) or normal saline was given intraperitoneally. Lung injury was assessed by a pathohistologic examination for neutrophil infiltration, pulmonary endothelial permeability, and inflammatory cytokines in lung tissue and bronchoalveolar lavage fluid. HUVECs were treated with or without BML-111 before incubation with LPS for 24 h. Boc-2 was also tested as a novel inhibitor of BML-111. A Transwell assay was used to evaluate the permeability of HUVECs. Junction protein expression was also assessed. RESULTS: BML-111 significantly improved the mouse survival rate, reduced body weight loss, attenuated the pulmonary pathologic changes, inhibited neutrophil infiltration and proinflammatory cytokine production, and mitigated endothelial hyperpermeability. The decreased expression of junction proteins induced by LPS in lung tissue and endothelial cells were upregulated by BML-111. In addition, BML-111 inhibited the activation of the Akt, ERK1/2, and p38 MAPK signaling pathways. However, the beneficial effects of BML-111 were abolished by Boc-2. CONCLUSIONS: BML-111 attenuated lung injury in endotoxemic mice and mitigated endothelial hyperpermeability by upregulating the expression of junction proteins.


Assuntos
Lesão Pulmonar Aguda/prevenção & controle , Endotoxemia/complicações , Ácidos Heptanoicos/uso terapêutico , Substâncias Protetoras/uso terapêutico , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/mortalidade , Animais , Biomarcadores/metabolismo , Permeabilidade Capilar/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Endotoxemia/metabolismo , Ácidos Heptanoicos/farmacologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Injeções Intraperitoneais , Lipopolissacarídeos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Substâncias Protetoras/farmacologia , Distribuição Aleatória , Proteínas de Junções Íntimas/metabolismo , Regulação para Cima/efeitos dos fármacos
11.
Clin Ther ; 37(8): 1740-50, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26159841

RESUMO

PURPOSE: The aim of this meta-analysis was to investigate the effects of atorvastatin on serum levels of high-sensitivity C-reactive protein (hs-CRP) and total cholesterol in atrial fibrillation (AF) patients in Asia. METHODS: By searching English and Chinese language-based electronic databases (ie, PubMed, EBSCO, Ovid, SpringerLink, Wiley, Web of Science, Wanfang database, China National Knowledge Infrastructure, and VIP database), we identified 13 studies relevant to our topic of interest. Data were collected from the 13 studies and analyzed with Comprehensive Meta-Analysis software (version 2.0, Biostat Inc., Englewood, New Jersey). FINDINGS: Initially, our database searches retrieved 356 studies (45 in English, 311 in Chinese). Thirteen studies were selected for the meta-analysis following stringent criteria. The data included 1239 patients with AF, of whom 634 were treated with atorvastatin and included in the treatment group, and 605 patients were treated with conventional treatment and included in the control group. The results of our meta-analysis suggested that the serum levels of hs-CRP (mg/L) and total cholesterol (mmol/L) in the treatment group were significantly lower than those of the control group (hs-CRP: standardized mean difference = 0.962; 95% CI, 0.629-1.295, P < 0.001; total cholesterol: standardized mean difference = 1.400; 95% CI, 0.653-2.146, P < 0.001). IMPLICATIONS: The findings of this study suggest that atorvastatin may be very effective in decreasing serum levels of hs-CRP and total cholesterol to prevent cardiovascular events.


Assuntos
Atorvastatina/farmacologia , Fibrilação Atrial/sangue , Proteína C-Reativa/efeitos dos fármacos , Colesterol/sangue , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Atorvastatina/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Proteína C-Reativa/metabolismo , Ácidos Heptanoicos/farmacologia , Ácidos Heptanoicos/uso terapêutico , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Pirróis/farmacologia , Pirróis/uso terapêutico , Resultado do Tratamento
12.
Expert Opin Drug Saf ; 14(9): 1445-55, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26134926

