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1.
PLoS One ; 15(9): e0238163, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32881885

RESUMO

OBJECTIVE: We evaluated the effects of grape juice (Vitis labrusca L.) on dyslipidemia, resistance to insulin, and left ventricular hypertrophy (LVH) in mice homozygous for the absence of the LDL receptor gene (LDLr -/-) under a hyperlipidemic diet. METHODOLOGY: We divided 30 male mice (3 months old) into three groups (n = 10); the HL group was fed a high-fat diet, the HLU group received a high-fat diet and 2 g/kg/day of grape juice, and the HLS group was fed a high-fat diet and simvastatin (20 mg/kg/day). We assessed the blood pressure profile of the mice. We also determined the levels of C-reactive protein (CRP) and lipid profile, glycemic and insulinemic profiles, and calculated the HOMA-IR. Cardiomyocyte hypertrophy, interstitial collagen deposit, and the expression of CD40 ligand (CD40L) and metalloproteinases 2 and 9 were assessed immunohistologically. RESULTS: After 60 days, the mice treated with grape juice showed similar results as those of the group treated with simvastatin. The use of grape fruit attenuated dyslipidemia and insulin resistance and significantly increased the levels of high cholesterol density lipoproteins (HDLc). The antioxidant potential of phenolic compounds associated with the increase in HDLc levels in the mice of the HLU group prevented the development of LVH and arterial hypertension since it inhibited the inflammatory response induced by the CD40 pathway and its ligand CD40L. Consequently, there was a lower expression of MMP-2 and MMP-9 and lower serum levels of CRP. CONCLUSION: Grape juice has a hypolipidemic and cardiac protective potential, presenting a similar effect as that of simvastatin through a direct antioxidant action of phenolic compounds, or indirectly, via antioxidant action and anti-inflammatory activity of the HDLc. These results suggest that grape juice is a functional food possessing a high potential to prevent cardiovascular diseases.


Assuntos
Dislipidemias/patologia , Sucos de Frutas e Vegetais , Hipertrofia Ventricular Esquerda/prevenção & controle , Vitis/química , Animais , Pressão Sanguínea/efeitos dos fármacos , Proteína C-Reativa/análise , Ligante de CD40/genética , Ligante de CD40/metabolismo , Colágeno/metabolismo , Dieta Hiperlipídica , Dislipidemias/tratamento farmacológico , Sucos de Frutas e Vegetais/análise , Ventrículos do Coração/patologia , Hipertrofia Ventricular Esquerda/patologia , Masculino , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Substâncias Protetoras/química , Substâncias Protetoras/uso terapêutico , Receptores de LDL/deficiência , Receptores de LDL/genética , Sinvastatina/uso terapêutico , Vitis/metabolismo
2.
Artigo em Inglês | MEDLINE | ID: mdl-32872631

RESUMO

(1) Background: Statin is the mainstay of treatment for the primary prevention of atherosclerotic cardiocerebrovascular diseases (CCVDs) in adults with hypercholesterolemia. This study aims to investigate the differences in effect on primary composite outcomes (CCVDs and CCVD-related deaths) among five statins in hypercholesterolemic individuals. (2) Methods: This retrospective study is based on the Korean National Health Insurance Service-National Health Screening Cohort. Participants, aged 40 to 69 years at baseline, were categorized into five statin-treated groups (pitavastatin, atorvastatin, rosuvastatin, simvastatin, and pravastatin) and two untreated groups (untreated hypercholesterolemia and no hypercholesterolemia). (3) Results: A total of 161,583 individuals was included. The median follow-up period was 8.2 years. Compared with the pitavastatin group, the hazard ratios (HRs; 95% confidence intervals (CIs)) for CCVDs and CCVD-related deaths of the atorvastatin, rosuvastatin, simvastatin, pravastatin, untreated hypercholesterolemia, and no-hypercholesterolemia groups were 0.969 (0.567-1.657), 0.988 (0.533-1.832), 0.862 (0.490-1.518), 0.906 (0.326-2.515), 2.665 (1.556-4.562), and 0.656 (0.388-1.110), respectively, in men and 1.124 (0.632-1.999), 1.119 (0.582-2.152), 1.324 (0.730-2.400), 1.023 (0.330-3.171), 2.650 (1.476-4.758), and 0.921 (0.522-1.625), respectively, in women, after being fully adjusted. (4) Conclusions: No significant differences among the five statins were observed, but there was an increased risk in untreated hypercholesterolemic individuals, for CCVDs and CCVDs-related deaths in individuals with hypercholesterolemia of either sex.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Transtornos Cerebrovasculares/prevenção & controle , Inibidores de Hidroximetilglutaril-CoA Redutases , Hipercolesterolemia , Adulto , Idoso , Atorvastatina/uso terapêutico , Doenças Cardiovasculares/mortalidade , Transtornos Cerebrovasculares/etiologia , Transtornos Cerebrovasculares/mortalidade , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipercolesterolemia/complicações , Hipercolesterolemia/tratamento farmacológico , Hipercolesterolemia/etiologia , Masculino , Pessoa de Meia-Idade , Pravastatina/uso terapêutico , Prevenção Primária , Pirróis , Quinolinas/uso terapêutico , Estudos Retrospectivos , Rosuvastatina Cálcica/uso terapêutico , Sinvastatina/uso terapêutico
3.
Life Sci ; 254: 117701, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32387414

RESUMO

AIMS: During illnesses caused by infectious disease, a suite of brain-mediated responses called sickness syndrome occurs, triggering behavioral and physiological (fever) changes. Simvastatin is widely used as a lipid-lowering medication that has beneficial immunomodulatory properties. This study investigated the effects of simvastatin in a mouse model of sickness syndrome by systemic administration of lipopolysaccharide (LPS). MAIN METHODS: Male mice were pretreated with vehicle or simvastatin (40 mg/kg, p.o.) for 7 days and received LPS (200 µg/kg, i.p.) or sterile saline. We investigated the behavioral effects in male mice 2 h after LPS administration using tests screening for depressive-like behavior and locomotor activity alterations. Changes in body temperature were measured by biotelemetry probe preimplanted in the peritoneal cavity to evaluate the effect of simvastatin on the thermoregulatory response during immunological challenge. KEY FINDINGS: Pretreatment with simvastatin blunted most of the assessed parameters related to sickness syndrome, including depressive-like behavior and depressed locomotor activity, and attenuated LPS-induced fever. These data are consistent with simvastatin promoting alterations in peripheral febrigenic signaling (plasma levels of TNF-α, IL-1ß, and IL-10). SIGNIFICANCE: Our data provide further evidence of the capacity of simvastatin to attenuate sickness behavior and fever induced by immunological challenge through a mechanism related to changes in the profile of cytokine production.


Assuntos
Modelos Animais de Doenças , Endotoxemia/tratamento farmacológico , Febre/fisiopatologia , Comportamento de Doença , Sinvastatina/uso terapêutico , Animais , Endotoxemia/fisiopatologia , Humanos , Masculino , Camundongos
4.
Cardiovasc Diabetol ; 19(1): 28, 2020 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-32138746