RESUMO

INTRODUCTION: The combination of ezetimibe and atorvastatin (Liptruzet - referred to in this article as eze/ator), has recently been approved by the FDA for reducing low-density lipoprotein cholesterol (LDL-c) in patients with primary or mixed hyperlipidemia as in case of homozygous familial hypercholesterolemia. It helps block intestinal absorption of cholesterol and it inhibits the production of cholesterol in the liver. AREAS COVERED: The safety and effectiveness of the eze/ator combination as treatment of hyperlipidemia. Medline was searched for atorvastatin and/or ezetimibe. EXPERT OPINION: The combination of (eze/ator) is proven to be effective in lowering LDL-c. It is not only a safe and effective treatment of hyperlipidemia, but it also reduces inflammatory markers and atherosclerosis. It is not yet clear, however, whether the combination therapy can decrease the risk of diabetes associated with statin administration. Insulin sensitivity is improved by the single administration of ezetimibe, a finding that is documented by several clinical and animal studies. More specifically, ezetimibe has been shown to decrease insulin resistance associated with nonalcoholic fatty liver disease (NAFLD). The effects of combination therapy that have to be explored in future research and clinical trials include whether this combination can be used in the treatment of NAFLD, cholesterol gallstones and portal hypertension.


Assuntos
Anticolesterolemiantes/efeitos adversos , Azetidinas/efeitos adversos , Ácidos Heptanoicos/efeitos adversos , Hiperlipidemias/tratamento farmacológico , Pirróis/efeitos adversos , Animais , Anticolesterolemiantes/uso terapêutico , Azetidinas/uso terapêutico , LDL-Colesterol/sangue , Aprovação de Drogas , Combinação de Medicamentos , Ácidos Heptanoicos/uso terapêutico , Humanos , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Resistência à Insulina , Pirróis/uso terapêutico
14.
J Am Coll Cardiol ; 65(21): 2291-8, 2015 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-26022817

RESUMO

BACKGROUND: Hemodialysis patients are high absorbers of intestinal cholesterol; they benefit less than other patient groups from statin therapy, which inhibits cholesterol synthesis. OBJECTIVES: This study sought to investigate whether the individual cholesterol absorption rate affects atorvastatin's effectiveness to reduce cardiovascular risk in hemodialysis patients. METHODS: This post-hoc analysis included 1,030 participants in the German Diabetes and Dialysis Study (4D) who were randomized to either 20 mg of atorvastatin (n=519) or placebo (n=511). The primary endpoint was a composite of major cardiovascular events. Secondary endpoints included all-cause mortality and all cardiac events. Tertiles of the cholestanol-to-cholesterol ratio, which is an established biomarker of cholesterol absorption, were used to identify high and low cholesterol absorbers. RESULTS: A total of 454 primary endpoints occurred. On multivariate time-to-event analyses, the interaction term between tertiles and treatment with atorvastatin was significantly associated with the risk of reaching the primary endpoint. Stratified analysis by cholestanol-to-cholesterol ratio tertiles confirmed this effect modification: atorvastatin reduced the risk of reaching the primary endpoint in the first tertile (hazard ratio [HR]: 0.72; p=0.049), but not the second (HR: 0.79; p=0.225) or third tertiles (HR: 1.21; p=0.287). Atorvastatin consistently significantly reduced all-cause mortality and the risk of all cardiac events in only the first tertile. CONCLUSIONS: Intestinal cholesterol absorption, as reflected by cholestanol-to-cholesterol ratios, predicts the effectiveness of atorvastatin to reduce cardiovascular risk in hemodialysis patients. Those with low cholesterol absorption appear to benefit from treatment with atorvastatin, whereas those with high absorption do not benefit.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Colesterol/metabolismo , Ácidos Heptanoicos/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Absorção Intestinal , Falência Renal Crônica/metabolismo , Pirróis/uso terapêutico , Idoso , Atorvastatina , Doenças Cardiovasculares/epidemiologia , Colestanol/sangue , Feminino , Humanos , Falência Renal Crônica/complicações , Falência Renal Crônica/terapia , Masculino , Pessoa de Meia-Idade , Diálise Renal
16.
Ned Tijdschr Geneeskd ; 159: A8695, 2015.
Artigo em Holandês | MEDLINE | ID: mdl-25990330