RESUMO

BACKGROUND: The Action to Control Cardiovascular Risk in Diabetes (ACCORD)-Lipid study found no evidence of a beneficial effect of statin-fibrate combined treatment, compared to statins alone, on cardiovascular outcomes and mortality in type 2 diabetes mellitus after 5 years of active treatment. However, a beneficial reduction in major CVD events was shown in a pre-specified sub-group of participants with dyslipidemia. The extended follow-up of this trial provides the opportunity to further investigate possible beneficial effects of fibrates in this group of patients. We aimed to evaluate possible "legacy effects" of fibrate add-on therapy on mortality and major cardiovascular outcomes in patients with dyslipidemia. METHODS: The ACCORD-lipid study was a randomized controlled trial of 5518 participants assigned to receive simvastatin plus fenofibrate vs simvastatin plus placebo. After randomized treatment allocation had finished at the end of the trial, all surviving participants were invited to attend an extended follow-up study (ACCORDION) to continue prospective collection of clinical outcomes. We undertook a secondary analysis of trial and post-trial data in patients who had dyslipidemia. The primary outcome was all-cause and cardiovascular mortality, and secondary outcomes were nonfatal myocardial infarction, stroke, congestive heart failure and major coronary heart disease. We used an intention-to-treat approach to analysis to make comparisons between the original randomized treatment groups. RESULTS: 853 participants with dyslipidemia had survived at the end of the trial. Most participants continued to use statins, but few used fibrates in either group during the post-trial period. The incidence rates in the fenofibrate group were lower with respect to all-cause mortality, CVD mortality, nonfatal myocardial infarction, congestive heart failure and major coronary heart disease than those in the placebo group over a post-trial follow-up. Allocation to the combined fibrate-statin treatment arm during the trial period had a beneficial legacy effect on all-cause mortality (adjusted HR = 0.65, 95% CI 0.45-0.94; P = 0.02). CONCLUSIONS: Fibrate treatment during the initial trial period was associated with a legacy benefit of improved survival over a post-trial follow-up. These findings support re-evaluation of fibrates as an add-on strategy to statins in order to reduce cardiovascular risk in diabetic patients with dyslipidemia. Trial registration clinicaltrials.gov, Identifier: NCT00000620.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/tratamento farmacológico , Dislipidemias/tratamento farmacológico , Fenofibrato/uso terapêutico , Lipídeos/sangue , Sinvastatina/uso terapêutico , Idoso , Biomarcadores/sangue , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/mortalidade , Causas de Morte , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/mortalidade , Quimioterapia Combinada , Dislipidemias/sangue , Dislipidemias/diagnóstico , Dislipidemias/mortalidade , Feminino , Fenofibrato/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Sinvastatina/efeitos adversos , Fatores de Tempo , Resultado do Tratamento
5.
Clin Oral Investig ; 24(4): 1479-1491, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31925587

RESUMO

OBJECTIVE: The objective is to compare new bone formation in critical defects in healthy, diabetic, and osteoporotic rats filled with hydroxyapatite (HA) alone and HA combined with simvastatin (SV). MATERIALS AND METHODS: A total of 48 adult female Sprague-Dawley rats were randomized into three groups (n = 16 per group): Group, 1 healthy; Group 2, diabetics; and Group 3, osteoporotics. Streptozotocin was used to induce type 1 diabetes in Group 2, while bilateral ovariectomy was used to induce osteoporosis in Group 3. The central portion of the rat mandibular symphysis was used as a physiological critical bone defect. In each group, eight defects were filled with HA alone and eight with HA combined with SV. The animals were sacrificed at 4 and 8 weeks, and the mandibles were processed for micro-computed tomography to analyze radiological union and bone mineral density (BMD); histological analysis of the bone union; and immunohistochemical analysis, which included immunoreactivity of vascular endothelial growth factor (VEGF) and bone morphogenetic protein 2 (BMP-2). RESULTS: In all groups (healthy, diabetics, and osteoporotics), the defects filled with HA + SV presented greater radiological bone union, BMD, histological bone union, and more VEGF and BMP-2 positivity, in comparison with bone defects treated with HA alone. CONCLUSIONS: Combined application of HA and SV improves bone regeneration in mandibular critical bone defects compared with application of HA alone in healthy, diabetic, and osteoporotic rats. CLINICAL RELEVANCE: This study might help to patients with osteoporosis or uncontrolled diabetes type 1, but future studies should be done.


Assuntos
Regeneração Óssea , Durapatita/uso terapêutico , Mandíbula , Osteogênese , Sinvastatina/uso terapêutico , Animais , Proteína Morfogenética Óssea 2/metabolismo , Diabetes Mellitus Experimental/complicações , Feminino , Osteoporose , Ovariectomia , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Fator A de Crescimento do Endotélio Vascular/metabolismo , Microtomografia por Raio-X
6.
J Orthop Res ; 38(2): 297-310, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31471919

RESUMO

Giant cell tumor of bone (GCTB) is a locally aggressive destructive bone lesion. The management of pulmonary metastasis and local recurrence after the surgical treatment of GCTB remains a challenge. Pathologically, stromal cells in GCTB are known as primary neoplastic cells and are recognized as incompletely differentiated preosteoblasts. Therefore, inducing GCTB stromal cells to differentiate into cells with a mature osteoblastic phenotype may stop tumor growth and recurrence. In this study, we aimed to investigate how simvastatin, a clinically approved and commonly used statin that has been known to promote the maturation of cells of the osteogenic lineage, affects GCTB stromal cells. We found that simvastatin effectively inhibited cell viability by suppressing proliferation and by inducing apoptosis in GCTB stromal cells. Moreover, simvastatin treatment upregulated the expression of genes related to osteogenic maturation, such as runt-related transcription factor 2, osteopontin, and osteocalcin, and increased the mineralization of the extracellular matrix in GCTB stromal cells. Ingenuity pathway analysis was used to discover that the vitamin D receptor pathway was involved in the simvastatin-induced osteogenic differentiation of GCTB stromal cells by upregulating the 1,25-dihydroxyvitamin D metabolism. Taken together, this in vitro study demonstrates the antitumor and differentiation-promoting effects of simvastatin on GCTB stromal cells and suggests the possibility of using simvastatin as an adjuvant therapy for GCTB. These findings support further clinical investigation of the efficacy of using simvastatin as an adjuvant therapy for GCTB to reduce recurrence and distant metastasis after surgical treatment. © 2019 Orthopedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:297-310, 2020.


Assuntos
Tumor de Células Gigantes do Osso/tratamento farmacológico , Hipolipemiantes/uso terapêutico , Sinvastatina/uso terapêutico , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Tumor de Células Gigantes do Osso/metabolismo , Humanos , Hipolipemiantes/farmacologia , Sinvastatina/farmacologia , Células Estromais/efeitos dos fármacos , Células Estromais/metabolismo , Vitamina D/análogos & derivados , Vitamina D/metabolismo
7.
J Periodontal Res ; 55(1): 85-95, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31448832

RESUMO

BACKGROUND: Perforated barrier membranes (PBM) were suggested to enhance periodontal regeneration by allowing positive charity of wanted elements from the gingival tissue side. The present study was designed to evaluate clinically and biochemically the use of PBM combined with simvastatin (SMV) gel with and without an associated EDTA gel root surface etching as a suggested option that could improve SMV availability and clinical outcomes of PBM. METHODS: Forty patients having moderate-to-severe chronic periodontitis with 40 intrabony defects were randomly divided into four treatment groups (10 sites each). Patients in group 1 received 1.2% SMV gel and covering the defect with occlusive membrane (OM). Patients in group 2 received 1.2% SMV gel and covering the defect with PBM. Group 3 received 24% EDTA root surface etching, 1.2% SMV gel, and defect coverage with OM (eOM). Patients in group 4 were treated as in group 3 but the defect was covered with PBM (ePBM). Clinical parameters were recorded at baseline before surgical procedures and were reassessed at 6 and 9 months after therapy. The mean concentration of SMV in gingival crevicular fluid (GCF) was estimated by reverse-phase high-performance liquid chromatography at days 1, 7, 14, 21, and 30. RESULTS: At 6- and 9-month observation periods, groups 3 and 4 showed a statistically significant improvement in PD reduction and CAL gain compared with groups 1 and 2. Group 4 showed a statistically significant more defect fill compared with groups 1, 2, and 3 (P ≤ .05). Group 2 showed statistically significant higher defect fill compared with group 1 and group 3 (P < .05). Bone density was significantly increased with no significant difference between the four groups at 6- and 9-month observation periods. SMV-GCF concentration in group 4 showed the highest mean concentration with no significant difference than that of group 3. CONCLUSION: The use of perforated barrier membranes in association with SMV enhances the clinical hard tissue parameters compared with occlusive ones in treating intrabony periodontal defects. Moreover, EDTA root surface treatment could enhance SMV availability in the defect area.