RESUMO

The Dutch campaign 'Verstandig kiezen', based on the American programme 'Choosing wisely', aims to improve quality in healthcare, with attention to cost control. The 'Choosing wisely'-based programme can be applied in the choice of a statin. Atorvastatin and rosuvastatin are regarded as equal choices in various guidelines regarding cardiovascular risk management. Generic atorvastatin is available, and is approximately 25 times cheaper than rosuvastatin in almost equipotent doses. Rosuvastatin provides a greater LDL reduction than atorvastatin. Patient LDL targets can usually be achieved with atorvastatin, and rosuvastatin is not needed. At group level, there are no relevant differences in adverse-events profile between both statins. Atorvastatin and rosuvastatin do have different pharmacokinetic interactions. When changing medication, good provision of information is a prerequisite for patient satisfaction and compliance. We advise use of atorvastatin instead of rosuvastatin as drug of choice when the LDL target is not reached using simvastatin. However, under specific conditions, rosuvastatin should be the treatment of choice. Efficacy and adverse effects should then be evaluated at individual patient level.


Assuntos
Doenças Cardiovasculares/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Qualidade da Assistência à Saúde , Atorvastatina , Fluorbenzenos/economia , Fluorbenzenos/farmacocinética , Fluorbenzenos/uso terapêutico , Custos de Cuidados de Saúde , Ácidos Heptanoicos/economia , Ácidos Heptanoicos/farmacocinética , Ácidos Heptanoicos/uso terapêutico , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/economia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacocinética , Pirimidinas/economia , Pirimidinas/farmacocinética , Pirimidinas/uso terapêutico , Pirróis/economia , Pirróis/farmacocinética , Pirróis/uso terapêutico , Fatores de Risco , Rosuvastatina Cálcica , Sinvastatina/economia , Sinvastatina/farmacocinética , Sinvastatina/uso terapêutico , Sulfonamidas/economia , Sulfonamidas/farmacocinética , Sulfonamidas/uso terapêutico
17.
J Am Coll Cardiol ; 65(13): 1286-1295, 2015 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-25835440

RESUMO

BACKGROUND: Oxidized phospholipids on apolipoprotein B-100 (OxPL-apoB) is a biomarker of increased risk for major adverse cardiovascular events (MACE) in community cohorts, but its role in patients with stable coronary heart disease (CHD) is unknown. OBJECTIVES: This study sought to examine the relationship between these oxidative biomarkers and cardiovascular outcomes in patients with established CHD. METHODS: In a random sample from the TNT (Treating to New Targets) trial, OxPL-apoB levels were measured in 1,503 patients at randomization (after an 8-week run-in period taking atorvastatin 10 mg) and 1 year after being randomized to atorvastatin 10 or 80 mg. We examined the association between baseline levels of OxPL-apoB and MACE, defined as death from CHD, nonfatal myocardial infarction, resuscitation after cardiac arrest, and fatal/nonfatal stroke, as well as the effect of statin therapy on OxPL-apoB levels and MACE. RESULTS: Patients with events (n = 156) had higher randomization levels of OxPL-apoB than those without events (p = 0.025). For the overall cohort, randomization levels of OxPL-apoB predicted subsequent MACE (hazard ratio [HR]: 1.21; 95% confidence interval: 1.04 to 1.41; p = 0.018) per doubling and tertile 3 versus tertile 1 (hazard ratio: 1.69; 95% confidence interval [CI]: 1.14 to 2.49; p = 0.01) after multivariate adjustment for age, sex, body mass index, among others, and treatment assignment. In the atorvastatin 10-mg group, tertile 3 was associated with a higher risk of MACE compared to the first tertile (HR: 2.08; 95% CI: 1.20 to 3.61; p = 0.01) but this was not significant in the atorvastatin 80-mg group (HR: 1.40; 95% CI: 0.80 to 2.46; p = 0.24). CONCLUSIONS: Elevated OxPL-apoB levels predict secondary MACE in patients with stable CHD, a risk that is mitigated by atorvastatin 80 mg. (A Study to Determine the Degree of Additional Reduction in CV Risk in Lowering LDL Below Minimum Target Levels [TNT]; NCT00327691).