Assuntos
Perda do Osso Alveolar/terapia , Regeneração Tecidual Guiada Periodontal , Membranas Artificiais , Sinvastatina/uso terapêutico , Adulto , Perda do Osso Alveolar/cirurgia , Ácido Edético , Feminino , Seguimentos , Líquido do Sulco Gengival , Humanos , Masculino , Pessoa de Meia-Idade , Perda da Inserção Periodontal , Bolsa Periodontal , Estudos Prospectivos , Resultado do Tratamento
8.
J Clin Neurosci ; 72: 174-179, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31874811

RESUMO

BACKGROUND: Statin therapy has become one of the most important advances in stroke secondary prevention. Nevertheless, statin therapy in patients with cardioembolic stroke has not been supported by clinical evidence yet. This study aimed to investigate the effect of statins on the neurological outcomes after a cardioembolic stroke. METHODS: We conducted a prospective cohort study including consecutive patients with cardioembolic stroke. Subjects were classified into non-statin, simvastatin 20 mg, simvastatin 40 mg, and high-potency statin groups. After 2 years, the functional outcome, stroke recurrence, major cardiovascular events, and mortality were assessed. RESULTS: Among the 91 patients included in our cohort, there were 18 (19.8%) patients without statins, 30 (33.0%) with simvastatin 20 mg, 38 (41.7%) with simvastatin 40 mg and 5 (5.5%) with high-potency statins. Using simvastatin 40 mg was associated with a significantly lower incidence of stroke recurrence lower. Patients with simvastatin 40 mg and high-potency statins presented the best functional recovery throughout the follow-up (p < 0.01). CONCLUSIONS: The use of statins in patients with cardioembolic stroke may be beneficial in some cases, preventing stroke recurrence and improving functional outcomes.


Assuntos
Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/mortalidade , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/mortalidade , Idoso , Estudos de Coortes , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Prevenção Secundária/métodos , Sinvastatina/uso terapêutico
9.
Int J Mol Sci ; 20(23)2019 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-31801292

RESUMO

: Duchenne muscular dystrophy (DMD) is one of the most severe forms of inherited muscular dystrophies. The disease is caused by the lack of dystrophin, a structurally essential protein; hence, a definitive cure would necessarily have to pass through some form of gene and/or cell therapy. Cell- and genetic-based therapeutics for DMD have been explored since the 1990s and recently, two of the latter have been approved for clinical use, but their efficacy is still very low. In parallel, there have been great ongoing efforts aimed at targeting the downstream pathogenic effects of dystrophin deficiency using classical pharmacological approaches, with synthetic or biological molecules. However, as it is always the case with rare diseases, R&D costs for new drugs can represent a major hurdle for researchers and patients alike. This problem can be greatly alleviated by experimenting the use of molecules that had originally been developed for different conditions, a process known as drug repurposing or drug repositioning. In this review, we will describe the state of the art of such an approach for DMD, both in the context of clinical trials and pre-clinical studies.