Assuntos
Apolipoproteína B-100/sangue , Doenças Cardiovasculares/etiologia , Doença das Coronárias/tratamento farmacológico , Ácidos Heptanoicos/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Fosfolipídeos/sangue , Pirróis/uso terapêutico , Idoso , Atorvastatina , Biomarcadores/sangue , Doença das Coronárias/sangue , Feminino , Ácidos Heptanoicos/administração & dosagem , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Masculino , Pessoa de Meia-Idade , Oxirredução , Pirróis/administração & dosagem , Fatores de Risco
18.
Zhen Ci Yan Jiu ; 40(1): 61-4, 2015 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-25845223

RESUMO

OBJECTIVE: To observe the clinical effect of acupuncture therapy combined with Lipitor in the treatment of primary hyperlipidemia (spleen deficiency and food stagnation type). METHODS: Sixty primary hyperlipidemia patients (spleen deficiency and food stagnation type) were equally randomized into medication group and acupuncture plus medication group. Patients of both groups were treated by oral administration of Lipitor (20 mg/tablet, one tablet per day) for 6 weeks. Manual acupuncture stimulation was applied to Baihui (GV 20), Zhongwan (CV 12), and bilateral Zusanli (ST 36), Sanyinjiao (SP 6), Yin-lingquan (SP 9) and Fenglong (ST 40) for 40 min, twice daily for 6 weeks except the weekends. Serum total cholesterol (TC), triglyceride (TG), high density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol (LDL-C) were detected by using a full-automatic biochemistry analyzer before and after the treatment. The therapeutic effect was assessed according to the standards described in "Guide Principles for Clinical Researches of New Chinese Herbal Drugs". RESULTS: After the treatment, the levels of serum TC, TG of the two groups were significantly decreased in comparison with pre-treatment in the same one group (P<0.05), and the therapeutic effect of the acupuncture+medication group was significantly superior to that of simple medication group in lowering serum TC, TG and LDL-C levels and heightening HDL-C levels (P<0.05). Of the two 30 cases in the medication and acupuncture+medication groups, 2 (6.7%) and 7 (23.3%) were basically controlled in their blood-lipid levels, 10 (33.3%) and 15 (50.0%) had a marked improvement, 10 (33.3%) and 6 (20.0%) were improved, and 8 (26.7%) and 2 (6.7%) were invalid, with the effective rates being 73.3% and 93.3%, respectively. CONCLUSION: Acupuncture combined with administration of Lipitor is effective in improving primary hyperlipidemia in patients, which is superior to administration of simple Lipitor.


Assuntos
Terapia por Acupuntura , Ácidos Heptanoicos/uso terapêutico , Hiperlipidemias/terapia , Pirróis/uso terapêutico , Adulto , Idoso , Atorvastatina , LDL-Colesterol/metabolismo , Terapia Combinada , Feminino , Humanos , Hiperlipidemias/tratamento farmacológico , Hiperlipidemias/metabolismo , Masculino , Pessoa de Meia-Idade , Triglicerídeos/metabolismo
20.
Circ Res ; 116(9): 1579-98, 2015 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-25908730

RESUMO

Patients with peripheral artery disease (PAD) are at heightened risk of both systemic cardiovascular adverse events, as well as limb-related morbidity. The optimal management of patients with PAD requires a comprehensive treatment strategy incorporating both lifestyle changes, including smoking cessation and exercise, as well as optimal medical therapy. Pharmacological therapies for patients with PAD are targeted both at modifying broad risk factors for major adverse cardiovascular events, as well as reducing limb-related morbidity. Observational data suggest that indicated pharmacological treatments are greatly underutilized in PAD, underscoring the need for improvements in patient identification and care delivery. Ongoing trials of novel therapies in patients with PAD will further inform pharmacological strategies to reduce both systemic cardiovascular risk and limb-related morbidity.


Assuntos
Exercício Físico , Estilo de Vida , Doença Arterial Periférica/tratamento farmacológico , Doença Arterial Periférica/prevenção & controle , Abandono do Hábito de Fumar , Atorvastatina , Ácidos Heptanoicos/uso terapêutico , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Inibidores da Agregação de Plaquetas/uso terapêutico , Pirróis/uso terapêutico , Sinvastatina/uso terapêutico , Resultado do Tratamento
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