Assuntos
Reposicionamento de Medicamentos/métodos , Distrofia Muscular de Duchenne/tratamento farmacológico , Fármacos Neuromusculares/uso terapêutico , Prednisona/uso terapêutico , Animais , Ensaios Clínicos como Assunto , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Distrofina/deficiência , Distrofina/genética , Gentamicinas/uso terapêutico , Humanos , Metformina/uso terapêutico , Camundongos Transgênicos , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/metabolismo , Distrofia Muscular de Duchenne/patologia , Pregnenodionas/uso terapêutico , Sinvastatina/uso terapêutico , Tadalafila/uso terapêutico , Tamoxifeno/uso terapêutico
10.
BMJ Case Rep ; 12(11)2019 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-31772127

RESUMO

A 73-year-old woman presented with an acute exacerbation of her long-standing psoriasis. Ciclosporin was commenced due to the severity of her symptoms resulting in remission within 2 weeks. Full blood count, urea and electrolytes following initiation of treatment were unremarkable, although she complained of muscle aches, which was attributed to her known multiple sclerosis. Three weeks later she was admitted to the hospital with diarrhoea and vomiting. Repeat blood tests revealed raised creatinine (528 µmol/L (normal range (NR) n=45-84 µmol/L)), urea (32.6 mmol/L (NR 2.5-7.8 mmol/L)) and creatine kinase (6792 IU/L (NR 25-200 IU/L)) levels and reduced estimated glomerular filtration rate of 7. A diagnosis of acute kidney injury secondary to rhabdomyolysis was made due to an interaction between ciclosporin and simvastatin, precipitated by the dehydration from gastroenteritis. Haemofiltration was required to stabilise her renal function and she made a complete recovery.


Assuntos
Lesão Renal Aguda/etiologia , Anticolesterolemiantes/efeitos adversos , Ciclosporina/efeitos adversos , Imunossupressores/efeitos adversos , Rabdomiólise/induzido quimicamente , Sinvastatina/efeitos adversos , Lesão Renal Aguda/sangue , Idoso , Anticolesterolemiantes/uso terapêutico , Creatina Quinase/sangue , Creatinina/sangue , Ciclosporina/uso terapêutico , Diagnóstico Diferencial , Diarreia/diagnóstico , Diarreia/etiologia , Interações Medicamentosas , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Hemofiltração/métodos , Humanos , Imunossupressores/uso terapêutico , Rabdomiólise/complicações , Rabdomiólise/diagnóstico , Sinvastatina/uso terapêutico , Resultado do Tratamento , Vômito/diagnóstico , Vômito/etiologia
11.
Basic Res Cardiol ; 115(1): 2, 2019 11 28.
Artigo em Inglês | MEDLINE | ID: mdl-31781960

RESUMO

The success of therapies targeting myocardial reperfusion injury is limited, while the cardioprotective impact of mitigating ischemia-related damage remains less explored. We have recently shown in a pig model that the intravenous administration of a modified atorvastatin preparation during ischemia attenuates the rise of cardiac ischemia injury biomarkers. In the following study, we sought to investigate the mechanisms behind these ischemia-related cardioprotective effects. Ischemia was induced by 90 min total coronary balloon occlusion in pigs fed a normocholesterolemic regime. Fifteen minutes after the onset of ischemia, animals were randomized to receive intravenous atorvastatin preparation (IV-atorva) or vehicle. After ischemia animals were euthanized to assess the effect of IV-atorva treatment on gene and protein levels/activation of senescence-, apoptosis-, and cardioprotective/metabolic-related markers. Proof-of-concept studies were carried out in mice and rats in which treatments or vehicle were administered 15 min after initiation of ischemia induced by permanent coronary ligation. Western-blot analyses revealed that in the ischemic myocardium of IV-atorva-treated pigs, RhoA was inactivated, phosphorylation of p53 and caspase-3 was reduced and AMPK was activated with the consequent regulation of the mTOR/raptor-signaling pathway. IV-atorva-treated rats showed, as compared to vehicle, a significant reduction (60%) in scar size assessed at 1 month by histological staining, and mice studies demonstrated the causal involvement of AMPK activation in IV-atorva mediated cardioprotective effects. We demonstrate in pigs and rodents that prompt intravenous treatment with atorvastatin during ischemia limits cardiac cell death and reduces infarct size through AMPK signaling.


Assuntos
Atorvastatina/farmacologia , Coração/efeitos dos fármacos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Isquemia Miocárdica/tratamento farmacológico , Proteínas Quinases Ativadas por AMP/metabolismo , Administração Intravenosa , Animais , Apoptose/efeitos dos fármacos , Atorvastatina/uso terapêutico , Senescência Celular/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Masculino , Camundongos , Isquemia Miocárdica/metabolismo , Infiltração de Neutrófilos/efeitos dos fármacos , Distribuição Aleatória , Ratos , Proteína Regulatória Associada a mTOR/metabolismo , Sinvastatina/farmacologia , Sinvastatina/uso terapêutico , Suínos , Serina-Treonina Quinases TOR/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismo
12.
Am J Cardiol ; 124(11): 1736-1740, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31586530

RESUMO

In this study, we aimed to determine if pretreatment low-density lipoprotein (LDL) levels and aortic stenosis (AS) severity alter the efficacy of lipid-lowering therapy on reducing aortic valve replacement (AVR). We used 1,687 patients with asymptomatic mild-to-moderate AS, who were randomly assigned (1:1) to 40/10 mg simvastatin/ezetimibe combination versus. placebo in the simvastatin and ezetimibe in aortic stenosis (SEAS) trial. Pretreatment LDL levels (>4 mmol/L) and peak aortic jet velocity (3 m/s) were used to partition study participants into 4 groups, which were followed for a primary endpoint of AVR. Cox regression with tests for interaction was used to study the effect of randomized treatment in each subgroup. During a median follow-up of 4.3 years (IQR 4.2 to 4.7 years; total 7,396 patient-years of follow-up), 478 (28%) patients underwent AVR and 146 (9%) died. A significant risk dependency was detected between simvastatin/ezetimibe combination, LDL levels and mild versus moderate AS on rates of AVR (p = 0.01 for interaction). In stratified analyses, randomized treatment, therefore, reduced the rate of AVR in patients with LDL levels >4 mmol and mild AS at baseline (HR 0.4; 95% CI: 0.2 to 0.9). There was no detectable effect of randomized treatment on the need for AVR in the 3 other participants subgroups. We conclude, that in a secondary analysis from a prospective randomized clinical trial, treatment with simvastatin/ezetimibe combination reduced the need for AVR in a subset of patients with mild AS and high pretreatment LDL levels (Unique identifier on clinicaltrials.gov: NCT00092677).


Assuntos
Estenose da Valva Aórtica/terapia , Valva Aórtica/cirurgia , Ezetimiba/uso terapêutico , Implante de Prótese de Valva Cardíaca/tendências , Lipoproteínas LDL/sangue , Sinvastatina/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Anticolesterolemiantes/uso terapêutico , Valva Aórtica/diagnóstico por imagem , Estenose da Valva Aórtica/complicações , Estenose da Valva Aórtica/diagnóstico , Doenças Assintomáticas , Biomarcadores/sangue , Progressão da Doença , Método Duplo-Cego , Quimioterapia Combinada , Dislipidemias/sangue , Dislipidemias/complicações , Dislipidemias/tratamento farmacológico , Ecocardiografia Doppler , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento
13.
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
14.
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
15.
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
16.
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
17.
Am J Respir Crit Care Med ; 200(10): 1282-1293, 2019 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-31206313

RESUMO

Rationale: Population studies suggest improved sepsis outcomes with statins, but the results of randomized controlled trials in patients with sepsis and organ dysfunction in critical care settings have broadly been negative. In vitro data suggest that statins modulate age-related neutrophil functions, improving neutrophil responses to infection, but only in older patients and at high doses.Objectives: To determine if high-dose simvastatin improves neutrophil functions and is safe and tolerated in hospitalized older adults with community-acquired pneumonia with sepsis (CAP + S) not admitted to critical care.Methods: We conducted a randomized, double-blind, placebo-controlled pilot study of simvastatin 80 mg or placebo for 7 days for patients with CAP + S aged 55 years or older admitted to a secondary care hospital. The Day 4 primary endpoint was change in neutrophil extracellular trap formation (NETosis). Day 4 secondary endpoints included neutrophil chemotaxis, safety and tolerability, Sequential Organ Failure Assessment score, mortality, readmission, and markers of tissue degradation/inflammation.Measurements and Main Results: Four days of simvastatin adjuvant therapy in patients with CAP + S was associated with improvements in systemic neutrophil function (NETosis and chemotaxis), a reduction in systemic neutrophil elastase burden, and improved Sequential Organ Failure Assessment scores compared with placebo. A post hoc analysis demonstrated that simvastatin therapy was associated with improved hospitalization-free survival compared with placebo. Simvastatin was well tolerated in this elderly and multimorbid patient group with common coprescription of macrolide antibiotics.Conclusions: This pilot study supports high-dose simvastatin as an adjuvant therapy for CAP + S in an older and milder disease cohort than assessed previously. A definitive multicenter study is now warranted in this population to assess the likelihood of benefit and harm.Clinical trial registered with EudraCT (2012-00343-29).


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Neutrófilos/efeitos dos fármacos , Pneumonia/tratamento farmacológico , Sepse/tratamento farmacológico , Sinvastatina/uso terapêutico , Idoso , Infecções Comunitárias Adquiridas/tratamento farmacológico , Feminino , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Resultado do Tratamento
18.
Proc Natl Acad Sci U S A ; 116(22): 11020-11027, 2019 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-31072935

RESUMO

Understanding the mode of action of drugs is a challenge with conventional methods in clinical trials. Here, we aimed to explore whether simvastatin effects on brain atrophy and disability in secondary progressive multiple sclerosis (SPMS) are mediated by reducing cholesterol or are independent of cholesterol. We applied structural equation models to the MS-STAT trial in which 140 patients with SPMS were randomized to receive placebo or simvastatin. At baseline, after 1 and 2 years, patients underwent brain magnetic resonance imaging; their cognitive and physical disability were assessed on the block design test and Expanded Disability Status Scale (EDSS), and serum total cholesterol levels were measured. We calculated the percentage brain volume change (brain atrophy). We compared two models to select the most likely one: a cholesterol-dependent model with a cholesterol-independent model. The cholesterol-independent model was the most likely option. When we deconstructed the total treatment effect into indirect effects, which were mediated by brain atrophy, and direct effects, simvastatin had a direct effect (independent of serum cholesterol) on both the EDSS, which explained 69% of the overall treatment effect on EDSS, and brain atrophy, which, in turn, was responsible for 31% of the total treatment effect on EDSS [ß = -0.037; 95% credible interval (CI) = -0.075, -0.010]. This suggests that simvastatin's beneficial effects in MS are independent of its effect on lowering peripheral cholesterol levels, implicating a role for upstream intermediate metabolites of the cholesterol synthesis pathway. Importantly, it demonstrates that computational models can elucidate the causal architecture underlying treatment effects in clinical trials of progressive MS.


Assuntos
Modelos Estatísticos , Esclerose Múltipla Crônica Progressiva , Sinvastatina/uso terapêutico , Adulto , Atrofia , Encéfalo/patologia , Causalidade , Colesterol/sangue , Ensaios Clínicos como Assunto , Progressão da Doença , Humanos , Pessoa de Meia-Idade , Esclerose Múltipla Crônica Progressiva/tratamento farmacológico , Esclerose Múltipla Crônica Progressiva/patologia
19.
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
20.
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
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